An exploratory analysis of routine ferritin measurement upon admission and the prognostic implications of low-grade ferritinemia during inflammation.

BACKGROUND: Serum ferritin is usually measured in the presence of anemia or in suspected iron overload syndromes. Ferritin is also an acute-phase protein that is elevated during systemic inflammation. However, the prognostic value of routinely measuring ferritin upon admission to a medical facility is not clear. Therefore, we examined the association between ferritin concentrations measured at the time of hospital admission with 30-day and long-term mortality. METHODS: We obtained routine ferritin measurements taken within 24 hours of admission in 2,859 patients hospitalized in an internal medicine department. Multiple clinical and laboratory parameters were used to assess the association between ferritin and overall mortality during a median follow-up of 15 months (interquartile range [IQR] 8-22). RESULTS: Ferritin levels were associated with increased 30-day mortality rates (odds ratio [OR] 1.04, 95% confidence interval [CI] 1.03-1.06) for each 100 ng/ml increase. Patients with intermediate (78-220 ng/ml) and high (>221 ng/ml) ferritin concentrations (2nd and 3rd tertiles) had higher 30-day mortality rates even after adjustment for age, sex, and existing co-morbidities (OR 2.05, 95% CI 1.70-2.5). Long-term overall mortality rates demonstrated a similar pattern across ferritin tertiles (hazard ratio [HR] 1.54, 95% CI 1.39-1.71). CONCLUSIONS: Routine admission ferritin concentrations are linearly and independently correlated with excess mortality risk in hospitalized patients, even those with apparently "normal" ferritin concentrations (<300 mg/ml). Thus, low-grade ferritinemia might not be an innocent finding in the context of the inflammatory response. Its potential biological and therapeutic implications warrant future research.

The CRP troponin test (CTT) stratifies mortality risk in patients with non-ST elevation myocardial infarction (NSTEMI).

INTRODUCTION: The C-reactive protein (CRP)-troponin-test (CTT) comprises simultaneous serial measurements of CRP and cardiac troponin and might reflect the systemic inflammatory response in patients with acute coronary syndrome. We sought to test its ability to stratify the short- and long-term mortality risk in patients with non-ST elevation myocardial infarction (NSTEMI). METHODS: We examined 1,675 patients diagnosed with NSTEMI on discharge who had at least two successive measurements of combined CRP and cardiac troponin within 48 h of admission. A tree classifier model determined which measurements and cutoffs could be used to best predict mortality during a median follow-up of 3 years [IQR 1.8-4.3]. RESULTS: Patients with high CRP levels ( > 90th percentile, >54 mg/L) had a higher 30-day mortality rate regardless of their troponin test findings (16.7% vs. 2.9%, p < 0.01). However, among patients with "normal" CRP levels ( < 54 mg/L), those who had high troponin levels ( > 80th percentile, 4,918 ng/L) had a higher 30-day mortality rate than patients with normal CRP and troponin concentrations (7% vs. 2%, p < 0.01). The CTT test result was an independent predictor for overall mortality even after adjusting for age, sex, and comorbidities (HR = 2.28 [95% CI 1.56-3.37], p < 0.01 for patients with high troponin and high CRP levels). CONCLUSIONS: Early serial CTT results may stratify mortality risk in patients with NSTEMI, especially those with "normal" CRP levels. The CTT could potentially assess the impact of inflammation during myocardial necrosis on the outcomes of patients with NSTEMI and identify patients who could benefit from novel anti-inflammatory therapies.

Biomarker-Guided Assessment of Acute Kidney Injury Phenotypes E among ST-Segment Elevation Myocardial Infarction Patients.

Recent practice guidelines recommended the use of new stress, functional, and damage biomarkers in clinical practice to prevent and manage acute kidney injury (AKI). Biomarkers are one of the tools used to define various AKI phenotypes and provide prognostic information regardless of an acute decline in renal function. We investigated the incidence and possible implications of AKI phenotypes among ST elevation myocardial infarction patient treated with primary coronary intervention. We included 281 patients with STEMI treated with PCI. Neutrophil gelatinase associated lipocalin (NGAL) was utilized to determine structural renal damage and functional AKI was determined using the KDIGO criteria. Patients were stratified into four AKI phenotypes: no AKI, subclinical AKI, hemodynamic AKI, and severe AKI. Patients were assessed for in-hospital adverse events (MACE). A total of 46 patients (44%) had subclinical AKI, 17 (16%) had hemodynamic AKI, and 42 (40%) had severe AKI. We observed a gradual and significant increase in the occurrence of MACE between the groups being highest among patients with severe AKI (10% vs. 19% vs. 29% vs. 43%; p < 0.001). In a multivariable regression model, any AKI phenotype was independently associated with MACE with an odds ratio of 4.15 (95% CI 2.1−8.3, p < 0.001,) for subclinical AKI, 4.51 (95% CI 1.61−12.69; p = 0.004) for hemodynamic AKI, and 12.9 (95% CI 5.59−30.1, p < 0.001) for severe AKI. In conclusion, among STEMI patients, AKI is a heterogeneous condition consisting of distinct phenotypes, addition of novel biomarkers may overcome the limitations of sCr-based AKI definitions to improve AKI phenotyping and direct potential therapies.

Early Detection of Inflammation-Prone STEMI Patients Using the CRP Troponin Test (CTT).

Elevated concentrations of C-reactive protein (CRP) early during an acute coronary syndrome (ACS) may reflect the magnitude of the inflammatory response to myocardial damage and are associated with worse outcome. However, the routine measurement of both CRP and cardiac troponin simultaneously in the setting of ST-segment myocardial infarction (STEMI) is not used broadly. Here, we sought to identify and characterize individuals who are prone to an elevated inflammatory response following STEMI by using a combined CRP and troponin test (CTT) and determine their short- and long-term outcome. We retrospectively examined 1186 patients with the diagnosis of acute STEMI, who had at least two successive measurements of combined CRP and cardiac troponin (up to 6 h apart), all within the first 48 h of admission. We used Chi-Square Automatic Interaction Detector (CHAID) tree analysis to determine which parameters, timing (baseline vs. serial measurements), and cut-offs should be used to predict mortality. Patients with high CRP concentrations (above 90th percentile, >33 mg/L) had higher 30 day and all-cause mortality rates compared to the rest of the cohort, regardless of their troponin test status (above or below 118,000 ng/L); 14.4% vs. 2.7%, p < 0.01. Furthermore, patients with both high CRP and high troponin levels on their second measurement had the highest 30-day mortality rates compared to the rest of the cohort; 21.4% vs. 3.7%, p < 0.01. These patients also had the highest all-cause mortality rates after a median follow-up of 4.5 years compared to the rest of the cohort; 42.9% vs. 12.7%, p < 0.01. In conclusion, serial measurements of both CRP and cardiac troponin might detect patients at increased risk for short-and long-term mortality following STEMI. We suggest the future use of the combined CTT as a potential early marker for inflammatory-prone patients with worse outcomes following ACS. This sub-type of patients might benefit from early anti-inflammatory therapy such as colchicine and anti-interleukin-1ß agents.

Association of a Third Dose of BNT162b2 Vaccine With Incidence of SARS-CoV-2 Infection Among Health Care Workers in Israel.

Importance: Administration of a BNT162b2 booster dose (Pfizer-BioNTech) to fully vaccinated individuals aged 60 years and older was significantly associated with lower risk of SARS-CoV-2 infection and severe illness. Data are lacking on the effectiveness of booster doses for younger individuals and health care workers. Objective: To estimate the association of a BNT162b2 booster dose with SARS-CoV-2 infections among health care workers who were previously vaccinated with a 2-dose series of BNT162b2. Design, Setting, and Participants: This was a prospective cohort study conducted at a tertiary medical center in Tel Aviv, Israel. The study cohort included 1928 immunocompetent health care workers who were previously vaccinated with a 2-dose series of BNT162b2, and had enrolled between August 8 and 19, 2021, with final follow-up reported through September 20, 2021. Screening for SARS-CoV-2 infection was performed every 14 days. Anti-spike protein receptor binding domain IgG titers were determined at baseline and 1 month after enrollment. Cox regression with time-dependent analysis was used to estimate hazard ratios of SARS-CoV-2 infection between booster-immunized status and 2-dose vaccinated (booster-nonimmunized) status. Exposures: Vaccination with a booster dose of BNT162b2 vaccine. Main Outcomes and Measures: The primary outcome was SARS-CoV-2 infection, as confirmed by reverse transcriptase-polymerase chain reaction. Results: Among 1928 participants, the median age was 44 years (IQR, 36-52 years) and 1381 were women (71.6%). Participants completed the 2-dose vaccination series a median of 210 days (IQR, 205-213 days) before study enrollment. A total of 1650 participants (85.6%) received the booster dose. During a median follow-up of 39 days (IQR, 35-41 days), SARS-CoV-2 infection occurred in 44 participants (incidence rate, 60.2 per 100 000 person-days); 31 (70.5%) were symptomatic. Five SARS-CoV-2 infections occurred in booster-immunized participants and 39 in booster-nonimmunized participants (incidence rate, 12.8 vs 116 per 100 000 person-days, respectively). In a time-dependent Cox regression analysis, the adjusted hazard ratio of SARS-CoV-2 infection for booster-immunized vs booster-nonimmunized participants was 0.07 (95% CI, 0.02-0.20). Conclusions and Relevance: Among health care workers at a single center in Israel who were previously vaccinated with a 2-dose series of BNT162b2, administration of a booster dose compared with not receiving one was associated with a significantly lower rate of SARS-CoV-2 infection over a median of 39 days of follow-up. Ongoing surveillance is required to assess durability of the findings.

The association between C-reactive protein and common blood tests in apparently healthy individuals undergoing a routine health examination.

BACKGROUND: C-reactive protein (CRP) is considered a marker of inflammation. We sought to evaluate the association between CRP level and commonly use blood tests in apparently healthy population. METHODS: A cross-sectional study of all visits in a routine health examination center between 1/2002 and 7/2018. CRP, complete blood count and chemistry blood panel were evaluated in each visit. Visits of individuals who had CRP above the 99th percentile or use statins were excluded. Correlation between CRP and blood tests was evaluated in the whole cohort as well as in sub-populations. RESULTS: Blood parameters of 33,261 visits were included. Moderate positive correlation between CRP and white blood cells count (r = 0.269), neutrophils count (r = 0.275), triglycerides (r = 0.275), alkaline phosphatase (r = 0.221) and gamma glutamyl transpeptidase (r = 0.220) was evaluated. Correlation with triglycerides was stronger in female then in males (r = 0.38 vs. 0.25). Uric acid was positively correlated in females and males. In participants under 30 years, inverse correlation with hemoglobin, creatinine and albumin levels and positive correlation with cholesterol were documented. CONCLUSION: Significant moderate association between CRP and several blood tests was evaluated in apparently healthy population. This information should be used for further studies of the relationship between inflammation and biological processes.

Effect of anti-C5 antibody on recuperation from ischemia/reperfusion-induced acute kidney injury.

AbstractAim: The complement system is activated in acute kidney injury (AKI). Anti-C5 antibody targets the common terminal portion of the complement cascade that generate the terminal complex C5b-9 and has a renal-protective effect in paroxysmal nocturnal hemoglobinuria. However, the anti-C5 antibody's role in ischemia/reperfusion (I/R)-induced AKI has not been fully investigated. We therefore evaluated its effect on the pathophysiological cascade of I/R-induced AKI.Methods: Sprague-Dawley rats underwent unilateral right kidney nephrectomies with simultaneous clamping of the contralateral hilum for 60 min (ischemia), followed by reperfusion. In addition to a placebo, two treatment groups received either high or low doses of anti-C5 monoclonal antibody. After 48 h, the rats were euthanized, blood was drawn to evaluate systemic inflammation and to estimate glomerular filtration rate (GFR). The remaining kidney was removed for pathological evaluation and intra-renal complement activation.Results: I/R induced significant intra-renal complement activation and systemic inflammation compared with unilateral nephrectomy group. The anti-C5 antibody ameliorated the intra-renal complement activation (intra-renal C3 and C6), reduced systemic inflammation (C-reactive protein, and systemic C3), decreased intra-renal acute tubular necrosis damage and improved GFR (seen by the sensitive marker, serum cystatin C; 1.63 mg/L (I/R + placebo), 1.36 mg/L (I/R + low dose) and 1.21 mg/L (I/R + high dose), p = .08 and .03 compared with I/R + placebo).Conclusion: In I/R-induced AKI, the monoclonal anti-C5 complement factor ameliorates intra renal complement activation, decreases local and systemic inflammation and may improve GFR.

Is Induced Sputum A Useful Noninvasive Tool in the Diagnosis of Pulmonary Sarcoidosis?

OBJECTIVES: In patients with pulmonary sarcoidosis, the provocation of sputum expectoration through the inhalation of hypertonic saline has been investigated as an alternative diagnostic tool for invasive procedures. We aimed to assess the diagnostic value of induced sputum (IS) by observing its cell distribution in patients with a confirmed histopathological diagnosis of sarcoidosis. MATERIALS AND METHODS: In this prospective, cross-sectional study, we compared the IS results of 20 patients with a histopathologically confirmed pulmonary sarcoidosis diagnosis and 24 healthy volunteers. The percentages of macrophages, lymphocytes, neutrophils, and eosinophils in IS and the CD4/CD8 ratio were compared. RESULTS: The percentage of lymphocytes in IS was significantly higher in the pulmonary sarcoidosis patients compared to the control group (41.6% vs 8.9%, p<0.001). There were no significant differences in the other IS cell percentages and CD4+/CD8+ ratio between the groups. Sputum induction was well tolerated. CONCLUSION: Sputum induced by the inhalation of hypertonic saline is a safe, inexpensive, less invasive, and easily repeated method and can be a valuable alternative to other invasive methods in the diagnosis of pulmonary sarcoidosis.

Human mesenchymal stromal cells ameliorate complement induced inflammatory cascade and improve renal functions in a rat model of ischemia-reperfusion induced acute kidney injury.

INTRODUCTION: The primary rational for using mesenchymal stromal cells (MSCs) to rejuvenate damaged tissue is mostly based on their capacity to trans-differentiate and repair injured organs. However, previous studies have demonstrated that MSCs are beneficial even at very early stages, before differentiation and proliferation can be expected. The aim of the current study was to investigate the multifaceted immunological effects of systemically administrating MSCs in the setting of acute kidney injury (AKI) induced by ischemic-reperfusion (I/R). METHODS: A rat model of I/R induced AKI was used. The rats underwent a unilateral nephrectomy with simultaneously clamping the contralateral kidney for 60 minutes. Four treatment groups received intravenously, increasing doses of human MSCs and after 48 hours, the rats were sacrificed. Blood was taken to evaluate renal functions and to measure systemic inflammatory markers. Kidneys were taken for histopathologic examinations and evaluations of intra-renal complement activation and inflammatory mediators. RESULTS: Renal functions improved in U shaped dose dependent manner. Mean serum creatinine levels were 4.5, 2.9, 2.6, 1.7 and 4.1 mg/dL in I/R + placebo, I/R + 150x103 cells, I/R + 250x103 cells, I/R + 500x103 cells and I/R + 1,000x103 cells respectfully (p-values<0.05). Urea demonstrated consistent results with the same U shape improvement manner. The extensive activation of the complement system was ameliorated in the MSCs treatment groups. In addition, MSCs significantly decreased intra-renal levels of IL-1ß and TNF-α. It should be noted that the highest doses of MSCs induced renal hypoxia, marked by the Hypoxy-probe staining. CONCLUSIONS: The early beneficial effect of MSCs in the setting of AKI may be attributed to their immunomodulatory effects. Safe treatment with MSCs can block the deleterious activation of the complement cascade and alleviate the hazardous inflammatory mediator-related cascade.

The value of cerebrospinal fluid lactate levels in diagnosing CSF infections in pediatric neurosurgical patients.

PURPOSE: Diagnosis of cerebrospinal fluid (CSF) infections in patients following neurosurgical procedures can be challenging. CSF lactate (LCSF) has been shown to assist in differentiating bacterial from non-bacterial meningitis in non-neurosurgical patients. The use of lactate in diagnosing CSF-related infections following neurosurgical procedures has been described in adults. The goal of this study was to describe the role of LCSF levels in diagnosing CSF-related infections among neurosurgical children. METHODS: We retrospectively collected data for all pediatric patients treated at a large tertiary pediatric neurosurgical department, for whom CSF samples were collected over a 2-year period. Lactate levels were correlated with other CSF parameters, surgical parameters, presence of CSF infection, and source of CSF sample (lumbar, ventricular, or pseudomeningocele). RESULTS: A total of 215 CSF samples from 162 patients were analyzed. We found a correlation between lactate levels and other CSF parameters. Lactate levels displayed an inconsistent correlation with infection depending on sample origin. Irrespective of the CSF source, lactate levels could not sufficiently discriminate between those with or without infection. Lactate levels were correlated with recent surgery, and, in some of the subgroups, to the extent of blood in CSF. CONCLUSIONS: LCSF levels are influenced by many factors, including the source of sample, recent surgery, and the presence of subarachnoid or ventricular blood secondary to surgery. The added value of LCSF for diagnosing CSF infections in children with a history of neurosurgical procedures is unclear and may be influenced by the extent of blood in the CSF.

Value of Cerebrospinal Fluid Lactate Levels in Diagnosing Shunt Infections in Pediatric Patients.

OBJECTIVE: The diagnosis and timely treatment of shunt infections (SI) in children is of paramount importance. In some cases, the standard cerebrospinal fluid (CSF) variables will not be sufficient for an accurate diagnosis of SI. CSF lactate (LCSF) has been found to assist in differentiating bacterial from nonbacterial meningitis in non-neurosurgical patients. To the best of our knowledge, the use of lactate in diagnosing or confirming the presence of SI has not yet been discussed. The goal of the present study was to describe the role of LCSF levels in children with shunts and Ommaya reservoirs and to evaluate its role in the accurate diagnosis of shunt-related infection. METHODS: We retrospectively collected data for a consecutive series of pediatric patients treated at a large tertiary pediatric neurosurgical department, for whom CSF samples from shunts had been collected during a 2-year period (2016-2017). The lactate levels were correlated with the presence of SI. RESULTS: A total of 61 CSF samples were analyzed, with 6 SIs found. The LCSF levels and white blood cell count were both found to correlate with the presence of CSF infections. A cutoff value of ≥2.95 mmol/L reached a sensitivity of 83%, specificity of 83%, and positive predictive value of 50%. LCSF <2.95 mmol/L had a negative predictive value of 96%. CONCLUSIONS: LCSF levels can be used as an additional chemical marker for the diagnosis and confirmation of SIs. An LCSF value of <2.95 mmol/L had a high negative predictive value.

NLRP3 inflammasome activity is upregulated in an in-vitro model of COPD exacerbation.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is an inflammatory disease characterized by a progressive and irreversible deterioration of lung function. Exacerbations of COPD have prolonged negative effects on pulmonary function and a major impact on health status and outcomes. NLRP3 inflammasome is a cardinal component of the inflammatory response, with marked evidence in stable and exacerbations of COPD. The aim of our study was to evaluate the NLRP3 inflammasome activity during COPD exacerbation by using an in vitro model. METHODS: A549 cells were stimulated with different concentrations (10%, 4%, 2%) of cigarette smoke extract (CSE) with or without LPS (0.1µg/ml) for 24 hours. Cell viability was assessed by using XTT test. Levels of inflammatory cytokines (IL-8, MCP-1, and IL-1ß) were measured by ELISA and the activity level of NLRP-3 was evaluated by flow cytometry. RESULTS: Cells exposed to CSE present an increase in inflammatory cytokines (IL-8 and MCP-1) production in a dose-dependent manner. Incubation with LPS to these cells results in higher levels of IL-8 and MCP-1 compared to stimulation of CSE alone. NLRP3 inflammasome activity and IL-1ß levels were significantly increased in cells exposed to both CSE and LPS compared to CSE alone. CONCLUSIONS: NLRP3 inflammasome is upregulated in an in-vitro model of COPD and COPD exacerbation. Our findings provide novel biomarkers for COPD exacerbation and may present new targets for future research.

Characteristics of apparently healthy individuals with a very low C-reactive protein.

BACKGROUND: The importance of the inflammatory processes and C-reactive protein (CRP) evaluation was observed. Only few studies used cut-off value <1 mg/L. We sought to evaluate the association between very low CRP (vlCRP) and health status, to describe the repetition of vlCRP and to identify predictors for repetition. METHODS: A historical cohort study of all participants who underwent a routine annual check-up between January 2002 and July 2018 at the Tel Aviv Sourasky medical center. CRP test was evaluated in all participants. Individuals who use statins or with CRP >10 mg/L were excluded. CRP ≤0.12 mg/L was considered as vlCRP. RESULTS: The final study cohort included 14,161 individuals. Of them, 5065 were females and mean age was 43.4 years (SD 10.6). vlCRP at first check-up was observed in 1299 (9.2%) of the participants. In multivariable analysis, older age, hyperlipidemia, hypertension and smoking were significantly associated with lower probability of vlCRP. At the second check-up, 50.1% vlCRP repetition was observed with no significant predictor from previous visit. CONCLUSION: vlCRP is associated with younger age, non-smoking, and absence of hyperlipidemia and of hypertension. However, it may also be part of the individual physiology.

Sputum Anticitrullinated Protein Antibodies in Patients With Long-standing Rheumatoid Arthritis.

OBJECTIVE: The aim of this study was to evaluate the presence of autoantibodies to cyclic citrullinated synthetic peptides (ACPAs) in the sputum of patients with long-standing rheumatoid arthritis (RA). METHODS: Nineteen consecutive RA patients and 16 age- and sex-matched control subjects participated in this cross-sectional study. All underwent complete lung function tests and provided induced sputum. Antibodies to citrullinated (CitP) and the corresponding norleucine-containing (NorP) peptides in the sputum of the RA patients and control subjects, as well as in the serum of the RA patients, were determined by enzyme-linked immunosorbent assay. RESULTS: Patients with RA had the following characteristics: mean disease duration of 12 years, Disease Activity Score for 28 joints of 3.44, and Sharp-van der Heijde score of 57.5. Ten of the 19 RA patients showed high titers of ACPAs in their sera. Four of the seropositive (40%), none of the seronegative RA patients, and only 1 of the control subjects showed detectable levels of ACPAs in their sputum. The ratio between the reactivity with CitP and NorP peptides in the sputum was significantly higher in RA sputum than in control sputum (1.33 ± 1.2 vs. 0.64 ± 0.14, P = 0.02). A positive correlation was found between sputum ACPAs and age, serum ACPAs, sputum anti-NorP, serum anti-CitP/NorP reactivity ratio, and the proportion of neutrophils and lymphocytes in the sputum. No significant correlation was found between sputum ACPAs and disease severity, history of smoking, lung function tests, or treatment for RA. CONCLUSIONS: Anticitrullinated protein/peptide antibodies can be detected in the sputum of RA patients and are correlated with the presence in the serum.

Response of Renal Podocytes to Excessive Hydrostatic Pressure: a Pathophysiologic Cascade in a Malignant Hypertension Model.

BACKGROUND/AIMS: Renal injuries induced by increased intra-glomerular pressure coincide with podocyte detachment from the glomerular basement membrane (GBM). In previous studies, it was demonstrated that mesangial cells have a crucial role in the pathogenesis of malignant hypertension. However, the exact pathophysiological cascade responsible for podocyte detachment and its relationship with mesangial cells has not been fully elucidated yet and this was the aim of the current study. METHODS: Rat renal mesangial or podocytes were exposed to high hydrostatic pressure in an in-vitro model of malignant hypertension. The resulted effects on podocyte detachment, apoptosis and expression of podocin and integrinß1 in addition to Angiotensin-II and TGF-ß1 generation were evaluated. To simulate the paracrine effect podocytes were placed in mesangial cell media pre-exposed to pressure, or in media enriched with Angiotensin-II, TGF-ß1 or receptor blockers. RESULTS: High pressure resulted in increased Angiotensin-II levels in mesangial and podocyte cells. Angiotensin-II via the AT1 receptors reduced podocin expression and integrinß1, culminating in detachment of both viable and apoptotic podocytes. Mesangial cells exposed to pressure had a greater increase in Angiotensin-II than pressure-exposed podocytes. The massively increased concentration of Angiotensin-II by mesangial cells, together with increased TGF-ß1 production, resulted in increased apoptosis and detachment of non-viable apoptotic podocytes. Unlike the direct effect of pressure on podocytes, the mesangial mediated effects were not related to changes in adhesion proteins expression. CONCLUSIONS: Hypertension induces podocyte detachment by autocrine and paracrine effects. In a direct response to pressure, podocytes increase Angiotensin-II levels. This leads, via AT1 receptors, to structural changes in adhesion proteins, culminating in viable podocyte detachment. Paracrine effects of hypertension, mediated by mesangial cells, lead to higher levels of both Angiotensin-II and TGF-ß1, culminating in apoptosis and detachment of non-viable podocytes.

Aging leads to impaired epicutaneous sensitization that causes attenuated allergy and pulmonary inflammation in mice.

Aging is associated with altered decreased barrier function in the skin, which can lead to different types of immunoglobulin E (IgE)-mediated sensitization to environmental allergens. Yet, allergen-specific respiratory sensitization among the elderly is not well described. The aim of this study was to investigate the effect of aging on allergic pulmonary inflammation induced by epicutaneous sensitization of mechanically irritated skin in mice. For this purpose, 6-week-, 6-month-, and 18-month-old female BALB/c mice, underwent epicutaneous sensitization with ovalbumin (OVA) or phosphate buffered saline (PBS), followed by an inhaled OVA challenge. Blood OVA-specific IgE levels measured after epicutaneous sensitization, as well as, bronchial alveolar lavage fluids (BALF) leucocyte, eosinophil, and cytokine levels measured after OVA inhalation challenge were similar among the 6-week-old (young) and 6-month-old (adult) groups. However, significantly decreased levels of systemic OVA IgE, and BALF leukocyte, eosinophil and T helper cell type 2 cytokine levels, were measured after OVA inhalation challenge in elderly (18-month-old) mice compared to the other groups of mice. In addition, interleukin-10 (IL-10), a regulatory suppressor cytokine, was more abundant in the BALF of the elderly group after epicutaneous sensitization and inhalation challenge. Our results suggest that elderly mice have a reduced allergic response to induced sensitization with OVA, possibly regulated by increased IL-10 levels.

Differential pattern of deposition of nanoparticles in the airways of exposed workers.

Ultrafine particles (UFP) have been postulated to significantly contribute to the adverse health effects associated with exposure to particulate matter (PM). Due to their extremely small size (aerodynamic diameter <100 nm), UFP are able to deposit deep within the lung after inhalation and evade many mechanisms responsible for the clearance of larger particles. There is a lack of biologically relevant personal exposure metrics for exposure to occupational- and environmental-related micro- and nano-sized PM. The aim of the present study is to assess UFP in induced sputum (IS) and exhaled breath condensate (EBC) as possible biomarkers for assessing lung function impairment. Sputum induction and EBC testing were performed by conventional methods. UFP particles were assessed with the NanoSight LM20 (NanoSight Ltd, London, UK). The subjects included 35 exposed and 25 non-exposed workers. There were no group differences in pulmonary function test results and differential cell counts, but 63.6% of the exposed subjects had a higher percentage of neutrophils (OR3.28 p = 0.03) compared to the non-exposed subjects. The exposed subjects had higher percentages of UFP between 10 and 50 nm (69.45 ± 18.70 vs 60.11 ± 17.52 for the non-exposed group, p = 0.004). No differences were found in the IS samples. Years of exposure correlated positively to UFP content (r = 0.342 p = 0.01) and macrophage content (r = -0.327 p = 0.03). The percentage of small fraction of UFP in EBC, but not IS, is higher in exposed workers, and EBC may be a sensitive biomarker to assess exposure to nanoparticles.

A novel alternative to environmental monitoring to detect workers at risk for beryllium exposure-related health effects.

The purpose of this study was to describe a methodology for surveillance and monitoring of beryllium exposure using biological monitoring to complement environmental monitoring. Eighty-three Israeli dental technicians (mean age 41.6 ± 1.36 years) and 80 American nuclear machining workers (54.9 ± 1.21 years) were enrolled. Biological monitoring was carried out by analyzing particle size (laser technique) and shape (image analysis) in 131/163 (80.3%) induced sputum samples (Dipa Analyser, Donner Tech, Or Aquiva, Israel). Environmental monitoring was carried out only in the United States (Sioutas impactor, SKC, Inc., Eighty Four, Pa.). Pulmonary function testing performance and induced sputum retrieval were done by conventional methods. Sixty-three Israeli workers and 37 American workers were followed up for at least 2 years. Biological monitoring by induced sputum indicated that a >92% accumulation of <5 µm particles correlated significantly to a positive beryllium lymphocyte proliferation test result (OR 3.8, 95% CI 1.2-11.4, p = 0.015) among all participants. Environmental monitoring showed that beryllium particles were <1 µm, and this small fraction (0.1-1 µ) was significantly more highly accumulated in nuclear machining workers compared to dental technicians. The small fractions positively correlated with induced sputum macrophages (r = 0.21 p = 0.01) and negatively correlated with diffusion lung carbon monoxide single breath (DLCO-SB r = 0.180 p = 0.04) in all subjects. Years of exposure were positively correlated to the number of accumulated particles 2-3 µ in diameter (r = 0.2, p = 0.02) and negatively correlated to forced expiratory volume in one second/forced vital capacity findings (r = -0.18, p = 0.02). DLCO was decreased in both groups after two years of monitoring. Biological monitoring is more informative than environmental monitoring in the surveillance and monitoring of workers in beryllium industries. Induced sputum is a feasible and promising biomonitoring method that should be included in the surveillance of exposed workers.

Biological exposure metrics of beryllium-exposed dental technicians.

Beryllium is commonly used in the dental industry. This study investigates the association between particle size and shape in induced sputum (IS) with beryllium exposure and oxidative stress in 83 dental technicians. Particle size and shape were defined by laser and video, whereas beryllium exposure data came from self-reports and beryllium lymphocyte proliferation test (BeLPT) results. Heme oxygenase-1 (HO1) gene expression in IS was evaluated by quantitative polymerase chain reaction. A high content of particles (92%) in IS >5 µ in size is correlated to a positive BeLPT risk (odds ratio [OR] = 3.4, 95% confidence interval [CI]: 0.9-13). Use of masks, hoods, and type of exposure yielded differences in the transparency of IS particles (gray level) and modulate HO1 levels. These results indicate that parameters of size and shape of particles in IS are sensitive to workplace hygiene, affect the level of oxidative stress, and may be potential markers for monitoring hazardous dust exposures.

Simplified detection of eosinophils in induced sputum.

OBJECTIVE AND DESIGN: The induction of sputum is a safe, noninvasive method of studying airway inflammation in asthma, but the method of analyzing the samples is laborious and requires well-trained technicians using highly specialized laboratory equipment. We introduce a shorter and simpler modification of the process for identifying eosinophilic inflammation from induced sputum (IS) samples. MATERIAL: Samples of 81 patients referred for IS assessment of respiratory diseases were studied. Four different assessment approaches were studied in comparison with the conventional method of selecting plugs proposed by the European Respiratory Society/American Thoracic Society task force. RESULTS: One modification of the conventional method of IS processing emerged as simpler to execute and less technologically demanding than the original one (13.0 ± 18.2 vs. 15.4 ± 22.4% eosinophils, P = 0.19). CONCLUSION: The simpler approach should now encourage the use of IS as a convenient procedure for evaluating eosinophilic inflammation in less sophisticated laboratories.