Diagnostic significance of the histopathology of bone marrow macrophages in forensic autopsies

Forensic pathologists often encounter autopsies that require an assessment of antemortem general conditions (e.g., infection, metabolic disorders). To establish evaluation clues for such cases, we quantitatively examined macrophages and the general pathology of bone marrow in samples from 180 forensic autopsy cases of decedents with various conditions. Hematoxylin-eosin staining, Berlin blue staining, and immunostainings for CD163, CD138, and CD61 were performed. We determined the numbers per field (density) of total macrophages, swollen macrophages, macrophages with hemophagocytosis, and hemosiderin-laden macrophages. Each density was standardized by identifying its ratio to the total number of macrophages. The decedents' background data (cause of death, other pathological findings, postmortem interval, antemortem symptoms, and presence of resuscitation) were extracted. No correlations were found between the postmortem interval and the other decedent data, indicating that these data are not affected by postmortem changes. In the group in which inflammatory disease was the cause of death, there were significant elevations in the ratio of the swollen macrophage density to total macrophages. Significantly higher ratios of the density of swollen and hemophagocytic macrophages were observed in the group in which conditions with a prolonged agonal period were the cause of death. The group with a return of spontaneous circulation to resuscitation showed a significantly higher ratio of macrophage density with hemophagocytosis. This study provides the first statistical analysis focused on bone marrow histopathology in forensic autopsies. The results will be useful for elucidating causes of death and agonal-period conditions.     

Hip Displacement in Cerebral Palsy: The Role of Surveillance

IntroductionHip displacement is common in cerebral palsy (CP) and is related to the severity of neurological and functional impairment. It is a silent, but progressive disease, and can result in significant morbidity and decreased quality of life, if left untreated. The pathophysiology of hip displacement in CP is a combination of hip flexor-adductor muscle spasticity, abductor muscle weakness, and delayed weight-bearing, resulting in proximal femoral deformities and progressive acetabular dysplasia. Due to a lack of symptoms in the early stages of hip displacement, the diagnosis is easily missed. Awareness of this condition and regular surveillance by clinical examination and serial radiographs of the hips are the key to early diagnosis and treatment.Hip surveillance programmesSeveral population-based studies from around the world have demonstrated that universal hip surveillance in children with CP allows early detection of hip displacement and appropriate early intervention, with a resultant decrease in painful dislocations. Global hip surveillance models are based upon the patients’ age, functional level determined by the Gross Motor Function Classification system (GMFCS), gait classification, standardized clinical exam, and radiographic indices such as the migration percentage (MP), as critical indicators of progressive hip displacement.ConclusionDespite 25 years of evidence showing the efficacy of established hip surveillance programmes, there is poor awareness among healthcare professionals in India about the importance of regular hip surveillance in children with CP. There is a need for professional organizations to develop evidence-based guidelines for hip surveillance which are relevant to the Indian context.     

Family Physician Clinical Inertia in Managing Hypoglycemia

AimsClinical inertia behaviour affects family physicians managing chronic disease such as diabetes. Literature addressing clinical inertia in the management of hypoglycemia is scarce. The objectives of this study were to create a measurement for physician clinical inertia in managing hypoglycemia (ClinInert_InHypoDM), and to determine physicians’ characteristics associated with clinical inertia.MethodsThe study was a secondary analysis of data provided by family physicians from the InHypo-DM Study, applying exploratory factor analysis. Principal axis factoring with an Oblimin rotation was employed to detect underlying factors associated with physician behaviors. Multiple linear regression was used to determine association between the ClinInert_InHypoDM scores and physician characteristics.ResultsFactor analysis identified a statistically sound 12-item one-factor scale for clinical inertia behavior. No statistically significant differences in clinical inertia score for the studied independent variables were found.ConclusionsThis study provides a scale for assessing clinical inertia in the management of hypoglycemia. Further testing this scale in other family physician populations will provide deeper understanding about the characteristics and factors that influence clinical inertia. The knowledge derived from better understanding clinical inertia in primary care has potential to improve outcomes for patients with diabetes.     

Coupling online control and inhibitory systems in children with Developmental Coordination Disorder: Goal-directed reaching

For children with Developmental Coordination Disorder (DCD), the real-time coupling between frontal executive function and online motor control has not been explored despite reported deficits in each domain. The aim of the present study was to investigate how children with DCD enlist online control under task constraints that compel the need for inhibitory control. A total of 129 school children were sampled from mainstream primary schools. Forty-two children who met research criteria for DCD were compared with 87 typically developing controls on a modified double-jump reaching task. Children within each skill group were divided into three age bands: younger (6–7 years), mid-aged (8–9), and older (10–12). Online control was compared between groups as a function of trial type (non-jump, jump, anti-jump). Overall, results showed that while movement times were similar between skill groups under simple task constraints (non-jump), on perturbation (or jump) trials the DCD group were significantly slower than controls and corrected trajectories later. Critically, the DCD group was further disadvantaged by anti-jump trials where inhibitory control was required; however, this effect reduced with age. While coupling online control and executive systems is not well developed in younger and mid-aged children, there is evidence of age-appropriate coupling in older children. Longitudinal data are needed to clarify this intriguing finding. The theoretical and applied implications of these results are discussed.     

miR-30c Impedes Glioblastoma Cell Proliferation and Migration by Targeting SOX9

miR-30c has been acknowledged as a tumor suppressor in various human cancers, such as ovarian cancer, gastric cancer, and prostate cancer. However, the role of miR-30c in glioblastoma (GBM) needs to be investigated. In our study, we found that the expression of miR-30c was significantly downregulated in GBM tissues and cell lines. We found that overexpression of miR-30c inhibited cellular proliferation of GBM cells in vitro and in vivo. More GBM cells were arrested in the G₀ phase after miR-30c overexpression. Moreover, we showed that miR-30c overexpression suppressed the migration and invasion of GBM cells. Mechanistically, we found that SOX9 was a direct target of miR-30c in GBM cells. Overexpression of miR-30c inhibited the mRNA and protein levels of SOX9 in GBM cells. Moreover, there was a negative correlation between the expression of miR-30c and SOX9 in GBM tissues. Finally, we showed that restoration of SOX9 in GBM cells reversed the proliferation, migration, and invasion of GBM cells transfected with miR-30c mimic. Collectively, our results demonstrated that miR-30c suppressed the proliferation, migration, and invasion of GBM cells via targeting SOX9.     

Development of an IgG-Fc fusion COVID-19 subunit vaccine,AKS-452

AKS-452 is a biologically-engineered vaccine comprising an Fc fusion protein of the SARS-CoV-2 viral spike protein receptor binding domain antigen (Ag) and human IgG1 Fc (SP/RBD-Fc) in clinical development for the induction and augmentation of neutralizing IgG titers against SARS-CoV-2 viral infection to address the COVID-19 pandemic. The Fc moiety is designed to enhance immunogenicity by increasing uptake via Fc-receptors (FcγR) on Ag-presenting cells (APCs) and prolonging exposure due to neonatal Fc receptor (FcRn) recycling. AKS-452 induced approximately 20-fold greater neutralizing IgG titers in mice relative to those induced by SP/RBD without the Fc moiety and induced comparable long-term neutralizing titers with a single dose vs. two doses. To further enhance immunogenicity, AKS-452 was evaluated in formulations containing a panel of adjuvants in which the water-in-oil adjuvant, Montanide™ ISA 720, enhanced neutralizing IgG titers by approximately 7-fold after one and two doses in mice, including the neutralization of live SARS-CoV-2 virus infection of VERO-E6 cells. Furthermore, ISA 720-adjuvanted AKS-452 was immunogenic in rabbits and non-human primates (NHPs) and protected from infection and clinical symptoms with live SARS-CoV-2 virus in NHPs (USA-WA1/2020 viral strain) and the K18 human ACE2-trangenic (K18-huACE2-Tg) mouse (South African B.1.351 viral variant). These preclinical studies support the initiation of Phase I clinical studies with adjuvanted AKS-452 with the expectation that this room-temperature stable, Fc-fusion subunit vaccine can be rapidly and inexpensively manufactured to provide billions of doses per year especially in regions where the cold-chain is difficult to maintain.     

Neural Correlates of Failed Inhibitory Control as an Early Marker of Disordered Eating in Adolescents

BackgroundBinge eating and other forms of disordered eating behavior (DEB) are associated with failed inhibitory control. This study investigated the neural correlates of failed inhibitory control as a potential biomarker for DEB.MethodsThe study used prospective longitudinal data from the European IMAGEN study adolescent cohort. Participants completed baseline assessments (questionnaires and a brain scan [functional magnetic resonance imaging]) at 14 years of age and a follow-up assessment (questionnaires) at 16 years of age. Self-reported binge eating and/or purging were used to indicate presence of DEB. Neural correlates of failed inhibition were assessed using the stop signal task. Participants were categorized as healthy control subjects (reported no DEB at both time points), maintainers (reported DEB at both time points), recoverers (reported DEB at baseline only), and developers (reported DEB at follow-up only). Forty-three individuals per group with complete scanning data were matched on gender, age, puberty, and intelligence (N = 172).ResultsAt baseline, despite similar task performance, incorrectly responding to stop signals (failed inhibitory control) was associated with greater recruitment of the medial prefrontal cortex and anterior cingulate cortex in the developers compared with healthy control subjects and recoverers.ConclusionsGreater recruitment of the medial prefrontal and anterior cingulate regions during failed inhibition accords with abnormal evaluation of errors contributing to DEB development. As this precedes symptom onset and is evident despite normal task performance, neural responses during failed inhibition may be a useful biomarker of vulnerability for DEB. This study highlights the potential value of prospective neuroimaging studies for identifying markers of illness before the emergence of behavior changes.     

The oncogenic impact of RNF2 on cell proliferation,invasion and migration through EMT on mammary carcinoma

Mammary carcinoma (MC) is one of most common malignancy in women, and ring finger protein 2 (RNF2) possesses various roles in vast human tumors. In MC tissues as well as in cell lines RNF2 exhibited high expression, had significant association with tumor size, lymph node status, TNM stage, patients’ poor survival, and promoted cell proliferation, colony formation, cell migration and invasion of MC cell lines which was mediated by downregulation of E-cadherin protein. These data reveal that RNF2 protein plays a vital role in the development of MC and may be a potential therapy target of MC.