The Influence of Bisphenol a on the Nitrergic Nervous Structures in the Domestic Porcine Uterus.

Bisphenol A (BPA) is one of the most common environmental pollutants among endocrine disruptors. Due to its similarity to estrogen, BPA may affect estrogen receptors and show adverse effects on many internal organs. The reproductive system is particularly vulnerable to the impact of BPA, but knowledge about BPA-induced changes in the innervation of the uterus is relatively scarce. Therefore, this study aimed to investigate the influence of various doses of BPA on nitrergic nerves supplying the uterus with the double immunofluorescence method. It has been shown that even low doses of BPA caused an increase in the number of nitrergic nerves in the uterine wall and changed their neurochemical characterization. During the present study, changes in the number of nitrergic nerves simultaneously immunoreactive to substance P, vasoactive intestinal polypeptide, pituitary adenylate cyclase-activating peptide, and/or cocaine- and amphetamine-regulated transcript were found under the influence of BPA. The obtained results strongly suggest that nitrergic nerves in the uterine wall participate in adaptive and/or protective processes aimed at homeostasis maintenance in the uterine activity under the impact of BPA.

Somatostatin as an Active Substance in the Mammalian Enteric Nervous System.

Somatostatin (SOM) is an active substance which most commonly occurs in endocrine cells, as well as in the central and peripheral nervous system. One of the parts of the nervous system where the presence of SOM has been confirmed is the enteric nervous system (ENS), located in the wall of the gastrointestinal (GI) tract. It regulates most of the functions of the stomach and intestine and it is characterized by complex organization and a high degree of independence from the central nervous system. SOM has been described in the ENS of numerous mammal species and its main functions in the GI tract are connected with the inhibition of the intestinal motility and secretory activity. Moreover, SOM participates in sensory and pain stimuli conduction, modulation of the release of other neuronal factors, and regulation of blood flow in the intestinal vessels. This peptide is also involved in the pathological processes in the GI tract and is known as an anti-inflammatory agent. This paper, which focuses primarily on the distribution of SOM in the ENS and extrinsic intestinal innervation in various mammalian species, is a review of studies concerning this issue published from 1973 to the present.

Identification of neuropeptide y in superior cervical ganglion neurons that project to the oesophagus - A combined immunohistochemical labelling and retrograde tracing study in pigs.

Neuropeptide Y (NPY) is a neuronal active substance taking part in the regulation of gastrointestinal (GI) tract activity. This study used retrograde neuronal tracing and immunofluorescence methods to analyse NPY-positive neurons located in superior cervical ganglion and supplying the cervical oesophagus in the pig. The presence of NPY was observed in 30% of all neurons supplying the part of oesophagus studied. Probably the number of Fast Blue (FB) positive cells depends on the area of the wall injected with FB and the fragment of oesophagus studied. Therefore, the obtained results indicate that the described peptide is an important factor in the extrinsic innervation of this part of the GI tract.

The Influence of Bisphenol A (BPA) on Neuregulin 1-Like Immunoreactive Nerve Fibers in the Wall of Porcine Uterus.

Bisphenol A (BPA), a substance commonly used in the manufacture of plastics, shows multidirectional negative effects on humans and animals. Due to similarities to estrogens, BPA initially leads to disorders in the reproductive system. On the other hand, it is known that neuregulin 1 (NRG-1) is an active substance which enhances the survivability of cells, inhibits apoptosis, and protects tissues against damaging factors. Because the influence of BPA on the nervous system has also been described, the aim of the present study was to investigate for the first time the influence of various doses of BPA on neuregulin 1-like immunoreactive (NRG-1-LI) nerves located in the porcine uterus using the routine single- and double-immunofluorescence technique. The obtained results have shown that BPA increases the number and affects the neurochemical characterization of NRG-1-LI in the uterus, and changes are visible even under the impact of small doses of this toxin. The character of observed changes depended on the dose of BPA and the part of the uterus studied. These observations suggest that NRG-1 in nerves supplying the uterus may play roles in adaptive and protective mechanisms under the impact of BPA.

Co-localization of zinc transporter 3 (ZnT3) with sensory neuromediators and/or neuromodulators in the enteric nervous system of the porcine esophagus.

Zinc transporter 3 (ZnT3) is one of the zinc transporters family. It is closely connected to the nervous system, where enables the transport of zinc ions from the cytoplasm to synaptic vesicles. This substance has been described within the central and peripheral nervous system, especially in the enteric nervous system (ENS). The aim of the present study was to describe the co-localization of ZnT3 with selected neuromediators and/or neuromodulators participating in sensory stimuli conduction in neurons of the ENS within the porcine esophagus. Co-localization of ZnT3 with substance P (SP), leucine enkephalin (LENK) and calcitonin gene-related peptide (CGRP) was studied using standard double-immunofluorescence technique. The obtained results show that ZnT3, SP and/or LENK may occur in the same enteric neurons, and the degree of co-localization of these substances clearly depends on the fragment of esophagus studied and the type of enteric ganglia. In contrast, the co-localization of ZnT3 with CGRP was not observed during the present investigation. The obtained results suggest that ZnT3 in the ENS may be involved in the conduction of sensory and/or pain stimuli.

Bisphenol A Causes Liver Damage and Selectively Alters the Neurochemical Coding of Intrahepatic Parasympathetic Nerves in Juvenile Porcine Models under Physiological Conditions.

Bisphenol A (BPA) is an extremely common polymer that is used in typical everyday products throughout the world, especially in food and beverage containers. Within the last ten years, it has been found that the BPA monomer tends to leach into foodstuffs, and nanogram concentrations of it may cause a variety of deleterious health effects. These health problems are very evident in developing children and in young adults. The aim of this study was to expose developing pigs to dietary BPA at both legally acceptable and ten-fold higher levels. Livers that had been exposed to BPA showed vacuolar degeneration, sinusoidal dilatation, vascular congestion and glycogen depletion that increased with exposure levels. Furthermore, the livers of these models were then examined for irregularities and double-labeled immunofluorescence was used to check the innervated hepatic samples for varying neuronal expression of selected neuronal markers in the parasympathetic nervous system (PSNS). It was found that both the PSNS and all of the neuronal markers showed increased expression, with some of them being significant even at recommended safe exposure levels. The implications are quite serious since these effects have been observed at recommended safe levels with expression increasing in-line with exposure levels. The increased neuronal markers studied here have been previously correlated with behavioral/psychological disorders of children and young adults, as well as with childhood obesity and diabetes. However, further research must be performed in order to develop a mechanism for the above-mentioned correlations.

Sensorineural deafness in purebred white Devon Rex cats.

BACKGROUND: Data regarding congenital sensorineural deafness (CSD) in client-owned, white Devon Rex cats is limited because most of the information on this disease comes from experiments on mixed-breed cats. OBJECTIVES: Provide data on the occurrence of CSD in a population of client-owned purebred white Devon Rex cats. ANIMALS: Forty client-owned, purebred, white Devon Rex cats examined at 2 different facilities. Median age of the examined cats was 19 weeks. METHODS: Hearing status was defined by use of brainstem auditory evoked responses. RESULTS: The occurrence of sensorineural deafness in the studied population of Devon Rex cats was estimated at 10%. Unilateral and bilateral deafness occurred equally often, with 2 individuals having each (ie, 5.0%). No association between the occurrence of CSD and sex could be found, χ2 (1, n = 40) = 0.001 (P > .99). No association between blue irises and deafness was noted in the studied population, χ2 (1, n = 40) < 0.01 (P > .99). CONCLUSIONS: The occurrence of CSD in a population of client-owned, white Devon Rex cats was found to be lower compared with data obtained in previously conducted studies of deafness in purebred cats. In the studied population of Devon Rex cats, no association between blue irises and CSD was found.

Biomonitoring of parabens in wild boars through hair samples analysis.

Parabens are compounds widely utilized in the industry as preservative additives to personal care products, cosmetics and food. They pollute the environment and penetrate to the living organisms through the digestive tract, respiratory system and skin. Till now the knowledge about exposure of terrestrial wild mammals to parabens is extremely scarce. Therefore, this study for the first time assessed the concentration levels of five parabens commonly used in industry (methylparaben-MeP, ethylparaben-EtP propylparaben-PrP, benzylparaben -BeP and butylparaben-BuP). Substances have been analyzed in hair samples collected from wild boars using liquid chromatography-mass spectrometry (LC-MS) method. The hair is a matrix, which allows to study long-term exposure of organisms to parabens. During this study MeP was noted in 96.3% of samples with mean 88.3±72.9 pg/mg, PrP in 87.0% of samples with mean 8.5±3.3 pg/mg, BeP in 44.4% of samples with mean 17.2±12.3 pg/mg and EtP in 11.1% of samples with mean 17.2±4.8 pg/mg. In turn BuP was noted only in 3.7% of samples with concentration levels below limit of quantification (2.6 pg/mg). Statistically significant intragender differences in parabens levels have not been noted. Only BeP concentration levels depended on industrialization and density of human population of area, where the animals lived. This study indicates that wild boars are exposed to parabens, especially to MeP and PrP, and analysis of the hair seems to be a useful tool of biomonitoring of parabens in wild mammals.

Biomonitoring of benzophenones in guano samples of wild bats in Poland.

Benzophenones (BPs) are substances used in the production of sunscreens, cosmetics, and personal care products. However, there is a lack of knowledge of BPs in wild animals. Therefore, the study aimed to assess the concentration of selected BPs commonly used in the cosmetic industry in guano samples collected from 4 colonies of greater mouse-eared bats (Myotis myotis). Liquid chromatography with tandem mass spectrometry (LC-MS/MS) was used to determine guano concentrations of benzophenone 1 (BP-1), benzophenone 2 (BP-2), benzophenone 3 (BP-3) and benzophenone 8 (BP-8). BP-1 levels above the method quantification limit (MQL) were noted in 97.5% of samples and fluctuated from <0.1 ng/g to 259 ng/g (mean 41.50 ng/g, median 34.8). The second most common was BP-3, which fluctuated from <0.1 ng/g to 19 ng/g (mean 6.67 ng/g, median 5.05), and its levels higher than MQL were observed in 40% of samples. BP-2 and BP-8 concentrations did not exceed the method detection limit (0.04 ng/g) in any analyzed sample. There were visible differences in the BP-1 and BP-3 levels among the studied bat colonies. Mean BP-1 concentration fluctuated from 11.23±13.13 ng/g to 76.71±65.51 ng/g and differed significantly between the colonies. Mean BP-3 concentration fluctuated from 5.03±6.03 ng/g to 9.18±7.65 mg/g, but it did not differ significantly between the colonies. The results show that guano is a suitable matrix for the assessment of wildlife exposure to BPs. This could be particularly advantageous in protected species, where not disturbing and stressing the animals are crucial.

Exposure assessment to bisphenol A (BPA) and its analogues bisphenol S (BPS) and bisphenol F (BPF) in wild boars by hair analysis.

Bisphenols are widely used in various branches of industry for the production of plastics. They penetrate to the natural environment and thus living organisms. As endocrine disruptors, bisphenols have adverse effects on various internal organs and systems. Contrary to humans, the knowledge of the exposure of wild terrestrial mammals to bisphenols is extremely limited. Therefore, this study for the first time assessed the exposure level of wild boars to three bisphenols commonly used in industry (i.e. bisphenol A - BPA, bisphenol S - BPS and bisphenol F - BPF) using hair sample analysis in liquid chromatography-mass spectrometry (LC-MS). The presence of BPA and/or BPS has been noted in the samples collected from >80 % of animals included in the study (n = 54), while the presence of BPF was not found in any sample. At least one of the bisphenols was present in every sample tested. Mean concentrations of BPA and BPS in the hair of wild boars were 151.40 ± 135.10 pg/mg dry weight (dw.) and 29.40 ± 36.97 pg./mg dw, respectively. Concentrations of BPA and BPS in females were statistically higher than in males (p < 0.05). Moreover, statistically significantly higher concentration levels of BPA (and not BPS) in the areas with higher degree of industrialization and higher human population density were also found. This is the first study concerning the use of hair samples to assess the exposure of wild terrestrial mammals to bisphenols. The obtained results show that an analysis of the hair may be a useful tool of biomonitoring bisphenols in wild animals. The presence of BPA and BPS in wild boar hair in relatively high concentration also suggests that these substances may have an influence on the health status not only in humans and aquatic animals, but also in wild terrestrial mammals. However, many aspects connected with this issue are not clear and require further study.

Evaluation of Parabens and Bisphenol A Concentration Levels in Wild Bat Guano Samples.

Parabens and bisphenol A are synthetic compounds found in many everyday objects, including bottles, food containers, personal care products, cosmetics and medicines. These substances may penetrate the environment and living organisms, on which they have a negative impact. Till now, numerous studies have described parabens and BPA in humans, but knowledge about terrestrial wild mammals' exposure to these compounds is very limited. Therefore, during this study, the most common concentration levels of BPA and parabens were selected (such as methyl paraben-MeP, ethyl paraben-EtP, propyl paraben-PrP and butyl paraben-BuP) and analyzed in guano samples collected in summer (nursery) colonies of greater mouse-eared bats (Myotis myotis) using liquid chromatography with the tandem mass spectrometry (LC-MS-MS) method. MeP has been found in all guano samples and its median concentration levels amounted to 39.6 ng/g. Other parabens were present in smaller number of samples (from 5% for BuP to 62.5% for EtP) and in lower concentrations. Median concentration levels of these substances achieved 0.95 ng/g, 1.45 ng/g and 15.56 ng/g for EtP, PrP and BuP, respectively. BPA concentration levels did not exceed the method quantification limit (5 ng/g dw) in any sample. The present study has shown that wild bats are exposed to parabens and BPA, and guano samples are a suitable matrix for studies on wild animal exposure to these substances.

Assessment of perfluoroalkyl substances concentration levels in wild bat guano samples.

Perfluoroalkyl substances (PFASs) are substances commonly used in the production of various everyday objects, including among others kitchen dishes, cosmetics, or clothes. They penetrate to the environment and living organisms causing disturbances in the functioning of many internal organs and systems. Due to environmental pollution, wildlife is also exposed to PFASs, but the knowledge about this issue is rather limited. The aim of this study was to evaluate the exposure of wild greater mouse-eared bats (Myotis myotis), living in Poland, to six selected PFASs: five perfluoroalkyl carboxylic acids (perfluorobutanoic acid-PFBuA, perfluoropentanoic acid-PFPeA, perfluorohexanoic acid-PFHxA, perfluoroheptanoic acid-PFHpA, perfluorooctanoic acid-PFOA) and perfluorooctane sulfonic acid (PFOS) through the analysis of guano samples with liquid chromatography with tandem mass spectrometry (LC-MS-MS) method. To our knowledge this is the first study concerning the PFASs levels in bats, as well as using guano samples to evaluate the exposure of wild mammals to these substances. A total of 40 guano samples were collected from 4 bats summer (nursery) colonies located in various parts of Poland. The presence of PFASs mentioned were detected in all colonies studied, and concentration levels of these substances were sampling dependent. The highest concentration levels were observed in the case of PFPeA [1.34 and 3060 ng/g dry weight (dw)] and PFHxA (8.30-314 ng/g dw). This study confirms the exposure of wild bats to PFASs.

Endocrine Disruptor Bisphenol a Affects the Neurochemical Profile of Nerve Fibers in the Aortic Arch Wall in the Domestic Pig.

Bisphenol A (BPA) is a synthetic compound utilized in industry for the production of various plastics. BPA penetrates into the environment and adversely affects living organisms. Therefore, the influence of various BPA dosages on the neurochemical characteristics of nerve fibers located in the aortic branch wall was investigated in this study utilizing a double immunofluorescence method. It was found that BPA in concentration of 0.5 mg/kg body weight/day causes a clear increase in the density of nerves within aortic branch walls immunoreactive to cocaine- and amphetamine-regulated transcript (CART), calcitonin gene-related peptide (CGRP), neuronal isoform of nitric oxide synthase (nNOS), pituitary adenylate cyclase-activating peptide (PACAP), and vasoactive intestinal polypeptide (VIP). Nerves containing galanin (GAL) and/or somatostatin (SOM) did not change when BPA was introduced into the system. Changes noted after administration of BPA at a dose of 0.05 mg/kg body weight/day were less visible and concerned fibers immunoreactive to CART, CGRP, and/or PACAP. The obtained results show that BPA affects the neurochemical coding of nerves in the aortic branch wall. These fluctuations may be the first signs of the influence of this substance on blood vessels and may also be at the root of the disturbances in the cardiovascular system.

Changes in the Neurochemical Characterization of Enteric Neurons in the Porcine Duodenum After Administration of Low-Dose Salmonella Enteritidis Lipopolysaccharides.

Lipopolysaccharides (LPS), also known as lipoglycans or endotoxins, form part of the outer membrane of Gram-negative bacteria. Previous studies have described the various harmful impacts of LPS on humans and animals. Nevertheless, many aspects of these effects are still not fully explained. One of them is the influence of endotoxins on the neurochemical characterization of neurons within the enteric nervous system (ENS), which is found in the intestinal wall and plays important adaptive roles during pathological processes and exposures. In this study, the impact of a low single dose of Salmonella Enteritidis LPS on the duodenal enteric neurons immunoreactive to substance P (SP), vasoactive intestinal polypeptide (VIP), pituitary adenylate cyclase activating peptide (PACAP-27), and cocaine- and amphetamine-regulated transcript (CART) was studied using a double immunofluorescence technique. During the study, it was shown that even a low dose of LPS affects the number of enteric neurons containing the neuropeptides studied, and these changes were dependent on the type of the enteric plexus. The most visible changes concerned the SP-like immunoreactive (LI) neurons in the outer submucous plexus (LPS caused an increase in the percentage of these neurons from15.74 ± 0.61 to 21.72 ± 0.79%). Furthermore, the VIP-LI neurons in the inner submucous plexus were seen to decrease from 12.64 ± 0.83 to 5.96 ± 0.58%. The mechanisms behind these noted fluctuations are not clear, but it may be connected with the pro-inflammatory and neurotoxic activity of LPS.

Increased PACAP- and DßH-Positive Hepatic Nerve Fibers after Bisphenol A Exposure.

Bisphenol A (BPA) is an endocrine-disrupting compound (EDC) that can be found nearly everywhere in our polluted world. BPA has been correlated with pathophysiologies that include psychological disorders, especially in children. This study used juvenile porcine models to investigate the effects of BPA on the liver of developing vertebrates in order to determine the effects of BPA on innervated hepatic samples with the use of double-labeled immunofluorescence. This study specifically investigated the sympathetic nervous system (SNS) colocalized with a specific neural marker (PACAP) that has previously been correlated with specific pathophysiologies in the literature. In the liver, it was observed that there were significantly increased nerve fibers in the SNS colocalized with the neural marker PACAP after exposure to BPA at concentrations considered to be "safe" with the same or more profound effects at higher exposure levels. The implications of childhood exposure to BPA are then discussed with regard to several correlation studies that have linked BPA exposure to behavioral/psychological disorders. It is possible that BPA exposure in childhood may upregulate the SNS and PACAP levels, thereby contributing to the correlations in the literature.

Chemically-Induced Inflammation Changes the Number of Nitrergic Nervous Structures in the Muscular Layer of the Porcine Descending Colon.

The enteric nervous system (ENS) is the part of the nervous system that is located in the wall of the gastrointestinal tract and regulates the majority of the functions of the stomach and intestine. Enteric neurons may contain various active substances that act as neuromediators and/or neuromodulators. One of them is a gaseous substance, namely nitric oxide (NO). It is known that NO in the gastrointestinal (GI) tract may possess inhibitory functions; however, many of the aspects connected with the roles of this substance, especially during pathological states, remain not fully understood. An experiment is performed here with 15 pigs divided into 3 groups: C group (without any treatment), C1 group ("sham" operated), and C2 group, in which experimental inflammation was induced. The aim of this study is to investigate the influence of inflammation on nitrergic nervous structures in the muscular layer of the porcine descending colon using an immunofluorescence method. The obtained results show that inflammation causes an increase in the percentage of nitric oxide synthase (nNOS)-positive neurons in the myenteric plexus of the ENS, as well as the number of nitrergic nerve fibers in the muscular layer of the descending colon. The obtained results suggest that NO is involved in the pathological condition of the large bowel and probably takes part in neuroprotective and/or adaptive processes.

Aspirin Administration Affects Neurochemical Characterization of Substance P-Like Immunoreactive (SP-LI) Nodose Ganglia Neurons Supplying the Porcine Stomach.

BACKGROUND: Acetylsalicylic acid (ASA) is a commonly used anti-inflammatory, antipyretic, and analgesic drug, which has many side effects on the gastric mucosal layer. Despite this, knowledge concerning the influence of ASA on neuronal cells supplying the stomach is very scanty. METHODS: This investigation was performed on ten immature gilts of the Large White Polish race divided into two groups (five animals in each): a control group and animals which were treated with ASA. The retrograde neuronal tracer Fast Blue (FB) was injected into the prepyloric region of the stomach in all animals. ASA was then given orally to the experimental (ASA) group of gilts from the seventh day after FB injection to the 27th day of the experiment. After this period, all animals were euthanized. Immediately after euthanasia, nodose ganglia (NG) were collected and subjected to a standard double-labelling immunofluorescence technique using antibodies directed toward substance P (SP) and other selected neuronal factors, such as galanin (GAL), neuronal isoform of nitric oxide synthase (nNOS), vasoactive intestinal polypeptide (VIP), and calcitonin gene-related peptide (CGRP). Key Results. The obtained results show that SP-LI neurons located in NG supplying the porcine stomach were also immunoreactive to all the above-mentioned neuronal factors. Moreover, ASA administration caused an increase in the degree of colocalization of SP with other neuronal active substances, and the most visible changes concerned the number of neurons simultaneously immunoreactive to SP and CGRP. Conclusions and Inferences. These observations indicate that the population of SP-LI neurons supplying the stomach is not homogeneous and may undergo changes after ASA administration. These changes are probably connected with inflammatory processes and/or neuroprotective reactions although their exact mechanisms remain unknown.

The Influence of High and Low Doses of Acrylamide on Porcine Erythropoiesis.

INTRODUCTION: Due to the widespread occurrence of acrylamide in the environment, its likely carcinogen status, and the suitability of the pig model as a human analogue, the authors decided to evaluate the impact of high and low doses of this compound on the processes of erythropoiesis in swine bone marrow. MATERIAL AND METHODS: The experiment was carried out on Danish Landrace pigs at the age of eight weeks and body weight about 20 kg. The animals were divided into three equal groups consisting of five pigs in each. Control animals received empty gelatin capsules (placebos). Animals from the first experimental group received a low dose of acrylamide of 0.5 µg/kg b.w./day (> 99% purity; Sigma-Aldrich, Poland), and animals from the second experimental group received a dose 10 times higher. Placebos and acrylamide capsules were administered with feed every morning for 28 days. After anaesthetisation of the animals, bone marrow from the femur was collected into tubes without an anticoagulant on days 0 and 28. After drying and staining, bone marrow smears were subjected to detailed cytological evaluation using a light microscope. RESULTS: This study showed that high and low doses of acrylamide affected the process of porcine erythropoiesis. The cytotoxic effect of acrylamide on this process was demonstrated in a change of the polychromatic erythroblasts/normochromatic erythroblasts ratio. CONCLUSION: Both doses of acrylamide caused a decrease in the number of ortho- and polychromatic erythroblasts.

Historical Surgical Treatments in Polish Veterinary Medicine.

Several methods of surgical treatments have been used in the history of Polish veterinary medicine, many of which have now been forgotten. In the present study, a review was conducted of Polish-language veterinary medicine books published from the 16th century (when the first books in Polish were printed) to the 20th century. The article contains a description of the most popular surgical methods used in animal treatment in Poland over the centuries including, among others, bloodletting, setons, fonticulus and cauterization. This article reviews historical veterinary methods and traces the development of Polish veterinary medicine from ancient cures often based on humoral theory to a modern branch of biologic science.

Effect of Simvastatin on Thrombopoiesis in Porcine Bone Marrow.

INTRODUCTION: Statins are pharmacological agents commonly used to lower serum cholesterol level. The aim of the experiment was to investigate the effect of the statin simvastatin on thrombopoiesis in the porcine model because it is the closest to the human one regarding physiological and genetic similarities. MATERIAL AND METHODS: The study was conducted on a group of 32 pigs randomly divided into two equal groups: control and experimental. The pigs were treated for 28 and 56 days with simvastatin in a dose of 40 mg per day per animal. Cytological evaluation of bone marrow smears was performed to assess the average number of all types of cells during thrombopoiesis as was analysis of haematological parameters to assess PLT and MPV. RESULTS: During the course of the experiment statistically significant changes in the number of promegakaryocytes were observed. Other parameters also showed some fluctuations during the study. However, these changes were not statistically significant. CONCLUSION: The obtained results clearly indicate a toxic influence of simvastatin on the process of thrombopoiesis and prove that statins reduce mean platelet volume, thus affecting the process of clot formation through the period of administration in a duration-dependent manner.