The burden of alcohol on health care during COVID-19

Alcohol's impact on global health is substantial and of a similar order of magnitude to that from COVID-19. Alcohol now also poses specific concerns, such as increased risk of severe lung infections, domestic violence, child abuse, depression and suicide. Its use is unlikely to aid physical distancing or other preventative behavioural measures. Globally, alcohol contributes to 20% of injury and 11.5% of non-injury emergency room presentations. We provide some broad comparisons between alcohol-attributable and COVID-19-related hospitalisations and deaths in North America using most recent data. For example, for Canada in 2017 it was recently estimated there were 105 065 alcohol-attributable hospitalisations which represent a substantially higher rate over time than the 10 521 COVID-19 hospitalisations reported during the first 5 months of the pandemic. Despite the current importance of protecting health-care services, most governments have deemed alcohol sales to be as essential as food, fuel and pharmaceuticals. In many countries, alcohol is now more readily available and affordable than ever before, a situation global alcohol producers benefit from and have helped engineer. We argue that to protect frontline health-care services and public health more generally, it is essential that modest, evidence-based restrictions on alcohol prices, availability and marketing are introduced. In particular, we recommend increases in excise taxation coupled with minimum unit pricing to both reduce impacts on health-care services and provide much-needed revenues for governments at this critical time.     

Expression of CD27-CD70 on early B cell progenitors in the bone marrow: implication for diagnosis and therapy of childhood ALL

OBJECTIVE: CD27, a member of the TNF receptor family, plays an important role in lymphoid proliferation, differentiation and apoptosis. This study addresses the expression of CD27 and its ligand, CD70, in children with acute lymphoblastic leukemia (ALL) and the possible role of this receptor-ligand pair in the pathogenesis of ALL. PATIENTS AND METHODS: Expression of CD27 and CD70 was evaluated with three-color flow cytometry in blood and bone marrow (BM) samples in children with ALL and controls. The biological role of these molecules on leukemic cell proliferation was studied in an in vitro culture system. RESULTS: The expression of the membrane bound CD27, as well as membrane bound CD70, on CD19(+) cells in the BM was significantly increased in ALL children compared to the expression found in the controls. Importantly, a substantial reduction in the in vitro proliferation of leukemic cells could be observed when the leukemic cells were cultured in presence of a blocking anti-human CD70 monoclonal antibody. The level of soluble CD27 (sCD27) in serum was also investigated and found to be significantly elevated in leukemic children as compared to healthy children. CONCLUSION: The high expression of CD27 and CD70 on ALL cells may represent an amplification of the normal CD27-CD70 expression present on early B cell progenitors. Our finding suggests that interference with CD27-CD70 interaction may represent novel treatment opportunities in ALL. Further studies are required to pin-point the role of this receptor-ligand pair in normal and malignant hematopoiesis.     

Invariant chain induces B cell maturation in a process that is independent of its chaperonic activity

Early stages of B cell development take place in the bone marrow, resulting in formation of immature B cells, which migrate to the spleen for their final differentiation into mature cells. This final maturation step is essential for B cells to become responsive to antigens and to participate in the immune response. Previously, we showed that the MHC class II chaperone, invariant chain (Ii), controls the differentiation of B cells from the immature to the mature stage. In this study, by generating transgenic mice expressing truncated Ii lacking its luminal domain, we could dissect the chaperonin activity of Ii from its role in B cell maturation. We demonstrate in vivo that Ii N-terminal domain is directly involved in the maturation of B cells and is sufficient to promote B cell differentiation.     

Targeting the nuclear antigen 1 of Epstein-Barr virus to the human endocytic receptor DEC-205 stimulates protective T-cell responses

Dendritic cells (DCs) express many endocytic receptors that deliver antigens for major histocompatibility class (MHC) I and II presentation to CD8(+) and CD4(+) T cells, respectively. Here, we show that targeting Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA1) to one of them, the human multilectin DEC-205 receptor, in the presence of the DC maturation stimulus poly(I:C), expanded EBNA1-specific CD4(+) and CD8(+) memory T cells, and these lymphocytes could control the outgrowth of autologous EBV-infected B cells in vitro. In addition, using a novel mouse model with reconstituted human immune system components, we demonstrated that vaccination with alphaDEC-205-EBNA1 antibodies primed EBNA1-specific IFN-gamma-secreting T cells and also induced anti-EBNA1 antibodies in a subset of immunized mice. Because EBNA1 is the one EBV antigen that is expressed in all proliferating cells infected with this virus, our data suggest that DEC-205 targeting should be explored as a vaccination approach against symptomatic primary EBV infection and against EBV-associated malignancies.     

Altered expression of the receptor-ligand pair CXCR5/CXCL13 in B cells during chronic HIV-1 infection

HIV-1 infection is associated with B-cell abnormalities, such as hypergammaglobulinemia, poor immunization responses, and loss of serologic memory. To determine whether altered expression of chemokine receptors and their ligands may play a role in B-cell dysfunctions during HIV-1 infection, the expression of CXC chemokine receptor 4 (CXCR4), CXCR5, and CC chemokine receptor 7 (CCR7) and their respective ligands on CD19(+) B cells were examined in HIV-1-infected patients and controls. We report a decreased CXCR5 expression on B cells from patients (P < .05), a phenomenon associated with a low CD4 T-cell count (< 350 cells/microL). Interestingly, an increased expression of CXC chemokine ligand 13 (CXCL13), the ligand for CXCR5, was found in peripheral B cells from HIV-1-infected patients. Moreover, on B-cell activation in vitro, CXCL13 was secreted in culture. CXCL13(+) B cells were also found in the lymph nodes of HIV-1-infected patients, but not in control tissue. B-cell migration toward CXCL13, CXCL12, and CC chemokine ligand 21 (CCL21), ligands for CXCR5, CXCR4, and CCR7 was also evaluated. In patients with a low CD4 T-cell count, migration toward all ligands was increased. Our findings indicate that altered expression of the chemokine receptor-ligand pair, CXCR5/CXCL13, may participate in the establishment of B-cell dysfunctions during HIV-1 infection.     

TAK1-mediated autophagy and fatty acid oxidation prevent hepatosteatosis and tumorigenesis

The MAP kinase kinase kinase TGFβ-activated kinase 1 (TAK1) is activated by TLRs, IL-1, TNF, and TGFβ and in turn activates IKK-NF-κB and JNK, which regulate cell survival, growth, tumorigenesis, and metabolism. TAK1 signaling also upregulates AMPK activity and autophagy. Here, we investigated TAK1-dependent regulation of autophagy, lipid metabolism, and tumorigenesis in the liver. Fasted mice with hepatocyte-specific deletion of Tak1 exhibited severe hepatosteatosis with increased mTORC1 activity and suppression of autophagy compared with their WT counterparts. TAK1-deficient hepatocytes exhibited suppressed AMPK activity and autophagy in response to starvation or metformin treatment; however, ectopic activation of AMPK restored autophagy in these cells. Peroxisome proliferator–activated receptor α (PPARα) target genes and β-oxidation, which regulate hepatic lipid degradation, were also suppressed in hepatocytes lacking TAK1. Due to suppression of autophagy and β-oxidation, a high-fat diet challenge aggravated steatohepatitis in mice with hepatocyte-specific deletion of Tak1. Notably, inhibition of mTORC1 restored autophagy and PPARα target gene expression in TAK1-deficient livers, indicating that TAK1 acts upstream of mTORC1. mTORC1 inhibition also suppressed spontaneous liver fibrosis and hepatocarcinogenesis in animals with hepatocyte-specific deletion of Tak1. These data indicate that TAK1 regulates hepatic lipid metabolism and tumorigenesis via the AMPK/mTORC1 axis, affecting both autophagy and PPARα activity.     

NK cell survival mediated through the regulatory synapse with human DCs requires IL-15Ralpha

DCs activate NK cells during innate immune responses to viral infections. However, the composition and kinetics of the immunological synapse mediating this interaction are largely unknown. Here, we report the rapid formation of an immunological synapse between human resting NK cells and mature DCs. Although inhibitory NK cell receptors were polarized to this synapse, where they are known to protect mature DCs from NK cell lysis, the NK cell also received activation signals that induced mobilization of intracellular calcium and CD69 upregulation. The high-affinity component of the receptor for IL-15, IL-15Ralpha, accumulated at the synapse center on NK cells, and blocking of IL-15Ralpha increased NK cell apoptosis and diminished NK cell survival during their interaction with DCs. Furthermore, IL-15Ralpha-deficient NK cells, obtained from donors with a history of infectious mononucleosis, showed diminished survival in culture with DCs. Synapse formation was required for IL-15Ralpha-mediated NK cell survival, because synapse disruption by adhesion molecule blocking decreased DC-induced NK cell survival. These results identify what we believe to be a novel regulatory NK cell synapse with hallmarks of spatially separated inhibitory and activating interactions at its center. We suggest that this synapse formation enables optimal NK cell activation by DCs during innate immune responses.     

Identification, course, and treatment of depression after admission for a cardiac condition: rationale and patient characteristics for the Identifying Depression As a Comorbid Condition (IDACC) project

Background

Given the prevalence of cardiovascular disease and the high rates of depression among cardiac patients, there is a need to develop practical ways to identify this population and provide pragmatic general-practitioner-based interventions for managing depression as a comorbid condition.

Method

The Identifying Depression As a Comorbid Condition (IDACC) study employed a hybrid design, incorporating a randomized controlled trial nested within a prospective cohort study. IDACC screened for depression in patients hospitalized in South Australia for a range of cardiac conditions, with outcome measures monitored for 12 months after discharge. The subgroup identified as depressed was entered into the nested IDACC trial, which tests the hypothesis that identifying depression and offering an evidence-based intervention to general practitioners, incorporating multidisciplinary telephone case conferencing, will reduce levels of depression, improve quality of life, and reduce associated economic costs.

Results

At baseline, 46.3% of 1455 participants screened were classified as depression cases on the basis of their score on the Center for Epidemiological Studies Depression Scale (≥16) or the Hospital Anxiety and Depression Scale (≥8). Elevated scores were associated with being younger, female, divorced or separated, not employed, living alone, having a lower level of education, and having poorer health and quality of life. Nearly one fifth (19.4%) of participants had Center for Epidemiological Studies Depression Scale scores >27, which is indicative of major depression.

Conclusions

This project confirms, in an Australian setting, the high prevalence of depressive symptoms among hospitalized cardiac patients. Follow-up over 12 months will enhance understanding of the natural history of depression in cardiac patients, while the nested trial will inform on effectiveness of an intervention involving tailored advice and support to general practitioners.