An industrial risk: Beryllium

Beryllium is a vocational disease factor and berylliumexposure can potentially lead to Chronic Beryllium Disease(CBD) in 2-6 % of workers. While acute lymphocyticpneumonia occurred in individuals who were exposedto high doses of beryllium, low dose exposure to berylliumfollowed by a long subclinical period can cause CBDcharacterized with chronic granulomatosis. It has beenobserved that varying amounts of beryllium exposureare necessary to produce symptoms of CBD or berylliumsensitization (BeS). Genetic differences between patientsmay be the underlying cause of these dose-effects andfurther study of the differences in patients exposed to berylliummay lead to earlier diagnosis and the identificationof biomarkers of CBD. In this review, it is summarizedthe general properties of beryllium exposure, the immunopathogenesisand genetic differences of beryllium-induceddiseases, genotoxicity and the carcinogenic effectsof beryllium. J Clin Exp Invest 2012; 3(1): 141-14

Bringing Packed Red Blood Cells to the Point of Combat Injury: Are We There Yet?

INTRODUCTION: Hemorrhage is the leading cause of injury related pre-hospital mortality. We investigated worst case scenarios and possible requirements of Turkish Military. As we plan to use blood resources during casualty transport, the impact of transport related mechanical stress on PRBC (packed red blood cell) were analyzed. MATERIAL AND METHODS: The in vitro experiment was performed in the environmental test laboratories of ASELSAN(R). Operational vibrations of potential casualty transport mediums such as Sikorsky Helicopters, Kirpi(R) Armoured Vehicle and NATO vibration standardsoftware MIL-STD-810G were recorded. The most powerful mechanical stress, which was created by the NATO standard, was applied to 15 units of fresh (7 day) PRBC in a blood cooler box. The vibrations were simulated by TDS v895 Medium-Force Shaker Device. On site blood samples were analyzed at 0, 6th and 24th hours for biochemical and biomechanical analyses. RESULTS: The mean age of fresh and old PRBCs was 4.9 (SD +/- 2.2) and 32.8 (SD +/- 11.8) days, respectively. Six-hour mechanical damage of fresh PRBC was demonstrated by increased erythrocyte fragmentation rates (p=0.015), hemolysis rates (p=0.003), supernatant potassium levels (p=0.003) and decreased hematocrit levels (p=0.015). Old PRBC hemolysis rates (p=0.015), supernatant potassium levels (p=0.015), supernatant Hb (p=0.015) were increased and Htc levels were decreased (p=0.015) within 6 hours. Two (%13) units of fresh and none of the old PRBC were eligible for transfusion after 6 hours of mechanical stress. CONCLUSION: When the austere combat environment was simulated for 24 hours, fresh and old PRBC hemolysis rates were above the quality criteria. Currently, a technology to overcome this mechanical damage does not seem to exist. In the light of the above data, a new national project is being performed

A case of Wiskott-Aldrich syndrome with de novo mutation at exon 4

Wiskott-Aldrich syndrome (WAS) is an X-linked disorder characterized by thrombocytopenia, eczema and immunodeficiency. Clinical features of the disease are highly varied; therefore, the diagnosis is sometimes difficult, especially in solitary cases or cases with milder forms of the disease. However, the identification of the WASP gene has made possible a definite WAS diagnosis for these cases. In this report, we present a 26-month-old boy who had received several ineffective treatments for chronic immune thrombocytopenic purpura. He was then suspected to have WAS because of the early onset of thrombocytopenia and small platelets. The diagnosis became definite with the detection of a de novo mutation at exon 4 of the WASP gene, Arg138Pro, through mutation analysis

Plasma Chemerin Levels Are Increased in ST Elevation Myocardial Infarction Patients with High Thrombus Burden

Objective. To investigate plasma chemerin levels in ST elevation myocardial infarction (STEMI) patients and find out possible relationships between plasma chemerin levels and angiographic characteristics. Patients and Methods. Ninety-seven consecutive patients who presented with STEMI and underwent primary percutaneous coronary intervention (PCI) with coronary stents were enrolled, and 30 age- and sex-matched patients with stable angina pectoris who underwent coronary angiography formed the control group. Angiographic characteristics of the patients including thrombolysis in myocardial infarction (TIMI) thrombus and Gensini scores were noted. Blood samples were taken to detect several biochemical markers including plasma chemerin levels at the admission to hospital. Results. Serum chemerin and C-reactive protein (CRP) levels were significantly increased in patients with STEMI. Among STEMI patients, serum chemerin levels were significantly higher in patients with high thrombus burden (581.5 ± 173.7 versus 451.3 ± 101.2 mg/dL, p<0.001). CRP levels and peak creatine kinase-MB (CK-MB) levels were higher, and left ventricular ejection fraction and post-PCI TIMI flow were lower in patients with high thrombus burden. After multivariate analysis, serum chemerin levels were also higher in patients with high thrombus grade (odds ratio: 1.009 (1.005–1.014), p<0.001). Besides, serum chemerin levels were also found to be significantly correlated with CRP r=0.47,p<0.001 and peak CK-MB r=0.376,p<0.001 levels. Conclusions. Results from our study have demonstrated for the first time that chemerin levels were higher in STEMI patients with greater thrombus burden and higher level of inflammation

X-linked recessive TLR7 deficiency in ~1% of men under 60 years old with life-threatening COVID-19

Autosomal inborn errors of type I IFN immunity and autoantibodies against these cytokines underlie at least 10% of critical COVID-19 pneumonia cases. We report very rare, biochemically deleterious X-linked TLR7 variants in 16 unrelated male individuals aged 7 to 71 years (mean: 36.7 years) from a cohort of 1,202 male patients aged 0.5 to 99 years (mean: 52.9 years) with unexplained critical COVID-19 pneumonia. None of the 331 asymptomatically or mildly infected male individuals aged 1.3 to 102 years (mean: 38.7 years) tested carry such TLR7 variants (p = 3.5 × 10-5). The phenotypes of five hemizygous relatives of index cases infected with SARS-CoV-2 include asymptomatic or mild infection (n=2, 5 and 38 years), or moderate (n=1, 5 years), severe (n=1, 27 years), or critical (n=1, 29 years) pneumonia. Two boys (aged 7 and 12 years) from a cohort of 262 male patients with severe COVID-19 pneumonia (mean: 51.0 years) are hemizygous for a deleterious TLR7 variant. The cumulative allele frequency for deleterious TLR7 variants in the male general population is < 6.5x10-4 We also show that blood B cell lines and myeloid cell subsets from the patients do not respond to TLR7 stimulation, a phenotype rescued by wild-type TLR7 The patients' blood plasmacytoid dendritic cells (pDCs) produce low levels of type I IFNs in response to SARS-CoV-2. Overall, X-linked recessive TLR7 deficiency is a highly penetrant genetic etiology of critical COVID-19 pneumonia, in about 1.8% of male patients below the age of 60 years. Human TLR7 and pDCs are essential for protective type I IFN immunity against SARS-CoV-2 in the respiratory tract

Autoantibodies against type I IFNs in patients with life-threatening COVID-19

Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-w (IFN-w) (13 patients), against the 13 types of IFN-a (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

Background: We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15–20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases. Methods: We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded. Results: No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5–528.7, P = 1.1 × 10−4) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR = 3.70[95%CI 1.3–8.2], P = 2.1 × 10−4). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR = 19.65[95%CI 2.1–2635.4], P = 3.4 × 10−3), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR = 4.40[9%CI 2.3–8.4], P = 7.7 × 10−8). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD] = 43.3 [20.3] years) than the other patients (56.0 [17.3] years; P = 1.68 × 10−5). Conclusions: Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60&nbsp;years old