Human TLR-7-, -8-, and -9-mediated induction of IFN-alpha/beta and -lambda Is IRAK-4 dependent and redundant for protective immunity to viruses

Five TLRs are thought to play an important role in antiviral immunity, sensing viral products and inducing IFN-alpha/beta and -lambda. Surprisingly, patients with a defect of IRAK-4, a critical kinase downstream from TLRs, are resistant to common viruses. We show here that IFN-alpha/beta and -lambda induction via TLR-7, TLR-8, and TLR-9 was abolished in IRAK-4-deficient blood cells. In contrast, IFN-alpha/beta and -lambda were induced normally by TLR-3 and TLR-4 agonists. Moreover, IFN-beta and -lambda were normally induced by TLR-3 agonists and viruses in IRAK-4-deficient fibroblasts. We further show that IFN-alpha/beta and -lambda production in response to 9 of 11 viruses tested was normal or weakly affected in IRAK-4-deficient blood cells. Thus, IRAK-4-deficient patients may control viral infections by TLR-3- and TLR-4-dependent and/or TLR-independent production of IFNs. The TLR-7-, TLR-8-, and TLR-9-dependent induction of IFN-alpha/beta and -lambda is strictly IRAK-4 dependent and paradoxically redundant for protective immunity to most viruses in humans.     

Bioreactions at the tissue/hydroxyapatite interface

The events at the hydroxyapatite implant material/tissue interface in the rat middle ear were studied by light microscopy, autoradiography, morphometry, transmission electron microscopy (TEM), scanning electron microscopy (SEM), and X-ray microanalysis. Deposition of calcium, partially in the form of calcium phosphate, was found at the interface. Resorption of the implant material occurred as the result of mono- and multinuclear phagocyte activity. Resorption decreased 6 mnth after the operation, possibly due to the decreasing number of phagocytes at the interface and the increasing amount of bone in the macropores.     

Strain differences in peritoneal macrophage activity and susceptibility to experimental allergic encephalomyelitis induction in rats

The objective of the present study was to investigate the relevance of peripheral macrophage activity for the susceptibility to the induction of experimental allergic encephalomyelitis (EAE). Rats of EAE-susceptible Dark Agouti and EAEresistant Albino Oxford strain were immunized with guinea pig spinal cord homogenate (DA_GPSC and AO_GPSC), while non-immunized rats served as controls (DA_NIM, AO_NIM). On day 15 after immunization rats were sacrificed and their peritoneal macrophages tested for adherence capacity, zymosan phagocytosis and respiratory burst. Macrophages from AONIM rats exhibited lower adherence capacity and higher phagocytosis and H₂O₂ production when compared to macrophages from DANIM rats. Immunization with GPSC decreased adherence and phagocytosis and increased H₂O₂ production in macrophages from AO rats, but did not influence these activities in macrophages from DA rats. The results from the present study suggest that inflammatory activities of macrophages from AO rats could be considered as regulatory mechanisms connected with the resistance to EAE induction.     

Effect of IFN-gamma on expression of HLA in bare-lymphocyte syndrome-like cell line HAJ

We compared HLA antigen expression on new B-lymphoblastoid cell line (B-LCL) HAJ with that on B-LCLs expressing normal HLA levels as well as on B-LCLs derived from bare lymphocyte syndrome (BLS) patients and in vitro mutated B-LCLs of BLS-like phenotype. HAJ cells had no expression of HLA class II and low expression of class I antigens similarly to some of BLS B-LCLs, although HAJ cell line was derived from lymphocytes of HLA class I- and class II-normally expressing donor. HAJ cells displayed B lymphocyte markers, surface immunoglobulin and CD19. Culture of HAJ cells in the presence of interferon y resulted in HLA class I antigen upregulation, but did not restore class II expression. The cell line HAJ may prove useful for studies on factors influencing HLA class I cell surface expression.     

Effects of Coronavirus Disease Pandemic on Tuberculosis Notifications,Malawi

The coronavirus disease (COVID-19) pandemic might affect tuberculosis (TB) diagnosis and patient care. We analyzed a citywide electronic TB register in Blantyre, Malawi and interviewed TB officers. Malawi did not have an official COVID-19 lockdown but closed schools and borders on March 23, 2020. In an interrupted time series analysis, we noted an immediate 35.9% reduction in TB notifications in April 2020; notifications recovered to near prepandemic numbers by December 2020. However, 333 fewer cumulative TB notifications were received than anticipated. Women and girls were affected more (30.7% fewer cases) than men and boys (20.9% fewer cases). Fear of COVID-19 infection, temporary facility closures, inadequate personal protective equipment, and COVID-19 stigma because of similar symptoms to TB were mentioned as reasons for fewer people being diagnosed with TB. Public health measures could benefit control of both TB and COVID-19, but only if TB diagnostic services remain accessible and are considered safe to attend.     

Racial Disparities in Eligibility for Preemptive Waitlisting for Kidney Transplantation and Modification of eGFR Thresholds to Equalize Waitlist Time

BackgroundPatients may accrue wait time for kidney transplantation when their eGFR is ≤20 ml/min. However, Black patients have faster progression of their kidney disease compared with White patients, which may lead to disparities in accruable time on the kidney transplant waitlist before dialysis initiation.MethodsWe compared differences in accruable wait time and transplant preparation by CKD-EPI estimating equations in Chronic Renal Insufficiency Cohort participants, on the basis of estimates of kidney function by creatinine (eGFR_cr), cystatin C (eGFR_cys), or both (eGFR_cr-cys). We used Weibull accelerated failure time models to determine the association between race (non-Hispanic Black or non-Hispanic White) and time to ESKD from an eGFR of ≤20 ml/min per 1.73 m². We then estimated how much higher the eGFR threshold for waitlisting would be required to achieve equity in accruable preemptive wait time for the two groups.ResultsBy eGFR_cr, 444 CRIC participants were eligible for waitlist registration, but the potential time between eGFR ≤20 ml/min per 1.73 m² and ESKD was 32% shorter for Blacks versus Whites. By eGFR_cys, 435 participants were eligible, and Blacks had 35% shorter potential wait time compared with Whites. By the eGFR_cr-cys equation, 461 participants were eligible, and Blacks had a 31% shorter potential wait time than Whites. We estimated that registering Blacks on the waitlist as early as an eGFR of 24–25 ml/min per 1.73 m² might improve racial equity in accruable wait time before ESKD onset.ConclusionsPolicies allowing for waitlist registration at higher GFR levels for Black patients compared with White patients could theoretically attenuate disparities in accruable wait time and improve racial equity in transplant access.     

ASO Visual Abstract: Association of Obesity with Worse Operative and Oncologic Outcomes Among Patients Undergoing Gastric Cancer Resection

Annals of Surgical Oncology -