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Purpose: The in vivo antitumor activity of a novel topoisomerase I inhibitor, J-107088, was tested in athymic nude mice bearing subcutaneous or intracranial pediatric and adult malignant CNS tumor-derived xenografts.Methods: J-107088 was administered to animals on days 1-5 and 8-12 via intraperitoneal injection at a dose of 54 mg/kg (162 mg/m2) per day in 10% dimethyl sulfoxide in 0.9% saline. The xenografts evaluated were derived from a childhood glioblastoma multiforme (D-456 MG), a childhood medulloblastoma (D-341 MED), an adult anaplastic astrocytoma (D-54 MG), an adult glioblastoma multiforme (D-245 MG), and a procarbazine-resistant subline of D-245 MG [D-245 MG (PR)].Results: J-107088 produced regressions and significant growth inhibition in all five of the xenograft lines growing subcutaneously. Growth delays ranged from 7.6 days with D-245 MG to 62.1 days with D-456 MG (P < 0.001). J-107088 also produced an 83% increase in survival in mice bearing intracranial D-456 MG (P < 0.001).Conclusion: These results indicate that J-107088 may be active in the treatment of childhood and adult malignant brain tumors and provide the rationale for initiation of clinical trials with this agent. [ABSTRACT FROM AUTHOR]

Introduction: Data on medulloblastoma outcomes and experiences in low- and middle-income countries, especially in Latin America, is limited. This study examines challenges in Mexico's healthcare system, focusing on assessing outcomes for children with medulloblastoma in a tertiary care setting., Methods: A retrospective analysis was conducted, involving 284 patients treated at 21 pediatric oncology centers in Mexico., Results: High-risk patients exhibited markedly lower event-free survival than standard-risk patients (43.5% vs. 78.3%, p<0.001). Influential factors on survival included anaplastic subtype (HR 2.4, p=0.003), metastatic disease (HR 1.9, p=0.001); residual tumor >1.5cm², and lower radiotherapy doses significantly impacted event-free survival (EFS) and overall survival (OS). Platinum-based chemotherapy showed better results compared to the ICE protocol in terms of OS and EFS, which was associated with higher toxicity. Patients under 3 years old displayed notably lower OS and EFS compared to older children (36.1% vs. 55.9%, p=0.01)., Competing Interests: Author DO was employed by ICON PLC. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Salceda-Rivera, Tejocote-Romero, Osorio, Bellido-Magaña, López-Facundo, Anaya-Aguirre, Ortiz-Morales, Rivera-Luna, Reyes-Gutiérrez, Rivera-Gómez, Velasco-Hidalgo, Cortés-Alva, Lagarda-Arrechea, Arreguín-González, Benito-Reséndiz, Chávez-Gallegos, Pérez-Rivera, Gaytán-Fernández, León-Espitia, Domínguez-Sánchez, Leal-Cavazos, Simón-González, Larios-Farak, Macías-García, García-Espinosa, Guerrero-Maymes, Casillas-Toral and González-Ramella.)

Importance: Lipoxygenases (LOXs) are enzymes that catalyze the deoxygenation of polyunsaturated fatty acids such as linoleic and arachidonic acid. These modifications create signaling molecules that are best characterized for modulating the immune response. Deletion of the first lipoxygenase-like enzyme characterized for Toxoplasma gondii (TgLOXL1) generated a less virulent strain, and infected mice showed a decreased immune response. This virulence defect was dependent on the mouse cytokine interferon gamma IFNγ. TgLOXL1 changes location from inside the parasite in tissue culture conditions to vesicular structures within the host immune cells during mouse infection. These results suggest that TgLOXL1 plays a role in the modification of the host immune response in mice., Competing Interests: The authors declare no conflict of interest.

There are several Entamoeba species that colonize humans, but only Entamoeba histolytica causes severe disease. E. histolytica is transmitted through the fecal-oral route to colonize the intestinal tract of 50 million people worldwide. The current mouse model to study E. histolytica intestinal infection directly delivers the parasite into the surgically exposed cecum, which circumvents the natural route of infection. To develop a fecal-oral mouse model, we screened our vivarium for a natural murine Entamoeba colonizer via a pan- Entamoeba PCR targeting the 18S ribosomal gene. We determined that C57BL/6 mice were chronically colonized by Entamoeba muris. This amoeba is closely related to E. histolytica, as determined by 18S sequencing and cross-reactivity with an E. histolytica-specific antibody. In contrast, outbred Swiss Webster (SW) mice were not chronically colonized by E. muris. We orally challenged SW mice with 1 × 10 5 E. muris cysts and discovered they were susceptible to infection, with peak cyst shedding occurring between 5 and 7 days postinfection. Most infected SW mice did not lose weight significantly but trended toward decreased weight gain throughout the experiment compared to mock-infected controls. Infected mice treated with paromomycin, an antibiotic used against noninvasive intestinal disease, do not become colonized by E. muris . Within the intestinal tract, E. muris localizes exclusively to the cecum and colon. Purified E. muris cysts treated with bovine bile in vitro excyst into mobile, pretrophozoite stages. Overall, this work describes a novel fecal-oral mouse model for the important global pathogen E. histolytica. IMPORTANCE Infection with parasites from the Entamoeba genus are significantly underreported causes of diarrheal disease that disproportionally impact tropical regions. There are several species of Entamoeba that infect humans to cause a range of symptoms from asymptomatic colonization of the intestinal tract to invasive disease with dissemination. All Entamoeba species are spread via the fecal-oral route in contaminated food and water. Studying the life cycle of Entamoeba , from host colonization to infectious fecal cyst production, can provide targets for vaccine and drug development. Because there is not an oral challenge rodent model, we screened for a mouse Entamoeba species and identified Entamoeba muris as a natural colonizer. We determine the peak of infection after an oral challenge, the efficacy of paromomycin treatment, the intestinal tract localization, and the cues that trigger excystation. This oral infection mouse model will be valuable for the development of novel therapeutic options for Entamoeba infections.

Autism spectrum disorder (ASD) presents with two core symptoms, impairments in social communication and the presence of restricted, repetitive behaviors (RRBs). RRBs are commonly linked to a lack of behavioral flexibility, having a significant negative impact on daily functioning for ASD individuals and their caregivers. Commonly utilized tests of behavioral flexibility employ a traditional deterministic reward approach where choices are either correct or incorrect throughout testing. The incorporation of an 80 %/20 % probabilistic reversal learning paradigm allows for the examination of flexible behavior in the face of variable outcomes, a more ecologically relevant approach. In this task, one specific choice is reinforced on 80 % of trials and the opposite or incorrect choice is reinforced on 20% of trials. Upon successful discrimination learning, the reward contingencies are switched so that the correct choice is now reinforced 20% of trials and the incorrect choice reinforced 80 % of trials, making it the new optimal choice. This translational task has been previously validated in ASD individuals and animal models of ASD, including the BTBR T + tf/J strain. Our lab and others have demonstrated that male BTBR T + tf/J mice have higher expression of lower order RRBs and display deficits in spatial probabilistic reversal learning tasks using a T-maze apparatus. Instead, female BTBR mice do not express the same lower order RRBs and results are mixed on whether females demonstrate similar probabilistic reversal learning deficits in a T-maze. Therefore, the purpose of this study was to assess the validity of using operant chambers to examine BTBR mouse performance on an 80 %/20 % probabilistic reversal learning task and to also examine the sex-specific differences in reversal learning performance in both mouse strains. Results show that BTBR mice, irrespective of sex, were impaired on the reversal learning, requiring more days and trials to reach reversal criterion compared to C57BL/6J mice. These results parallel previous strain findings in the spatial dependent T-maze task in male mice. Further error analysis showed that the impaired behavioral flexibility was due to elevated regressive errors and lose-shift probabilities. BTBR mice have more difficulty maintaining new choice patterns compared to C57BL/6J mice, which supports findings utilizing a spatial T-maze task. Together, these findings further support the use of the BTBR mouse as preclinical models of ASD due to their validity as an ASD model., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Restricted, repetitive behaviors (RRBs) are commonly divided into two behavioral categories, lower-order and higher-order RRBs. Individuals displaying lower-order motoric RRBs may express repetitive hand flapping behaviors, body rocking back and forth movements, and continuous body spinning. Higher-order RRBs most commonly cover the behavior inflexibility and cognitive rigidity commonly found in disorders such as autism spectrum disorder and obsessive-compulsive disorder. Various neuropsychiatric disorders are plagued by RRBs yet no FDA-approved treatments have been identified. In rodents, lower-order RRBs are commonly measured through various tasks, such as repetitive self-grooming, marble burying, and stereotypic motor behaviors. This review focuses on the effects that modulation of specific serotonin receptors have on lower-order RRBs. Although there is research examining how changes in 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3, 5-HT6, and 5-HT7 receptor modulation, more research has focused on the 5-HT1A, 5-HT2A, and 5-HT2C receptors. The accumulating data suggest that increasing 5-HT1A activation decreases RRBs while blocking 5-HT1A activation has no effect on RRBs. While there are mixed findings regarding the impact of 5-HT2A modulation on RRBs, the general trend shows mixed effects of 5-HT2A receptor activation RRB expression, whereas blockade generally decreases RRBs. 5-HT2C receptor activation can modulate RRBs in either direction depending on the 5-HT2C drug used, blocking 5-HT2C activation only seems to show therapeutic properties when 5-HT2C activation is already elevated. The other 5-HT receptors have been explored far less but show promise as potential targets for regulating RRBs. Although it is less clear due to the involvement of 5-HT1D, 5-HT1A activation increases RRBs, and blocking 5-HT1A tends to decrease RRBs. 5-HT2B activation could reduce RRBs, while inhibiting 5-HT2B does not impact RRBs. Increasing 5-HT3 has not been shown to affect RRBs. Yet, increases in RRBs have been observed in Htr3a KO mice. 5-HT6 receptor activation can increase RRBs, while blocking 5-HT6 activity tends to decrease RRBs. Lastly, neither increasing or blocking 5-HT7 activity can reduce RRBs. In sum, there is no uniform pattern in whether all specific 5-HT receptors affect RRBs in either direction, instead, there is evidence suggesting that different 5-HT receptors can modulate RRBs in different directions. Further researching the less explored receptors and aiming to understand why these receptors can differently modulate RRBs, may play a key role in developing therapeutics that treat RRBs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Alvarez, Cavazos, Morales, Lopez and Amodeo.)

Pharmacological activation of the serotonin (5-HT) 1B and 5-HT1A receptors has been shown to induce OCD-like perseverative circling and locomotor stereotypy in rodents. Although, several studies have examined how activation of these receptors facilitates these motor-associated OCD-like behaviors, it is not known how acute 5-HT1B and 5-HT1A activation impacts behavioral inflexibility, a common trait related to OCD. The current study examined how acute 5-HT1B/1A receptor agonist RU24969 treatment at 0.01, 0.1, and 1.0 mg/kg impacted behavioral flexibility in both female and male C57BL/6J mice. Behavioral flexibility was tested using a spatial reversal learning task, with probabilistic reward contingencies. In addition, locomotor activity and anxiety-like behaviors were also measured. RU24969 at 0.1 and 1.0 mg/kg impaired behavioral flexibility in both female and male C57BL/6J mice. RU24969 treatment at 1.0 mg/kg reduced locomotor activity in male mice, although RU24969 treatment did not significantly reduce locomotor activity in female mice. In the open field, 1.0 mg/kg elevated anxiety-like behavior in male mice only. Overall, these results demonstrate that acute 5-HT1B and 5-HT1A receptor activation leads to impairments in behavioral flexibility, a common trait associated with OCD., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Animals with a chronic infection of the parasite Toxoplasma gondii are protected against lethal secondary infection with other pathogens. Our group previously determined that soluble T. gondii antigens (STAg) can mimic this protection and be used as a treatment against several lethal pathogens. Because treatments are limited for the parasite Cryptosporidium parvum, we tested STAg as a C. parvum therapeutic. We determined that STAg treatment reduced C. parvum Iowa II oocyst shedding in gamma interferon knockout (IFN-γ-KO) mice. Murine intestinal sections were then sequenced to define the IFN-γ-independent transcriptomic response to C. parvum infection. Gene Ontology and transcript abundance comparisons showed host immune response and metabolism changes. Transcripts for type I interferon-responsive genes were more abundant in C. parvum-infected mice treated with STAg. Comparisons between phosphate-buffered saline (PBS) and STAg treatments showed no significant differences in C. parvum gene expression. C. parvum transcript abundance was highest in the ileum and mucin-like glycoproteins and the GDP-fucose transporter were among the most abundant. These results will assist the field in determining both host- and parasite-directed future therapeutic targets.

Competing Interests: The authors have declared that no competing interests exist.

Muscular deficiencies between the quadriceps and hamstrings are prevalent among women and often lead to knee injury and ACL tears. The purpose of this study was to examine whether short term resistance training with or without blood flow restriction (BFR) could improve hamstring:quadricep ratios (H:Q) and reduce the chance for injury. Women ( n = 14; 18-25 yrs) were randomly assigned to either a traditional resistance training (RT: n = 8) or BFR resistance training in combination with traditional RT (RT+BFR: n = 6) group. Subjects trained 3 days/week for 6 weeks. The RT group completed 3 sets of 10 reps at 70% of their one-repetition maximum (1RM) with 1-minute rest between sets. The RT+BFR group completed the first 5 exercises similar to the RT group but performed the two-leg hamstring curl under blood flow restriction at 50% of occlusive pressure and 30% 1RM, completing 4 sets (30, 15, 15, 15) with 30 seconds rest between sets. Training effects were assessed using a two-way repeated measures ANOVA. Statistical significance was set at p≤0.05. There were significant ( p < 0.05) main effects for time, with all muscle groups increasing strength but no significant main effects or interaction for the H:Q ratios at four testing speeds (60°/s, 180°/s, 240°/s, and 300°/s). This study found that hamstring strength with low load (30% 1RM) BFR training was improved to a similar extent as the hamstrings trained with the traditional high load (75% 1RM) program even though less external weight was used during training. H:Q ratios showed small non-significant increases post-training for both groups.

The synthetic cathinones represent an important class of designer drugs. The widespread attention and publicity associated with these psychostimulants have resulted in numerous legislative actions at state and federal levels throughout the USA. These amphetamine-like compounds are characterized by a β-keto functional group. Although the synthetic cathinones share many properties of their phenethylamine counterparts, the presence of the ketone moiety is responsible for a number of unique and distinct differences in terms of their chemical characteristics and properties. Thermal degradation of methcathinone was first reported several decades ago but has received limited attention. In this study, we identified in situ thermal degradation products for 18 cathinones during gas chromatography-mass spectrometry (GC-MS) analysis. Oxidative degradation arises from the loss of two hydrogens, yielding a characteristic 2 Da mass shift. Degradation products were characterized by prominent iminium base peaks with mass-to-charge ratios 2 Da lower than the parent drug, and in the case of the pyrrolidine-containing cathinones, prominent molecular ions arising from the 2,3-enamine. Chromatographic and mass spectroscopic data are described for 4-ethylmethcathinone, 4-methylethcathinone, buphedrone, butylone, ethcathinone, ethylone, flephedrone, 3,4-methylenedioxy-α-pyrrolidinobutiophenone, 3,4-methylenedioxypyrovalerone, mephedrone, methcathinone, methedrone, methylone, 4-methyl-α-pyrrolidinobutiophenone, naphyrone, pentedrone, pentylone and pyrovalerone. Degradation was minimized by lowering injection temperatures, residence time in the inlet and eliminating active sites during chromatographic analysis. Chromatographic and mass spectral data for the cathinone degradation products are presented and discussed within the context of forensic toxicological analysis, selection of appropriate instrumental methods and implications for the interpretation of results., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

This study aimed to determine whether changes in initial restrictive pressures (IRP, tightness of the cuff before inflation with air) affect tissue oxygenation, lactate production and leg strength before, during and after knee extension exercises. The cuff was positioned on the right thigh, and the IRP of either 40-45 or 60-65 mmHg were applied randomly prior to inflating the cuff to the final restrictive pressure (the pressure reached after inflating the cuff with air). Subjects performed four sets (30, 15, 15 and 15 reps) of isotonic knee extensions with 1-min rest between sets. Tissue oxygenation and blood lactate levels were assessed prior to, during and after exercise, and leg strength was assessed pre- and postexercise. There were significant condition by time interactions (P<0·01) and main effects for both condition (P<0·01) and time (P<0·01) for tissue oxygenation, deoxyhaemoglobin, total haemoglobin. Significant main effects were detected for both condition (P<0·01) and time (P<0·01) for leg strength values. There was only a significant time main effect for lactate concentrations. This study is the first to show that a higher IRP had a significant impact on percent tissue oxygenation, leg strength and deoxygenated haemoglobin accumulation during exercise., (© 2013 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd.)

Background: The non-invasive diagnosis of vertebral osteomyelitis is a difficult one. Studies confirm MRI as the gold standard with 92% sensitivity and 94% specificity. Scintigraphy combined with Tc99-Ga67 used to be the procedure of choice before the advent of PET with labeled glucose, which has a high sensitivity and specificity, but cannot distinguish a focus of infection from inflammation. Scintigraphy with UBI29-41 is an infection-specific study that was recently described in the literature. There are no studies showing its value in the diagnosis of vertebral osteomyelitis., Objective: The purpose of the study is to show that the Tc99-UBI29-41 scan has 99% sensitivity for vertebral osteomyelitis., Methods: This is a study of a diagnostic test. The case series was composed of the records of UBI scans performed at the Nuclear Medicine Department, HcHMAE. The scans were interpreted in a blind and independent fashion by 2 experienced observers. The final diagnosis was obtained with the histopathologic study or a microbiologic culture or with the clinical findings after a follow-up of at least 6 months. The sensitivity, specificity, positive and negative predictive values, and the positive and negative probability ratio were determined, always using a 95% confidence interval (CI). The sample size necessary to show 99% sensitivity with a 95% CI and a statistical power of 80% was 15 patients. The concordance with the kappa index was determined., Results: Twenty-seven patients with suspected vertebral osteomyelitis were included; 15 males and 12 females, with a mean age of 50 years (SD = 16). Fourteen patients had a history of surgery and 12 had metallic implants. Nine patients had a history if spinal infiltrations. The number of patients with a positive scan was 20. The sensitivity for detecting pyogenic vertebral osteomyelitis was 100% (CI: 0.901-1) and the specificity was 87.5% (CI: 0.647-0.875). The positive predictive value was 0.95 (CI: 0.859-0.950), and the negative predictive value was 1 (CI: 0.739-1). The intra- and interobserver kappa value was 1., Conclusions: The UBI scan showed 100% sensitivity and 88% specificity for vertebral osteomyelitis. Although the role of this method in the diagnostic protocol of the patient with suspected vertebral osteomyelitis has not yet been defined, the scan was useful in this group of patients to arrive at a certain diagnosis.

Objective: The objective of our study was to assess the visibility of the fetal corpus callosum and soft palate on standard single-shot fast spin-echo (SSFSE) imaging versus real-time (RT) SSFSE imaging., Subjects and Methods: Part 1 of the study was a prospective analysis using a questionnaire rating the ease of use and utility of RT imaging. Part 2 of the study was a retrospective analysis of 69 fetal MRI studies with RT sagittal midline imaging of the head, face, or both. Standard and RT SSFSE image sets were de-identified, randomized, and shown to three pediatric neuroradiologists who rated on a 5-point scale whether the images were midline and how well they could see and characterize as normal the corpus callosum and secondary palate. The imaging results were correlated with postnatal diagnosis. Statistical methods included the Wilcoxon's signed rank test, McNemar chi-square test, and analysis of variance., Results: Prospectively, the RT SSFSE technique was ranked as excellent in all the categories assessed. Retrospective analysis showed that the midline view obtained with RT SSFSE imaging was helpful in diagnosing the normal and abnormal secondary palate, allowing improved diagnosis of 19 (30.6%) of 62 cases of normal palate and four (57.1%) of seven cases of abnormal palate, when compared with the standard SSFSE technique. RT SSFSE imaging improved the ability to diagnose a normal corpus callosum on the midline view in 13 (27.6%) of 47 fetuses of 20 or more weeks gestational age., Conclusion: The RT SSFSE technique can aid in obtaining images in planes that are critical to the evaluation of a moving fetus, particularly when a midline sagittal view of the corpus callosum or palate is required. The use of this technique may lead to improved diagnosis of CNS or orofacial abnormalities in fetuses.

Two radiolabeled analogues of 6-benzyloxy-9H-purin-2-ylamine (O(6)-benzylguanine; BG) potentially useful in the in vivo mapping of O(6)-alkylguanine-DNA alkyltransferase (AGT) were synthesized. Fluorine-18 labeling of the known 6-(4-fluoro-benzyloxy)-9H-purin-2-ylamine (FBG; 6) was accomplished by the condensation of 4-[(18)F]fluorobenzyl alcohol with 2-aminopurin-6-yltrimethylammonium chloride (4) or 2-amino-6-chloropurine in average decay-corrected radiochemical yields of 40 and 25%, respectively. Unlabeled 6-(3-iodo-benzyloxy)-9H-purin-2-ylamine (IBG; 7) was prepared from 4 and 3-iodobenzyl alcohol. Radioiodination of 9, prepared from 7 in two steps, and subsequent deprotection gave [(131)I]7 in about 70% overall radiochemical yield. The IC(50) values for the inactivation of AGT from CHO cells transfected with pCMV-AGT were 15 nM for IBG and 50 nM for FBG. The binding of [(18)F]6 and [(131)I]7 to purified AGT was specific and saturable with both exhibiting similar IC(50) values (5-6 microM).