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Current Pharmaceutical Design 2022MDPV (3,4-methylenedioxypyrovalerone) is a synthetic stimulant that blocks transmitter uptake at transporters for dopamine and norepinephrine. Less is known about MDPV...
BACKGROUND
MDPV (3,4-methylenedioxypyrovalerone) is a synthetic stimulant that blocks transmitter uptake at transporters for dopamine and norepinephrine. Less is known about MDPV pharmacokinetics, especially with respect to brain concentrations of the drug and its metabolites.
OBJECTIVES
The goal of the present study was: 1) to determine brain concentrations of MDPV and its metabolites, 3,4-dihydroxypyrovalerone (3,4-catechol-PV) and 4-hydroxy-3-methoxy-pyrovalerone (4-OH-3-MeOPV), after administration of MDPV, and 2) to relate brain pharmacokinetic measures to pharmacodynamic endpoints in the same subjects.
METHODS
Male Sprague-Dawley rats (300-400 g) received s.c. MDPV injection (1, 2, or 4 mg/kg) or its saline vehicle. Groups of rats were decapitated at 40 min and 240 min postinjection. Locomotor behavior was rated before decapitation, and the core temperature was obtained. Plasma and frontal cortex were analyzed to quantitate MDPV and its metabolites. Striatal samples were analyzed to measure dopamine, serotonin (5-HT), and their metabolites.
RESULTS
MDPV displayed brain-to-plasma ratios greater than 1 (range 8.8-12.1), whereas 3,4-catechol-PV and 4-OH-3-MeO-PV showed ratios less than 1 (range 0-0.3). MDPV increased behavioural scores reflective of locomotor stimulation at 40 and 240 min and produced slight hyperthermia at 240 min. MDPV had no effect on striatal dopamine but produced an increase in the metabolite homovanillic acid (HVA). Brain MDPV concentrations were positively correlated with behavioural scores and striatal HVA but not with other endpoints.
CONCLUSION
The behavioural effects of MDPV are related to brain concentrations of the parent drug and not its metabolites. The modest effects of MDPV on monoamine systems suggest that other non-monoamine mechanisms may contribute to the effects of the drug in vivo.
Topics: Animals; Rats; Male; Serotonin; Dopamine; Rats, Sprague-Dawley; Homovanillic Acid; Pyrrolidines; Brain; Norepinephrine; Dose-Response Relationship, Drug
PubMed: 36082866
DOI: 10.2174/1381612828666220907100036 -
FASEB BioAdvances Feb 2023Excitability and contraction of cardiac muscle from brain-dead donors critically influence the success of heart transplantation. Membrane physiology, Ca-handling, and...
Excitability and contraction of cardiac muscle from brain-dead donors critically influence the success of heart transplantation. Membrane physiology, Ca-handling, and force production of cardiac muscle and the contractile properties of coronary arteries were studied in hearts of brain-dead pigs. Cardiac muscle and vascular function after 12 h brain death (decapitation between C2 and C3) were compared with properties of fresh tissue. In both isolated cardiomyocytes (whole-cell patch clamp) and trabecular muscle (conventional microelectrodes), action potential duration was shorter in brain dead, compared to controls. Cellular shortening and Ca transients were attenuated in the brain dead, and linked to lower mRNA expression of L-type calcium channels and a slightly lower I,, current, as well as to a lower expression of phospholamban. The current-voltage relationship and the current above the equilibrium potential of the inward K (I) channel were altered in the brain-dead group, associated with lower mRNA expression of the Kir2.2 channel. Delayed K currents were detected (I, I) and were not different between groups. The transient outward K current (I) was not observed in the pig heart. Coronary arteries exhibited increased contractility and sensitivity to the thromboxane analogue (U46619), and unaltered endothelial relaxation. In conclusion, brain death involves changes in cardiac cellular excitation which might lower contractility after transplantation. Changes in the inward rectifier K channel can be associated with an increased risk for arrhythmia. Increased reactivity of coronary arteries may lead to increased risk of vascular spasm, although endothelial relaxant function was well preserved.
PubMed: 36816513
DOI: 10.1096/fba.2022-00104 -
Neuro Endocrinology Letters Dec 2015The very word "anatomy" tells us about this branch's connection with dissection. Studies of anatomy have taken place for approximately 2.300 years already. Anatomy's...
The very word "anatomy" tells us about this branch's connection with dissection. Studies of anatomy have taken place for approximately 2.300 years already. Anatomy's birthplace lies in Greece and Egypt. Knowledge in this specific field of science was necessary during surgical procedures in ophthalmology and obstetrics. Embalming took place without public disapproval just like autopsies and manipulation with relics. Thus, anatomical dissection became part of later forensic sciences. Anatomical studies on humans themselves, which needed to be compared with the knowledge gained through studying procedures performed on animals, elicited public disapprobation and prohibition. When faced with a shortage of cadavers, anatomists resorted to obtaining bodies of the executed and suicide victims - since torture, public display of the mutilated body, (including anatomical autopsy), were perceived as an intensification of the death penalty. Decapitation and hanging were the main execution methods meted out for death sentences. Anatomists preferred intact bodies for dissection; hence, convicts could thus avoid torture. This paper lists examples of how this process was resolved. It concerns the manners of killing, vivisection on people in the antiquity and middle-ages, experiments before the execution and after, vivifying from seeming death, experiments with galvanizing electricity on fresh cadavers, evaluating of sensibility after guillotine execution, and making perfect anatomical preparations and publications during Nazism from fresh bodies of the executed.
PubMed: 26859596
DOI: No ID Found -
European Archives of... Oct 2017The aim of our study was to evaluate the audiological protective effects of etanercept using distortion product otoacoustic emission (DPOAE) in rats with hearing loss...
The aim of our study was to evaluate the audiological protective effects of etanercept using distortion product otoacoustic emission (DPOAE) in rats with hearing loss due to cisplatin ototoxicity. The study began with 36 healthy female albino rats; 31 rats had good measurements in DPOAE and were included in the study. On day 0, a single dose of etanercept was given by intraperitoneal administration to 15 rats (etanercept group). No medication was given to the control group. After 24 h, 16 mg/kg cisplatin was given to all rats. DPOAE measurements were performed on the 3rd, 7th, and 21st day. After the DPOAE test on the 21st day, the animals were killed by decapitation. Between-group and intra-group comparisons were made using the data of the two groups. A statistically significant difference was observed on the 3rd day at 4921 Hz and higher frequencies, on the 7th day at 6064 Hz and higher frequencies, and on the 21st day at 6494 Hz and higher frequencies (p < 0.05). We observed 10% ototoxicity in the etanercept group and 56% ototoxicity in the control group. A single dose of etanercept 1 day before cisplatin administration decreases cisplatin ototoxicity in the early period. This effect comes to the fore especially over 4500 Hz frequencies at 65 dB and higher.
Topics: Animals; Antineoplastic Agents; Cisplatin; Etanercept; Hearing Loss; Otoacoustic Emissions, Spontaneous; Protective Agents; Rats; Treatment Outcome
PubMed: 28730299
DOI: 10.1007/s00405-017-4677-6 -
Journal of Forensic and Legal Medicine Jul 2019Decapitation resulting by vehicle-assisted ligature strangulation is a suicide method rarely described in the literature. The lesions observed at autopsy have a common... (Review)
Review
Decapitation resulting by vehicle-assisted ligature strangulation is a suicide method rarely described in the literature. The lesions observed at autopsy have a common morphology with to those found in post-hanging decapitation. They depend on the force applied by the acceleration of the vehicle, the slope of the road and the characteristics of the link used. They can also mimic a stabbing homicide. We report the case of a 43-year-old man who used a long steel rope, attached between his neck and a streetlight, and started his vehicle, causing a complete decapitation. The results of the autopsy provided information on the morphology of the cervical lesions, but also on the causes of death. In spite of decapitation, the histological examination of the organs confirmed the presence of asphyxiation process by a mechanical origin that occurred before decapitation.
Topics: Adult; Asphyxia; Automobiles; Decapitation; Forensic Pathology; Humans; Male; Suicide
PubMed: 31146145
DOI: 10.1016/j.jflm.2019.05.015 -
Scientific Reports Feb 2022Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway is important in the process of inflammation and fibrosis. The adenosine...
Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway is important in the process of inflammation and fibrosis. The adenosine 5'-monophosphate-activated protein kinase (AMPK) enzyme can affect JAK/STAT pathway. Tofacitinib is a pan-JAK inhibitör. Metformin activates AMPK enzyme. We aimed to investigate the therapeutic efficacy of tofacitinib and metformin on IL-17 and TGF-β cytokines, skin fibrosis and inflammation in mouse model of systemic sclerosis (SSc). 40 Balb/c female mice were divided into 4 groups: (control, sham (BLM), tofacitinib and metformin). The mice in the tofacitinib group received oral tofacitinib (20 mg/kg/daily) and mice in the metformin group received oral metformin (50 mg/kg/day) for 28 days. At the end of 4th week, all groups of mice were decapitated and tissue samples were taken for analysis. Histopathological analysis of skin tissue was performed, and mRNA expressions of collagen 3A, IL-17 and TGF-β were assessed by real-time PCR and ELISA. Repeated BLM injections had induced dermal fibrosis. Moreover, the tissue levels of collagen 3A, IL-17 and TGF-β were elevated in the BLM group. Tofacitinib and metformin mitigated dermal fibrosis. They reduced dermal thickness and tissue collagen 3A, IL-17 and TGF-β levels. Tofacitinib and metformin demonstrated anti-inflammatory and anti-fibrotic effects in the mouse model of SSc.
Topics: Animals; Drug Therapy, Combination; Female; Fibrosis; Metformin; Mice; Mice, Inbred BALB C; Piperidines; Pyrimidines; Scleroderma, Systemic; Skin
PubMed: 35169250
DOI: 10.1038/s41598-022-06581-1 -
The Medico-legal Journal Jun 2019Examination of skeletonised remains for the cause and manner of death is a highly challenging task for forensic experts. We report an unusual case of postmortem...
Examination of skeletonised remains for the cause and manner of death is a highly challenging task for forensic experts. We report an unusual case of postmortem decapitation following hanging with the presence of a well-preserved ligature mark in the partially skeletonised body. Careful death scene investigation, interpretation of circumstantial evidence and meticulous autopsy provided information on the cause and manner of death.
Topics: Autopsy; Decapitation; Humans; Ligation; Neck Injuries
PubMed: 31107160
DOI: 10.1177/0025817219830598 -
Cureus Jan 2023Since the development of the infamous guillotine in the French Revolution, physicians have debated how long consciousness persists in decapitated heads. Fueled by... (Review)
Review
Since the development of the infamous guillotine in the French Revolution, physicians have debated how long consciousness persists in decapitated heads. Fueled by anecdotes of severed heads that blink, blush, and appear to retain intelligence, numerous experiments have investigated this macabre subject for nearly 250 years. In this paper, we examine the evidence, both historical and modern, and ultimately conclude that, while the truth may never be fully known, all evidence appears to indicate that loss of consciousness appears to occur within seconds of decapitation. The rumors that circulated through the European consciousness during the Terror of the French Revolution appear to be just that - curious urban legends from an awed and terrified public.
PubMed: 36819446
DOI: 10.7759/cureus.33830 -
Radiography (London, England : 1995) Oct 2023The porcine model shows structural features comparable to that of humans and are routinely used within research, due to the ethical, legal, and practical use of...
INTRODUCTION
The porcine model shows structural features comparable to that of humans and are routinely used within research, due to the ethical, legal, and practical use of post-mortem human samples. Methods for obtaining high quality and comparable reference data using standardised acquisition protocols are essential.
METHODS
The decapitated heads of three adult white sows were subjected to radiographic imaging before and after cranial trauma (9 mm, Heckler and Koch MP5). Digital radiographs were generated using a Siemens MULTIX TOP system with an Agfa digital detector, with foam blocks and sandbags as ancillary equipment. An iterative approach was adopted by the authors to generate reproducible radiographic views from two perpendicular angles. Specimens were kept at 5 °C and wrapped in polythene bags to reduce the impact of putrefaction.
RESULTS
Standardised head radiography technique was developed for superior-inferior and lateral views demonstrating porcine anatomy. Key parameters included: automatic exposure control for tube current (∼4 mAs), tube voltage of 73 kVp, 100 cm source to image receptor distance, and an anti-scatter grid. Slight variances in specimen morphology, developmental status, and soft tissue changes did not affect imaging outcomes.
CONCLUSION
The technique and positioning proposed in this study allows for the acquisition of high quality and reproducible radiographic images for comparable ballistic research datasets. Specimen positioning and centring of the primary beam may be applied across porcine breeds, although individual radiographic parameters may differ according to equipment specifications and specimen size.
IMPLICATIONS FOR PRACTICE
Development of a reproducible radiographic technique of porcine heads in forensic and veterinary research.
Topics: Adult; Humans; Swine; Animals; Female; Radiographic Image Enhancement; Phantoms, Imaging; Radiography
PubMed: 37595528
DOI: 10.1016/j.radi.2023.08.001 -
Cells Aug 2021The sperm flagellum is essential for the transport of the genetic material toward the oocyte and thus the transmission of the genetic information to the next generation.... (Review)
Review
The sperm flagellum is essential for the transport of the genetic material toward the oocyte and thus the transmission of the genetic information to the next generation. During the haploid phase of spermatogenesis, i.e., spermiogenesis, a morphological and molecular restructuring of the male germ cell, the round spermatid, takes place that includes the silencing and compaction of the nucleus, the formation of the acrosomal vesicle from the Golgi apparatus, the formation of the sperm tail, and, finally, the shedding of excessive cytoplasm. Sperm tail formation starts in the round spermatid stage when the pair of centrioles moves toward the posterior pole of the nucleus. The sperm tail, eventually, becomes located opposed to the acrosomal vesicle, which develops at the anterior pole of the nucleus. The centriole pair tightly attaches to the nucleus, forming a nuclear membrane indentation. An articular structure is formed around the centriole pair known as the connecting piece, situated in the neck region and linking the sperm head to the tail, also named the head-to-tail coupling apparatus or, in short, HTCA. Finally, the sperm tail grows out from the distal centriole that is now transformed into the basal body of the flagellum. However, a centriole pair is found in nearly all cells of the body. In somatic cells, it accumulates a large mass of proteins, the pericentriolar material (PCM), that together constitute the centrosome, which is the main microtubule-organizing center of the cell, essential not only for the structuring of the cytoskeleton and the overall cellular organization but also for mitotic spindle formation and chromosome segregation. However, in post-mitotic (G1 or G0) cells, the centrosome is transformed into the basal body. In this case, one of the centrioles, which is always the oldest or mother centriole, grows the axoneme of a cilium. Most cells of the body carry a single cilium known as the primary cilium that serves as an antenna sensing the cell's environment. Besides, specialized cells develop multiple motile cilia differing in substructure from the immotile primary cilia that are essential in moving fluids or cargos over the cellular surface. Impairment of cilia formation causes numerous severe syndromes that are collectively subsumed as ciliopathies. This comparative overview serves to illustrate the molecular mechanisms of basal body formation, their similarities, and dissimilarities, in somatic versus male germ cells, by discussing the involved proteins/genes and their expression, localization, and function. The review, thus, aimed to provide a deeper knowledge of the molecular players that is essential for the expansion of clinical diagnostics and treatment of male fertility disorders.
Topics: Basal Bodies; Centrosome; Germ Cells; Humans; Infertility, Male; Male; Spermatogenesis
PubMed: 34571916
DOI: 10.3390/cells10092266