Tissue-resident alveolar macrophages reduce O3-induced inflammation via MerTK mediated efferocytosis.

Lung inflammation, caused by acute exposure to ozone (O3) - one of the six criteria air pollutants - is a significant source of morbidity in susceptible individuals. Alveolar macrophages (AMØs) are the most abundant immune cells in the normal lung and their number increases following O3 exposure. However, the role of AMØs in promoting or limiting O3-induced lung inflammation has not been clearly defined. Here, we used a mouse model of acute O3 exposure, lineage tracing, genetic knockouts, and data from O3-exposed human volunteers to define the role and ontogeny of AMØs during acute O3 exposure. Lineage tracing experiments showed that 12, 24, and 72 h after exposure to O3 (2 ppm) for 3h all AMØs were tissue-resident origin. Similarly, in humans exposed to FA and O3 (200 ppb) for 135 minutes, we did not observe ~21h post-exposure an increase in monocyte-derived AMØs by flow cytometry. Highlighting a role for tissue-resident AMØs, we demonstrate that depletion of tissue-resident AMØs with clodronate-loaded liposomes led to persistence of neutrophils in the alveolar space after O3 exposure, suggesting that impaired neutrophil clearance (i.e., efferocytosis) leads to prolonged lung inflammation. Moreover, depletion of tissue-resident AMØ demonstrated reduced clearance of intratracheally instilled apoptotic Jurkat cells, consistent with reduced efferocytosis. Genetic ablation of MerTK - a key receptor involved in efferocytosis - also resulted in impaired clearance of apoptotic neutrophils followed O3 exposure. Overall, these findings underscore the pivotal role of tissue-resident AMØs in resolving O3-induced inflammation via MerTK-mediated efferocytosis.

Co-occurrence of pneumoconiosis with COPD, pneumonia and lung cancer.

BACKGROUND: Pneumoconiosis is a well-documented occupational disease that is linked to conditions such as chronic obstructive pulmonary disease (COPD), pneumonia and congestive heart failure. Pneumoconiosis prevalence has decreased in the United States, but it remains implicated in tens of thousands of deaths worldwide per year. AIMS: To provide a recent update on associations of pneumoconiosis and smoking status with various pulmonary diseases in the United States. METHODS: The CDC's National Vital Statistics System was analysed on the entity axis using ICD-10 codes for pulmonary disease and potential lung injury with a cohort of those aged 15 and older during the years 2010-2019. The cases of evaluated diseases were scaled to rates per 100 000 and compared through analysis of variance. RESULTS: Pneumoconiosis and smoking history were each associated with an increased rate of COPD, but combined, were associated with an even higher rate of COPD than either factor alone. Smoking history was associated with an increased rate of lung cancer, but pneumoconiosis status was only linked to increased lung cancer prevalence in non-smokers. Both pneumoconiosis and smoking were associated with an increased rate of pneumonia, but combined, had no deviation from the pneumonia rate in those with pneumoconiosis alone. Finally, pneumoconiosis status was associated with decreased rates of non-lung cancers and sepsis. CONCLUSIONS: Although pneumoconiosis has become less common in the United States through regulatory and industrial shifts, it is still a significant risk factor for co-occurring pulmonary diseases and will likely remain relevant as international demands for mining, construction and manufacturing change.

Novel Mechanisms of Ozone-Induced Pulmonary Inflammation and Resolution, and the Potential Protective Role of Scavenger Receptor BI.

INTRODUCTION: Increases in ambient levels of ozone (O3), a criteria air pollutant, have been associated with increased susceptibility and exacerbations of chronic pulmonary diseases through lung injury and inflammation. O3 induces pulmonary inflammation, in part by generating damage-associated molecular patterns (DAMPs), which are recognized by pattern recognition receptors (PRRs), such as toll-like receptors (TLRs) and scavenger receptors (SRs). This inflammatory response is mediated in part by alveolar macrophages (AMs), which highly express PRRs, including scavenger receptor BI (SR-BI). Once pulmonary inflammation has been induced, an active process of resolution occurs in order to prevent secondary necrosis and to restore tissue homeostasis. The processes known to promote the resolution of inflammation include the clearance by macrophages of apoptotic cells, known as efferocytosis, and the production of specialized pro-resolving mediators (SPMs). Impaired efferocytosis and production of SPMs have been associated with the pathogenesis of chronic lung diseases; however, these impairments have yet to be linked with exposure to air pollutants. SPECIFIC AIMS: The primary goals of this study were: Aim 1 - to define the role of SR-BI in O3-derived pulmonary inflammation and resolution of injury; and Aim 2 - to determine if O3 exposure alters pulmonary production of SPMs and processes known to promote the resolution of pulmonary inflammation and injury. METHODS: To address Aim 1, female wild-type (WT) and SR-BI-deficient, or knock-out (SR-BI KO), mice were exposed to either O3 or filtered air. In one set of experiments mice were instilled with an oxidized phospholipid (oxPL). Bronchoalveolar lavage fluid (BALF) and lung tissue were collected for the analyses of inflammatory and injury markers and oxPL. To estimate efferocytosis, mice were administered apoptotic cells (derived from the Jurkat T cell line) after O3 or filtered air exposure.To address Aim 2, male WT mice were exposed to either O3 or filtered air, and levels of SPMs were assessed in the lung, as well as markers of inflammation and injury in BALF. In some experiments SPMs were administered before exposure to O3or filtered air, to determine whether SPMs could mitigate inflammatory or resolution responses. Efferocytosis was measured as in Aim 1. RESULTS: For Aim 1, SR-BI protein levels increased in the lung tissue of mice exposed to O3, compared with mice exposed to filtered air. Compared with WT controls, SR-BI KO mice had a significant increase in the number of neutrophils in their airspace 24 hours post O3 exposure. The oxPL levels increased in the airspace of both WT and SR-BI KO mice after O3 exposure, compared with filtered air controls. Four hours after instillation of an oxPL, SR-BI KO mice had an increase in BALF neutrophils and total protein, and a nonsignificant increase in macrophages compared with WT controls. O3 exposure decreased efferocytosis in both WT and SR-BI KO female mice.For Aim 2, mice given SPM supplementation before O3 exposure showed significantly increased AM efferocytosis when compared with the O3exposure control mice and also showed some mitigation of the effects of O3 on inflammation and injury. Several SPMs and their precursors were measured in lung tissue using reverse-phase high performance liquid chromatography (HPLC) with tandem mass spectrometry (MS/MS). At 24 hours after O3 exposure 14R-hydroxydocosahexaenoic acid (HDHA) and 10,17-dihydroxydocosahexaenoic acid (diHDoHE) were significantly decreased in lung tissue, but at 6 hours after exposure, levels of these SPMs increased. CONCLUSIONS: Our findings identify novel mechanisms by which O3 may induce pulmonary inflammation and also increase susceptibility to and exacerbations of chronic lung diseases.

Screen-detected colorectal cancers show improved cancer-specific survival when compared with cancers diagnosed via the 2-week suspected colorectal cancer referral guidelines.

AIM: Biennial screening for colorectal cancer using faecal occult blood testing has been shown to reduce the relative risk of mortality from colorectal cancer. The Norwich screening centre commenced screening in July 2006 and so far has diagnosed over 350 patients with colorectal cancer. We compared the stage at diagnosis and cancer-specific mortality and survival in patients diagnosed through screening with a cohort of symptomatic patients with colorectal cancer within the same age range. METHOD: A comparative analysis was undertaken of all screen-detected colorectal cancer patients diagnosed between July 2006 and December 2010, with an age-matched group of patients diagnosed in the Norfolk and Norwich Hospital through the 2-week suspected colorectal cancer guidelines. RESULTS: Three hundred and fifty-six cases of colorectal cancer were diagnosed through the screening programme, in patients with an age range of 60-79 years. In the same time period, 292 patients in the same age range were diagnosed with colorectal cancer through the 2-week suspected colorectal cancer pathway. Sixteen patients in the screening group had evidence of metastatic disease at presentation compared with 62 in the symptomatic group (χ(2) , P<0.001). The proportion of T1/T2 and Dukes A cancers was significantly greater in the screening group (χ(2) , P < 0.001). There were 21 colorectal cancer-related deaths in the screening group compared with 66 in the symptomatic group. Survival analysis curves showed significantly better survival in the screening group (log-rank analysis P<0.001). CONCLUSION: Screening for colorectal cancer identifies cancers at a significantly earlier stage than in symptomatic patients, with subsequent improvement in cancer-specific survival.

Teaching corner: Regional anaesthesia for ophthalmic surgery.

Performing safe and effective regional anaesthesia for ophthalmic surgery is an important skill for anaesthetic and ophthalmologic practitioners. Akinetic sharp-needle blocks are generally safe but rare, sight and life threatening complications occur. Sub-Tenon's block using a blunt canula provides akinesa and is a safer alternative but serious complications have been reported. This review provides an introduction to the relevant anatomy, local anaesthetic drugs and commonly used techniques and a practical guide to their safe performance.

Teaching Corner: Regional Anaesthesia for Ophthalmic Surgery

Performing safe and effective regional anaesthesia for ophthalmic surgery is an important skill for anaesthetic and ophthalmologic practitioners. Akinetic sharp-needle blocks are generally safe but rare; sight and life threatening complications occur. Sub-Tenon's block using a blunt canula provides akinesa and is a safer alternative but serious complications have been reported. This review provides an introduction to the relevant anatomy; local anaesthetic drugs and commonly used techniques and a practical guide to their safe performance

Prospective randomized trial of laparoscopic gastrojejunostomy versus duodenal stenting for malignant gastric outflow obstruction.

BACKGROUND: We prospectively compared laparoscopic gastrojejunostomy with duodenal stenting as a means of palliating malignant gastric outflow obstruction. METHODS: A total of 27 patients with malignant gastric outflow obstruction were randomized to either laparoscopic gastrojejunostomy (LGJ) or duodenal stenting (DS) over a 3-year period. RESULTS: Thirteen patients underwent successful LGJ and 10 had successful DS. Eight patients had complications after LGJ, but none had complications after DS. Patients who underwent LGJ had a significant increase in visual analog pain score at day 1 (p = 0.05), and also had a longer hospital stay compared to those who underwent DS (11.4 vs. 5.2 days, p = 0.02). After DS, patients experienced an improvement in physical health at 1 month as measured using the Short Form-36 (SF-36) questionnaire (p < 0.01). There was no change following LGJ. CONCLUSION: Duodenal stenting is a safe means of palliating malignant gastric outflow obstruction. It offers significant advantages for patients compared with minimal-access surgery.

Correction of sickle cell disease in transgenic mouse models by gene therapy.

Sickle cell disease (SCD) is caused by a single point mutation in the human betaA globin gene that results in the formation of an abnormal hemoglobin [HbS (alpha2betaS2)]. We designed a betaA globin gene variant that prevents HbS polymerization and introduced it into a lentiviral vector we optimized for transfer to hematopoietic stem cells and gene expression in the adult red blood cell lineage. Long-term expression (up to 10 months) was achieved, without preselection, in all transplanted mice with erythroid-specific accumulation of the antisickling protein in up to 52% of total hemoglobin and 99% of circulating red blood cells. In two mouse SCD models, Berkeley and SAD, inhibition of red blood cell dehydration and sickling was achieved with correction of hematological parameters, splenomegaly, and prevention of the characteristic urine concentration defect.

Development of a rapidly deployed Department of Energy emergency response element.

The Federal Radiological Emergency Response Plan (FRERP) directs the Department of Energy (DOE) to maintain a viable, timely, and fully documented response option capable of supporting the responsible Lead Federal Agency in the event of a radiological emergency impacting any state or United States territory (e.g., CONUS). In addition, the DOE maintains a response option to support radiological emergencies outside the continental United States (OCONUS). While the OCONUS mission is not governed by the FRERP, this response is operationally similar to that assigned to the DOE by the FRERP The DOE is prepared to alert, activate, and deploy radiological response teams to augment the Radiological Assistance Program and/or local responders. The Radiological Monitoring and Assessment Center (RMAC) is a phased response that integrates with the Federal Radiological Monitoring and Assessment Center (FRMAC) in CONUS environments and represents a stand-alone DOE response for OCONUS environments. The FRMAC/RMAC Phase I was formally "stood up" as an operational element in April 1999. The FRMAC/RMAC Phase II proposed "stand-up" date is midyear 2000.

Phenotype of mice lacking functional Deleted in colorectal cancer (Dcc) gene.

The DCC (Deleted in colorectal cancer) gene was first identified as a candidate for a tumour-suppressor gene on human chromosome 18q. More recently, in vitro studies in rodents have provided evidence that DCC might function as a receptor for the axonal chemoattractant netrin-1. Inactivation of the murine Dcc gene caused defects in axonal projections that are similar to those observed in netrin-1-deficient mice but did not affect growth, differentiation, morphogenesis or tumorigenesis in mouse intestine. These observations fail to support a tumour-suppressor function for Dcc, but are consistent with the hypothesis that DCC is a component of a receptor for netrin-1.

The effect of continuing penicillamine and gold treatment on the course of penicillamine and gold nephropathy.

The effect of continuing penicillamine or gold treatment was examined in 53 patients with biopsy proven penicillamine (32) or gold (21) nephropathy. Thirty-two patients stopped penicillamine or gold treatment as soon as proteinuria was detected whilst 21 patients continued treatment for periods of 2-11 months. The 24-hour creatinine clearance and urinary protein excretion were measured serially for a median period of 6 years. No significant differences were observed in the initial or maximum proteinuria, the duration of the proteinuria or in the initial or latest creatinine clearances between the groups of patients. These results indicate that penicillamine or gold treatment may be continued for short periods under close supervision despite moderate proteinuria without causing permanent renal damage. As several alternative non-nephrotoxic agents are available for the treatment of rheumatoid arthritis, continued treatment with penicillamine or gold despite proteinuria is seldom indicated.

British postgraduate training in pathology.

There is growing pressure for a review of postgraduate training in pathology. The establishment of monodisciplinary practice, the rapid advancement of subspecialities with their attendant problems of recruitment, and the decline of research activity by those in training identifies the need for an early change in the pattern of training.