Animal Studies Research Articles

Clinical and preclinical insights into high-dose ambroxol therapy for Gaucher disease type 2 and 3: A comprehensive systematic review

RationaleGaucher disease (GD), an autosomal recessive lysosomal storage disease, results from GBA1 variants causing glucocerebrosidase (GCase) deficiency. While enzyme replacement therapy (ERT) helps with systemic symptoms, neurological complications in GD2 and GD3 persist due to the blood-brain-barrier (BBB) limiting ERT efficacy. Ambroxol, a BBB-permeable chaperone, enhances GCase activity. Our review explores high-dose ambroxol's therapeutic potential, both preclinical and clinical, in GD2 and GD3. MethodsPubMed was searched for studies published before March 2023, including clinical, animal, and in vitro studies focusing on the effect of high-dose ambroxol in GD2 and GD3. A narrative synthesis was performed. ResultsNine in vitro, three animal, and eight clinical studies were included, demonstrating varied responses to ambroxol across diverse outcome measures. In vitro and animal studies demonstrated reduced endoplasmatic reticulum stress due to the relocation of GCase from the ER to the lysosomes. In vitro cell lines exhibited varying degrees of increased GCase activity. Clinical trials observed reduced lyso-GL1 levels in plasma (41–89%) and cerebrospinal fluid (CSF) (26–97%), alongside increased GCase activity in GD3 patients. Ambroxol exhibited varying effects on neurological outcomes and development. No severe adverse events were reported. ConclusionHigh-dose ambroxol shows promise in managing neurological manifestations in GD3, albeit with uncertainties resulting from genetic heterogeneity and variable response. Further clinical trials, are essential for elucidating dosage-response relationships and refining treatment outcomes and strategies for neuronopathic GD.

Increased risky choice during forced abstinence from fentanyl on the cued rat gambling task.

The use of illicit opioids has arguably never been more risky; street drug potency can be dangerously high, is often unknown to the consumer, and results in multiple daily fatalities worldwide. Furthermore, substance use disorder (SUD) is associated with increased maladaptive, risky decisions in laboratory-based gambling tasks. Animal studies can help determine whether this decision-making deficit is a cause or consequence of drug use. However, most experiments have only assessed psychostimulant drugs. To assess differences in decision-making strategies both before, during, and after self-administration of fentanyl in male and female Long Evans rats. Male and female Long Evans rats were trained to perform the rat gambling task (rGT), loosely based on the Iowa Gambling Task (IGT) used clinically, and/or self-administer fentanyl. We used the cued version of the rGT, in which sound and light stimuli signal sugar pellet rewards, as cocaine self-administration has the greatest effects on decision making in this task variant. After training on the cued rGT, female rats self-administered fentanyl more readily, an effect that was most apparent in optimal decision-makers. Contrary to previous reports using cocaine self-administration, decision-making was unaffected during fentanyl self-administration training in either sex. However, risky decision-making increased throughout forced abstinence from fentanyl in males. These findings complement those from human subjects, in whom preference for uncertain outcomes increased before relapse. These data highlight an abstinence-induced change in cognition that is unique to opiates as compared to psychostimulants, and which may critically contribute to the maintenance of addiction and relapse.

The addition of mesenchymal stem cells in a bioabsorbable scaffold does not enhance tendon healing after a repair of rotator cuff tear.

The purpose of the study is to evaluate the healing potential of a full-thickness tendon defect in the rotator cuff of rabbits using a bioabsorbable scaffold impregnated with bone marrow-mesenchymal stem cells (BM-MSCs) or rotator cuff-derived mesenchymal stem cells (RC-MSCs). Sixteen adult rabbits were subjected to a full-thickness rotator cuff deficit. Rabbits were randomly assigned to four groups of four animals. In Group 0 (control), the deficit was left untreated. In Group 1, the deficit was treated with a single synthetic scaffold alone. In Group 2, the deficit was treated with the previous scaffold loaded with allogeneic BM-MSCs. In Group 3, the deficit was treated with the previous scaffold loaded with allogenic RC-MSCs. After animal sacrifice, tissue samples were subjected to histological and immunohistochemical analysis. Group 1 showed the highest mean tendon maturing score (15.3 ± 0.9) postoperatively, being significantly higher, in comparison to groups 0, 2 and 3 (p = 0.01, 0.02 and 0.01, respectively). Group 1 showed the highest mean collagen I/collagen III ratio (1.4 ± 0.8) postoperatively but without any statistical significance. The utilization of MSCs in rotator cuff repair in a rabbit model has not been associated with an enhancement in tendon healing in 16 weeks postoperatively, in comparison to controls and bioabsorbable scaffolds. The addition of MSCs does not result in better rotator cuff healing. Not applicable. This is an animal study.

Effective strategies for managing trimethoprim-sulfamethoxazole and levofloxacin-resistant Stenotrophomonas maltophilia infections: bridging the gap between scientific evidence and clinical practice.

To discuss the therapeutic options available for the management of difficult-to-treat strains of Stenotrophomonas maltophilia (Sma), namely those resistant to trimethoprim-sulfamethoxazole and fluoroquinolones. Recent pharmacological studies have highlighted the fact that current breakpoints for first-line antibiotics against Sma are too high. In light of these data, it is likely that the prevalence of difficult-to-treat (DTR) Sma is underestimated worldwide. Two promising alternatives for treating DTR strains are cefiderocol and the combination of aztreonam and an L2 inhibitor. However, clinical trials are currently very limited for these antibiotics and no comparative studies have been carried out to date. It is important to note that the clinical efficacy of cefiderocol appears to be inferior to that initially anticipated from in-vitro and animal studies. Consequently, minocycline and ceftazidime may remain viable options if they are used against strains with a low minimum inhibitory concentration. We advise against the use of intravenous polymyxins and tigecycline. Finally, recent literature does not support the systematic use of combination therapy or long-course treatments. In the coming years, phage therapy may become a promising approach against DTR Sma infections. Overall, clinical comparative studies focused on DTR strains are required in order to provide more accurate and actionable information for therapeutic decisions.

Apical periodontitis as an aggravating factor for the severity of rheumatoid arthritis: An animal study.

The present study investigated the influence of apical periodontitis (AP) on the severity of rheumatoid arthritis (RA) using a Wistar rat model. Forty male Wistar rats were distributed across four groups (n = 10) based on the induction of RA and AP: Control, RA, AP, and RA + AP. RA was induced through two immunisations with type II collagen emulsified in incomplete Freund's adjuvant, followed by one immunisation with complete Freund's adjuvant. After 21 days of RA induction, AP was induced by exposing the pulp of four molars. Animals were euthanized after 28 days of pulp exposure. Through the experiment, visual and behavioural assessments tracked RA development and the knees and hind paw joints were measured. Micro-computed tomography scans of knees and hind paws, as well as mandibles and maxillae, were conducted to evaluate RA severity and the presence of AP, respectively. Serum samples were collected to analyse proinflammatory cytokines (IL-1β, IL-2, IL-17, and TNF-α). Non-parametric data were analysed using the Kruskal-Wallis test followed by Student-Newman-Keuls test, while one-way anova followed by Tukey's test was performed for parametric data. A significance level of 5% was employed. All molars submitted to access cavity developed AP. All joints subjected to arthritis induction developed the disease, with AP + RA demonstrating a higher arthritis severity when compared to the RA group (p < .05). RA + AP group displayed a significantly larger hind paw and knee circumference compared to the RA group (p < .05). Micro-CT images of RA and RA + AP groups revealed joints with erosions and bone deformities, with a significantly lower bone surface density, lower trabecular number and higher trabecular separation in the hind paw and a significantly lower percent bone volume and higher trabecular separation in the knees of RA + AP group compared to RA group (p < .05). RA + AP group exhibited a significantly higher level of TNF-α and a lower level of IL-2 compared to all other groups (p < .05). Both RA and RA + AP groups had significantly higher IL-17 levels (p < .05), while there was no significant difference in IL-1β levels among the groups (p > .05). The findings from this study underscore a possible relationship between apical periodontitis and the exacerbation of rheumatoid arthritis.

The Development of a Novel Peristaltic Test Stand “Swallow-Sim” for the Mechanical Evaluation of Esophageal Stents

Abstract The development of medical products begins with the “in silico” phase, where the development and simulation of new stent types are carried out. This is followed by the “in vitro” phase. Here, tests are done in a test stand to obtain initial conclusions about the interaction of the environment. The approval process is completed in the “in vivo” phase, where testing in living beings happen. Here, preclinical studies are carried out in animals first, followed by clinical studies on patients. A big part of the development fails in this final phase, as this is where the interactions of all influences from the stent environment are investigated. Since this not only causes high costs for the developers but also unnecessarily destroys living resources in animal studies, this publication describes the development of a test stand called “Swallow-Sim” that superimposes the mechanical influences of the esophagus, the chemical stress caused by hydrochloric acid and increased body temperature. Furthermore, tests of the acting pressures are carried out using esophageal manometry, a temperature test of the test stand and a test run of the gastric juice. At the end of this publication, the results are evaluated with a six-week test of a Nickel Titanium Naval Ordnance Laboratory stent, which loses much of its mechanical properties and is partially destroyed by the load. The results show a clear correlation with the findings from reality. The test stand should be further optimized and examined in more detail in further tests and subjected to a reality check.

The effect of endometriosis on the fertility of women

Endometriosis is defined by the presence of ectopic endometrial tissue outside the uterus, frequently located on pelvic organs such as the fallopian tubes and ovaries, and occasionally beyond the pelvic region. This condition manifests as dysmenorrhea, chronic pelvic pain, dyspareunia, and subfertility. Despite extensive research, the etiology and pathogenesis of endometriosis remain unclear, with laparoscopy being the definitive diagnostic method. The association between endometriosis and infertility has been extensively debated. Endometriosis can impair fertility by disrupting embryo implantation, altering hormone levels, and compromising oocyte quality. This literature review aims to examine the effects of endometriosis on female fertility. The review encompasses documents from clinical trials with control groups involving 196 to 22,416 reproductive-age participants (25-42 years), and case studies published over the past thirty-seven years from various regions (USA, Australia, Turkey, Africa, and Europe. Reputable databases such as BMJ, NEJM, Elsevier, AJR, Medline, and PubMed were utilized, with references compiled in the bibliography. A risk-benefit analysis indicates that up to 50% of women with endometriosis experience infertility. Consensus on treatment options remains elusive. The relationship between endometriosis and infertility is supported by studies of both fertile and infertile women, animal studies, donor sperm studies, and in vitro fertilization outcomes. Diagnostic methodologies based on endometrial changes are providing insights into potential mechanisms of infertility, especially in women with milder disease. However, clinical management of endometriosis-related infertility has not shown conclusive success beyond in vitro fertilization.

Association of breast milk-derived arachidonic acid-induced infant gut dysbiosis with the onset of atopic dermatitis

ObjectiveThe specific breast milk-derived metabolites that mediate host–microbiota interactions and contribute to the onset of atopic dermatitis (AD) remain unknown and require further investigation.DesignWe enrolled 250 mother–infant pairs and collected...

Urinary and Fecal Excretion of 121 Environmental Chemicals in Pet Dogs and Cats: Significance of Feces in Biomonitoring of Exposures.

Laboratory animal studies have reported the biliary excretion of chemicals following exposure. Nevertheless, feces are rarely used as a matrix in biomonitoring of chemical exposures. In this study, feces and urine from pet dogs and cats were analyzed for the presence of 45 plasticizers, 45 environmental phenols, and 31 pesticides. Thirty-two analytes were detected in ≥70% pet feces, while up to 29 analytes were frequently (≥70%) found in urine. The sum concentrations of all analytes (∑All) in pet feces were significantly higher than those measured in urine (median: 393-666 ng/g wet weight in feces vs 216-464 ng/mL in urine). Plasticizers were the dominant class of chemicals, accounting for 81-97% and 69-77% of ∑All in urine and feces, respectively. Analyte concentrations measured in paired urine and feces exhibited weak correlations. The excretion rates of the chemicals via urine and feces were calculated through a reverse dosimetry approach. Low-molecular-weight phthalates excreted predominantly in urine, whereas high-molecular-weight phthalates and several organophosphate triesters were excreted predominantly in feces. The fecal excretion rates of parabens, benzophenones, bisphenols, naphthalene, 2,4-dichloronicotinic acid, and 4-nitrophenol were similar to or higher than those of urinary excretion. Our results suggest that feces are an important matrix in biomonitoring of exposure to environmental chemicals.

Using Quality by Design Tools to Study Gel Formulation from Brassica juncea Leaves and Conducting its In vitro, In vivo, Molecular Docking, and ADMET Analyses.

This research aims to create a gel formulation of Brassica juncea leaf extract and assess its anti-inflammatory properties using an in silico study. The anti-inflamma-tory activity has been compared with Diclofenac molecules in PDB id: 4Z69. Further, the Ab-sorption, Distribution, Metabolism, Excretion, and Toxicity analysis has been performed to en-sure the therapeutic potential and safety of the drug development process. The Quality by De-sign tool has been applied to optimize formulation development. The extracted gel is characterized by performing Fourier transformer infrared, zeta potential, particle size, Scanning Electron Microscope, and entrapment efficiency. Further, the formulation is evaluated by examining its viscosity, spreadability, and pH measurement. An In-vitro study of all nine extract suspensions was conducted to determine the drug contents at 276 nm. The optimized suspension has shown the maximum percentage of drug release (82%) in 10 hours of study. Animal study for anti-inflammatory activity was performed, and results of all five groups of animals compared the % inhibition of paw edema at three hours; gel (56.70 %), standard (47.86 %), and (39.72 %) were found. The research could conclude that the anti-inflammatory activity of gel formulation is high compared to extract, and a molecular docking study validates the anti-inflammatory ther-apeutic effects. ADMET analysis ensures the therapeutic effects and their safety.

Eugenol: A Potential Modulator of Human Platelet Activation and Mouse Mesenteric Vascular Thrombosis via an Innovative cPLA2-NF-κB Signaling Axis

Background: Platelets, a type of anucleated cell, play a crucial role in cardiovascular diseases (CVDs). Therefore, targeting platelet activation is essential for mitigating CVDs. Endogenous agonists, such as collagen, activate platelets by initiating signal transduction through specific platelet receptors, leading to platelet aggregation. Eugenol, primarily sourced from clove oil, is known for its antibacterial, anticancer, and anti-inflammatory properties, making it a valuable medicinal agent. In our previous study, eugenol was shown to inhibit platelet aggregation induced by collagen and arachidonic acid. We concluded that eugenol exerts a potent inhibitory effect on platelet activation by targeting the PLCγ2–PKC and cPLA2-TxA2 pathways, thereby suppressing platelet aggregation. In our current study, we found that eugenol significantly inhibits NF-κB activation. This led us to investigate the relationship between the NF-κB and cPLA2 pathways to elucidate how eugenol suppresses platelet activation. Methods: In this study, we prepared platelet suspensions from the blood of healthy human donors to evaluate the inhibitory mechanisms of eugenol on platelet activation. We utilized immunoblotting and confocal microscopy to analyze these mechanisms in detail. Additionally, we assessed the anti-thrombotic effect of eugenol by observing fluorescein-induced platelet plug formation in the mesenteric microvessels of mice. Results: For immunoblotting and confocal microscopy studies, eugenol significantly inhibited NF-κB-mediated signaling events stimulated by collagen in human platelets. Specifically, it reduced the phosphorylation of IKK and p65 and prevented the degradation of IκBα. Additionally, CAY10502, a cPLA2 inhibitor, significantly reduced NF-κB-mediated signaling events. In contrast, BAY11-7082, an IKK inhibitor, did not affect collagen-stimulated cPLA2 phosphorylation. These findings suggest that cPLA2 acts as an upstream regulator of NF-κB activation during platelet activation. Furthermore, both BAY11-7082 and CAY10502 significantly reduced the collagen-induced rise in intracellular calcium levels. In the animal study, eugenol demonstrated potential as an anti-thrombotic agent by significantly reducing platelet plug formation in fluorescein-irradiated mouse mesenteric microvessels. Conclusion: Our study uncovered a novel pathway in platelet activation involving the cPLA2-NF-κB axis, which plays a key role in the antiplatelet effects of eugenol. These findings suggest that eugenol could serve as a valuable and potent prophylactic or therapeutic option for arterial thrombosis.

Refinement of intranasal delivery in rats: A cadaveric study.

The intranasal route enables direct delivery of multiple substances from the nose to the brain, through olfactory and trigeminal pathways, bypassing the blood-brain barrier and avoiding systemic absorption. Despite the potential of this route, the various administration approaches make data reproducibility and interpretation challenging, emphasizing the necessity to establish a consistent methodology. Considering this, the aim of our study was to assess and compare the distribution of two dye volumes (30 µl and 50 µl) in the nasal cavity of rat cadavers. We employed three distinct methods of intranasal delivery: nose drops, by pipette tip, or cannula inserted into the nasal cavity. The results indicated that for both volumes, using the nose drops and the pipette tip methods, the dye dispersion occurred mainly in the vestibule, respiratory and olfactory regions, without reaching the olfactory bulbs. Using the cannula method, the deposition predominantly occurred in the respiratory and olfactory regions, with the dye reaching 66.7% and 100% of the olfactory bulbs, respectively, to low and high volume. Furthermore, the results demonstrated differences between the two volumes, in the pharynx, larynx, trachea, septal window, and incisive papilla, where an increased dye presence was observed with the 50 µl instillation across all three methods. According to our results, the intranasal delivery with a cannula was the most effective method for dye deposition in the olfactory region. However, further studies in live animals will be necessary to determine and refine the administration method that consistently allows specific deposition in the olfactory system.

Ultrasound-guided quadratus lumborum block in sheep: A cadaveric study.

This prospective anatomical study aimed to establish an ultrasound-guided technique to the quadratus lumborum (QL) plane in sheep cadavers. Thirteen cadavers, weighing less than 117 kg, were included. In phase 1, one cadaver underwent dissection and two cadavers underwent 3D computed tomographic reconstruction for anatomical evaluation of the thoracolumbar region. In phase 2, two cadavers were used to compare two ultrasound techniques to the QL plane: lateral to the QL muscle with a transversal approach (LQL) and transmuscular between QL and psoas muscles with a longitudinal approach (TQL). For LQL, the reference was the first lumbar transverse process, whereas for TQL, it was the intertransverse region between the first and second lumbar vertebrae. The needle was advanced in-plane towards the specific target for each technique and a total of four injections were performed using 0.4 ml kg-1 of a dye-lidocaine solution. In phase 3, 10 cadavers received bilateral LQL injections (n = 20). All cadavers were then dissected to evaluate spread of dye. In phase 2, following LQL injections, no dye was observed in undesired locations; however, the dye was noted in the retroperitoneal space (1/2) after TQL injections. In phase 3, the 13th thoracic, first, second, third lumbar nerves, and sympathetic trunk segments were stained in 80%, 95%, 100%, 45% and 35% of the injections, respectively. In conclusion, the LQL technique was feasible, allowing staining of the spinal nerves innervating the cranial abdomen in sheep cadavers. Further studies in live animals are warranted.

Transmission of Norwegian reindeer CWD to sheep by intracerebral inoculation results in an unusual phenotype and prion distribution

Chronic wasting disease (CWD), a prion disease affecting cervids, has been known in North America (NA) since the 1960s and emerged in Norway in 2016. Surveillance and studies have revealed that there are different forms of CWD in Fennoscandia: contagious CWD in Norwegian reindeer and sporadic CWD in moose and red deer. Experimental studies have demonstrated that NA CWD prions can infect various species, but thus far, there have been no reports of natural transmission to non-cervid species. In vitro and laboratory animal studies of the Norwegian CWD strains suggest that these strains are different from the NA strains. In this work, we describe the intracerebral transmission of reindeer CWD to six scrapie-susceptible sheep. Detection methods included immunohistochemistry (IHC), western blot (WB), enzyme-linked immunosorbent assay (ELISA), real-time quaking-induced conversion (RT-QuIC) and protein misfolding cyclic amplification (PMCA). In the brain, grey matter vacuolation was limited, while all sheep exhibited vacuolation of the white matter. IHC and WB conventional detection techniques failed to detect prions; however, positive seeding activity with the RT-QuIC and PMCA amplification techniques was observed in the central nervous system of all but one sheep. Prions were robustly amplified in the lymph nodes of all animals, mainly by RT-QuIC. Additionally, two lymph nodes were positive by WB, and one was positive by ELISA. These findings suggest that sheep can propagate reindeer CWD prions after intracerebral inoculation, resulting in an unusual disease phenotype and prion distribution with a low amount of detectable prions.

Reshaping tumor microenvironment by regulating local cytokines expression with a portable smart blue-light controlled device

Cytokines have attracted sustained attention due to their multi-functional cellular response in immunotherapy. However, their application was limited to their short half-time, narrow therapeutic window, and undesired side effects. To address this issue, we developed a portable smart blue-light controlled (PSLC) device based on optogenetic technology. By combining this PSLC device with blue-light controlled gene modules, we successfully achieved the targeted regulation of cytokine expression within the tumor microenvironment. To alter the tumor microenvironment of solid tumors, pro-inflammatory cytokines were selected as blue-light controlled molecules. The results show that blue-light effectively regulates the expression of pro-inflammatory cytokines both in vitro and in vivo. This strategy leads to enhanced and activated tumor-infiltrating immune cells, which facilitated to overcome the immunosuppressive microenvironment, resulting in significant tumor shrinkage in tumor-bearing mice. Hence, our study offers a unique strategy for cytokine therapy and a convenient device for animal studies in optogenetic immunotherapy.

German Chamomile (Matricaria chamomilla L.) Flower Extract, Its Amino Acid Preparations and 3D-Printed Dosage Forms: Phytochemical, Pharmacological, Technological, and Molecular Docking Study

German chamomile (Matricaria chamomilla L.) is an essential oil- containing medicinal plant used worldwide. The aim of this study was to gain knowledge of the phytochemical composition and the analgesic and soporific activity of Matricaria chamomilla L. (German chamomile) flower extract and its amino acid preparations, to predict the mechanisms of their effects by molecular docking and to develop aqueous printing gels and novel 3D-printed oral dosage forms for the flower extracts. In total, 22 polyphenolic compounds and 14 amino acids were identified and quantified in the M. chamomilla extracts. In vivo animal studies with rodents showed that the oral administration of such extracts revealed the potential for treating of sleep disorders and diseases accompanied by pain. Amino acids were found to potentiate these effects. Glycine enhanced the analgesic activity the most, while lysine and β-alanine improved the soporific activity. The molecular docking analysis revealed a high probability of γ-aminobutyric acid type A (GABAA) and N-methyl-D-aspartate (NMDA) receptor antagonism and 5-lipoxygenase (LOX-5) inhibition by the extracts. A polyethylene oxide (PEO)-based gel composition with the M. chamomilla extracts was proposed for preparing a novel 3D-printed dosage form for oral administration. These 3D-printed extract preparations can be used, for example, in dietary supplement applications.

An update on pacemaking in the myometrium.

Timely and efficient contractions of the smooth muscle of the uterus - the myometrium - are crucial to a successful pregnancy outcome. These episodic contractions are regulated by spontaneous action potentials changing cell and tissue electrical excitability. In this short review we will document and discuss current knowledge of these processes. Those seeking a conclusive account of myometrial pacemaking mechanisms, or indeed a definitive description of the anatomical site of uterine pacemaking, may be disappointed. Rather, after almost a century of investigation, and in spite of promising studies in the last decade or so, there remain many gaps in our knowledge. We review the progress that has been made using recent technologies including in vivo and ex vivo imaging and electrophysiology and computational modelling, taking evidence from studies of animal and human myometrium, with particular emphasis on what may occur in the latter. We have prioritized physiological studies that bring us closer to understanding function. From our analyses we suggest that in human myometrium there is no fixed pacemaking site, but rather mobile, initiation sites produce the connectivity for synchronizing electrical and contractile activity. We call for more studies and funding, as physiological understanding of pacemaking gives hope to being better able to treat clinical conditions such as preterm and dysfunctional labours.

Evaluating the role of 7-Tesla magnetic resonance imaging in neurosurgery: Trends in literature since clinical approval.

After approval for clinical use in 2017, early investigations of ultra-high-field abdominal magnetic resonance imaging (MRI) have demonstrated its feasibility as well as diagnostic capabilities in neuroimaging. However, there are no to few systematic reviews covering the entirety of its neurosurgical applications as well as the trends in the literature with regard to the aforementioned application. To assess the impact of 7-Tesla MRI (7T MRI) on neurosurgery, focusing on its applications in diagnosis, treatment planning, and postoperative assessment, and to systematically analyze and identify patterns and trends in the existing literature related to the utilization of 7T MRI in neurosurgical contexts. A systematic search of PubMed was conducted for studies published between January 1, 2017, and December 31, 2023, using MeSH terms related to 7T MRI and neurosurgery. The inclusion criteria were: Studies involving patients of all ages, meta-analyses, systematic reviews, and original research. The exclusion criteria were: Pre-prints, studies with insufficient data (e.g., case reports and letters), non-English publications, and studies involving animal subjects. Data synthesis involved standardized extraction forms, and a narrative synthesis was performed. We identified 219 records from PubMed within our defined period, with no duplicates or exclusions before screening. After screening, 125 articles were excluded for not meeting inclusion criteria, leaving 94 reports. Of these, 2 were irrelevant to neurosurgery and 7 were animal studies, resulting in 85 studies included in our systematic review. Data were categorized by neurosurgical procedures and diseases treated using 7T MRI. We also analyzed publications by country and the number of 7T MRI facilities per country was also presented. Experimental studies were classified into comparison and non-comparison studies based on whether 7T MRI was compared to lower field strengths. 7T MRI holds great potential in improving the characterization and understanding of various neurological and psychiatric conditions that may be neurosurgically treated. These include epilepsy, pituitary adenoma, Parkinson's disease, cerebrovascular diseases, trigeminal neuralgia, traumatic head injury, multiple sclerosis, glioma, and psychiatric disorders. Superiority of 7T MRI over lower field strengths was demonstrated in terms of image quality, lesion detection, and tissue characterization. Findings suggest the need for accelerated global distribution of 7T magnetic resonance systems and increased training for radiologists to ensure safe and effective integration into routine clinical practice.

The role of fibrosis in endometriosis: a systematic review.

Fibrosis is an important pathological feature of endometriotic lesions of all subtypes. Fibrosis is present in and around endometriotic lesions, and a central role in its development is played by myofibroblasts, which are cells derived mainly after epithelial-to-mesenchymal transition (EMT) and fibroblast-to-myofibroblast transdifferentiation (FMT). Transforming growth factor-β (TGF-β) has a key role in this myofibroblastic differentiation. Myofibroblasts deposit extracellular matrix (ECM) and have contracting abilities, leading to a stiff micro-environment. These aspects are hypothesized to be involved in the origin of endometriosis-associated pain. Additionally, similarities between endometriosis-related fibrosis and other fibrotic diseases, such as systemic sclerosis or lung fibrosis, indicate that targeting fibrosis could be a potential therapeutic strategy for non-hormonal therapy for endometriosis. This review aims to summarize the current knowledge and to highlight the knowledge gaps about the role of fibrosis in endometriosis. A comprehensive literature overview about the role of fibrosis in endometriosis can improve the efficiency of fibrosis-oriented research in endometriosis. A systematic literature search was performed in three biomedical databases using search terms for 'endometriosis', 'fibrosis', 'myofibroblasts', 'collagen', and 'α-smooth muscle actin'. Original studies were included if they reported about fibrosis and endometriosis. Both preclinical in vitro and animal studies, as well as research concerning human subjects were included. Our search yielded 3441 results, of which 142 studies were included in this review. Most studies scored a high to moderate risk of bias according to the bias assessment tools. The studies were divided in three categories: human observational studies, experimental studies with human-derived material, and animal studies. The observational studies showed details about the histologic appearance of fibrosis in endometriosis and the co-occurrence of nerves and immune cells in lesions. The in vitro studies identified several pro-fibrotic pathways in relation to endometriosis. The animal studies mainly assessed the effect of potential therapeutic strategies to halt or regress fibrosis, for example targeting platelets or mast cells. This review shows the central role of fibrosis and its main cellular driver, the myofibroblast, in endometriosis. Platelets and TGF-β have a pivotal role in pro-fibrotic signaling. The presence of nerves and neuropeptides is closely associated with fibrosis in endometriotic lesions, and is likely a cause of endometriosis-associated pain. The process of fibrotic development after EMT and FMT shares characteristics with other fibrotic diseases, so exploring similarities in endometriosis with known processes in diseases like systemic sclerosis, idiopathic pulmonary fibrosis or liver cirrhosis is relevant and a promising direction to explore new treatment strategies. The close relationship with nerves appears rather unique for endometriosis-related fibrosis and is not observed in other fibrotic diseases. N/A.

Selecting the Most Relevant Mouse Strains for Evaluating Radiation-Induced Multiple Tissue Injury after Leg-Shielded Partial-Body Gamma Irradiation.

Animal studies are needed that best simulate a large-scale, inhomogeneous body exposure after a radiological or nuclear incident and that provides a platform for future development of medical countermeasures. A partial-body irradiation (PBI) model using 137Cs gamma rays with hind limb (tibia) shielding was developed and assessed for the sequalae of radiation injuries to gastrointestinal tract, bone marrow (BM) and lung and among different genetic mouse strains (C57BL/6J, C57L/J, CBA/J and FVB/NJ). In this case, a marginal level of BM shielding (∼2%) provided adequate protection against lethality from infection and hemorrhage and enabled escalation of radiation doses with evaluation of both acute and delayed radiation syndromes. A steep radiation dose-dependent body weight loss was observed over the first 5 days attributed to enteritis with C57BL/6J mice appearing to be the most sensitive strain. Peripheral blood cell analysis revealed significant depression and recovery of leukocytes and platelets over the first month after PBI and were comparable among the four different mouse strains. Latent pulmonary injury was observed on micro-CT imaging at 4 months in C57L/J mice and confirmed histologically as severe pneumonitis that was lethal at 12 Gy. The lethality and radiological densitometry (HUs) dose responses were comparable to previous studies on C57L/J mice after total-body irradiation (TBI) and BM transplant rescue as well as after localized whole-thorax irradiation (WTI). Indeed, the lethal radiation doses and latency appeared similar for pneumonitis appearing in rhesus macaques after WTI or PBI as well as predicted for patients given systemic radiotherapy. In contrast, PBI treatment of C57BL/6 mice at a higher dose of 14 Gy had far longer survival times and developed extreme and debilitating pIeural effusions; an anomaly as similarly reported in previous thorax irradiation studies on this mouse strain. In summary, a radiation exposure model that delivers PBI to unanesthetized mice in a device that provides consistent shielding of the hind limb BM was developed for 137Cs gamma rays with physical characteristics and relevance to relatively high photon energies expected from the detonation of a nuclear device or accidental release of ionizing radiation. Standard strains such as C57BL/6J mice may be used reliably for early GI or hematological radiation syndromes while the C57L/J mouse strain stands out as the most appropriate for evaluating the delayed pulmonary effects of acute radiation exposure and recapitulating this disease in humans.