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BACKGROUND: Autism spectrum disorder (ASD) is characterized by persistent social interaction impairments and is male-biased in prevalence. We have established naturally occurring low sociality in male rhesus monkeys as a model for the social features of ASD. Low-social male monkeys exhibit reduced social interactions and increased autistic-like trait burden, with both measures highly correlated and strongly linked to low cerebrospinal fluid (CSF) arginine vasopressin (AVP) concentration. Little is known, however, about the behavioral and neurochemical profiles of female rhesus monkeys, and whether low sociality in females is a tractable model for ASD. METHODS: Social behavior assessments (ethological observations; a reverse-translated autistic trait measurement scale, the macaque Social Responsiveness Scale-Revised [mSRS-R]) were completed on N = 88 outdoor-housed female rhesus monkeys during the non-breeding season. CSF and blood samples were collected from a subset of N = 16 monkeys across the frequency distribution of non-social behavior, and AVP and oxytocin (OXT) concentrations were quantified. Data were analyzed using general linear models. RESULTS: Non-social behavior frequency and mSRS-R scores were continuously distributed across the general female monkey population, as previously found for male monkeys. However, dominance rank significantly predicted mSRS-R scores in females, with higher-ranking individuals showing fewer autistic-like traits, a relationship not previously observed in males from this colony. Females differed from males in several other respects: Social behavior frequencies were unrelated to mSRS-R scores, and AVP concentration was unrelated to any social behavior measure. Blood and CSF concentrations of AVP were positively correlated in females; no significant relationship involving any OXT measure was found. LIMITATIONS: This study sample was small, and did not consider genetic, environmental, or other neurochemical measures that may be related to female mSRS-R scores. CONCLUSIONS: Dominance rank is the most significant predictor of autistic-like traits in female rhesus monkeys, and CSF neuropeptide concentrations are unrelated to measures of female social functioning (in contrast to prior CSF AVP findings in male rhesus monkeys and male and female autistic children). Although preliminary, this evidence suggests that the strong matrilineal organization of this species may limit the usefulness of low sociality in female rhesus monkeys as a tractable model for ASD.

Neuroaxonal dystrophy (NAD) is a neurodegenerative disease characterized by spheroid (swollen axon) formation in the nervous system. In the present study, we focused on a newly established autosomal recessive mutant strain of F344-kk/kk rats with hind limb gait abnormalities and ataxia from a young age. Histopathologically, a number of axonal spheroids were observed throughout the central nervous system, including the spinal cord (mainly in the dorsal cord), brain stem, and cerebellum in F344-kk/kk rats. Transmission electron microscopic observation of the spinal cord revealed accumulation of electron-dense bodies, degenerated abnormal mitochondria, as well as membranous or tubular structures in the axonal spheroids. Based on these neuropathological findings, F344-kk/kk rats were diagnosed with NAD. By a positional cloning approach, we identified a missense mutation (V95E) in the Hspa8 (heat shock protein family A (Hsp70) member 8) gene located on chromosome 8 of the F344-kk/kk rat genome. Furthermore, we developed the Hspa8 knock-in (KI) rats with the V95E mutation using the CRISPR-Cas system. Homozygous Hspa8-KI rats exhibited ataxia and axonal spheroids similar to those of F344-kk/kk rats. The V95E mutant HSC70 protein exhibited the significant but modest decrease in the maximum hydrolysis rate of ATPase when stimulated by co-chaperons DnaJB4 and BAG1 in vitro, which suggests the functional deficit in the V95E HSC70. Together, our findings provide the first evidence that the genetic alteration of the Hspa8 gene caused NAD in mammals.

The first International Conference on Unconventional Animal Models of Alzheimers Disease and Aging (UAMAA) took place on December 13-16, 2023, in Santiago, Chile. The Alzheimers disease (AD) research field is currently in search for new and unconventional models that could hold greater translational potential than transgenic mouse models. Thus this UAMAA conference is timely and significant. The event consisted of 6 sessions with talks from 28 world-class scientists from all over the world. These animal models of interest include the degu (Octodon degu), the dog (Canis familiaris), and certain species of nonhuman primates that may better recapitulate neuropathology and cognitive impairments in human AD. Our conference has provided a formal forum to discuss and highlight new research directions, alternative animal models, and innovative approaches for the AD and aging research field.

BACKGROUND: Establishing an objective and standard animal model of bone nonunion is essential for experimental studies and treatment of nonunion. OBJECTIVE: To establish an objective animal model for experimental studies of nonunion. METHODS: Specific pathogen-free male Wistar rats were selected and prepared by cutting off a 5 mm bone defect in the middle femur, peeling off a large periosteum and removing bone marrow. Animal models were fixed with a 1.2 mm Kirschner wire. At 1, 4 and 8 weeks, bone nonunion was observed by gross specimen observation, X-ray examination and histopathological examination. RESULTS AND CONCLUSION: The gross specimen, X-ray film and histopathological examination showed that there was no callus formation in the bone defect area, the broken end was filled with fiber tissue, and the bone callus was rare or even invisible. To conclude, the rat model of nonunion can be successfully established by osteotomy of the middle femur, large periosteum peeling and bone marrow removal. This modeling method is simple, reliable and effective. [ABSTRACT FROM AUTHOR]

BACKGROUND: “Tendon off-position” is a disease name included in the International Classification of Diseases 11th Revision, and also a clinical indication of manipulation, acupuncture and other treatments. However, its specific mechanism is still unclear. It is urgent to establish an animal model that can reflect the clinical and pathological characteristics of “tendon off-position,” so as to further study the mechanism of effective clinical treatments. OBJECTIVE: To establish an animal model of “tendon off-position” in rats based on isometric contraction of skeletal muscles, and to explore the changes of skeletal muscle function and morphological phenotype after “tendon off-position.” METHODS: Sixty rats were randomly divided into control group, static-loading group and extra loading group, with twenty rats in each group. Rats in the control group were kept normally without treatment. In the latter two groups, the rats were fixed by the self-made static-loading modeling device and a static-loading (the body mass of each rats was applied as the static-loading) was applied to cause sustained isometric contraction of the upper limb muscles. Then, animal models of “tendon off-position” were successfully established. In the extra loading group, 50% of the body mass was added to the ankle joint after modeling. The skeletal muscle samples were harvested at 2 and 4 weeks after modeling. The changes of limb grip strength, wet mass of skeletal muscle, and serum levels of creatine kinase-muscle and lactate dehydrogenase A were measured, and the changes of skeletal muscle histomorphology and ultrastructure were observed. RESULTS AND CONCLUSION: At 2 weeks after modeling, the rats in the static-loading group and extra loading group showed significantly decreased grip strength and wet muscle mass, significantly increased serum levels of creatine kinase-muscle and lactate dehydrogenase A, and abnormal muscle fiber morphology and structure accompanied by a large number of deposited collagen fibers. Electron microscopy results showed that the structure of myofibrils was disordered, the Z-line was distorted, and the light and dark boundaries were blurred. At 4 weeks after modeling, the grip strength of the model rats was increased compared with that at 2 weeks, the serum creatine kinase-muscle and lactate dehydrogenase A levels were decreased, and the changes of muscle fiber morphology and ultrastructure were recovered to varying degrees. It is suggested that the rat skeletal muscle injury model based on continuous isometric contraction of skeletal muscle can well reflect the pathological characteristics of “tendon off-position” at 2 weeks, and can be used to study the mechanism of acupuncture and manipulation in the treatment of “tendon off-position.” [ABSTRACT FROM AUTHOR]

Heart weight is a routine measurement at post-mortem examination. An increased heart weight is associated with pre-existing heart disease and sudden cardiac death. However, during decomposition, the heart weight measured at post-mortem examination may not reflect the weight at the time of death. A previous study showed that heart dimensions can be used to estimate heart weight. This study documents the changes in heart dimensions during decomposition using porcine and ovine animal models. It shows that, in contrast to heart weight, which decreases in the post-mortem interval, the heart dimensions increase. Heart width increases and subsequently plateaus at the end of the 18 days to a mean of 6 and 8 mm in ovine and porcine hearts, whereas the length continues to increase. Using the results of this study, in conjunction with previous published literature, the heart width may be used as a parameter to estimate heart weight and determine cardiac hypertrophy at the time of death in decomposed hearts. [ABSTRACT FROM AUTHOR]

Aim Methods Results Conclusions The influence of hypercholesterolemia on the development of apical periodontitis (AP) is inconclusive. Recent studies revealed that cholesterol metabolite 27‐hydoxycholesterol (27HC) can affect cellular responses to bacterial infections and oestrogen status and raloxifene may influence its action. Herein, we aimed to examine the impact of 27HC on production of inflammatory mediators by macrophages and the regulatory function of raloxifene. The contribution of 27HC to AP development and the therapeutic effect of raloxifene were evaluated in a rat model.Murine macrophages J774 cells were used. The expression of inducible nitric oxide synthase (iNOS) was examined by Western blot. The concentrations of C‐C motif chemokine ligand (CCL) 2 and 27HC were assessed by enzyme‐linked immunosorbent assay. Colorimetric assay was used to evaluate cholesterol levels. Experimental AP was induced in ovariectomized (OVX) or un‐operated rats receiving high‐fat/high‐cholesterol diet (HFHCD) or normal diet (ND). Micro‐computed tomography and immunohistochemistry were employed to evaluate disease severity and the therapeutic effect of raloxifene.Cholesterol enhanced 27HC production in macrophages. 27HC induced iNOS and CCL2 synthesis by macrophages and estradiol suppressed the responses. In our animal model of AP, HFHCD plus OVX significantly augmented serum and lesion tissue levels of 27HC (p < .05 versus the ND group). Lesion size, infiltration of CD68+ cells, and iNOS+ monocytes were increased in parallel with 27HC accumulation. Raloxifene inhibited pro‐inflammatory effects of 27HC on macrophages and suppressed AP progression in HFHCD/OVX rats (p < .05 versus the vehicle control group).Our results suggested that 27HC contributes to AP aggravation associated with hypercholesterolemia. Oestrogen deficiency may both enhance 27HC production and exacerbate its downstream action. [ABSTRACT FROM AUTHOR]

Introduction Despite the significant need for mechanical ventilation in- and out-of-hospital, mechanical ventilators remain inaccessible in many instances because of cost or size constraints. Mechanical ventilation is especially critical in trauma scenarios, but the impractical size and weight of standard mechanical ventilators restrict first responders from carrying them in medical aid bags, leading to reliance on imprecise manual bag-mask ventilation. This is particularly important in combat-related injury, where airway compromise and respiratory failure are leading causes of preventable death, but medics are left without necessary mechanical ventilation. To address the serious gaps in mechanical ventilation accessibility, we are developing an Autonomous, Modular, and Portable Ventilation platform (AMP-Vent) suitable for austere environments, prolonged critical care, surgical applications, mass casualty incidents, and stockpiling. The core system is remarkably compact, weighing <2.3 kg, and can fit inside a shoebox (23.4 cm × 17.8 cm × 10.7 cm). Notably, this device is 65% lighter than standard transport ventilators and astoundingly 96% lighter than typical intensive care unit ventilators. Beyond its exceptional portability, AMP-Vent can be manufactured at less than one-tenth the cost of conventional ventilators. Despite its reduced size and cost, the system's functionality is uncompromised. The core system is equipped with closed-loop sensors and advanced modes of ventilation (pressure-control, volume-control, and synchronized intermittent mandatory ventilation), enabling quality care in a portable form factor. The current prototype has undergone preliminary preclinical testing and optimization through trials using a breathing simulator (ASL 5000) and in a large animal model (swine). This report aims to introduce a novel ventilation system and substantiate its promising performance through evidence gathered from preclinical studies. Materials and Methods Lung simulator testing was performed using the ASL 5000, in accordance with table 201.105 "pressure-control inflation-type testing" from ISO 80601-2-12:2020. Following simulations, AMP-Vent was tested in healthy 10-kg female domestic piglets. The Children's Hospital of Philadelphia Institutional Animal Care and Use Committee approved all animal procedures. Swine received 4-min blocks of alternating ventilation, where AMP-Vent and a conventional anesthesia ventilator (GE AISYS CS2) were used to titrate to varied end-tidal carbon dioxide (EtCO2) goals with the initial ventilator switching for each ascending target (35, 40, 45, 50, 55 mmHg). Results During ASL 5000 simulations, AMP-Vent exhibited consistent performance under varied conditions, maintaining a coefficient of variation of 2% or less within each test. In a large animal study, AMP-Vent maintained EtCO2 and SpO2 targets with comparable performance to a conventional anesthesia ventilator (GE AISYS CS2). Furthermore, the comparison of minute ventilation (V e) distributions between the conventional anesthesia ventilator and AMP-Vent at several EtCO2 goals (35, 40, 45, 50, and 55 mmHg) revealed no statistically significant differences (p  = 0.46 using the Kruskal–Wallis rank sum test). Conclusions Preclinical results from this study highlight AMP-Vent's core functionality and consistent performance across varied scenarios. AMP-Vent sets a benchmark for portability with its remarkably compact design, positioning it to revolutionize trauma care in previously inaccessible medical scenarios. [ABSTRACT FROM AUTHOR]

Introduction While the 44-mm clay penetration criterion was developed in the 1970s for soft body armor applications, and the researchers acknowledged the need to conduct additional tests, the same behind the armor blunt trauma displacement limit is used for both soft and hard body armor evaluations and design considerations. Because the human thoraco-abdominal contents are heterogeneous, have different skeletal coverage, and have different functional requirements, the same level of penetration limit does not imply the same level of protection. It is important to determine the regional responses of different thoraco-abdominal organs to better describe human tolerance and improve the current behind armor blunt trauma standard. The purpose of this study was to report on the methods, procedures, and data collected from swine. Materials and Methods Live swine tests were conducted after obtaining approvals from the local institution and the Army Care and Use Review Office of the U.S. Department of Defense. Trachea tubes and an intravenous line were introduced before administering anesthesia. Pressure transducers were inserted into the lungs and aorta. An indenter simulating the backface deformation profiles produced by body armor from military-relevant ballistics to human cadavers was used to deliver impact loading to the liver region. A triaxial accelerometer was included in the indenter design. The animals were monitored for 6 hours, necropsies were performed, and injuries were identified. Biomechanical data of the energy, velocity, deflection, viscous criterion, force, and impulse variables were obtained for each test. Results Peak accelerations, velocities, deflections, forces, impulse, and energies ranged from 897 to 5,808 g, 21 to 59 m/s, 1.96 to 8.87 cm, 2.3 to 13.1 kN, 1.1 to 7.1 Ns, and 58 to 387 J, respectively. The peak viscous criterion ranged from 0.8 to 5.8 m/s. All animals survived the 6-hour survival period. Three animals responded with liver lacerations while the remaining 4 did not have any injuries. Conclusion The experimental design based on parallel tests with whole body human cadavers and cadaver swine was found to be successful in delivering controlled impacts to the liver region of live swine and reproducing liver injuries. Previously used biomechanical measures as potential candidates for injury criteria development were obtained. Using this proven model, tests with additional samples are needed to develop injury risk curves for liver impacts and obtain regional (liver) injury criteria. [ABSTRACT FROM AUTHOR]

Introduction Auditory injuries induced by repeated exposures to blasts reduce the operational performance capability and the life quality of military personnel. The treatment for blast-induced progressive hearing damage is lacking. We have recently investigated the therapeutic function of liraglutide, a glucagon-like peptide-1 receptor agonist, to mitigate blast-induced hearing damage in the animal model of chinchilla, under different blast intensities, wearing earplugs (EPs) or not during blasts, and drug-treatment plan. The goal of this study was to investigate the therapeutical function of liraglutide by comparing the results obtained under different conditions. Materials and Methods Previous studies on chinchillas from two under-blast ear conditions (EP/open), two blast plans (G1: 6 blasts at 3–5 psi or G2:3 blasts at 15–25 psi), and three treatment plans (blast control, pre-blast drug treatment, and post-blast drug treatment) were summarized. The auditory brainstem response (ABR), distortion product otoacoustic emission (DPOAE), and middle latency response (MLR) recorded within 14 days after the blasts were used. Statistical analysis was performed to evaluate the effect of liraglutide under different conditions Results ABR threshold shifts indicated that the conditions of the EP and open ears were substantially different. Results from EP chinchillas indicated that the pre-blast treatment reduced the acute ABR threshold elevation on the day of blasts, and the significance of such an effect increased with the blast level. Liraglutide-treated open chinchillas showed lower ABR threshold shifts at the later stage of the experiment regardless of the blast levels. The DPOAE was less damaged after G2 blasts compared to G1 when pre-blast liraglutide was administrated. Lower post-blast MLR amplitudes were observed in the pre-blast treatment groups. Conclusions This study indicated that the liraglutide mitigated the blast-induced auditory injuries. In EP ears, the pre-blast administration of liraglutide reduced the severity of blast-induced acute damage in ears with EP protection, especially under G2. In animals with open ears, the effect of liraglutide on the restoration of hearing increased with time. The liraglutide potentially benefits post-blast hearing through multiple approaches with different mechanics. [ABSTRACT FROM AUTHOR]

Introduction Non-compressible torso hemorrhagic (NCTH) shock is the leading cause of potentially survivable trauma on the battlefield. New hypotensive drug therapies are urgently required to resuscitate and protect the heart and brain following NCTH. Our aim was to examine the strengths and limitations of permissive hypotension and discuss the development of small-volume adenosine, lidocaine, and Mg2+ (ALM) fluid resuscitation in rats and pigs. Materials and Methods For review of permissive hypotension, a literature search was performed from inception up to November 2023 using PubMed, Cochrane, and Embase databases, with inclusion of animal studies, clinical trials and reviews with military and clinical relevance. For the preclinical study, adult female pigs underwent laparoscopic liver resection. After 30 minutes of bleeding, animals were resuscitated with 4 mL/kg 3% NaCl ± ALM bolus followed 60 minutes later with 4 h 3 mL/kg/h 0.9% NaCl ± ALM drip (n  = 10 per group), then blood transfusion. Mean arterial pressure (MAP) and cardiac output (CO) were continuously measured via a left ventricular pressure catheter and pulmonary artery catheter, respectively. Systemic vascular resistance (SVR) was calculated using the formula: 80 × (MAP − CVP)/CI. Oxygen delivery was calculated as the product of CO and arterial oxygen content. Results Targeting a MAP of ∼50 mmHg can be harmful or beneficial, depending on how CO and SVR are regulated. A theoretical example shows that for the same MAP of 50 mmHg, a higher CO and lower SVR can lead to a nearly 2-fold increase in O2 supply. We further show that in animal models of NCTH, 3% NaCl ALM bolus and 0.9% NaCl ALM drip induce a hypotensive, high flow, vasodilatory state with maintained tissue O2 supply and neuroprotection. ALM therapy increases survival by resuscitating the heart, reducing internal bleeding by correcting coagulopathy, and decreasing secondary injury. Conclusions In rat and pig models of NCTH, small-volume ALM therapy resuscitates at hypotensive pressures by increasing CO and reducing SVR. This strategy is associated with heart and brain protection and maintained tissue O2 delivery. Translational studies are required to determine reproducibility and optimal component dosing. ALM therapy may find wide utility in prehospital and far-forward military environments. [ABSTRACT FROM AUTHOR]

Introduction Disease and non-battle injury (DNBI) has historically been the leading casualty type among service members in warfare and a leading health problem confronting military personnel, resulting in significant loss of manpower. Studies show a significant increase in disease burden for DNBI when compared to combat-related injuries. Understanding the causes of and trends in DNBI may help guide efforts to develop preventive measures and help increase medical readiness and resiliency. However, despite its significant disease burden within the military population, DNBI remains less studied than battle injury. In this review, we aimed to evaluate the recently published literature on DNBI and to describe the characteristics of these recently published studies. Materials and Methods This systematic review is reported in the Prospective Register of Systematic Reviews database. The systematic search for published articles was conducted through July 21, 2022, in Cumulative Index of Nursing and Allied Health, Cochrane Library, Defense Technical Information Center, Embase, and PubMed. Guided by the Preferred Reporting Items for Systematic Reviews and Meta-analyses, the investigators independently screened the reference lists on the Covidence website (covidence.org). An article was excluded if it met any of the following criteria: (1) Published not in English; (2) published before 2010; (3) data used before 2001; (4) case reports, commentaries, and editorial letters; (5) systematic reviews or narrative reviews; (6) used animal models; (7) mechanical or biomechanical studies; (8) outcome was combat injury or non-specified; (9) sample was veterans, DoD civilians, contractors, local nationals, foreign military, and others; (10) sample was U.S. Military academy; (11) sample was non-deployed; (12) bioterrorism study; (13) qualitative study. The full-text review of 2 independent investigators reached 96% overall agreement (166 of 173 articles; κ = 0.89). Disagreements were resolved by a third reviewer. Study characteristics and outcomes were extracted from each article. Risk of bias was assessed using the Newcastle-Ottawa Scale. Meta-analysis of pooled estimates of incidence rates for disease (D), non-battle injury (NBI), and combined DNBI was created using random-effects models. Results Of the 3,401 articles, 173 were included for the full review and 29 (16.8%) met all inclusion criteria. Of the 29 studies included, 21 (72.4%) were retrospective designs, 5 (17.2%) were prospective designs, and 3 (10.3%) were surveys. Across all studies, the median number of total cases reported was 1,626 (interquartile range: 619.5-10,203). The results of meta-analyses for 8 studies with reported incidence rates (per 1,000 person-years) for D (n  = 3), NBI (n  = 7), and DNBI (n  = 5) showed pooled incidence rates of 22.18 per 1,000 person-years for D, 19.86 per 1,000 person-years for NBI, and 50.97 per 1,000 person-years for combined DNBI. Among 3 studies with incidence rates for D, NBI, and battle injury, the incidence rates were 20.32 per 1,000 person-years for D, 6.88 per 1,000 person-years for NBI, and 6.83 per 1,000 person-years for battle injury. Conclusions DNBI remains the leading cause of morbidity in conflicts involving the U.S. Military over the last 20 years. More research with stronger designs and consistent measurement is needed to improve medical readiness and maintain force lethality. Level of Evidence Systematic Review and Meta-Analysis, Level III. [ABSTRACT FROM AUTHOR]

Rabbits are routinely used as a natural model of fetal growth restriction (FGR); however, no studies have confirmed that rabbits have FGR. This study aimed to characterize the fetoplacental unit (FPU) in healthy pregnant rabbits using diffusion-weighted MRI and stereology. A secondary objective of the study was to describe the associations among findings from diffusion-weighted MRI (DW-MRI), fetal weight measurement and histological analysis of the placenta. Pregnant rabbits underwent DW-MRI under general anesthesia on embryonic day 28 of pregnancy. MR imaging was performed at 3.0 T. The apparent diffusion coefficient (ADC) values were calculated for the fetal brain, liver, and placenta. The placenta was analyzed by stereology (volume density of trophoblasts, the maternal blood space and fetal vessels). Each fetus and placenta were weighed. Two groups of fetuses were defined according to the position in the uterine horn (Cervix group versus Ovary group). We analyzed 20 FPUs from 5 pregnant rabbits. Fetuses and placentas were significantly lighter in the Cervix group than in the Ovary group (34.7 ± 3.7 g vs. 40.2 ± 5.4 g; p = 0.02). Volume density analysis revealed that the percentage of fetal vessels, the maternal blood space and trophoblasts was not significantly affected by the position of the fetus in the uterine horn. There was no difference in ADC values according to the position of the fetus in the uterine horn, and there was no correlation between ADC values and fetal weight. The findings of a multimodal evaluation of the placenta in a rabbit model of FGR suggested is not a natural model of fetal growth restriction. • In rabbits, the fetus closest to the ovary is heavier than the one near the cervix. • It is possible to use DW-MRI to assess placental function in rabbits. • Rabbits do not appear to be a natural model for intrauterine growth restriction. [ABSTRACT FROM AUTHOR]

Among the causes of the progression of intervertebral disc (IVD) degeneration (IDD) is the loss of nutrient intake to the IVD through the microcirculation disruption of the subendplate. Also, the vertebral body fracture intervenes in the degeneration the adjacent IVD. This research aimed to create an animal model of IDD using these 2 strategies. Thirty male Sprague-Dawley rats were split into 3 groups: a control group, a middle vertebral body injury (MI) associated with ethanol injection (MI + EtOH) group, and an MI associated with phosphate-buffered saline injection group. A vertebral body fracture with or without endplate injection of ethanol was generated by either drilling a hole in the center of a caudal rat vertebral body to form a fracture with an unabated endplate or drilling a hole in the center of a rat coccygeal vertebral body with endplate injection of ethanol to establish a vertebral body fracture with endplate damage. X-ray, macroscopic, histologic, and biochemical evaluations were utilized to assess IDD at weeks 3 and 6. According to X-ray findings, the MI + EtOH group demonstrated a significant decrease in intervertebral space height over time in comparison to the 2 other groups. The water content also was significantly decreased. Macroscopic and histological analysis demonstrated progressive degenerative changes in the IVD of the MI + EtOH group. The caudal vertebra fracture with ethanol injection is more likely to induce degeneration of adjacent IVD. This model effectively reproduced IDD, which may serve as a theoretical basis for future clinical intervention for IDD. [ABSTRACT FROM AUTHOR]

For centuries, aging was considered inevitable and immutable. Geroscience provides the conceptual framework to shift this focus toward a new view that regards aging as an active biological process, and the biological age of an individual as a modifiable entity. Significant steps forward have been made toward the identification of biomarkers for and measures of biological age, yet knowledge gaps in geroscience are still numerous. Animal models of aging are the focus of this perspective, which discusses how experimental design can be optimized to inform and refine the development of translationally relevant measures and biomarkers of biological age. We provide recommendations to the field, including: the design of longitudinal studies in which subjects are deeply phenotyped via repeated multilevel behavioral/social/molecular assays; the need to consider sociobehavioral variables relevant for the species studied; and finally, the importance of assessing age of onset, severity of pathologies, and age-at-death. We highlight approaches to integrate biomarkers and measures of functional impairment using machine learning approaches designed to estimate biological age as well as to predict future health declines and mortality. We expect that advances in animal models of aging will be crucial for the future of translational geroscience but also for the next chapter of medicine. [ABSTRACT FROM AUTHOR]

Aim: Autophagy is involved in human apical periodontitis (AP). However, it is not clear whether autophagy is protective or destructive in bone loss via the receptor activator of nuclear factor‐κB ligand (RANKL)/RANK/osteoprotegerin (OPG) axis. This study aimed to investigate the involvement of autophagy via the RANKL/RANK/OPG axis during the development of AP in an experimental rat model. Methodology: Twenty‐four female Sprague–Dawley rats were divided into control, experimental AP (EAP) + saline, and EAP + 3‐methyladenine (An autophagy inhibitor, 3‐MA) groups. The control group did not receive any treatment. The EAP + saline group and the EAP + 3‐MA group received intraperitoneal injections of saline and 3‐MA, respectively, starting 1 week after the pulp was exposed. Specimens were collected for microcomputed tomography (micro‐CT) scanning, histological processing, and immunostaining to examine the expression of light chain 3 beta (LC3B), RANK, RANKL, and OPG. Data were analysed using one‐way analysis of variance (p <.05). Results: Micro‐CT showed greater bone loss in the EAP + 3‐MA group than in the EAP + saline group, indicated by an elevated trabecular space (Tb.Sp) (p <.05). Inflammatory cell infiltration was observed in the EAP + saline and EAP + 3‐MA groups. Compared with EAP + saline group, the EAP + 3‐MA group showed weaker expression of LC3B (p <.01) and OPG (p <.05), more intense expression of RANK (p <.01) and RANKL (p <.01), and a higher RANKL/OPG ratio (p <.05). Conclusion: Autophagy may exert a protective effect against AP by regulating the RANKL/RANK/OPG axis, thereby inhibiting excessive bone loss. [ABSTRACT FROM AUTHOR]

Shigella is an important human-adapted pathogen for which there is an increasing incidence of antimicrobial resistance and no effective vaccine. Modelling Shigella infection of humans has historically been difficult, but new technologies and animal models have emerged to recapitulate key hallmarks of shigellosis. The use of organ-on-chip technology, zebrafish infection models, transgenic mouse models, and human challenge studies all uniquely contribute to our understanding of Shigella infection biology. Recent advances have illuminated our understanding of Shigella pathogenesis, guiding vaccine strategies and moving us closer to human health impact. Shigella is an important human-adapted pathogen which contributes to a large global burden of diarrhoeal disease. Together with the increasing threat of antimicrobial resistance and lack of an effective vaccine, there is great urgency to identify novel therapeutics and preventatives to combat Shigella infection. In this review, we discuss the development of innovative technologies and animal models to study mechanisms underlying Shigella infection of humans. We examine recent literature introducing (i) the organ-on-chip model, and its substantial contribution towards understanding the biomechanics of Shigella infection, (ii) the zebrafish infection model, which has delivered transformative insights into the epidemiological success of clinical isolates and the innate immune response to Shigella , (iii) a pioneering oral mouse model of shigellosis, which has helped to discover new inflammasome biology and protective mechanisms against shigellosis , and (iv) the controlled human infection model, which has been effective in translating basic research into human health impact and assessing suitability of novel vaccine candidates. We consider the recent contributions of each model and discuss where the future of modelling Shigella infection lies. [ABSTRACT FROM AUTHOR]

Helicobacter pylori is a common resident in the stomach of at least half of the world's population and recent evidence suggest its emergence in other organs such as the pancreas. In this organ, the presence of H. pylori DNA has been reported in cats, although the functional implications remain unknown. In this work, we determined distinct features related to the H. pylori manifestation in pancreas in a rodent model, in order to analyse its functional and structural effect. Gerbils inoculated with H. pylori exhibited the presence of this bacterium, as revealed by the expression of some virulence factors, as CagA and OMPs in stomach and pancreas, and confirmed by urease activity, bacterial culture, PCR and immunofluorescence assays. Non-apparent morphological changes were observed in pancreatic tissue of infected animals; however, delocalization of intercellular junction proteins (claudin-1, claudin-4, occludin, ZO-1, E-cadherin, β-catenin, desmoglein-2 and desmoplakin I/II) and rearrangement of the actin-cytoskeleton were exhibited. This structural damage was consistent with alterations in the distribution of insulin and glucagon, and a systemic inflammation, event demonstrated by elevated IL-8 levels. Overall, these findings indicate that H. pylori can reach the pancreas, possibly affecting its function and contributing to the development of pancreatic diseases. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the role of Actinomyces on the development of MRONJ in an immunocompromised mouse model with periapical disease. Thirty ovariectomized C57BL/6 N female mice were treated with zoledronic acid (ZA) and dexamethasone (DX) for 12 weeks. At the eighth week of drug administration, pulpal exposure operation was performed on the lower right first molar in Group B and C, meanwhile Actinomyces inoculation was performed at the pulpal entrance of Group C. Group A received no operation as control. After 4 weeks, loads of total bacteria and Actinomyces in the oral cavity were assessed by real-time polymerase chain reaction (PCR). Mandibles were harvested for micro-computed tomography (CT) and histological analysis. Real-time PCR revealed positive detection of Actinomyces in 30% samples in Group C and negative detection in all samples in Group B and control group. Micro-CT examination demonstrated that in ZA treated mice, pulpal exposure significantly increased periapical bone loss, which was significantly aggravated by Actinomyces inoculation. Histological assessment showed vasodilation, acute exudative changes and pulp necrosis in Group B and C. The present study revealed that inoculation of Actinomyces compromises the bone quality but does not further aggravate bone necrosis significantly. [ABSTRACT FROM AUTHOR]

This systematic review, registered with Prospero, aims to identify an optimal animal model for meniscus repair research, moving from ex vivo experimentation to in vivo studies. Data sources included PubMed, Medline, all Evidence-Based Medicine Reviews, Web of Science, and Embase searched in March 2023. Studies were screened using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Extracted data including animal model, type of experiment, type of tear, surgical techniques, and measured outcomes, were recorded, reviewed, and analyzed by four independent reviewers. The SYstematic Review Centre for Laboratory animal Experimentation (SYRCLE) Rob tool was used for critical appraisal and risk of bias assessment. Out of 11,719 studies, 72 manuscripts were included for data extraction and analysis; 41 ex vivo extra-articular studies, 20 ex vivo intra-articular studies, and only 11 in vivo studies. Six animal models were employed: porcine, bovine, lapine, caprine, canine, and ovine. Longitudinal lesions were the most frequently studied tear pattern and sutures the most common repair technique. Studied outcomes focused mainly on biomechanical assessments and gross observations. This systematic review can guide researchers in their choice of animal model for meniscus repair research; it highlighted the strengths of the porcine, caprine, and bovine models for ex vivo cadaveric studies, while the porcine and caprine models were found to be more suited to in vivo studies due to their similarities with human anatomy. Research teams should familiarize themselves with the advantages and disadvantages of various animal models before initiating protocols to improve standardization in the field. [ABSTRACT FROM AUTHOR]

Exposure to infectious or non‐infectious immune activation during early development is a serious risk factor for long‐term behavioural dysfunctions. Mouse models of maternal immune activation (MIA) have increasingly been used to address neuronal and behavioural dysfunctions in response to prenatal infections. One commonly employed MIA model involves administering poly(I:C) (polyriboinosinic‐polyribocytdilic acid), a synthetic analogue of double‐stranded RNA, during gestation, which robustly induces an acute viral‐like inflammatory response. Using electroencephalography (EEG) and infrared (IR) activity recordings, we explored alterations in sleep/wake, circadian and locomotor activity patterns on the adult male offspring of poly(I:C)‐treated mothers. Our findings demonstrate that these offspring displayed reduced home cage activity during the (subjective) night under both light/dark or constant darkness conditions. In line with this finding, these mice exhibited an increase in non‐rapid eye movement (NREM) sleep duration as well as an increase in sleep spindles density. Following sleep deprivation, poly(I:C)‐exposed offspring extended NREM sleep duration and prolonged NREM sleep bouts during the dark phase as compared with non‐exposed mice. Additionally, these mice exhibited a significant alteration in NREM sleep EEG spectral power under heightened sleep pressure. Together, our study highlights the lasting effects of infection and/or immune activation during pregnancy on circadian activity and sleep/wake patterns in the offspring. [ABSTRACT FROM AUTHOR]

Chronic orofacial pain disorders are common debilitating conditions, affecting the trigeminal system. Its underlying pathophysiological mechanisms are still unclear and the therapy is often unsatisfactory, therefore, preclinical models are crucial to identify the key mediators and novel treatment options. Complete Freund's adjuvant (CFA)-induced orofacial inflammatory allodynia/hyperalgesia is commonly used in rodents, but it has not been validated with currently used drugs. Here we tested the effects of the adjuvant analgesic/antiepileptic voltage-gated Na+ channel blocker complex mechanism of action topiramate in comparison with the gold standard antimigraine serotonin 5-HT1B/D receptor agonist sumatriptan in this model. CFA was injected subcutaneously into the right whisker pad of male Sprague-Dawley rats (250-300 g), then mechanonociceptive threshold values were investigated with von Frey filaments (3, 5, and 7 days after CFA injection). Effects of topiramate (30 mg/kg per os) and sumatriptan (1 mg/kg subcutaneous) on the adjuvant-induced chronic inflammatory orofacial allodynia were investigated 60, 120, and 180 min after the treatments each day. To determine the optimal concentration for drug effect analysis, we tested the effects of two different CFA-concentrations (1 and 0.5 mg/mL) on mechanonociceptive thresholds. Both concentrations of CFA induced a chronic orofacial allodynia in 60% of all rats. Although, higher CFA concentration induced greater allodynia, much more stable threshold reduction was observed with the lower CFA concentration: on day 3 the thresholds decreased from 18.30 g to approximately 11 g (low) and 5 g (high), respectively, however a slight increase was observed in the case of higher CFA concentration (on days 5, 7, and 11). In all investigation days, topiramate showed significant anti-allodynic effect comparing the pre and post drug dose and comparing the vehicle treated to the drug treated groups. Sumatriptan also caused a significant threshold increase compared to pre dose thresholds (day 3) and also showed a slight anti-allodynic effect compared to the vehicle-treated group (day 3 and 5). In the present study CFA-induced chronic orofacial allodynia was reversed by topiramate in rats validating the model with the adjuvant analgesic. Other than establishing a validated orofacial pain-related syndrome model in rats, new ways are opened for the repurposing of topiramate. [ABSTRACT FROM AUTHOR]

Background Objectives Methods Results Conclusions Neuroaxonal dystrophy (NAD) is a group of inherited neurodegenerative disorders characterized primarily by the presence of spheroids (swollen axons) throughout the central nervous system. In humans, NAD is heterogeneous, both clinically and genetically. NAD has also been described to naturally occur in large animal models, such as dogs. A newly recognized disorder in Miniature American Shepherd dogs (MAS), consisting of a slowly progressive neurodegenerative syndrome, was diagnosed as NAD via histopathology.To describe the clinical and pathological phenotype together with the identification of the underlying genetic cause.Clinical and postmortem evaluations, together with a genome‐wide association study and autozygosity mapping approach, followed by whole‐genome sequencing.Affected dogs were typically young adults and displayed an abnormal gait characterized by pelvic limb weakness and ataxia. The underlying genetic cause was identified as a 1‐bp (base pair) deletion in RNF170 encoding ring finger protein 170, which perfectly segregates in an autosomal recessive pattern. This deletion is predicted to create a frameshift (XM_038559916.1:c.367delG) and early truncation of the RNF170 protein (XP_038415844.1:(p.Ala123Glnfs*11)). The age of this canine RNF170 variant was estimated at ~30 years, before the reproductive isolation of the MAS breed.RNF170 variants were previously identified in human patients with autosomal recessive spastic paraplegia‐85 (SPG85); this clinical phenotype shows similarities to the dogs described herein. We therefore propose that this novel MAS NAD could serve as an excellent large animal model for equivalent human diseases, particularly since affected dogs demonstrate a relatively long lifespan, which represents an opportunity for therapeutic trials. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: An increasing body of research implicates inflammatory processes, including alterations in the neutrophil-lymphocyte ratio (NLR), in the pathophysiology of psychiatric illness. The deer mouse (Peromyscus maniculatus bairdii) is commonly studied for its naturalistic expression of compulsive-like behaviour. Towards future efforts to gain an understanding of how innate and adaptive immune processes might be involved in this model, we aimed to study the effects of pegfilgrastim, a pegylated recombinant human granulocyte colony-stimulating factor (g-CSF) analogue, on the NLR of both male and female deer mice. Methods: Briefly, 54 deer mice (equally distributed between sexes) were exposed to a single injection with either control or pegfilgrastim (0.1 or 1 mg/kg) (n = 18 per group). Six mice of each group (three per sex) were euthanized on days two, four and seven post-administration, their blood collected and the NLR calculated. Data were analysed by means of ordinary three-way ANOVA, followed by Bonferroni post-hoc testing. Results: Irrespective of dose, pegfilgrastim resulted in higher NLR values in mice of both sexes at days four and seven of testing. However, female mice exposed to the higher dose, presented with significantly higher NLR values irrespective of time, compared to male mice exposed to the same. Conclusion: The data generated from this work highlight important dose- and sex-specific aspects of pegfilgrastim with female mice showing heighted elevation of the NLR in response to high-dose pegfilgrastim administration only. Since the innate immune components of male and female deer mice is differentially sensitive to g-CSF stimulation, our results provide a useful basis for further study of sex-specific immunological processes in deer mice. [ABSTRACT FROM AUTHOR]

BACKGROUND: The treatment for bacterial biofilms after internal fixation surgery is a very difficult problem in clinic. It is a great significance to establish an animal model of irrigation for treating bacterial biofilms in the early stage after internal fixation surgery. OBJECTIVE: To establish an animal model for treating bacterial biofilms with different drugs through irrigation in early stage after internal fixation surgery. METHODS: Six New Zealand white rabbits were selected. Bilateral femoral surfaces were exposed and drilled holes were made, and bone plates colonized with Pseudomonas aeruginosa (experimental group) and blank bone plates (blank control group) were implanted around the drilled holes on one side, and two drainage tubes were retained and fixed to serve as the “inlet” and “outlet,” respectively. The model was immersed for a certain period of time after simulated perfusion before rinsing. After the simulated irrigation, the plates were soaked for a certain time before washing. At 5 days postoperatively, the rabbits were observed for body temperature, wound condition, bacterial culture of drainage fluid, and crystalline violet staining and scanning electron microscopy of the bone plate. RESULTS AND CONCLUSION: Six rabbits had difficulty in moving the affected limbs after surgery and showed elevated body temperature at 2-4 days after surgery. Local swelling could be touched at some wounds in the experimental group, and the wounds in the blank control group healed well. The results of bacterial culture of drainage fluid showed that Pseudomonas aeruginosa diffused or spread in the experimental group. At 5 days after surgery, the plate in the experimental group became purple shown by crystalline violet staining, and the absorbance value at 570 nm detected by the microplate reader was 2.621±0.088, indicating the presence of bacteria. Scanning electron microscopy at 5 days after surgery showed that a large number of bacterial microcolonies appeared on the surface of the plate in the experimental group, forming a highly inhomogeneous three-dimensional structure similar to the “mushroom-like” and “tower-like” structures, with filamentous water channels connecting the “mushroom-like” structures, which were typical biofilm structures with high densities, while no obvious colonies were seen in the blank control group. Overall, this animal model simulates the state of infected biofilm formation due to early infection after internal fixation and provides an available method of irrigation with different drugs. [ABSTRACT FROM AUTHOR]

Hypoglycemia is common in people with type 1 diabetes. Sometimes, severe hypoglycemia can be fatal. The underlying mechanisms by which severe hypoglycemia can lead to death are unclear. The sympathetic nervous system is thought to be proarrhythmic. We hypothesized that norepinephrine is the main mediator of severe hypoglycemia‐induced fatal cardiac arrhythmias. To test this hypothesis, adult, non‐diabetic Sprague–Dawley rats were subjected to hyperinsulinemic‐severe hypoglycemic clamps (3 h, 10–15 mg/dL) during two different experiments: (1) intracerebroventricular (ICV) norepinephrine (n = 26) or artificial cerebrospinal fluid (aCSF) (n = 20) infusion or (2) blockade of norepinephrine release by intraperitoneal reserpine (n = 20) or control (n = 29). In experiment 1, brain norepinephrine infusion during severe hypoglycemia led to a 2.5‐fold increase in third‐degree heart block and a 24% incidence of ST elevation compared to no ST elevation in aCSF controls. In experiment 2, reserpine successfully reduced plasma and cardiac norepinephrine levels. During severe hypoglycemia, reserpine completely prevented second and third‐degree heart block and T wave increases, a marker of myocardial infarction, compared to controls. In conclusion, norepinephrine increases while reserpine, used to reduce norepinephrine nerve terminal release, reduces heart block and markers of myocardial infarction during severe hypoglycemia. [ABSTRACT FROM AUTHOR]

Simple Summary: Birds are highly exposed to pathogens leading to high risk of low egg production, high mortality rates and high costs of veterinary care. Moreover, the intense breeding of avian species for desirable production traits causes immunosuppressive stress. Therefore, line selection requires thorough knowledge not only of genetics but also of the immunology of poultry. The function of secondary (peripheral) lymphoid organs is to activate the immune response through the accumulation of antigens for the activation of naive B and T cells. This review aims to present the morphological characterization of chickens' secondary immune organs along with the latest and more outstanding scientific discoveries and their relevance not only in veterinary medicine but also in human medicine. The authors hope that this review will represent a useful source of information for the design of future experiments with animal models in terms of more tailored protocols and heightened awareness. Recent discoveries have indicated the importance of developing modern strategies for vaccinations, more ethical research models, and effective alternatives to antibiotic treatment in farm animals. Chickens (Gallus gallus) play a crucial role in this context given the commercial and economic relevance of poultry production worldwide and the search for analogies between the immune systems of humans and birds. Specifically, chicken secondary lymphoid tissues share similar features to their human counterparts. Chickens have several secondary or peripheral lymphoid tissues that are the sites where the adaptive immune response is initiated. The more general classification of these organs divides them into the spleen and skin-, pineal-, or mucosa-associated lymphoid tissues. Each of these tissues is further subdivided into separate lymphoid structures that perform specific and different functions along the animal's body. A review summarizing the state of the art of research on chicken secondary lymphoid organs is of great relevance for the design of future studies. [ABSTRACT FROM AUTHOR]

Background: Tissue engineering represents a promising field in regenerative medicine, with bioresorbable polymers such as polycaprolactone (PCL) playing a crucial role as scaffolds. These scaffolds support the growth and repair of tissues by mimicking the extracellular matrix. Objective: This study aimed to assess the in vivo performance of three-dimensional PCL scaffolds by evaluating their effects on bone repair in rat calvaria and the tissue reaction in subcutaneous implant sites, as well as their impact on major organs such as the kidneys, lungs, and liver. Methods: Three-dimensional scaffolds made of PCL were implanted in the subcutaneous tissue of rats' backs and calvaria. Histological analyses were conducted to observe the bone repair process in calvaria and the tissue response in subcutaneous implant sites. Additionally, the kidneys, lungs, and livers of the animals were examined for any adverse tissue alterations. Results: The histological analysis of the bone repair in calvaria revealed newly formed bone growing towards the center of the defects. In subcutaneous tissues, a thin fibrous capsule with collagenous fibers enveloping the implant was observed in all animals, indicating a positive tissue response. Importantly, no harmful alterations or signs of inflammation, hyperplasia, metaplasia, dysplasia, or hemorrhage were detected in the kidneys, lungs, and liver. Conclusions: The findings demonstrate that PCL scaffolds produced through additive manufacturing are biocompatible, non-cytotoxic, and bioresorbable, promoting osteoconduction without adverse effects on major organs. Hence, PCL is confirmed as a suitable biomaterial for further studies in tissue engineering and regenerative medicine. [ABSTRACT FROM AUTHOR]

Purpose: Megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) is defined as a congenital visceral myopathy with genetic mutations. However, the etiology and pathophysiology are not fully understood. We aimed to generate a gene leiomodin-1a (lmod1a) modification technique to establish a zebrafish model of MMIHS. Methods: We targeted lmod1a in zebrafish using CRISPR/Cas9. After confirming the genotype, we measured the expression levels of the target gene and protein associated with MMIHS. A gut transit assay and spatiotemporal mapping were conducted to analyze the intestinal function. Results: Genetic confirmation showed a 5-base-pair deletion in exon 1 of lmod1a, which caused a premature stop codon. We observed significant mRNA downregulation of lmod1a, myh11, myod1, and acta2 and the protein expression of Lmod1 and Acta2 in the mutant group. A functional analysis of the lmod1a mutant zebrafish showed that its intestinal peristalsis was fewer, slower, and shorter in comparison to the wild type. Conclusion: This study showed that targeted deletion of lmod1a in zebrafish resulted in depletion of MMIHS-related genes and proteins, resulting in intestinal hypoperistalsis. This model may have the potential to be utilized in future therapeutic approaches, such as drug discovery screening and gene repair therapy for MMIHS. [ABSTRACT FROM AUTHOR]

The key goal in lung donation remains the improvement of graft preservation with the ultimate objective of increasing the number and quality of lung transplants (LTx). Therefore, in recent years the field of graft preservation focused on improving outcomes related to solid organ regeneration and restoration. In this contest Ex-Vivo Lung Perfusion (EVLP) plays a crucial role with the purpose to increase the donor pool availability transforming marginal and/or declined donor lungs suitable for transplantation. Aim of this proof of concept is to test the safety, suitability and feasibility of a new tilting dome for EVLP designed considering the dorsal lung areas as the "Achilles' heel" of the EVLP due to a more fluid accumulation than in the supine standard position. [ABSTRACT FROM AUTHOR]

ABSTRACT Aim Materials and Methods Results Conclusions To assess the possibility of vertical alveolar ridge augmentation by means of activation of the periosteum.Six adult male Beagle dogs were used for the study. All premolars and first molars were extracted, and one vertical saucer‐shaped bony defect was created on each side of the mandible. After 3 months of healing, full‐thickness muco‐periosteal flaps were elevated, and one distraction device was placed on each side of the mandible. The distraction plate was left submerged, and the activation mechanism connected to the distraction rod was exposed intra‐orally. The protocol of periosteal activation (PP: periosteal ‘pumping’) was initiated after a latency of 7 days. The alternation of activation and relaxation at the rate of 0.35 mm/12 h during 5 days was followed by the sole activation of 0.35 mm/12 h for 5 days (PP group). Devices were left inactivated on the contralateral control side of the mandible (C group). All animals were euthanized after 8 weeks of consolidation. Samples were analysed histologically and by means of micro‐CT.New mature lamellar bone was formed over the pristine bone in all groups. More intensive signs of bone modelling and remodelling were observed in the PP group compared to the C group. Mean new bone, bone marrow, connective tissue and total volumetric densities were greater in the PP group (p < 0.001, p = 0.001, p = 0.003 and p < 0.001, respectively). No differences were observed in the relative area parameters. Total tissue volume and bone volume were higher in the PP group (p = 0.031 and p = 0.076, respectively), while the bone mineral densities were higher in the C group (p = 0.041 and p = 0.003, respectively). Trabecular number, trabecular thickness and trabecular separation values were similar between the two groups.Regeneration of vertical alveolar bone ridge defects may be enhanced by activation of the periosteum, without the application of bone grafting materials. [ABSTRACT FROM AUTHOR]

Because of the advent of genome-editing technology, gene knockout (KO) hamsters have become attractive research models for diverse diseases in humans. This study established a new KO model of diabetes by disrupting the insulin receptor substrate-2 (Irs2) gene in the golden (Syrian) hamster. Homozygous KO animals were born alive but with delayed postnatal growth until adulthood. They showed hyperglycemia, high HbA1c, and impaired glucose tolerance. However, they normally responded to insulin stimulation, unlike Irs2 KO mice, an obese type 2 diabetes (T2D) model. Consistent with this, Irs2 KO hamsters did not increase serum insulin levels upon glucose administration and showed β-cell hypoplasia in their pancreas. Thus, our Irs2 KO hamster provide a unique T2D animal model that is distinct from the obese T2D models. This model may contribute to a better understanding of the pathophysiology of human non-obese T2D with β-cell dysfunction, the most common type of T2D in East Asian countries, including Japan. [ABSTRACT FROM AUTHOR]

Background: Thyroid storm (TS), a life-threatening condition that can damage multiple organs, has limited therapeutic options. Hypercytokinemia is a suggested background, but the pathological condition is unclear and there are no appropriate animal models. We aimed to develop a TS mouse model by administration of triiodothyronine and lipopolysaccharide, and then to examine the effects of ghrelin on this model. Methods: We evaluated the use of serum IL-6 levels as a representative marker of hypercytokinemia in patients with TS. To establish the mouse model, preliminary experiments were conducted to determine the non-lethal doses of triiodothyronine and lipopolysaccharide when administered individually. As a TS model, C57BL/6 mice were administered with triiodothyronine 1.0 mg/kg (subcutaneously, once daily for seven consecutive days) and lipopolysaccharide 0.5 mg/kg (intraperitoneally, on day 7) to develop a lethal model with approximately 30% survival on day 8. We assessed the survival ratio, mouse sepsis scores and blood biomarkers (IL-6, metanephrine, alanine aminotransferase) and evaluated the effects of ghrelin 300 µg/kg on these parameters in TS model. Results: Serum IL-6 was increased in patients with TS compared with those with Graves' disease as the diseased control (18.2 vs. 2.85 pg/mL, P <.05, n = 4 each). The dosage for the murine TS model was triiodothyronine 1.0 mg/kg and lipopolysaccharide 0.5 mg/kg. The TS model group had increased mouse sepsis score, serum IL-6, metanephrine and alanine aminotransferase. In this model, the ghrelin improved the survival rate to 66.7% (P <.01, vs. 0% [saline-treated group]) as well as the mouse sepsis score, and it decreased the serum IL-6 and metanephrine. Conclusion: We established an animal model of TS that exhibits pathophysiological states similar to human TS with induction of serum IL-6 and other biomarkers by administration of T3 and LPS. The results suggest the potential effectiveness of ghrelin for TS in humans. [ABSTRACT FROM AUTHOR]

Laboratory models are central to microbiology research, advancing the understanding of bacterial physiology by mimicking natural environments, from soil to the human microbiome. When studying host-bacteria interactions, animal models enable investigators to examine bacterial dynamics associated with a host, and in the case of human infections, animal models are necessary to translate basic research into clinical treatments. Efforts toward improving animal infection models are typically based on reproducing host genotypes/phenotypes and disease manifestations, leaving a gap in how well the physiology of microbes reflects their behavior in a human host. Understanding bacterial physiology is vital because it dictates host response and bacterial interactions with antimicrobials. Thus, our goal was to develop an animal model that accurately recapitulates bacterial physiology in human infection. The system we chose to model was a chronic Pseudomonas aeruginosa respiratory infection in cystic fibrosis (CF). To accomplish this goal, we leveraged a framework that we recently developed to evaluate model accuracy by calculating the percentage of bacterial genes that are expressed similarly in a model to how they are expressed in their infection environment. We combined two complementary models of P. aeruginosa infection--an in vitro synthetic CF sputum model (SCFM2) and a mouse acute pneumonia model. This combined model captured the chronic physiology of P. aeruginosa in CF better than the standard mouse infection model, showing the power of a data-driven approach to refining animal models. In addition, the results of this work challenge the assumption that a chronic infection model requires long-term colonization. [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension (PAH) is a well-known complication of congenital heart disease (CHD). The lack of a satisfactory animal model for PAH associated with CHD (PAH-CHD) has limited progress in understanding the pathogenesis of PAH and the development of therapeutic agents. The development of a rat model for PAH associated with atrial septal defect (ASD) was achieved through atrial septal puncture and thermal ablation. Two and 4 weeks after modeling, hematoxylin and eosin staining showed that the vascular thickness, vascular thickness index, vascular area, and vascular area index in pulmonary arteries with an outer diameter of 50–300 μm in the PAH-ASD 2 and 4 weeks group were higher than those in the sham group (all P < 0.05). Alpha-smooth muscle actin (ɑ-SMA) staining showed that the medial thickness, medial thickness index, medial area, and medial area index in pulmonary arteries with an outer diameter of 50–300 µm at 2 and 4 weeks after modeling were significantly higher than those in the sham group (all P < 0.05). Additionally, mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR) in the PAH-ASD 2 and 4 weeks groups were significantly higher than those in the sham group (both P < 0.05). Elastin van Gieson staining showed that the vascular obstruction score in the PAH-ASD 2 and 4 weeks group was significantly higher than that in the sham group (both P < 0.05). The PAH-ASD rats were successfully generated. These findings suggest that our model would be useful for further research into the pathogenesis, prevention, and treatment of PAH-ASD. [ABSTRACT FROM AUTHOR]

Objective Methods Results Significance Many people with epilepsy experience comorbid anxiety and depression, and antidepressants remain a primary treatment for this. Emerging evidence suggests that these agents may modulate epileptogenesis to influence disease severity. Here, we assessed how treatment with the selective serotonin reuptake inhibitor (SSRI) antidepressant fluoxetine impacts epileptogenic, behavioral, and pathological sequelae following status epilepticus.Male Wistar rats received kainic acid to induce status epilepticus (SE) or vehicle (sham). Animals then received either fluoxetine (10 mg/kg/day) or vehicle for 8 weeks via subcutaneous osmotic pump. Video‐electroencephalography was recorded continuously until behavioral testing at day 56, including assessments of anxiety‐ and depression‐like behavior and spatial cognition. Postmortem immunocytochemistry studies examined mossy fiber sprouting.Fluoxetine treatment significantly accelerated epileptogenesis following SE, reducing the average period to the first spontaneous seizure (from 32 days [vehicle] to 6 days [fluoxetine], p < .01). Also, fluoxetine exposure magnified the severity of the resultant epilepsy, increasing seizure frequency compared to vehicle (p < .01). Exposure to fluoxetine was associated with improved anxiety‐ and depression‐like behaviors but significantly worsened cognition. Mossy fiber sprouting was more pronounced in fluoxetine‐treated rats compared to vehicle (p < .0001).Our studies demonstrate that, using a model exhibiting spontaneous seizures, epileptogenesis is accelerated and magnified by fluoxetine, an effect that may be related to more severe pathological neuroplasticity. The differential influence of fluoxetine on behavior indicates that different circuitry and mechanisms are responsible for these comorbidities. These findings suggest that caution should be exercised when prescribing SSRI antidepressants to people at risk of developing epilepsy. [ABSTRACT FROM AUTHOR]

To study a new method for establishing animal models of prenatal bronchopulmonary dysplasia (BPD), we used lung ultrasound score (LUS) to semi-quantitatively assess the severity of lung lesions in model rats. Lipopolysaccharide (LPS) was injected into the right lung of the fetus of the rat under ultrasound-guided, and the right lung of the neonates were scanning for LUS. Specimens were collected for pathological scoring and detection of pulmonary surfactant-associated glycoprotein (SP)-C and vascular endothelial growth factor (VEGF) expression quantity. The correlation between LUS and pathological scores was analyzed. (1) The animal models were consistent with the pathological manifestations of BPD. (2) It showed a strong positive correlation between LUS and pathological scores in animal models (r = 0.84, P < 0.005), and the expression quantity of SP-C and VEGF in lung tissue were decreased (both P < 0.05). Animal models established by ultrasound-guided puncture of the lung of rats and injection of LPS were consistent with the manifestation of BPD. This method could be used to establish animal models of BPD before birth, and the severity of BPD could be assessed by using LUS. [ABSTRACT FROM AUTHOR]

Objective To explore the imaging characteristics and clinical application value of infrared thermal imaging in a rat model of slow femoral venous blood flow. Methods Twelve Sprague-Dawley rats were randomly divided into two groups: the epinephrine group (model group) and the saline group (control group). The model group received 1 mg/mL epinephrine injections, while the control group received an equal volume of saline, administered twice. Two hours after the first injection, the rats were made to swim in ice water for 5 minutes. Infrared thermal imaging was used to measure the temperature of both sides of the femoral triangle region before and after modeling. Blood samples were collected from the abdominal aorta to test coagulation indicators and IL-6 levels, and the right femoral vein was subjected to pathological examination. Results In the model group, activated partial thromboplastin time (APTT) (P＜0.01) and thrombin time (TT) (P＜0.01) were significantly shorter than those in the control group, and IL-6 levels were higher (P=0.02). Histological examination of femoral vein sections showed normal vascular morphology with no clear inflammation or thrombosis. The highest pre-modeling temperature in the femoral triangle region of the model group was (35.34±0.47) ℃, and post-modeling was (36.57±0.94) ℃, showing a statistically significant difference (P＜0.01). The post-modeling highest temperature in the model group was higher than that in the saline group (P＜0.01). Conclusion Infrared thermal imaging of the rat model of slow femoral venous blood flow shows relatively high temperatures. With its non-invasive and radiation-free advantages, infrared thermal imaging can serve as an auxiliary diagnostic tool for slow blood flow conditions. [ABSTRACT FROM AUTHOR]

Most behavioral traits are known to be weakly heritable, possibly due to their extreme complexity and flexibility. Despite this general pattern, within-species variation in avian colony size choice has been reported to have a strong additive genetic component, but we are aware of no attempts to assess the heritability of avian sociality at the finer spatial scale. Here, we used an animal model and parent–offspring regression to quantify additive genetic variance in social phenotype (local nesting density) in a nonpasserine waterbird, the common tern Sterna hirundo. For this purpose, we used a novel experimental framework, where variation in the social environment was generated by providing birds with artificial patches of attractive nesting substrate that markedly varied in size. During 2011–2019, we collected data on social preferences for either low or high nesting density in over 250 individuals, either kin (mostly parent–offspring relationships) or non-kin recorded breeding multiple times across years. All heritability estimates of local nesting density were low (<0.10), irrespectively of fixed effects (sex and year) included in the models, data used in the modeling (all individuals vs. early recruits), or methodological approach (animal model vs. parent–offspring regression). We conclude that avian sociality, as measured at the local scale, may be much less heritable than colony size choice, as measured at the landscape level. Our study adds to the understanding of additive genetic variance in avian behavior, and it underlines a scale dependency in the heritability of behavioral traits. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) is a group of heterogeneous neurodevelopmental disabilities with persistent impairments in cognition, communication, and social behavior. Although environmental factors play a role in ASD etiopathogenesis, a growing body of evidence indicates that ASD is highly inherited. In the last two decades, the dramatic rise in the prevalence of ASD has interested researchers to explore the etiologic role of epigenetic marking and incredibly abnormal DNA methylation. This review aimed to explain the current understanding of the association between changes in DNA methylation signatures and ASD in patients or animal models. We reviewed studies reporting alterations in DNA methylation at specific genes as well as epigenome-wide association studies (EWASs). Finally, we hypothesized that specific changes in DNA methylation patterns could be considered a potential biomarker for ASD diagnosis and prognosis and even a target for pharmacological intervention. [ABSTRACT FROM AUTHOR]

The clustered regularly interspaced short palindromic repeats (CRISPR) and their associated protein (Cas) system is a gene editing technology guided by RNA endonuclease. The CRISPR-Cas12a (also known as CRISPR-Cpf1) system is extensively utilized in genome editing research due to its accuracy and high efficiency. In this paper, we primarily focus on the application of CRISPR-Cpf1 technology in the construction of disease models and gene therapy. Firstly, the structure and mechanism of the CRISPR-Cas system are introduced. Secondly, the similarities and differences between CRISPR-Cpf1 and CRISPR-Cas9 technologies are compared. Thirdly, the main focus is on the application of the CRISPR-Cpf1 system in cell and animal genome editing. Finally, the challenges faced by CRISPR-Cpf1 technology and corresponding strategies are analyzed. Although CRISPR-Cpf1 technology has certain off-target effects, it can effectively and accurately edit cell and animal genomes, and has significant advantages in the preclinical research. [ABSTRACT FROM AUTHOR]

Experimental animal models of ischemic spinal cord injury (iSCI) are essential for studying its pathogenesis and for developing new therapeutic strategies to improve functional recovery in humans. Many existing models, however, exhibit high variability or early lethality. A reliable experimental iSCI model would significantly advance novel treatment approaches for these severe neurological disorders. To this end, we have established a rat model of persistent iSCI with an extended lifespan. We have developed a novel iSCI model that induces localized ischemic lesions in the spinal cord of male Sprague-Dawley rats. This is achieved by cross clamping the descending aorta just rostral the azygos vein using an atraumatic bulldog clamp. The experimental iSCI model consistently demonstrated symptoms specific to spinal cord ischemia at the lumbar level. The procedure takes approximately 50 min and does not require specialized surgical equipment. It has a survival rate of 84%, a recovery rate of 40%, and a complication rate of 16%. We have successfully developed a rat model of persistent iSCI. This protocol proves to be highly reliable and holds promise for evaluating new therapeutic strategies aimed at promoting functional recovery in patients suffering from spinal cord ischemia. [ABSTRACT FROM AUTHOR]

Adenovirus infections of immunocompromised patients can cause life-threatening disseminated disease. While there are presently no drugs specifically approved to treat these infections, there are several compounds that showed efficacy against adenovirus in preclinical studies. For any such compound, low toxicity is an essential requirement. As cumulative drug effects can accentuate pathology, especially in patients with other morbidities, it is important to limit antiviral exposure to what is absolutely necessary. This is achievable by monitoring the virus burden of the patients and administering antivirals to suppress virus replication to a non-pathogenic level. We modeled such a system using Syrian hamsters infected with a replication-competent adenovirus vector, in which luciferase expression is coupled to virus replication. We found that virus replication could be followed in vivo in the same animal by repeated measurement of luciferase expression. To test the utility of an interrupted treatment regimen, we used NPP-669 and valganciclovir, two antiviral compounds with high and moderate anti-adenoviral efficacy, respectively. We found that short-term treatment of adenovirus-infected hamsters at times of peak virus replication can prevent virus-associated pathology. Thus, we believe that this animal model can be used to model different treatment regimens for anti-adenoviral compounds. [ABSTRACT FROM AUTHOR]

Autoimmune diseases often arise from conditions where the immune system is compromised. While lymphopenia-induced proliferation (LIP) is crucial for immune system development and maturation, it is also caused by environmental insults, such as infection, and becomes a risk factor for autoimmunity in adults. We used Dsg3H1 TCR transgenic mice, whose T cells are designed to recognize desmogrein-3, a skin antigen, to explore the impact of lymphopenia on post-thymic tolerance. Dsg3H1 mice are known to delete the most highly autoreactive T cells in the thymus, and develop only subtle immune-mediated pathology in the steady state. However, we found that transient lymphopenia induced by total body irradiation (TBI) or cyclophosphamide (CY) results in massive dermatitis in Dsg3H1 mice. The symptoms included expansion and development of self-reactive T cells, their differentiation into CD44high IL-17-producing helper T cells, and severe neutrophilic inflammation. Repopulation of FOXP3+ T regulatory cells after lymphopenia normally occurred, suggesting escape of skin-reactive conventional T cells from control by regulatory T cells. Furthermore, we found that a depletion of the intestinal microbiota by antibiotics prevents CY-induced dermatitis, indicating roles of the commensal intestinal microbiota in LIP and Th17 development in vivo. The current data suggested that post-thymic tolerance of Dsg3H1 mice is established on a fragile balance in the lymphoreplete immune environment and broken by the interplay between lymphopenia and intestinal microbiota. The dynamic phenotypes observed in Dsg3H1 mice prompt a re-evaluation of opportunistic lymphopenia together with the microbiota as pivotal environmental factors, impacting individuals with genetic predispositions for autoimmune diseases. [ABSTRACT FROM AUTHOR]

• Intrauterine position influences multiple outcomes of MIA in mice. • Being flanked by male neighbors in utero attenuates the impact of MIA. • Intrauterine position contribute to within-litter variability in mouse MIA models. Rodent models of maternal immune activation (MIA) are increasingly used as experimental tools in preclinical research of immune-mediated neurodevelopmental disorders and mental illnesses. Using a viral-like MIA model that is based on prenatal poly(I:C) exposure in mice, we have recently identified the existence of subgroups of MIA-exposed offspring that show dissociable behavioral, transcriptional, brain network and inflammatory profiles even under conditions of genetic homogeneity and identical MIA. Here, we tested the hypothesis that the intrauterine positions of fetuses, which are known to shape individual variability in litter-bearing mammals through variations in fetal hormone exposure, may contribute to the variable outcomes of MIA in mice. MIA was induced by maternal administration of poly(I:C) on gestation day 12 in C57BL/6N mice. Determining intrauterine positions using delivery by Cesarean section (C-section), we found that MIA-exposed offspring developing between female fetuses only (0M-MIA offspring) displayed significant deficits in sociability and sensorimotor gating at adult age, whereas MIA-exposed offspring developing between one or two males in utero (1/2M-MIA offspring) did not show the same deficits. These intrauterine position effects similarly emerged in male and female offspring. Furthermore, while MIA elevated fetal brain levels of pro- and anti-inflammatory cytokines independently of the precise intrauterine position and sex of adjacent fetuses during the acute phase, fetal brain levels of TNF-α remained elevated in 0M-MIA but not 1/2M-MIA offspring until the post-acute phase in late gestation. As expected, 1/2M offspring generally showed higher testosterone levels in the fetal brain during late gestation as compared to 0M offspring, confirming the transfer of testosterone from male fetuses to adjacent male or female fetuses. Taken together, our findings identify a novel source of within-litter variability contributing to heterogeneous outcomes of short- and long-term effects in a mouse model of MIA. In broader context, our findings highlight that individual differences in fetal exposure to hormonal and inflammatory signals may be a perinatal factor that shapes risk and resilience to MIA. [ABSTRACT FROM AUTHOR]

Simple Summary: Exercise is well known to decrease the risk of breast cancer. The cellular processes that contribute to exercise-induced cancer prevention are less known. We conducted an exercise training study in rats given a chemical to induce breast cancer. Exercise increased the length of time to development of breast cancer in rats. However, when we gave the rats an antibody which binds to a certain cellular protein (oncostatin M), exercise-induced protection against breast cancer was not observed. These observations may be useful in future studies as the oncostatin M protein is produced by muscles. Thus, these results support a link between muscle use during exercise and breast cancer prevention. Future studies may examine oncostatin M and other proteins produced by exercising muscles for their potential role in breast cancer prevention. Moderate-to-vigorous-intensity physical activity decreases the risk of breast cancer. The muscle-derived cytokine (myokine), oncostatin M (OSM), has been shown to decrease breast cancer cell proliferation. We hypothesized that OSM is involved in physical activity-induced breast cancer prevention, and that OSM antibody (Anti-OSM) administration would mitigate the effect of physical activity in a rat model of mammary carcinoma. Female Sprague Dawley rats were injected with 50 mg/kg N-methyl-N-nitrosourea to induce mammary carcinogenesis. During the 20-week study, rats were exercise trained (EX) or remained sedentary (SED). Additional groups were treated with Anti-OSM antibody (SED + Anti-OSM and EX + Anti-OSM) to explore the impact of OSM blockade on tumor latency. Exercise training consisted of treadmill acclimation and progressive increases in session duration, speed, and grade, until reaching 30 min/day, 20 m/min at 15% incline. Experimentally naïve, age-matched, female rats also completed an acute exercise test (AET) with time course blood draws to evaluate OSM plasma concentrations. Relative tumor-free survival time was significantly longer in EX animals (1.36 ± 0.39) compared to SED animals (1.00 ± 0.17; p = 0.009), SED + Anti-OSM animals (0.90 ± 0.23; p = 0.019), and EX + Anti-OSM animals (0.93 ± 0.74; p = 0.004). There were no significant differences in relative tumor latency between SED, SED + Anti-OSM, or EX + Anti-OSM animals. Following the AET, OSM plasma levels trended higher compared to baseline OSM levels (p = 0.080). In conclusion, we observed that exercise-induced delay of mammary tumor development was mitigated through Anti-OSM administration. Thus, future studies of the OSM mechanism are required to lay the groundwork for developing novel chemo-prevention strategies in women who are unable or unwilling to exercise. [ABSTRACT FROM AUTHOR]

Objective: This review will explore the categorization of migraine‐provoking molecules, their cellular actions, site of action and potential drug targets based on the migraine cascade model. Methods: Personal experience and literature. Results: Migraine impacts over 1 billion people worldwide but is underfunded in research. Recent progress, particularly through the human and animal provocation model, has deepened our understanding of its mechanisms. This model have identified endogenous neuropeptides such as calcitonin gene‐related peptide (CGRP) and pituitary adenylate cyclase‐activating peptide (PACAP) that induces controlled migraine‐like attacks leading to significant discoveries of their role in migraine. This knowledge led to the development of CGRP‐inhibiting drugs; a groundbreaking migraine treatment now accessible globally. Also a PACAP‐inhibiting drug was effective in a recent phase II trial. Notably, rodent studies have shed light on pain pathways and the mechanisms of various migraine‐inducing substances identifying novel drug targets. This is primarily done by using selective inhibitors that target specific signaling pathways of the known migraine triggers leading to the hypothesized cellular cascade model of migraine. Conclusion: The model of migraine presents numerous opportunities for innovative drug development. The future of new migraine treatments is limited only by the investment from pharmaceutical companies. [ABSTRACT FROM AUTHOR]

This study investigates the carcinogenic potential of chronic dermal exposure (16 weeks) to sulfuric acid (SA) in immunocompetent mice. Clinical assessments, histopathological analyses, immunohistochemical analyses and biochemical assays were conducted to evaluate skin irritation, oxidative stress biomarkers and the potential carcinogenic effect of SA. Results indicated that prolonged exposure to SA leads to various alterations in skin structure, notably inflammation, preneoplastic and neoplastic proliferation in hair follicles, as well as hyperkeratosis and acanthosis, resulting in an increased epidermal thickness of 98.50 ± 21.6 μm. Immunohistochemistry analysis further corroborates these observations, showcasing elevated nuclear expression of p53 and Ki‐67, with a significant mitotic index of (57.5% ± 2.5%). Moreover, biochemical analyses demonstrate that SA induces lipid peroxidation in the skin, evidenced by a high level of Malondialdehyde and a consequential reduction in catalase activity. These findings suggest that prolonged exposure to SA can induce skin neoplasms, highlighting the need for stringent safety measures in environments where SA is frequently used. This study underscores the potential occupational health risks associated with SA exposure. [ABSTRACT FROM AUTHOR]

Neuronal ceroid lipofuscinoses (NCL) are among the most prevalent neurodegenerative disorders of early life in humans. Disease‐causing variants have been described for 13 different NCL genes. In this study, a refined pathological characterization of a female rabbit with progressive neurological signs reminiscent of NCL was performed. Cytoplasmic pigment present in neurons was weakly positive with Sudan black B and autofluorescent. Immunohistology revealed astrogliosis, microgliosis and axonal degeneration. During the subsequent genetic investigation, the genome of the affected rabbit was sequenced and examined for private variants in NCL candidate genes. The analysis revealed a homozygous ~10.7 kb genomic duplication on chromosome 15 comprising parts of the MFSD8 gene, NC_013683.1:g.103,727,963_103,738,667dup. The duplication harbors two internal protein coding exons and is predicted to introduce a premature stop codon into the transcript, truncating ~50% of the wild‐type MFSD8 open reading frame encoding the major facilitator superfamily domain containing protein 8, XP_002717309.2:p.(Glu235Leufs*23). Biallelic loss‐of‐function variants in MFSD8 have been described to cause NCL7 in human patients, dogs and a single cat. The available clinical and pathological data, together with current knowledge about MFSD8 variants and their functional impact in other species, point to the MFSD8 duplication as a likely causative defect for the observed phenotype in the affected rabbit. [ABSTRACT FROM AUTHOR]

There are many models of lumbar disc degeneration, but mechanical stress-induced lumbar disc degeneration is rare. Here we propose a mechanical stress-induced lumbar disc degeneration model to better understand the molecular mechanism of lumbar disc degeneration under stress stimulation. To design a new model of lumbar disc degeneration under mechanical stress. The anatomic approach of the oblique lateral approach to lumbar fusion surgery was used to design a longitudinal compression device across the vertebral body of the rabbit to impose longitudinal load on the lumbar disc. New Zealand white rabbits (n=30) were used. Screws were used to cross the rabbits' lumbar vertebral bodies, and both sides of the screws were pressurized. Continuous compression was then performed for 28 days. Adjacent unpressurized lumbar discs serve as controls for pressurized lumbar discs. At 28 days after surgery, micro-computed tomography (CT) and magnetic resonance imaging (MRI) were performed on the rabbits' lumbar discs. After the imaging examination, lumbar disc samples were removed, Safranin-O fast green and immunofluorescence was performed to detect the expression level of intervertebral disc degeneration-related proteins. The CT results showed that the disc height did not decrease significantly after mechanical loading. The MRI results showed that the signals in the pressurized disc decreased 28 days after loading. The results of Safranin-O fast green showed that the cartilage component of the intervertebral disc after mechanical compression was significantly reduced. The immunofluorescence results showed that the expression of ADAMTS5 and MMP13 protein in the nucleus pulposus of the intervertebral disc after mechanical compression increased, while the expression of SOX9 decreased, and the difference was statistically significant. Aggrecan's protein expression decreased, but was not statistically significant. This study designed a reliable model of disc degeneration in rabbits. It is more likely to mimic disc compression in the human body. This animal model can be used as a basic model to study the molecular physiological mechanisms of discogenic low back pain. [ABSTRACT FROM AUTHOR]