Ionizing radiation induces myofibroblast differentiation via lactate dehydrogenase.

Pulmonary fibrosis is a common and dose-limiting side-effect of ionizing radiation used to treat cancers of the thoracic region. Few effective therapies are available for this disease. Pulmonary fibrosis is characterized by an accumulation of myofibroblasts and excess deposition of extracellular matrix proteins. Although prior studies have reported that ionizing radiation induces fibroblast to myofibroblast differentiation and collagen production, the mechanism remains unclear. Transforming growth factor-ß (TGF-ß) is a key profibrotic cytokine that drives myofibroblast differentiation and extracellular matrix production. However, its activation and precise role in radiation-induced fibrosis are poorly understood. Recently, we reported that lactate activates latent TGF-ß through a pH-dependent mechanism. Here, we wanted to test the hypothesis that ionizing radiation leads to excessive lactate production via expression of the enzyme lactate dehydrogenase-A (LDHA) to promote myofibroblast differentiation. We found that LDHA expression is increased in human and animal lung tissue exposed to ionizing radiation. We demonstrate that ionizing radiation induces LDHA, lactate production, and extracellular acidification in primary human lung fibroblasts in a dose-dependent manner. We also demonstrate that genetic and pharmacologic inhibition of LDHA protects against radiation-induced myofibroblast differentiation. Furthermore, LDHA inhibition protects from radiation-induced activation of TGF-ß. We propose a profibrotic feed forward loop, in which radiation induces LDHA expression and lactate production, which can lead to further activation of TGF-ß to drive the fibrotic process. These studies support the concept of LDHA as an important therapeutic target in radiation-induced pulmonary fibrosis.

Spatio-temporal analysis of tuberculous infection risk among clients of a homeless shelter during an outbreak.

SETTING: British Columbia (BC) has a low incidence of tuberculosis (TB), with the burden of endogenously acquired disease concentrated among vulnerable populations, including the homeless. In May 2008, a TB outbreak began in a BC homeless shelter, with a single index case seeding multiple secondary cases within the shelter. OBJECTIVE: To use nightly shelter records to quantify the risk of latent tuberculous infection (LTBI) among shelter clients as a function of their sleeping distance from and duration of exposure to the index case. DESIGN: Distance and duration of exposure were visualised and assessed using logistic regression with LTBI status as outcome. We used a novel machine learning approach to establish exposure thresholds that optimally separated infected and non-infected individuals. RESULTS: Of 161 exposed shelter clients, 58 had a recorded outcome of infected (n = 39) or non-infected (n = 19). Only duration of exposure to the index was associated with increased odds of infection (OR 1.26); stays of ⩾ 5 nights put shelter clients at higher odds of infection (OR 4.97). CONCLUSION: The unique data set and analytical approach suggested that, in a shelter environment, long-term clients are at highest risk of LTBI and should be prioritised for screening during an outbreak investigation.

A clonal outbreak of tuberculosis in a homeless population in the interior of British Columbia, Canada, 2008-2015.

A tuberculosis (TB) case was reported May 2008 in Kelowna, British Columbia, leading to a multi-year outbreak in homeless persons. The epidemiological characteristics and social networks of cases are described. Outbreak-related cases were identified from epidemiological information in medical records and from genotyping of TB isolates. Social network information from case interviews were used to identify potential locations of TB transmission, where symptom screening and tuberculin skin testing was conducted. Fifty-two cases that were predominantly male (47/52), Canadian-born (44/50), and were homeless or associated with homeless individuals (42/52) were reported from May 2008 to May 2014. Many isolates (40/49) had partial resistance to isoniazid. Transmission primarily occurred at two homeless shelters, with potential further transmission at sites visited by the general population. TB outbreaks in homeless populations can occur in small, low-incidence cities. Social network information helped prioritize sites for TB screening, thereby improving detection of persons with TB disease or latent infection for treatment.

Surveillance summary of hospitalized pediatric enterovirus D68 cases in Canada, September 2014.

BACKGROUND: Enterovirus D68 (EV-D68) has been detected infrequently and has not been associated with severe disease in Canada. In the early fall of 2014, following an unusual case increase in the United States, clusters of EV-D68 among children and some adults manifesting severe symptoms were reported in Canada. OBJECTIVE: To provide an initial epidemiological summary of pediatric cases hospitalized with EV-D68 in Canada. METHODS: A time-limited surveillance pilot was conducted collecting information on pediatric cases (less than 18 years of age) hospitalized with EV-D68 between September 1 and 30, 2014. RESULTS: In total, 268 cases were reported from Ontario (n=210), Alberta (n=45), and British Columbia (n=13). Of the 268 reported cases, 64.9% (n=174) were male; the sex difference was statistically significant (p<0.01). Age was reported for 255 cases, with a mean age for males of 5.4 years and for females of 5.3 years. For cases with data available, 6.8% (18/266) were admitted to an intensive care unit. Of those where clinical illness was recorded, respiratory illness alone was present in 98.3% (227/231), neurologic illness alone was present in 0.4% (n=1), and both illnesses were present in 0.9% of cases (n=2); cases with neither respiratory nor neurologic illness were rare (n=1). Of the 90 cases with additional clinical information available, 43.3% were reported as having asthma. No deaths were reported among the 268 cases. CONCLUSION: The EV-D68 outbreak in Canada in September 2014 represents the beginning of a novel outbreak associated with severe illness in children. These findings provide the first epidemiological summary of severe cases of EV-D68 as an emergent respiratory pathogen in Canada. The continued investigation of this pathogen is necessary to build on these results and capture the full spectrum of associated illness.

The prognostic significance of tumour-stroma ratio in oestrogen receptor-positive breast cancer.

BACKGROUND: A high percentage of stroma predicts poor survival in triple-negative breast cancers but is diminished in studies of unselected cases. We determined the prognostic significance of tumour-stroma ratio (TSR) in oestrogen receptor (ER)-positive male and female breast carcinomas. METHODS: TSR was measured in haematoxylin and eosin-stained tissue sections (118 female and 62 male). Relationship of TSR (cutoff 49%) to overall survival (OS) and relapse-free survival (RFS) was analysed. RESULTS: Tumours with ≥49% stroma were associated with better survival in female (OS P=0.008, HR=0.2-0.7; RFS P=0.006, HR=0.1-0.6) and male breast cancer (OS P=0.005, HR=0.05-0.6; RFS P=0.01, HR=0.87-5.6), confirmed in multivariate analysis. CONCLUSIONS: High stromal content was related to better survival in ER-positive breast cancers across both genders, contrasting data in triple-negative breast cancer and highlighting the importance of considering ER status when interpreting the prognostic value of TSR.

Malignant mesothelioma, hypoalbuminaemia and the effect of carboplatin/pemetrexed on survival.

AIMS: The incidence of malignant mesothelioma in the UK is increasing. The aim of this study was to determine the prognostic factors and assess the effect of carboplatin/pemetrexed chemotherapy on survival. MATERIALS AND METHODS: Cases of malignant mesothelioma diagnosed between 1998 and 2011 were stratified by year of diagnosis. Factors affecting survival were assessed by Cox's proportional hazards regression. RESULTS: In total, there were 202 new cases of malignant mesothelioma between 1998 and 2011. The age-standardised rate (95% confidence interval) increased from 2.84 (2.06-3.60) to 4.44 (3.50-5.4); P = 0.025. Chemotherapy use has increased since 2006: 52% versus 34% (P = 0.007). The median survival (interquartile range) by year diagnosed was 9 (4.0-21.9) versus 10 (3.8-20.1) months for 1998-2005 versus 2006-2011. Independent predictors of survival [hazard ratio (95% confidence interval)] were: histology, sarcomatoid 2.22 (1.49-3.31) and unspecified non-epithelioid 1.50 (1.06-2.14); Eastern Cooperative Oncology Group performance status ≥3 2.86 (1.64-5.00); hypoalbuminaemia 2.07 (1.47-2.92), carboplatin/pemetrexed chemotherapy 0.56 (0.38-0.80). CONCLUSION: The incidence of mesothelioma is increasing. Adverse prognostic factors include non-epithelioid histology, performance status and hypoalbuminaemia. Overall survival has not improved significantly, but treatment with carboplatin/pemetrexed chemotherapy is associated with a significant survival benefit.

Malignant mesothelioma presenting as a breast mass.

We present a case of a male patient with a breast mass, found to be a malignant mesothelioma. We discuss the diagnostic challenges, the need for heightened awareness in suspected cases, the histological classification of mesotheliomas and the treatments available. We believe this to be the second reported case of a mesothelioma presenting as a breast mass.

WE-G-217A-03: Respiratory-Related External/Internal Motion Based MR Image Reconstruction Using Dynamic Keyhole for Real-Time Tumor Monitoring.

PURPOSE: It is aim to test the hypothesis that a dynamic keyhole MRI reconstruction technique using external/internal respiratory surrogate position reduces acquisition time while retaining image quality for real-time tumor monitoring, compared to the conventional keyhole technique. METHODS: 46 thoracic MRI studies with 13 healthy human subjects have been acquired using a 3T GE MRI. Acquired MR images were reconstructed using zero-filling, conventional keyhole and the proposed respiratory motion based dynamic keyhole techniques; resultant images were then compared for image quality. Undersampled k-space rate in the phase encoding direction was determined based on the difference between the original image and the reconstructed image. The position of abdominal muscles and diaphragm were used to determine any excess data that exists in the overlaid temporal data. In addition, the feasibility of the dynamic keyhole method was applied using lung tumor MR images. RESULTS: The result from dynamic keyhole using respiratory motion demonstrated significant improvement compared with the zero-filling and conventional keyhole methods. Firstly, the dynamic keyhole method using external respiratory motion had an overlaid average of 79.7% (204 lines) of 256 lines from 46 datasets, compared to 63.9% in zero-filling and 74.3% in conventional keyhole. Secondly, dynamic keyhole method using internal diaphragm motion had an overlaid average of 84.5% (216 lines) of 256 lines from all datasets compared to 67.1% and 77.8% or zero-filling and conventional keyhole, respectively. Lastly, dynamic keyhole has been validated with one dataset involving lung tumor MR images. Image blurring artifacts and inferior resolution were not present in the final MR images using dynamic keyhole. CONCLUSIONS: Dynamic keyhole method using respiratory external/internal surrogate motion has been proposed to reconstruct MR images without image artifacts and with superior resolution. This method is applicable to MR images targeting lungs and other organs affected by respiratory motion for real-time tumor motion monitoring.

WE-G-213CD-07: Enhancing Respiratory Motion Prediction Accuracy Using Audiovisual (AV) Biofeedback.

PURPOSE: Prediction of respiratory-related tumor motion is hampered by irregularities present in the patient breathing patterns. Audiovisual (AV) biofeedback reduces irregularities, thereby producing a less complex breathing pattern. The aim of this project is to improve respiratory motion prediction accuracy using an AV biofeedback system. METHODS: An AV biofeedback system combined with real-time MRI was implemented in this project (4 human subjects across 5 studies (one subject had both an initial and follow-up study)). The AV biofeedback system consists of external marker positioned on the abdomen of human subjects, being tracked using an RPM system (Real-time Position Management, Varian) to guide the subject's breathing. Acquired respiratory data has been used as input for motion prediction through a dynamic multi-leaf collimator (DMLC) simulator developed by Prof. Keall. The prediction algorithm utilized was a kernel density estimation-based real-time prediction algorithm. A variety of prediction parameters were tested to determine optimum prediction performance. Prediction parameters adjusted were the delay time (DT) and training examples (TE); the parameters tested here were: DT/TE = 2500/1500, 2500/100, 1000/250, 500/250; Given that the data sampling rate was kept at 30 Hz, the resultant prediction training window lengths were 49.5, 8.25, 3.3 and 3.3seconds respectively. RESULTS: The mean difference between measured and predicted data for free breathing was 1.98±2.32mm; and 0.65±0.65mm for when AV biofeedback was implemented (reduction of error of 67%). The most accurate prediction results were attained using the parameters: DT/TE = 500 ms/250. CONCLUSIONS: This study demonstrates the improvement of respiratory motion prediction accuracy when AV biofeedback is implemented to produce a more regular breathing pattern.

Raising chickens in city backyards: the public health role.

There is increasing interest in raising chickens in urban settings across North America. Current regulations on backyard chickens vary by jurisdiction due to concerns about perceived health threats. Proposed negative impacts on public health and community well-being include infectious diseases acquired through rearing practices or consumption of eggs, inappropriate waste management, interaction with pests and predators and nuisance factors such as noise and odour. Proposed benefits are derived largely from the human-animal bond and from feelings of autonomy over food selection. The importance or validity of claims of positive and negative effects cannot be supported by literature specific to the urban agriculture context. Public health practitioners might approach this issue in a manner analogous to concerns over keeping domestic pets.

Anticancer Role of PPARgamma Agonists in Hematological Malignancies Found in the Vasculature, Marrow, and Eyes.

The use of targeted cancer therapies in combination with conventional chemotherapeutic agents and/or radiation treatment has increased overall survival of cancer patients. However, longer survival is accompanied by increased incidence of comorbidities due, in part, to drug side effects and toxicities. It is well accepted that inflammation and tumorigenesis are linked. Because peroxisome proliferator-activated receptor (PPAR)-gamma agonists are potent mediators of anti-inflammatory responses, it was a logical extension to examine the role of PPARgamma agonists in the treatment and prevention of cancer. This paper has two objectives: first to highlight the potential uses for PPARgamma agonists in anticancer therapy with special emphasis on their role when used as adjuvant or combined therapy in the treatment of hematological malignancies found in the vasculature, marrow, and eyes, and second, to review the potential role PPARgamma and/or its ligands may have in modulating cancer-associated angiogenesis and tumor-stromal microenvironment crosstalk in bone marrow.

Integrated magneto-optical traps on a chip using silicon pyramid structures.

We have integrated magneto-optical traps (MOTs) into an atom chip by etching pyramids into a silicon wafer. These have been used to trap atoms on the chip, directly from a room temperature vapor of rubidium. This new atom trapping method provides a simple way to integrate several atom sources on the same chip. It represents a substantial advance in atom chip technology and offers new possibilities for atom chip applications such as integrated single atom or photon sources and molecules on a chip.

Conservation of hydrophobicity within viral envelope glycoproteins reveals a putative hepatitis C virus fusion peptide.

The mechanism(s) by which hepatitis C virus (HCV) enters and infects cells remains unknown. Identifying the HCV fusion peptide(s) and understanding the early stages of infection may provide new opportunities for improved antiviral therapy. The HCV envelope glycoprotein E2 is thought to be a class II fusion protein. Class II fusion proteins are exemplified by the E protein of the tick-borne encephalitis virus (TBEV) and the E1 protein of the Semliki Forest virus (SFV). Analysis of the hydrophobicity profiles of four HCV E2 envelope glycoproteins revealed a region with a conserved three-pronged pattern of hydrophobicity, termed the tridentate (TD) region. The primary sequence of the TD region is highly conserved in all 490 HCV strains currently reported. The known fusion peptide loops of TBEV and SFV share the characteristic TD region hydrophobicity profile and significant sequence conservation in the TD region was identified in the E and E1 glycoproteins of members of the Flaviviridae and Togaviridae families, respectively. The HCV TD region peptides have membranotropic activity; in molecular dynamics (MD) simulations, the HCV TD region peptides insert into in a biomimetic bilayer in a similar manner to the TBEV fusion peptide and the peptides induce effective mixing of lipid membranes in a liposome fusion assay. Together these results indicate that the highly conserved TD region of the HCV E2 protein is a fusion peptide candidate and may be an important factor in the class II fusion mechanism.

Are you prepared? Defining occupational health resource needs to prevent infectious disease transmission in the health care sector.

This article discusses the extent of resource allocation to Occupational Health (OH) to prevent infectious disease exposure and transmission in British Columbia (B.C.). It also characterizes the delineation of roles and responsibilities within OH services in B.C. health care settings and highlights areas where improvements to current OH programs could be made to prevent and control occupational infections. Given the breadth of OH responsibilities, resource allocation in many health care institutions for these services is inadequate and roles and responsibilities may not be clearly delineated.

Sex differences in habitual physical activity and lung function decline in children with cystic fibrosis.

OBJECTIVES: To evaluate the feasibility of measuring habitual physical activity (HPA) in children with cystic fibrosis (CF) and to assess the relation between HPA and the rate of decline in FEV1 over a period of 2 years. STUDY DESIGN: At regular clinic visits, 109 patients (7 to 17 years; 56 girls) performed pulmonary function testing and completed the Habitual Activity Estimation Scale (HAES). Patients were divided into quartiles, based on activity levels derived from the HAES. RESULTS: Girls in the two lowest activity quartiles had a more rapid rate of decline FEV1 (-3.40% and -3.05% predicted, respectively) than girls in the two highest activity quartiles (-0.93% and +1.17% predicted, respectively) (P = .02). In boys, the rate of decline of FEV1 was similar in all activity quartiles (-1.95% predicted). Patients reported significantly more activity in summer compared with spring, winter, and fall (P < .0001), and boys reported greater activity than girls (6.5 +/- 2.9 vs 5.4 +/- 2.5 h/d, P < .05). CONCLUSIONS: The annual rate of change of FEV1 was related to activity quartile in girls but not in boys. This research suggests that an inactive lifestyle may partially explain the poorer survival of female patients with CF. The HAES is a feasible tool for routine follow-up of HPA in our CF clinic.

Tobacco-related-compound-induced nitrosative stress injury in the hamster cheek pouch.

The nitric oxide radical (*NO) released from tobacco-related compounds induces DNA damage, protein modifications, and cellular toxicity through the formation of peroxynitrite (ONOO-), the reaction product of *NO and the oxygen radical, superoxide. We hypothesize that tobacco-related compounds are cytotoxic and induce quantifiable DNA single-strand breaks in immortalized hamster cheek pouch (POII) cells, and that an amino acid marker of ONOO- injury, namely, 3-nitrotyrosine (3-NT), is detectable in hamster cheek pouch tissues chronically exposed to these compounds. We observed a dose-dependent decrease in POII cell viability with increasing tobacco-related compound concentrations, as well as a dose-dependent increase in DNA strand breaks. Semi-quantitative immunohistochemistry showed intense 3-NT immunoreactivity in hamster tissues treated with tobacco-related compounds compared with controls (p < 0.005). Our results suggest that tobacco-related compounds, including nicotine, are genotoxic, and that 3-NT is a quantifiable marker of ONOO- damage in intact hamster cheek pouch tissues.

Chloride persistence in a deiced access road drainage system.

Three years of field data, classical linear reservoir theory, and a new dissolution model confirm the hypothesis that residual chloride from highway deicing applications dissolves into precipitation throughout the year. The measured input includes 52 storm hyetographs and logs of salt and premix applications on an access road with a closed drainage system subject to runoff, interflow, and baseflow. The output data feature discharge and conductivity in an outlet weir measured continuously from February 1998 to May 2000. Individual storm hydrographs and pollutographs yield calibrated first flush dissolved chloride concentrations and residual solid chloride loads that persist at appreciable levels over the entire period of record. The storm calibrations imply a source strength w of 2.01 x 10(-6) s(-1) that accurately models chloride dissolution kinetics through three salt seasons on the access road. This w rests on physically plausible values for the depression storage depth zeta (3 mm) and porosity n (0.40) that store the residual chloride.

Disc excavation in dominant optic atrophy: differentiation from normal tension glaucoma.

OBJECTIVE: In patients with dominant optic atrophy (DOA, Kjer type), excavation of the optic nerve develops, and these patients may be misdiagnosed as having normal tension glaucoma (NTG). This study examined disc morphologic features in patients with DOA and explored features that help distinguish this condition from NTG. DESIGN: Noncomparative, observational case series. PARTICIPANTS: Patients with DOA who were seen at the Duke University Eye Center between 1987 and 1996 and who had bilateral optic nerve photographs. METHODS: Retrospective chart review of the results of visual acuity testing, visual field testing by Goldmann perimetry, color vision testing, intraocular pressure measurement, and observation of bilateral optic nerve photographs. MAIN OUTCOME MEASURES: Appearance of the optic disc and peripapillary zone in patients with DOA. RESULTS: Nine patients were identified. The mean age at the time of evaluation was 28 years (range, 11-62 years). Most patients had a mild to moderate reduction in visual acuity. Color vision as tested with Hardy-Rand-Rittler plates was reduced (4.0/10 +/- 4.2/10). A cup-to-disc ratio of more than 0.5 was observed in at least one eye of eight patients. A temporal wedge-shaped area of excavation was observed in 14 of the 18 eyes studied. Moderate to severe temporal pallor was observed in all of the eyes. Pallor of the remaining (noncupped) neuroretinal rim was also observed consistently, ranging from mild to moderate. A gray crescent and some degree of peripapillary atrophy were noted in all eyes. CONCLUSIONS: Several clinical features, including early age of onset, preferential loss of central vision, sparing of the peripheral fields, pallor of the remaining neuroretinal rim, and a family history of unexplained visual loss or optic atrophy, help to distinguish patients with DOA from those with NTG.

Practice management skills for the nurse practitioner.

The faculties of three schools of nursing involved in a collaborative family nurse practitioner (FNP) program designed a study to address issues involved in preparing the nurse practitioner for the challenges of practice management in the clinical environment. The purposes of the study were to (1) identify business concepts necessary to successfully manage a primary care practice; (2) determine which of these concepts should be incorporated into an FNP curriculum; and (3) clarify information to be taught regarding each identified concept. Fifty-four business concepts related to primary care were identified from a literature review. A survey was then developed to assess the extent to which the identified concepts were necessary for an FNP to effectively manage a practice. Seven experts and five FNP faculty responded to the survey. The Content Validity Index (CVI) defined by Lynn (1986) was applied and 20 concepts necessary for an FNP to effectively manage a practice were identified. A focus group that included nurse practitioners (both faculty and nonfaculty) from the three collaborative sites connected by interactive telecommunications determined that all 20 of the identified concepts should be included in an FNP curriculum. Additionally, the focus group clarified relevant information to be taught regarding each identified concept.