Natural Killer Cell Dysfunction and Its Role in COVID-19 van Eeden, Charmaine; Khan, Lamia; Osman, Mohammed S ...
International journal of molecular sciences,
2020-Sep-01, 2020-09-01, 20200901, Letnik:
21, Številka:
17
Journal Article
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When facing an acute viral infection, our immune systems need to function with finite precision to enable the elimination of the pathogen, whilst protecting our bodies from immune-related damage. In ...many instances however this "perfect balance" is not achieved, factors such as ageing, cancer, autoimmunity and cardiovascular disease all skew the immune response which is then further distorted by viral infection. In SARS-CoV-2, although the vast majority of COVID-19 cases are mild, as of 24 August 2020, over 800,000 people have died, many from the severe inflammatory cytokine release resulting in extreme clinical manifestations such as acute respiratory distress syndrome (ARDS) and hemophagocytic lymphohistiocytosis (HLH). Severe complications are more common in elderly patients and patients with cardiovascular diseases. Natural killer (NK) cells play a critical role in modulating the immune response and in both of these patient groups, NK cell effector functions are blunted. Preliminary studies in COVID-19 patients with severe disease suggests a reduction in NK cell number and function, resulting in decreased clearance of infected and activated cells, and unchecked elevation of tissue-damaging inflammation markers. SARS-CoV-2 infection skews the immune response towards an overwhelmingly inflammatory phenotype. Restoration of NK cell effector functions has the potential to correct the delicate immune balance required to effectively overcome SARS-CoV-2 infection.
Development of new tuberculosis (TB) drugs and alternative treatment strategies are urgently required to control the global spread of TB. Previous results have shown that vitamin D3 (vitD3) and ...4-phenyl butyrate (PBA) are potent inducers of the host defense peptide LL-37 that possess anti-mycobacterial effects.
To examine if oral adjunctive therapy with 5,000IU vitD3 or 2x500 mg PBA or PBA+vitD3 to standard chemotherapy would lead to enhanced recovery in sputum smear-positive pulmonary TB patients.
Adult TB patients (n = 288) were enrolled in a randomized, double-blind, placebo-controlled trial conducted in Bangladesh. Primary endpoints included proportions of patients with a negative sputum culture at week 4 and reduction in clinical symptoms at week 8. Clinical assessments and sputum smear microscopy were performed weekly up to week 4, fortnightly up to week 12 and at week 24; TB culture was performed at week 0, 4 and 8; concentrations of LL-37 in cells, 25-hydroxyvitamin D3 (25(OH)D3) in plasma and ex vivo bactericidal function of monocyte-derived macrophages (MDM) were determined at week 0, 4, 8, 12 and additionally at week 24 for plasma 25(OH)D3.
At week 4, 71% (46/65) of the patients in the PBA+vitD3-group (p = 0.001) and 61.3% (38/62) in the vitD3-group (p = 0.032) were culture negative compared to 42.2% (27/64) in the placebo-group. The odds of sputum culture being negative at week 4 was 3.42 times higher in the PBA+vitD3-group (p = 0.001) and 2.2 times higher in vitD3-group (p = 0.032) compared to placebo. The concentration of LL-37 in MDM was significantly higher in the PBA-group compared to placebo at week 12 (p = 0.034). Decline in intracellular Mtb growth in MDM was earlier in the PBA-group compared to placebo (log rank 11.38, p = 0.01).
Adjunct therapy with PBA+vitD3 or vitD3 or PBA to standard short-course therapy demonstrated beneficial effects towards clinical recovery and holds potential for host-directed-therapy in the treatment of TB.
clinicaltrials.gov NCT01580007.
Dengue or breakbone fever is one of the most important causes of febrile illness in children residing in tropical and subtropical regions. This mosquito-borne viral disease is mediated by the bite of ...the infected
Aedes
mosquito. Dengue infection has been expanding rapidly throughout the globe in the past few decades. The virus has hepatotoxic effects. However, the pathophysiology of liver involvement in dengue is still not entirely clear. The reported clinical spectrum of dengue hepatitis ranges from mild asymptomatic elevation in transaminaselevels to acute liver failure in children. This review focuses on hepatic manifestation, the pathogenesis of liver injury, and treatment option of the effects of dengue on the liver in the pediatric population.
OBJECTIVESSystemic sclerosis (SSc) is associated with secondary malignancies. Previous studies have suggested that mutated cancer proteins, such as RNA polymerase III, are autoantigens promoting an ...inflammatory response in SSc. However, it has never been previously investigated whether non-neoplastic tissue in SSc harbors mutations which may play a role in SSc pathogenesis. METHODSSkin biopsies were obtained from 8 sequential patients with a progressive form of early stage SSc (with severe skin and/or lung involvement). Areas of dermal fibrosis were microdissected and analyzed with deep, whole exome sequencing. Gene mutation patterns were compared to autologous buccal mucosal cells as a control. RESULTSSSc skin biopsies were hypermutated with an average of 58 mutations/106 base pairs. The mutational pattern in all samples exhibited a clock-like signature, which is ubiquitous in cancers and in senescent cells. Of the 1997 genes we identified which were mutated in at least two SSc patients, 39 genes represented cancer drivers (i.e. tumor suppressor genes or oncogenes) which are commonly found in gynecological, squamous and gastrointestinal cancer signatures. Of all the mutations, the most common mutated genes were important in regulating pathways related to epigenetic histone modifications, DNA repair and genome integrity. CONCLUSIONSSomatic hypermutation occurs in fibrotic skin in patients with early progressive SSc. Cancer driver gene mutations may potentially play a fundamental role in the pathogenesis of SSc.
Background: We aim to assess and compare the HNC trends between the First Nations and non-Indigenous population. Methods: HNC incidence (1998–2013) and mortality (1998–2015) data in First Nations ...people and non-Indigenous Australians were utilised from the Australian Cancer Database. The age-standardised incidence and mortality trends along with annual percentage changes were analysed using Joinpoint models. Age-standardised incidence and mortality rates according to remoteness, states, and five-year survival rates among First Nations people and non-Indigenous Australians were presented as graphs. Results: First Nations people had over twice the age-standardised incidence (2013; 29.8/100,000 vs. 14.7/100,000) and over 3.5 times the age-standardised mortality rates (2015; 14.2/100,000 vs. 4.1/100,000) than their non-Indigenous counterparts. Both populations saw a decline in mortality, but the decline was only statistically significant in non-Indigenous Australians (17.1% decline, 1998: 4.8/100,000, 2015: 4.1/100,000; p < 0.05). Across all remoteness levels and states, First Nations people consistently had higher age-standardised incidence and mortality rates. Furthermore, the five-year survival rate was lower by 25% in First Nations people. Conclusion: First Nations people continue to shoulder a disproportionate HNC burden compared to non-Indigenous Australians.
Histoplasmosis is a rare infectious condition with mainly pulmonary involvement. Disseminated histoplasmosis may occur in immunocompromised condition. It can present in different ways but jaundice ...and ascites is very uncommon.
A 8- year old girl visited to department of pediatric gastroenterology & nutrition, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh. Child presented with fever, jaundice and abdominal distension for 2 ½ months. There was no history of contact with tuberculosis patient and travelling to kala-azar, malaria endemic zone and no history of previous jaundice, blood or blood product transfusion, history of sib death, family history of jaundice or neuropsychiatric disorder, significant weight loss. On general examination she was fretful, febrile, moderately icteric, mildly pale, vitally stable, severely wasted and moderately stunted, skin survey revealed infected scabies, BCG vaccine mark was absent, generalized lymphadenopathy, hepato-splenomegaly and ascites present. After evaluating the physical findings, several investigations was done including lymphnode biopsy, then the case was finally diagnosed as Disseminated histoplasmosis with portal hypertension. Child was treated with injectable Deoxycholate Amphotericin B for 28 days and improved on follow up.
We suggest that children presenting with fever, jaundice, lymphadenopathy and hepatosplenomegaly and portal hypertension, disseminated histoplasmosis can be one differential.
Hepatitis C virus infection is an emerging problem for children and adolescents. Chronic HCV infection affects approximately 3.5–5 million children worldwide. Unaddressed HCV infection in children ...progresses to decompensated liver disease and hepatocellular carcinoma during adulthood. Early detection of HCV and the administration of appropriate antiviral therapy are required for the prevention of long-term morbidity associated with chronic HCV infection. The perinatal route is the most common source of childhood HCV infection. Anti-HCV positivity at or after 18 months of age necessitates an HCV-RNA assay after age 3 to recognize chronic HCV infection. Both anti-HCV and HCV-RNA positivity are the indications for antiviral therapy. At present, various combinations of oral, direct-acting antivirals (DAAs) have been approved for children above 3 years of age. Their efficacy is high. Apart from the effectiveness of DAA therapy, steps should be taken to screen pregnant women to prevent the transmission of viral infection from mother to child. To increase awareness about the mode of HCV spread, NAT-based tests in blood banks for better screening and making the DAAs available at a subsidized rate in the public sector are necessary to eradicate HCV infection.
Although the 24-hours urinary copper excretion is useful for the diagnosis of Wilson disease (WD), there are practical difficulties in the accurate and timed collection of urine samples. The purpose ...of this study was to verify if the spot morning urinary Copper/ Zinc (Cu/Zn) ratio could be used as a replacement parameter of 24-hours urinary copper excretion in the diagnosis of WD.
A cross-sectional study was conducted at the Department of Pediatric Gastroenterology and Nutrition, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh, from June 2019 to May 2021 on 67 children over three years of age who presented with liver disease. Twenty-seven children who fulfilled the inclusion criteria for WD were categorized into the test group, and the remaining forty children were considered to have non-Wilsonian liver disease and were categorized into the control group. Along with other laboratory investigations, spot morning urinary samples were estimated for the urinary Cu/Zn ratio in all patients and were compared to the 24-hour urinary copper excretion. The diagnostic value of the Cu/Zn ratio was then analyzed.
Correlation of spot morning urinary Cu/Zn ratio with 24-hours urinary copper excretion was found to be significant (r=0.60). The area under ROC curve with 95% confidence interval of morning urinary Cu/Zn ratio measured using 24-hours urine sample was 0.84 (standard error, 0.05;
<0.001).
Spot morning urinary Cu/Zn ratio seems to be a promising parameter for the replacement of 24-hours urinary copper excretion in the diagnosis of WD.
•COVID-19 vaccine uptake was significantly lower among people who use drugs (PWUD), especially those reporting methamphetamine and fentanyl use.•Besides substance use, lower vaccine uptake was ...associated with younger age and belief in vaccine misinformation.•As new COVID-19 vaccines become necessary strategies to engage PWUD will be necessary.
We describe the prevalence of COVID-19 vaccine uptake, substance use, and other factors associated with vaccine hesitancy among participants from nine North American cohort studies following a diverse group of individuals at risk for or living with HIV.
Between May 2021 and January 2022, participants completed a survey related to COVID-19 vaccination. Participants included those with and without substance use. Those responding as ‘no’ or ‘undecided’ to the question “Do you plan on getting the COVID-19 vaccine?” were categorized as vaccine hesitant. Differences between groups were evaluated using chi-square methods and multivariable log-binomial models were used to calculate prevalence ratios (PR) of COVID-19 vaccine hesitancy with separate models for each substance.
Among 1,696 participants, COVID-19 vaccination was deferred or declined by 16%. Vaccine hesitant participants were younger, with a greater proportion unstably housed (14.8% vs. 10.0%; p = 0.02), and not living with HIV (48.% vs. 36.6%; p <.01). Vaccine hesitant participants were also more likely to report cannabis (50.0% vs. 42.4%; p = 0.03), methamphetamine (14.0% vs. 8.2%; p <.01), or fentanyl use (5.5% vs. 2.8%; p = 0.03). Based on multivariable analyses methamphetamine or fentanyl use remained associated with COVID-19 vaccine hesitancy (Adjusted PR = 1.4; 95% CI 1.1–1.9 and Adjusted PR = 1.6; 95% CI 1.0–2.6, respectively).
As new COVID-19 vaccines and booster schedules become necessary, people who use drugs (PWUD) may remain vaccine hesitant. Strategies to engage hesitant populations such as PWUD will need to be tailored to include special types of outreach such as integration with substance use programs such as safe injection sites or recovery programs.
Early-life exposure to arsenic (As) increases risks of respiratory diseases/infections in children. However, data on the ability of the innate immune system to combat bacterial infections in the ...respiratory tracts of As-exposed children are scarce. To evaluate whether persistent low-dose As exposure alters innate immune function among children younger than 5 years-of-age, mothers and participating children (N = 51) that were members of the Health Effects of Arsenic Longitudinal Study (HEALS) cohort in rural Bangladesh were recruited. Household water As, past and concurrent maternal urinary As (U-As) as well as child U-As were all measured at enrollment. In addition, U-As metabolites were evaluated. Innate immune function was examined via measures of cathelicidin LL-37 in plasma, ex vivo monocyte-derived-macrophage (MDM)-mediated killing of Streptococcus pneumoniae (Spn), and serum bactericidal antibody (SBA) responses against Haemophilus influenzae type b (Hib). Cyto-/chemokines produced by isolated peripheral blood mononuclear cells (PBMC) were assayed using a Multiplex system. Multivariable linear regression analyses revealed that maternal (p < 0.01) and child (p = 0.02) U-As were positively associated with plasma LL-37 levels. Decreased MDM-mediated Spn killing (p = 0.05) and SBA responses (p = 0.02) were seen to be each associated with fractions of mono-methylarsonic acid (MMA; a U-As metabolite) in the children. In addition, U-As levels were seen to be negatively associated with PBMC formation of fractalkine and IL-7, and positively associated with that for IL-13, IL-17 and MIP-1α. These findings suggested that early-life As exposure may disrupt the innate host defense pathway in these children. It is possible that such disruptions may have health consequences later in life.
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