Analysis of Damage and Wound Healing in the Retinal Pigmented Epithelium.

Previous studies of retinal pigment epithelium (RPE) morphology found cell-level and spatial patterning differences in many quantitative metrics in comparing normal and disease conditions. However, most of these studies examined eyes from deceased animals. Here we sought to compare noninvasively imaged RPE cells from live mice to histopathology. We describe changes to improve noninvasive imaging of RPE in the live mouse. In retinal diseases, there can be invasion by Iba1-positive cells, which can be detected by noninvasive imaging techniques. Here we can detect potential Iba1-positive cells at the level of the RPE noninvasively.

An extended phase Ib study of epertinib, an orally active reversible dual EGFR/HER2 tyrosine kinase inhibitor, in patients with solid tumours.

BACKGROUND: Dose-escalation of epertinib (S-222611), a new potent oral EGFR/HER2 inhibitor, has established a recommended daily dose of 800 mg in patients with solid tumours. In this study, we have recruited a larger number of patients to assess further the safety, tolerability, pharmacokinetics (PKs) and antitumour activity. PATIENTS AND METHODS: Patients with solid tumours expressing EGFR or HER2 received a single dose of epertinib at 800 mg on Day 1 to assess PK over 7 days, followed by continuous once-daily dosing from Day 8. RESULTS: We treated 76 patients with breast (n = 27), upper gastrointestinal (GI; n = 30), head and neck (n = 12) or renal cancers (n = 7). Epertinib was well-tolerated with mostly grade I and II adverse events (AEs). The most frequent AE was diarrhoea, which was generally manageable with loperamide. The objective response rate (ORR) in patients with heavily pretreated breast and upper GI cancers was 16.0% (4 PRs) and 8.3% (1CR, 1PR), respectively. All six responding patients had HER2-positive tumours; the ORR for HER2-positive breast and upper GI cancer populations was 19.0% and 20.0%. Partial response in the brain disease of one breast cancer patient lasted 7.5 months. CONCLUSION: Once-daily dosing of epertinib at 800 mg was well-tolerated and demonstrated promising antitumour activity in patients with heavily pretreated HER2-positive breast and upper GI cancer, including those with brain metastases. EUDRACT NUMBER: 2009-017817-31.

Evaluation of hibergene loop-mediated isothermal amplification assay for detection of group B streptococcus in recto-vaginal swabs: a prospective diagnostic accuracy study.

OBJECTIVES: To prospectively evaluate HiberGene's loop-mediated isothermal amplification (LAMP) assay for detection of group B streptococcus (GBS) in maternal recto-vaginal swabs and compare it with enrichment culture. METHODS: Following ethical approval and informed written consent, two low vaginal and rectal swabs were obtained from 400 pregnant women. One swab was tested for GBS using the rapid LAMP assay (index test), the second swab was tested using enrichment culture (reference standard). Antimicrobial susceptibility testing was performed according to EUCAST guidelines. RESULTS: There were 376 concordant results, 20 discordant and four invalid LAMP results. Among discordant results, six were LAMP negative/culture positive and 14 were LAMP positive/culture negative. The sensitivity was 92.2%, specificity 95.6%, positive predictive value 83.5% and negative predictive value 98.1%. The prevalence of GBS carriage was 19.25% (77/400). Forty-eight of 77 GBS-positive women were colonized vaginally (62.3%) and 70 were colonized rectally (90.9%). Erythromycin resistance was 22.4% (17/76) and clindamycin resistance was 17.1% (13/76). CONCLUSIONS: The LAMP assay is a rapid and simple test with results available in approximately 1 h compared with 48 h for culture. The test has good sensitivity and specificity compared with enrichment culture. This test can be used for rapid antenatal GBS screening.

Development of a novel automated screening method for detection of FVIII Inhibitors.

INTRODUCTION: Factor VIII activity is routinely determined by measuring the activated partial thromboplastin time (aPTT) of a patient plasma sample and determining percent activity from a standard curve. To maximize the detection of a clotting factor inhibitor, a subjective assessment of parallelism of a patient curve compared with a standard curve is performed. We developed and validated an automated objective method to assess parallelism as a rapid screening tool for detection of an inhibitor to factor VIII during routine FVIII assays. METHODS: We performed FVIII assays on a subset of FVIII-deficient patients with hemophilia A with and without inhibitors. Utilizing a ratio of the slopes from parallelism curves obtained by an independent Microsoft excel program in patients compared with a normal standard curve, we determined a cutoff ratio predictive for presence of an inhibitor. RESULTS: A cutoff ratio of patient to control slopes of <0.45 for the detection of an inhibitor to FVIII was 100% sensitive and 91.6% specific, with a positive predictive value of 92.3% and a negative predictive value of 100%. CONCLUSION: Utilizing a ratio of the slopes from parallelism curves in patients with and without an inhibitor, we developed and validated a rapid, automated, and objective method to assess parallelism as an added screening tool for detection of an inhibitor to factor VIII during routine FVIII assays on a STAGO-based coagulation platform. This simple automated method has the potential to detect inhibitors to other clotting factors.

Death in the New Town: Edinburgh's hidden story of stonemasons' silicosis.

The building of the Edinburgh New Town, from the mid-18th to the mid-19th centuries, was a major advance in harmonious and elegant town planning. However, there is anecdotal evidence that it led to the occurrence of an epidemic of silicosis/tuberculosis among the stonemasons. We have reviewed contemporary accounts of the episode and early records of the understanding of silicosis. We have also studied the lung of a contemporary stonemason, preserved in the museum of the Royal College of Surgeons of Edinburgh, and confirmed the presence of silico-tuberculosis in it. The evidence shows that a major epidemic did occur, caused by a combination of factors. The size of the undertaking attracted many stonemasons to Edinburgh over a period of almost 100 years, intensively cutting and dressing stone. The principal stone worked was a very high-quartz sandstone, derived from the local Craigleith quarry, having properties that made it desirable for prestige buildings. However, even before the construction of the New Town, Craigleith sandstone was notorious for its dustiness and the Edinburgh stonemasons worked the stone in unventilated sheds. Stonemasons appeared to be aware of the risk of their trade, but little was known about preventive measures. It appears it was assumed that the risks to stonemasons disappeared after the Craigleith quarry closed, the employers emphasising (without evidence) the lack of health risks in other quarries, and the tragic episode appears to have been forgotten. However, we point to the continuing occurrence of silicosis among stonemasons to the present day; the importance of remembering such episodes is stressed lest the lessons of the past be forgotten.

James Craufurd Gregory, 19th century Scottish physicians, and the link between occupation as a coal miner and lung disease.

By the mid-19th century about 200,000 miners were employed in a UK coal mining industry still growing with the advances of the Industrial Revolution. Coal miners were long known to suffer poor health but the link to inhaling dust in the mines had not been made. In 1813 George Pearson was the first to suggest that darkening of lungs seen in normal individuals as they aged was caused by inhaled soot from burning oil, candles and coal, which were the common domestic sources of heat and light. In 1831 Dr James Craufurd Gregory first described black pigmentation and disease in the lungs of a deceased coal miner and linked this to pulmonary accumulation of coal mine dust. Gregory hypothesised that the black material seen at autopsy in the collier's lungs was inhaled coal dust and this was confirmed by chemical analysis carried out by Professor Sir Robert Christison. Gregory suggested that coal dust was the cause of the disease and warned physicians in mining areas to be vigilant for the disease. This first description of what came to be known as 'coal worker's pneumoconiosis' sparked a remarkable intellectual effort by physicians in Scotland, culminating in a large body of published work that led to the first understandings of this disease and its link to coalblackened lungs. This paper sets out the history of the role of Scottish physicians in gaining this understanding of coal worker's pneumoconiosis. It describes Gregory's case and the lung - recently discovered in the pathology collection of the Surgeons' Hall Museums, Edinburgh, where it has lain unnoticed for over 180 years - on which Gregory based his landmark paper.

In children 18 years and under, what promotes recurrent shoulder instability after traumatic anterior shoulder dislocation? A systematic review and meta-analysis of risk factors.

BACKGROUND: Skeletal maturity and age-related changes in the composition of the glenoid labrum and joint capsule may influence rates of recurrent instability in children. We systematically review risk factors which predispose children to recurrent shoulder instability. METHODS: The systematic review-concerned studies published before May 2015. Statistical analysis was undertaken to compare rates of recurrence for each extracted risk factor. Pooled ORs were analysed using random effects meta-analysis. RESULTS: 6 retrospective cohort studies met the inclusion criteria. 8 risk factors were identified across the studies including age, sex, shoulder dominance and injury side, mechanism of injury, state of physis closure, and Hill-Sachs and Bankart lesions. The rate of recurrent instability was 73%. Children aged 14-18 years were 24 times more likely to experience recurrent instability than children aged 13 years and less (93% vs 40%; OR=24.14, 95% CI (3.71 to 156.99), Z=3.33, p=0.001, I(2)=6.83%). There was a non-significant trend indicating males were 3.4 times more likely to experience recurrent instability (OR=3.44, 95% CI (0.98 to 12.06), Z=1.93, p=0.053, I(2)=0%). Analysis of one study found that children with a closed physis are 14 times more likely to experience recurrent instability compared with those with an open physis (OR=14.0, 95% CI (1.46 to 134.25), Z=2.29, p=0.02, I(2)=0%) . CONCLUSIONS: Male children aged 14 years and over had the greatest risk of recurrent shoulder instability following a first-time traumatic anterior shoulder dislocation. This meta-analysis summarises a mix of 6 acceptable and poor quality level III retrospective cohort studies. Further examination of this population with blinded prospective cohort studies will assist clinicians in the appropriate management of first-time traumatic anterior shoulder dislocation.

Risk factors which predispose first-time traumatic anterior shoulder dislocations to recurrent instability in adults: a systematic review and meta-analysis.

BACKGROUND: Recurrent instability following a first-time anterior traumatic shoulder dislocation may exceed 26%. We systematically reviewed risk factors which predispose this population to events of recurrence. METHODS: A systematic review of studies published before 1 July 2014. Risk factors which predispose recurrence following a first-time traumatic anterior shoulder dislocation were documented and rates of recurrence were compared. Pooled ORs were analysed using random-effects meta-analysis. RESULTS: Ten studies comprising 1324 participants met the criteria for inclusion. Recurrent instability following a first-time traumatic anterior shoulder dislocation was 39%. Increased risk of recurrent instability was reported in people aged 40 years and under (OR=13.46), in men (OR=3.18) and in people with hyperlaxity (OR=2.68). Decreased risk of recurrent instability was reported in people with a greater tuberosity fracture (OR=0.13). The rate of recurrent instability decreased as time from the initial dislocation increased. Other factors such as a bony Bankart lesion, nerve palsy and occupation influenced rates of recurrent instability. CONCLUSIONS: Sex, age at initial dislocation, time from initial dislocation, hyperlaxity and greater tuberosity fractures were key risk factors in at least two good quality cohort studies resulting in strong evidence as concluded in the GRADE criteria. Although bony Bankart lesions, Hill Sachs lesions, occupation, physiotherapy treatment and nerve palsy were risk factors for recurrent instability, the evidence was weak using the GRADE criteria-these findings relied on poorer quality studies or were inconsistent among studies.

Phase 1 dose-escalation study of S-222611, an oral reversible dual tyrosine kinase inhibitor of EGFR and HER2, in patients with solid tumours.

BACKGROUND: S-222611 is a reversible inhibitor of EGFR, HER2 and HER4 with preclinical activity in models expressing these proteins. We have performed a Phase 1 study to determine safety, maximum tolerated dose (MTD), pharmacokinetic profile (PK) and efficacy in patients with solid tumours expressing EGFR or HER2. PATIENTS AND METHODS: Subjects had advanced tumours not suitable for standard treatment, expressing EGFR or HER2, and/or with amplified HER2. Daily oral doses of S-222611 were escalated from 100mg to 1600 mg. Full plasma concentration profiles for drug and metabolites were obtained. RESULTS: 33 patients received S-222611. It was well tolerated, and the most common toxicities, almost all mild (grade 1 or 2), were diarrhoea, fatigue, rash and nausea. Only two dose-limiting toxicities occurred (diarrhoea and rash), which resolved on interruption. MTD was not reached. Plasma exposure increased with dose up to 800 mg, exceeding levels eliciting pre-clinical responses. The plasma terminal half-life was more than 24h, supporting once daily dosing. Responses were seen over a wide range of doses in oesophageal, breast and renal tumours, including a complete clinical response in a patient with HER2-positive breast carcinoma previously treated with lapatinib and trastuzumab. Four patients have remained on treatment for more than 12 months. Downregulation of pHER3 was seen in paired tumour biopsies from a responding patient. CONCLUSIONS: Continuous daily oral S-222611 is well tolerated, modulates oncogenic signalling, and has significant antitumour activity. The recommended Phase 2 dose, based on PK and efficacy, is 800 mg/day.

Physicochemical and toxicological profiling of ash from the 2010 and 2011 eruptions of Eyjafjallajökull and Grímsvötn volcanoes, Iceland using a rapid respiratory hazard assessment protocol.

The six week eruption of Eyjafjallajökull volcano in 2010 produced heavy ash fall in a sparsely populated area of southern and south eastern Iceland and disrupted European commercial flights for at least 6 days. We adopted a protocol for the rapid analysis of volcanic ash particles, for the purpose of informing respiratory health risk assessments. Ash collected from deposits underwent a multi-laboratory physicochemical and toxicological investigation of their mineralogical parameters associated with bio-reactivity, and selected in vitro toxicology assays related to pulmonary inflammatory responses. Ash from the eruption of Grímsvötn, Iceland, in 2011 was also studied. The results were benchmarked against ash from Soufrière Hills volcano, Montserrat, which has been extensively studied since the onset of eruptive activity in 1995. For Eyjafjallajökull, the grain size distributions were variable: 2-13 vol% of the bulk samples were <4 µm, with the most explosive phases of the eruption generating abundant respirable particulate matter. In contrast, the Grímsvötn ash was almost uniformly coarse (<3.5 vol%<4 µm material). Surface area ranged from 0.3 to 7.7 m2 g(-1) for Eyjafjallajökull but was very low for Grímsvötn (<0.6 m2 g(-1)). There were few fibre-like particles (which were unrelated to asbestos) and the crystalline silica content was negligible in both eruptions, whereas Soufrière Hills ash was cristobalite-rich with a known potential to cause silicosis. All samples displayed a low ability to deplete lung antioxidant defences, showed little haemolysis and low acute cytotoxicity in human alveolar type-1 like epithelial cells (TT1). However, cell-free tests showed substantial hydroxyl radical generation in the presence of hydrogen peroxide for Grímsvötn samples, as expected for basaltic, Fe-rich ash. Cellular mediators MCP-1, IL-6, and IL-8 showed chronic pro-inflammatory responses in Eyjafjallajökull, Grímsvötn and Soufrière Hills samples, despite substantial differences in the sample mineralogy and eruptive styles. The value of the pro-inflammatory profiles in differentiating the potential respiratory health hazard of volcanic ashes remains uncertain in a protocol designed to inform public health risk assessment, and further research on their role in volcanic crises is warranted.

Dental cone beam CT image quality possibly reduced by patient movement.

Patient artefacts in dental cone beam CT scans can happen for various reasons. These range from artefacts from metal restorations to movement. An audit was carried out in the Glasgow Dental Hospital analysing how many scans showed signs of "motion artefact", and then to assess if there was any correlation between patient age and movement artefacts. Specific age demographics were then analysed to see if these cohorts were at a higher risk of "movement artefacts".

Vascular access type and risk of mortality in a national prospective cohort of haemodialysis patients.

BACKGROUND: Central venous catheters (CVC) are a potential source of bacteraemia and have been associated with increased mortality in haemodialysis patients. We aimed to investigate the relationships between haemodialysis vascular access, taking into account changes in vascular access type during patients' lives, and cause specific mortality risk in a national cohort of dialysis patients. METHODS: Prospective cohort study including all patients receiving haemodialysis in Scotland at annual cross sectional surveys in 2009, 2010 and 2011. Data were collected through the Scottish Renal Registry and by a structured review of case records following death. Cox proportional hazards regression and multivariable logistic regression were used to model survival and risk of death from septicaemia respectively. RESULTS: Of a cohort of 2666 patients, 873 (32%) died during follow-up. After case-mix adjustment, patients using only tunnelled CVC during follow-up had a higher risk of all cause mortality across all strata of prior renal replacement therapy exposure [adjusted hazard ratio (HR): 1.83-2.08]. Case-mix adjusted risks of cardiovascular death (adjusted HR: 2.20-2.95) and infection-related death (adjusted HR: 3.10-3.63) were also higher in this group. Patients using tunnelled CVCs during follow-up and prior to death had 6.9-fold higher odds of death from septicaemia compared with those using only arteriovenous fistulae or grafts. CONCLUSION: Compared with an arteriovenous fistula or graft, sustained use of tunnelled CVCs for vascular access is associated with higher risks of all-cause, cardiovascular and infection-related mortality.

NiO and Co3O4 nanoparticles induce lung DTH-like responses and alveolar lipoproteinosis.

Lung exposure to metal oxide nanoparticles (NPs) comprising soluble metal haptens may produce T-helper cell type 1 (Th1)- and Th17-associated delayed-type hypersensitivity (DTH) responses and pulmonary alveolar proteinosis (PAP). In order to study this, haptenic metal oxide NPs (NiO, Co(3)O(4), Cr(2)O(3) and CuO) were instilled into the lungs of female Wistar rats, and the immunoinflammatory responses were assessed at 24 h and 4 weeks post-instillation. Primary culture of alveolar macrophages from Wistar rats was used to evaluate the effect of the NPs on the ability to clear surfactant. NiO NPs induced chronic interstitial inflammation and pro-inflammatory Th1 and Th17 immune responses characterised by increases in the cytokines monocyte chemotactic protein (MCP)-1/CCL2, interleukin (IL)-12 p40, interferon-γ and IL-17A, whilst similar pathological responses induced by Co(3)O(4) NPs were associated with increases in MCP-1/CCL2 and IL-12 p40. However, neither Cr(2)O(3) nor CuO NPs elicited immunoinflammatory reactions. PAP was induced by both NiO and Co(3)O(4) NPs during the chronic phase. PAP was associated with over-production of surfactant by proliferation of type II cells and impaired clearance of surfactant by macrophages. These findings have implications for the risk management of occupational NP exposure and provide evidence that haptenic metal oxide NPs can induce chronic progressive lung immune responses via a DTH-like mechanism.

The challenges of renal replacement therapy and renal palliative care in the elderly.

The main aim of this review is to let general practitioners and physicians understand what happens to older patients after referral to the renal service. Usually, most patients will be managed completely by the renal team, either because the patient requires dialysis or because conservative but specialised care is appropriate. The recent increase in dialysis rate can mostly be accounted for by older patients for whom such demanding treatment was previously thought to be contraindicated. The decision to dialyse the elderly still remains difficult, with recent data suggesting that if there are significant comorbidities the survival advantage of dialysis in patients over 75 years of age is unlikely to be more than four months. Towards the end of life, conservative treatment is not simply a decision not to dialyse, but comprises active disease management, including treatment of anaemia and other supportive care, which may become increasingly complex, e.g. pain relief with fentanyl and alfentanyl. Older patients who decide to accept dialysis treatment contend with all the usual end of life issues of older people. They have an additional option, denied to the rest of us, of dialysis withdrawal; this effectively allows them to die at a time of their choosing.

Quantification of the pathological response and fate in the lung and pleura of chrysotile in combination with fine particles compared to amosite-asbestos following short-term inhalation exposure.

The marked difference in biopersistence and pathological response between chrysotile and amphibole asbestos has been well documented. This study is unique in that it has examined a commercial chrysotile product that was used as a joint compound. The pathological response was quantified in the lung and translocation of fibers to and pathological response in the pleural cavity determined. This paper presents the final results from the study. Rats were exposed by inhalation 6 h/day for 5 days to a well-defined fiber aerosol. Subgroups were examined through 1 year. The translocation to and pathological response in the pleura was examined by scanning electron microscopy and confocal microscopy (CM) using noninvasive methods. The number and size of fibers was quantified using transmission electron microscopy and CM. This is the first study to use such techniques to characterize fiber translocation to and the response of the pleural cavity. Amosite fibers were found to remain partly or fully imbedded in the interstitial space through 1 year and quickly produced granulomas (0 days) and interstitial fibrosis (28 days). Amosite fibers were observed penetrating the visceral pleural wall and were found on the parietal pleural within 7 days postexposure with a concomitant inflammatory response seen by 14 days. Pleural fibrin deposition, fibrosis, and adhesions were observed, similar to that reported in humans in response to amphibole asbestos. No cellular or inflammatory response was observed in the lung or the pleural cavity in response to the chrysotile and sanded particles (CSP) exposure. These results provide confirmation of the important differences between CSP and amphibole asbestos.

Rhabdomyolysis following co-prescription of fusidic acid and atorvastatin.

The placebo-corrected incidence of rhabdomyolysis in a systematic review of 20 statin trials was 1.6/100,000 per year. It is likely to be higher than this in everyday clinical practice when statins are knowingly or inadvertently co-prescribed with drugs that interfere with their metabolism. We report a case of rhabdomyolysis causing muscle weakness and prolonging an episode of dialysis-dependent acute kidney injury, which occurred when fusidic acid was co-prescribed with atorvastatin. Renal function and muscle power recovered when both drugs were withdrawn. We found four other cases of rhabdomyolysis with fusidic acid and atorvastatin and three with fusidic acid and simvastatin in the literature, a review of which suggests that the risks of rhabdomyolysis vary with the extent to which an individual statin is dependent for its metabolism on the cytochrome P450 3A4 isoenzyme and the degree to which this isoenzyme's activity is inhibited by a particular antimicrobial. Of note, the interaction between statins and fusidic acid did not feature in seven of eight recent reviews of statin toxicity. Our case report highlights the importance of close monitoring of patients on statins, especially when new drugs are started or if patients become unwell, by checking creatine kinase and liver function tests and by examining for new muscle weakness. Our review of statin-antimicrobial drug interactions suggests that fusidic acid is another CYP450 3A4 enzyme inhibitor with the potential to cause rhabdomyolysis when co-prescribed with simvastatin and atorvastatin.

The pathological response and fate in the lung and pleura of chrysotile in combination with fine particles compared to amosite asbestos following short-term inhalation exposure: interim results.

The pathological response and translocation of a commercial chrysotile product similar to that which was used through the mid-1970s in a joint compound intended for sealing the interface between adjacent wall boards was evaluated in comparison to amosite asbestos. This study was unique in that it presents a combined real-world exposure and was the first study to investigate whether there were differences between chrysotile and amosite asbestos fibers in time course, size distribution, and pathological response in the pleural cavity. Rats were exposed by inhalation 6 h/day for 5 days to either sanded joint compound consisting of both chrysotile fibers and sanded joint compound particles (CSP) or amosite asbestos. Subgroups were examined through 1-year postexposure. No pathological response was observed at any time point in the CSP-exposure group. The long chrysotile fibers (L > 20 microm) cleared rapidly (T(1/2) of 4.5 days) and were not observed in the pleural cavity. In contrast, a rapid inflammatory response occurred in the lung following exposure to amosite resulting in Wagner grade 4 interstitial fibrosis within 28 days. Long amosite fibers had a T(1/2) > 1000 days and were observed in the pleural cavity within 7 days postexposure. By 90 days the long amosite fibers were associated with a marked inflammatory response on the parietal pleural. This study provides support that CSP following inhalation would not initiate an inflammatory response in the lung, and that the chrysotile fibers present do not migrate to, or cause an inflammatory response in the pleural cavity, the site of mesothelioma formation.

Diesel exhaust particles override natural injury-limiting pathways in the lung.

Induction of effective inflammation in the lung in response to environmental and microbial stimuli is dependent on cooperative signaling between leukocytes and lung tissue cells. We explored how these inflammatory networks are modulated by diesel exhaust particles (DEP) using cocultures of human monocytes with epithelial cells. Cocultures, or monoculture controls, were treated with DEP in the presence or absence of LPS or flagellin. Production of cytokines was explored by Western blotting and ELISA; cell signaling was analyzed by Western blotting. Here, we show that responses of epithelial cells to DEP are amplified by the presence of monocytes. DEP amplified the responses of cellular cocultures to very low doses of TLR agonists. In addition, in the presence of DEP, the responses induced by LPS or flagellin were less amenable to antagonism by the physiological IL-1 antagonist, IL-1ra. This was paralleled by the uncoupling of IL-1 production and release from monocytes, potentially attributable to an ability of DEP to sequester or degrade extracellular ATP. These data describe a model of inflammation where DEP amplifies responses to low concentrations of microbial agonists and alters the nature of the inflammatory milieu induced by TLR agonists.

A biopersistence study following exposure to chrysotile asbestos alone or in combination with fine particles.

In designing a study to evaluate the inhalation biopersistence of a chrysotile asbestos that was used as a component of a joint-compound, a feasibility study was initiated to evaluate the short-term biopersistence of the chrysotile alone and of the chrysotile in combination with the sanded reformulated joint-compound. Two groups of Wistar rats were exposed to either 7RF3 chrysotile (Group 2) or to 7RF3 chrysotile combined with aerosolized sanded joint-compound (Group 3). In addition, a control group was exposed to filtered-air. The chrysotile used in the Ready Mix joint compound is rapidly removed from the lung. The chrysotile alone exposure group had a clearance half-time of fibers L > 20 microm of 2.2 days; in the chrysotile plus sanded exposure group the clearance half-time of fibers L > 20 microm was 2.8 days. However, across all size ranges there was approximately an order of magnitude decrease in the mean number of fibers remaining in the lungs of Group 3 as compared to Group 2 despite similiar aerosol exposures. Histopathological examination showed that the chrysotile exposed lungs had the same appearance as the filtered-air controls. This study uniquely illustrates that additional concurrent exposure to an aerosol of the sanded joint-compound, with large numbers of fine-particles depositing in the lungs, accelerates the recruitment of macrophages, resulting in a tenfold decrease in the number of fibers remaining in the lung. The increased number of macrophages in the chrysotile/sanded joint exposure group was confirmed histologically, with this being the only exposure-related histological finding reported.

Concordance between in vitro and in vivo dosimetry in the proinflammatory effects of low-toxicity, low-solubility particles: the key role of the proximal alveolar region.

We previously demonstrated the importance of the surface area burden as the key dose metric in the elicitation of inflammation in rat lungs by low-solubility, low-toxicity particles (LSLTP). We have now explored the dosimetry of LSLTP in vitro using epithelial cell interleukin (IL)-8 gene expression as a surrogate for potential of particles to cause inflammation. The proximal alveolar region (PAR) of the lung has been identified as a key site for the retention of respirable particles, as it receives high deposition but has slow clearance compared to the larger airways. For these reasons, a few days after exposure to particles the residual dose is concentrated in the PAR region. Re-expressing our rat lung data as particle surface area burden per unit of PAR surface area we obtained a threshold value for onset of inflammation of 1 cm(2)/cm(2). We carried out dose responses in vitro for onset of IL-8 gene expression with the same particles as we had used in vivo. When we expressed the in vitro dose as surface area dose per unit A549cell culture surface area, we obtained a threshold of 1 cm(2)/cm(2). This concordance between proinflammatory effects in vivo (PMN in BAL) and in vitro (epithelial IL-8 gene expression) confirms and supports the utility of the particle surface area metric and the importance of the PAR. These studies also open the way for future in vitro approaches to studying proinflammatory effects of a range of toxic particles based on sound dosimetry that complements animal use in particle toxicology.