Acute bovine viral diarrhea virus infection inhibits expression of interferon tau-stimulated genes in bovine endometrium.

Bovine viral diarrhea virus (BVDV) can evade host detection by downregulation of interferon signaling pathways. Infection of cows with noncytopathic (ncp) BVDV can cause early embryonic mortality. Upregulation of type I interferon stimulated genes (ISGs) by blastocyst-secreted interferon tau (IFNT) is a crucial component of the maternal recognition of pregnancy (MRP) in ruminants. This study investigated the potential of acute BVDV infection to disrupt MRP by modulating endometrial ISG expression. Endometrial cells from 10 BVDV-free cows were cultured and treated with 0 or 100 ng/ml IFNT for 24 h in the absence or presence of ncpBVDV infection to yield four treatment groups: CONT, ncpBVDV, IFNT, or ncpBVDV+IFNT. ncpBVDV infection alone only upregulated TRIM56, but reduced mRNA expression of ISG15, MX2, BST2, and the proinflammatory cytokine IL1B. As anticipated, IFNT treatment alone significantly increased expression of all 17 ISGs tested. In contrast to the limited effect of ncpBVDV alone, the virus markedly inhibited IFNT-stimulated expression of 15 ISGs tested (ISG15, HERC5, USP18, DDX58, IFIH1, IFIT1, IFIT3, BST2, MX1, MX2, RSAD2, OAS1Y, SAMD9, GBP4, and PLAC8), together with ISG15 secreted protein. Only TRIM56 and IFI27 expression was unaltered. IL1B expression was reduced by the combined treatment. These results indicate that acute ncpBVDV infection may decrease uterine immunity and lead to MRP failure through inhibition of IFNT-stimulated endometrial ISG production. This in turn could reduce fertility and predispose cows to uterine disease, while evasion of the normal uterine immune response by ncpBVDV may contribute to maintenance and spreading of this economically important disease.

BVDV alters uterine prostaglandin production during pregnancy recognition in cows.

Embryonic mortality in cows is at least in part caused by failure of pregnancy recognition (PR). Evidence has shown that bovine viral diarrhoea virus (BVDV) infection can disrupt pregnancy. Prostaglandins (PG) play important roles in many reproductive processes, such as implantation. The aim of this study was to investigate the effect of BVDV infection on uterine PG production and PR using an in vitro PR model. Bovine uterine endometrial cells isolated from ten BVDV-free cows were cultured and treated with 0 or 100ng/mL interferon-τ (IFNT) in the absence or presence of non-cytopathic BVDV (ncpBVDV). PGF2α and PGE2 concentrations in the spent medium were measured using radioimmunoassays, and in the treated cells expression of the genes associated with PG production and signalling was quantified using qPCR. The results showed that the IFNT challenge significantly stimulated PTGS1 and PTGER3 mRNA expression and PGE2 production; however, these stimulatory effects were neutralised in the presence of ncpBVDV infection. ncpBVDV infection significantly increased PTGS1 and mPGES1 mRNA expression and decreased AKR1B1 expression, leading to increased PGE2 and decreased PGF2α concentrations and an increased PGE2:PGF2α ratio. The other tested genes, including PGR, ESR1, OXTR, PTGS2, PTGER2 and PTGFR, were not significantly altered by IFNT, ncpBVDV or their combination. Our study suggests that BVDV infection may impair PR by (1) inhibiting the effect of IFNT on uterine PG production and (2) inducing an endocrine switch of PG production from PGF2α to PGE2 to decrease uterine immunity, thereby predisposing the animals to uterine disease.

Recreational Marijuana Use, Adolescent Cognitive Development, and Schizophrenia Susceptibility.

Background: We investigated how low marijuana (MJ) use levels, the typical use pattern in most adolescent users, affect cognitive maturation and schizophrenia risk. Methods: In two complementary adolescent samples where the majority reported minimal MJ use, we compared cognitive performances before and after MJ use initiation. The Iowa sample (40 first-degree relatives and 54 second-degree relatives of patients with schizophrenia and 117 control subjects with no schizophrenia family history) underwent a battery of standardized neuropsychological tests at 0, 18, and 36 months. Based on self-administered Timeline Followback interviews, 26.5% of adolescents had emergent MJ use (eMJ) during follow-up. The second sample (n = 3463), derived from a birth cohort, received substance use and sustained attention assessments between ages 10 and 15 years. Mixed linear models and regression analyses tested the effects of eMJ on longitudinal changes in cognitive performance. Results: In the Iowa sample, longitudinal changes in 5 of 8 cognitive domains were significantly associated with eMJ. On sustained attention, visuospatial working memory, and executive sequencing, adolescents with eMJ showed less age-expected improved performance. In addition, first-degree relatives with eMJ were less improved on processing speed and executive reasoning than first-degree relatives without eMJ. In the birth cohort, greater intraindividual variability in reaction times (indicative of poorer sustained attention) was significantly associated with more frequent MJ use and with recreational use levels. Conclusions: Nonheavy MJ use disrupts normal adolescent maturation and compounds aberrant adolescent maturation associated with familial schizophrenia risk. These findings underscore the importance of reducing adolescent MJ access in the context of increased availability to high-potency MJ.

Impulsive decision making, brain cortical thickness and familial schizophrenia risk.

BACKGROUND: Schizophrenia (SZ) patients and their biological relatives are more impulsive than controls. Although greater impulsivity in SZ has been associated with dysfunction in prefrontal neural circuits implicated in reward processing, little is known regarding brain structural correlates of heightened impulsivity in unaffected adolescent relatives of SZ patients. METHODS: Impulsive decision-making was assessed using the delay discounting task in 174 adolescents: 36 first-degree relatives (FDR) and 50 second-degree relatives (SDR) of SZ patients, and 88 healthy controls with no SZ family history (NSFH). We contrasted MRI brain gray matter cortical thickness-discounting constant (k) relationships between these 3 comparison groups using well-validated statistical approaches. RESULTS: FDR had a distinct pattern in cortical thickness-k associations when compared to NSFH and SDR. Preference for immediate rewards (i.e. greater impulsivity) among FDR correlated with less cortical thickness within diffuse brain regions, including dorsolateral prefrontal (cognitive control network and motor/premotor cortex) and lateral temporal (auditory and visual association cortex) brain areas. CONCLUSIONS: Adolescent impulsive decision-making may serve as an informative phenotype of underlying brain circuitry dysfunction associated with SZ risk. Future research focusing on impulsivity in SZ will likely help advance understanding how dysfunctional interactions between cognitive and reward neural circuits contribute to the neurobiological basis of SZ.

Pediatric Survivorship: Considerations Following CAR T-Cell Therapy.

BACKGROUND: This article presents an overview of pediatric relapsed and refractory acute lymphoblastic leukemia (ALL) and chimeric antigen receptor (CAR) T-cell therapy in pediatric patients. OBJECTIVES: Acute and chronic post-CAR T-cell effects and considerations are discussed, along with survivorship considerations. METHODS: A case study illustrates the identification and management of physiologic and psychosocial sequelae. FINDINGS: B-cell aplasia, hypogammaglobulinemia, infections, and cumulative effects of CAR T-cell therapy and other treatments are a concern in the pediatric population. Unique to pediatric and young adult survivors of childbearing potential are implications for post-treatment fertility. Financial toxicities and psychosocial needs require a family-centered approach to interventions that address the impact of CAR T-cell therapy not only on the patient, but also on caregivers and siblings.

Prognostic Factors for Recovery of Vision in Canine Optic Neuritis of Unknown Etiology: 26 Dogs (2003-2018).

Optic neuritis (ON) is a recognized condition, yet factors influencing recovery of vision are currently unknown. The purpose of this study was to identify prognostic factors for recovery of vision in canine ON of unknown etiology. Clinical databases of three referral hospitals were searched for dogs with presumptive ON based on clinicopathologic, MRI/CT, and fundoscopic findings. Twenty-six dogs diagnosed with presumptive ON of unknown etiology, isolated (I-ON) and MUE-associated (MUE-ON), were included in the study. Their medical records were reviewed retrospectively, and the association of complete recovery of vision with signalment, clinicopathologic findings, and treatment was investigated. Datasets were tested for normality using the D'Agostino and Shapiro-Wilk tests. Individual datasets were compared using the Chi-squared test, Fisher's exact test, and the Mann-Whitney U-test. For multiple comparisons with parametric datasets, the one-way analysis of variance (ANOVA) was performed, and for non-parametric datasets, the Kruskal-Wallis test was performed to test for independence. For all data, averages are expressed as median with interquartile range and significance set at p < 0.05. Twenty-six dogs met the inclusion criteria. Median follow-up was 230 days (range 21-1901 days, mean 496 days). Six dogs (23%) achieved complete recovery and 20 dogs (77%) incomplete or no recovery of vision. The presence of a reactive pupillary light reflex (p = 0.013), the absence of fundoscopic lesions (p = 0.0006), a younger age (p = 0.038), and a lower cerebrospinal fluid (CSF) total nucleated cell count (TNCC) (p = 0.022) were statistically associated with complete recovery of vision. Dogs with I-ON were significantly younger (p = 0.046) and had lower CSF TNCC (p = 0.030) compared to the MUE-ON group. This study identified prognostic factors that may influence complete recovery of vision in dogs with ON. A larger cohort of dogs is required to determine whether these findings are robust and whether additional parameters aid accurate prognosis for recovery of vision in canine ON.

Toward gender-aware health care: evaluation of an intervention to enhance care for female patients in the VA setting.

In response to identified deficits in the provision of health care to female patients, we sought to improve healthcare workers' gender awareness- conceptualized as gender-role ideology, sensitivity, and knowledge related to female patients-through the application of a brief computerized educational intervention. This study, conducted in the Veterans Affairs (VA) health-care setting, involved a pretest-posttest equivalent control group design. We evaluated hypotheses using random coefficients regression, a technique that offers a number of advantages relative to repeated-measures ANOVA. Findings revealed significant improvements in sensitivity and knowledge for participants in the treatment condition compared to the control condition. With several exceptions, the intervention was similarly effective across employee groups.

Impulsivity in unaffected adolescent biological relatives of schizophrenia patients.

OBJECTIVE: Although schizophrenia is not a prototypic impulse-control disorder, patients report more impulsive behaviors, have higher rates of substance use, and show dysfunction in brain circuits that underlie impulsivity. We investigate impulsivity in unaffected biological relatives of schizophrenia patients to further understand the relationships between schizophrenia risk and impulse control during adolescence. METHOD: Group differences in impulsivity (UPPS-P Impulsive Behavior Scale and delay discounting) were tested in 210 adolescents contrasting 39 first- and 53 second-degree biological relatives of schizophrenia patients, and 118 subjects with no schizophrenia family history (NSFH). RESULTS: Compared to NSFH adolescents and to second-degree relatives, first-degree relatives of schizophrenia patients had increased impulsivity-related behaviors (higher UPPS-P Perseverance, Positive Urgency and Premeditation subscale scores) and greater preference for immediate rewards (smaller AUC and larger discounting constant). Second-degree relatives did not differ significantly from NSFH adolescents on self-report impulsive behaviors or on measures of impulsive decision-making. These group differences remained even after careful consideration of potential confounding factors. CONCLUSION: Impulsivity is associated with schizophrenia risk, and its severity increases with greater familial relatedness to the schizophrenia proband. Additional studies are needed to understand the role impulsivity may play in mediating schizophrenia susceptibility during adolescence.

Cerebral white matter correlates of delay discounting in adolescents.

The adolescent brain undergoes extensive structural white matter (WM) changes. Adolescence is also a critical time period during which cognitive, emotional and social maturation occurs in transition into adulthood. Compared to adults, adolescents are generally more impulsive with increased risk-taking behaviors. The goal of this study is to examine whether adolescent impulsivity may be related to cerebral WM maturation. In 89 healthy adolescents, we assessed impulsivity using the delay discounting task, and MRI WM volumes in brain regions previously implicated in delay discounting behaviors. We found that smaller delay discounting AUC (area under the curve) was associated with larger WM volumes in orbitofrontal, dorsolateral and medial prefrontal cortices (PFC) and motor cortex. There were no significant effects of AUC on WM volumes within somatosensory brain regions. In our sample, younger age was significantly associated with greater WM volumes in orbitofrontal and dorsolateral PFC subregions. Even after accounting for age-related effects, preference for immediate rewards (or greater impulsivity) still correlated with larger WM volumes in prefrontal regions known to mediate cognitive control. Our findings lend further support to the notion that reduced brain WM maturity may limit the ability in adolescents to forgo immediate rewards leading to greater impulsivity.