Mean plasma half-life of cyclocreatine was between 3.5 and 6.5 h. In conclusion, chronic administration of cyclocreatine by oral gavage in Sprague Dawley rats induced the seizures and microscopic lesions in the brain, testes and thyroid. Based on the results of this study the highest tested dose of 600 mg/kg/day (mean Cmax of 151.5 μg/mL; AUC0-24 of 1970 h*μg/mL) was considered the maximum tolerated dose (MTD) in SD rats.Consumers are commonly exposed to numerous chemical ingredients found in various formulated products especially household and personal care products. Therefore, identification of hazardous ingredients contained in those products should be performed at the early stages of product design to reduce the high cost of redesigning the products at the final stage. Thus, a systematic safety and health risk assessment methodology is required for the product formulation design. In this work, a two-step index-based methodology is presented to estimate the severity of the hazards and the magnitude of risks. In Tier 1 assessment, potential hazards of the ingredients were identified by following the Product Ingredient Safety Index (PISI). The basic toxicology information of ingredients was required for this assessment. In Tier 2 assessment, the extent of risks of the ingredients via dermal and inhalation exposure routes were evaluated. At this stage, the concentration of ingredients and the amount of exposure were considered. The value of Margin of Exposure (MOE) was used as an indicator in the development of Product Ingredient Exposure Index (PIEI). To demonstrate the proposed methodology, a case study on the evaluation of potential hazards and the risks from ingredients used in personal care product formulations were performed.In this study, the heterologous expression of an engineered thermostablle glucose oxidase from Aspergillus heteromophus CBS 117.55 was achieved in P. pastoris. This recombinant GoxAh was thermostable, with an optimal temperature range 25 °C-65 °C, and it was capable of retaining greater than 90% of its initial activity following a 10-min incubation at 75 °C. This enzyme had an optimum pH of 6.0, and it could retain above 80% of its initial activity following a 2-h incubation at a broad pH range (2.0-8.0). Moreover, GoxAh displayed excellent pepsin and trypsin resistance, and highly resistant to a range of tested metal ions and chemical reagents. These good properties make GoxAh a promising candidate for feed additive. The Km and kcat/Km values of GoxAh were 187 mM and 1.09/mM/s, which limited its widespread application to some degree. However, due to its excellent characteristics, GoxAh is still of potential economic value for high value-added areas, as well as a good initial enzyme for developing applicable feed enzyme by protein engineering.Metastasis is a critical cause of treatment failure and death in patients with advanced malignancies. Tumor cells can leave the primary site and enter the bloodstream; these circulating tumor cells then colonize target organs by overcoming blood shear stress, evading immune surveillance, and silencing the offensive capabilities of immune cells, eventually forming metastatic foci. From leaving the primary focus to the completion of distant metastasis, malignant tumor cells are supported and/or antagonized by certain immune cells. In particular, it has been found that myeloid granulocytes play an important role in this process. This review therefore aims to comprehensively describe the significance of neutrophils in solid tumor metastasis in terms of their supporting role in initiating the invasion and migration of tumor cells and assisting the colonization of circulating tumor cells in distant target organs, with the hope of providing insight into and ideas for anti-tumor metastasis treatment of tumor patients.

Prehospital perimortem caesarean delivery (PCD) is a rarely performed procedure. In this study, we aimed to examine all PCDs performed by the four Helicopter Emergency Medical Services in the Netherlands; to describe the procedures, outcomes, complications, and compliance with the recommended guidelines; and to formulate recommendations.

We performed a population-based retrospective cohort study of all consecutive maternal out-of-hospital cardiac arrests that underwent PCD in the prehospital setting between May 1995 and December 2019. Registered data included patient demographics, operator background, advanced life support interventions, and timelines. Resuscitation performance was evaluated according to the 2015 European Resuscitation Guidelines.

Seven patients underwent a prehospital PCD. Three mothers died on the scene, while four were transported to a hospital but died in the hospital. Seven neonates were born by PCD. One neonate died on the scene and six were transported to a hospital. Three neonates were eventually discharged from the hospital. Among the three surviving neonates, the periods from dispatch to start of PCD were 13, 14, and 21 min.

There was a low incidence of maternal perimortem caesarean deliveries in The Netherlands. Only some neonates survived after PCD. It is recommended that PCD be performed as quickly as possible. Due to the delay, the mother has a far lower chance of survival than the neonate. In fatal cases, autopsy is strongly recommended.

There was a low incidence of maternal perimortem caesarean deliveries in The Netherlands. Only some neonates survived after PCD. It is recommended that PCD be performed as quickly as possible. Due to the delay, the mother has a far lower chance of survival than the neonate. In fatal cases, autopsy is strongly recommended.

Serum protein electrophoresis (SPE) is a well-established technique to identify alterations in plasma protein profiles, caused by diseases as multiple myeloma (MM). In addition, it could be a cost-effective technique to discover new plasma biomarkers. Relation between MM and lysosomal storage diseases (LSDs) as Gaucher disease has been set out but, it has not been evaluated on other LSDs nor the utility of the SPE as first step on LSDs biomarkers discovery projects.

Stored plasma samples at diagnosis from several LSDs patients underwent analysis. Quality control was checked prior to the SPE was analyzed by capillary electrophoresis. The analysis for monoclonal spikes and the differences between each fraction on patients’ samples vs the control data previously published, were evaluated. Furthermore, immunoprotein quantification and free light chains ratio were done by nephelometry and turbidimetry.

Seventy-five samples of LSD patients at diagnosis, were assessed. The frequency of the MGUS on LSDs patients was not higher than in general population whereas one lysosomal acid lipase deficiency infant showed increased IgA and kappa deviation. Regarding to the usefulness of SPE in biomarkers discovery, statistically significant differences were observed on SPE fractions between LSDs and healthy population.

The evaluation of SPE fractions can be a useful tool to understand pathophysiologic aspects in LDSs and, to simplify new marker discovery projects. In some of them, the MGUS appearance is a risk factor for the MM development despite its frequency is not increased on the studied LSDs at diagnosis.

The evaluation of SPE fractions can be a useful tool to understand pathophysiologic aspects in LDSs and, to simplify new marker discovery projects. In some of them, the MGUS appearance is a risk factor for the MM development despite its frequency is not increased on the studied LSDs at diagnosis.Frailty is a clinical state characterized by an age-related unsteady state of the body, a decline in physiological function, and an increased vulnerability to adverse outcomes. Early diagnosis of frailty is important for improving the quality of life in older adults and promoting healthy aging. The biological mechanisms underlying frailty have been extensively studied in recent years. Combining assessment tools and biomarkers can facilitate the early diagnosis of frailty. However, there is a lack of stable and reliable frailty-related biomarkers for use in clinical practice. Advances in the multi-omics platforms have provided new information on the molecular mechanisms underlying frailty. Thus, identifying biomarkers using omics-based approaches helps explore the physiological mechanisms underlying frailty, and aids the evaluation of the risk of frailty development and progression. This article reviews the current status of frailty biomarkers from the genomics, transcriptomics, proteomics, and metabolomics perspectives.Anti-Müllerian hormone (AMH/Amh) plays a role in gonadal differentiation and function across vertebrates. In zebrafish we demonstrated that Amh deficiency caused severe gonadal dysgenesis and dysfunction. The mutant gonads showed extreme hypertrophy with accumulation of early germ cells in both sexes, namely spermatogonia in the testis and primary growth oocytes in the ovary. In amh mutant females, the folliculogenesis was normal in young fish but receded progressively in adults, which was accompanied by progressive decrease in follicle-stimulating hormone (fshb) expression. Interestingly the expression of fshb increased in the pituitary of juvenile amh mutant males but decreased in adults. The upregulation of fshb in mutant male juveniles was likely one of the mechanisms for triggering gonadal hypergrowth, whereas the downregulation of fshb in adults might involve a negative feedback by gonadal inhibin. Further analysis using mutants of fshb and growth differentiation factor 9 (gdf9) provided evidence for a role of FSH in triggering ovarian hypertrophy in young female amh mutant as well. In summary, the present study provided comprehensive genetic evidence for dual roles of Amh in controlling zebrafish gonadal homeostasis and gametogenesis in both sexes. Amh suppresses proliferation or accumulation of early germ cells (spermatogonia in testis and primary growth oocytes in ovary) while promoting their exit to advanced stages, and its action may involve both endocrine and paracrine pathways.We assessed differences in presentation and response to therapy in 394 consecutive patients who developed acute or chronic graft-versus-host disease (GVHD) after receiving their first allogeneic transplantation (HSCT) from a 10/10 HLA allele-matched unrelated donor (MUD; n = 179) using calcineurin inhibitors or a T cell-replete haploidentical donor (haplo; n = 215) and post-transplantation cyclophosphamide at our center between 2005 and 2017. The median duration of follow-up for survivors was 52.5 months. The cumulative incidences for grade II-IV and grade III-IV acute GVHD at day 180 post HCT were similar, at 39% and 14%, respectively, for haplo-HSCT compared with 50% and 16% for MUD HSCT (P not significant). Haplo-HSCT recipients had a lower cumulative incidence of moderate to severe chronic GVHD, at 22% (severe, 19%), compared with 31% (severe, 29%) for MUD HSCT recipients (P = .026). The time to onset of moderate to severe chronic GVHD was faster for haplo-HSCT recipients (213 days versus 280 days; P = .011). Among patients with grade II-IV acute GVHD, there was no significant between-group difference in organ involvement, with skin the most affected (75% for haplo-HSCT versus 70% for MUD HSCT), followed by the gastrointestinal tract (71% versus 69%) and liver (14% versus 17% MUD). For chronic GVHD, haplo-HSCT recipients had less involvement of the eyes (46% versus 75% for MUD; P less then .001) and of the joints/fascia (12% versus 36%; P = .001). Also for cGVHD patients, haplo-HSCT recipients and MUD HSCT recipients had similar all-cause mortality (22% versus 18%; P = .89), but the former were more likely to be off immunosuppression at 2 years post-HCT (63% versus 43%; P = .03) compared with MUD.