Vaccine adjuvants aluminum and monophosphoryl lipid A provide distinct signals to generate protective cytotoxic memory CD8 T cells

Vaccines can greatly reduce the spread of and deaths from many infectious diseases. However, many infections have no successful vaccines. Better understanding of the generation of protective CD8 memory T cells by vaccination is essential for the rational design of new vaccines that aim to prime cellular immune responses. Here we demonstrate that the combination of two adjuvants that are currently licensed for use in humans can be used to prime long-lived memory CD8 T cells that protect mice from viral challenge. The universally used adjuvant, aluminum salts, primed long-lived memory CD8 T cells; however, effective cytotoxic T-cell differentiation occurred only in the presence of an additional adjuvant, monophosphoryl lipid A (MPL). MPL-induced IL-6 was required for cytotoxic differentiation. The IL-6 acted by inducing granzyme B production and reducing expression of inhibitory molecule PD1 on the surface of the primed CD8 T cells. CD8 memory T cells generated by antigen delivered with both aluminum salts and MPL provided significant protection from influenza A challenge. These adjuvants could be used in human vaccines to prime protective memory CD8 T cells.     

Aortic complications after pediatric cardiac transplantation in patients with a previous Norwood reconstruction

Despite increasing surgical success with staged palliation of hypoplastic left heart syndrome and its variants, some of these children eventually may require cardiac transplantation. Sixteen (7.8%) of 206 children ≤18 years old undergoing primary heart transplantation had a previous Norwood palliation. Two (12.5%) developed significant aortic problems after transplantation related to the initial homograft reconstruction of the aorta. Patient 1 developed acute graft failure requiring extracorporeal membrane oxygenator support post-transplant. During acute retransplantation 2 days later, the new donor aorta was sewn to a remnant of the initial donor aorta rather than to the heavily calcified reconstructed native aorta. Two months later, the patient required reoperation for acute airway compression from an aortic pseudoaneurysm caused by necrosis of the bridge of aortic tissue from the first transplant. Patient 2 had multiple balloon dilatations of recurrent coarctation after transplantation. Eighteen years post-transplant, during work-up for chronic fever and weight loss, computerized tomography showed a mycotic aneurysm of the reconstructed transverse aorta with contained rupture necessitating removal and replacement of the entire reconstructed aorta. Although uncommon, aortic complications in pediatric heart transplant patients with previous Norwood arch reconstruction can present with unusual manifestations requiring heightened vigilance.     

Maternal social environment affects offspring cognition through behavioural and immune pathways in rats

The social environment of lactation is a key etiological factor for the occurrence of postpartum disorders affecting women and their children. Postpartum depression and anxiety disorders are highly prevalent in new mothers and negatively affect offspring’s cognitive development through mechanisms which are still unclear. Here, using a rat model, we manipulated the maternal social environment during lactation and explored the pathways through which social isolation (vs. the opportunity for limited social interaction with another lactating female, from 1 day before parturition to postpartum day 16) and chronic social conflict (daily exposure to a male intruder from postpartum day 2 to day 16) affect offspring learning and memory, measured at 40 to 60 days of age. We specifically explored the consequences of these social treatments on two main hypothesized mediators likely to affect offspring neurophysiological development: the quality of maternal care and maternal inflammation factors (brain‐derived neurotrophic factor, granulocyte‐macrophage colony‐stimulating factor, intercellular adhesion molecule 1, tissue inhibitor of metalloproteinases 1 and vascular endothelial growth factor) likely to influence offspring development through lactation. Maternal rats which had the opportunity to interact with another lactating female spent more time with their pups which, in turn, displayed improved working and reference memory. Social stress affected maternal plasma levels of cytokines that were associated with cognitive deficits in their offspring. However, females subjected to social stress were protected from these stress‐induced immune changes and associated offspring cognitive impairment by increased social affiliation. These results underscore the effects of social interaction for new mothers and their offspring and can be used to inform the development of clinical preventative measures and interventions.     

Cholinergic modulation of striatal nitric oxide‐producing interneurons

Striatal GABAergic interneurons that express nitric oxide synthase—so‐called low‐threshold spike interneurons (LTSIs)—play several key roles in the striatum. But what drives the activity of these interneurons is less well defined. To fill this gap, a combination of monosynaptic rabies virus mapping (msRVm), electrophysiological and optogenetic approaches were used in transgenic mice in which LTSIs expressed either Cre recombinase or a fluorescent reporter. The rabies virus studies revealed a striking similarity in the afferent connectomes of LTSIs and neighboring cholinergic interneurons, particularly regarding connections arising from the parafascicular nucleus of the thalamus and cingulate cortex. While optogenetic stimulation of cingulate inputs excited both cholinergic interneurons and LTSIs, thalamic stimulation excited cholinergic interneurons, but inhibited LTSIs. This inhibition was dependent on cholinergic interneurons and had two components: a previously described GABAergic element and one that was mediated by M4 muscarinic acetylcholine receptors. In addition to this phasic signal, cholinergic interneurons tonically excited LTSIs through a distinct, M1 muscarinic acetylcholine receptor pathway. This coordinated cholinergic modulation of LTSIs predisposed them to rhythmically burst in response to phasic thalamic activity, potentially reconfiguring striatal circuitry in response to salient environmental stimuli.     

The Protective Role of Parent Resilience on Mental Health and the Parent–Child Relationship During COVID-19

Child Psychiatry & Human Development - The COVID-19 pandemic is linked to particularly potent psychological effects for children and their caregivers while families adjust to new daily routines...