Non-invasive techniques for imaging in-vivo human corneal sub basal nerve mapping and migration rate in diabetic neuropathy

Purpose Corneal confocal microscopy (CCM) is a rapid non-invasive ophthalmic technique, which has been shown to diagnose and stratify the severity of diabetic neuropathy. Current morphometric techniques assess individual static images of the subbasal nerve plexus; this work explores the potential for non-invasive assessment of the wide-field morphology and dynamic changes of this plexus in vivo. Methods In this pilot study, laser scanning CCM was used to acquire maps (using a dynamic fixation target and semi-automated tiling software) of the central corneal sub-basal nerve plexus in 4 diabetic patients with and 6 without neuropathy and in 2 control subjects. Nerve migration was measured in an additional 7 diabetic patients with neuropathy, 4 without neuropathy and in 2 control subjects by repeating a modified version of the mapping procedure within 2-8 weeks, thus facilitating re-identification of distinctive nerve landmarks in the 2 montages. The rate of nerve movement was determined from these data and normalised to a weekly rate (µm/week), using customised software. Results Wide-field corneal nerve fibre length correlated significantly with the Neuropathy Disability Score (r = -0.58, p < 0.05), vibration perception (r = -0.66, p < 0.05) and peroneal conduction velocity (r = 0.67, p < 0.05). Central corneal nerve fibre length did not correlate with any of these measures of neuropathy (p > 0.05 for all). The rate of corneal nerve migration was 14.3 ± 1.1 µm/week in diabetic patients with neuropathy, 19.7 ± 13.3µm/week in diabetic patients without neuropathy, and 24.4 ± 9.8µm/week in control subjects; however, these differences were not significantly different (p = 0.543). Conclusions Our data demonstrate that it is possible to capture wide-field images of the corneal nerve plexus, and to quantify the rate of corneal nerve migration by repeating this procedure over a number of weeks. Further studies on larger sample sizes are required to determine the utility of this approach for the diagnosis and monitoring of diabetic neuropathy.

PTRF/cavin-1 neutralizes non-caveolar caveolin-1 microdomains in prostate cancer

Caveolin-1 has a complex role in prostate cancer and has been suggested to be a potential biomarker and therapeutic target. As mature caveolin-1 resides in caveolae, invaginated lipid raft domains at the plasma membrane, caveolae have been suggested as a tumor-promoting signaling platform in prostate cancer. However, caveola formation requires both caveolin-1 and cavin-1 (also known as PTRF; polymerase I and transcript release factor). Here, we examined the expression of cavin-1 in prostate epithelia and stroma using tissue microarray including normal, non-malignant and malignant prostate tissues. We found that caveolin-1 was induced without the presence of cavin-1 in advanced prostate carcinoma, an expression pattern mirrored in the PC-3 cell line. In contrast, normal prostate epithelia expressed neither caveolin-1 nor cavin-1, while prostate stroma highly expressed both caveolin-1 and cavin-1. Utilizing PC-3 cells as a suitable model for caveolin-1-positive advanced prostate cancer, we found that cavin-1 expression in PC-3 cells inhibits anchorage-independent growth, and reduces in vivo tumor growth and metastasis in an orthotopic prostate cancer xenograft mouse model. The expression of α-smooth muscle actin in stroma along with interleukin-6 (IL-6) in cancer cells was also decreased in tumors of mice bearing PC-3-cavin-1 tumor cells. To determine whether cavin-1 acts by neutralizing caveolin-1, we expressed cavin-1 in caveolin-1-negative prostate cancer LNCaP and 22Rv1 cells. Caveolin-1 but not cavin-1 expression increased anchorage-independent growth in LNCaP and 22Rv1 cells. Cavin-1 co-expression reversed caveolin-1 effects in caveolin-1-positive LNCaP cells. Taken together, these results suggest that caveolin-1 in advanced prostate cancer is present outside of caveolae, because of the lack of cavin-1 expression. Cavin-1 expression attenuates the effects of non-caveolar caveolin-1 microdomains partly via reduced IL-6 microenvironmental function. With circulating caveolin-1 as a potential biomarker for advanced prostate cancer, identification of the molecular pathways affected by cavin-1 could provide novel therapeutic targets.

The effect of hip muscle strengthening on pain and disability for individuals with non-specific low back pain : a randomized controlled trial

Introduction Clinical guidelines for the treatment of chronic low back pain suggest the use of supervised exercise. Motor control (MC) based exercise is widely used within clinical practice but its efficacy is equivalent to general exercise therapy. MC exercise targets the trunk musculature. Considering the mechanical links between the hip, pelvis, and lumbar spine, surprisingly little focus has been on investigating the contribution of the hip musculature to lumbopelvic support. The purpose of this study is to compare the efficacy of two exercise programs for the treatment of non-specific low back pain (NSLBP). Methods Eighty individuals aged 18-65 years of age were randomized into two groups to participate in this trial. The primary outcome measures included self-reported pain intensity (0-100mm VAS) and percent disability (Oswestry Disability Index V2). Bilateral measures of hip strength (N/kg) and two dimensional frontal plane mechanics (º) were the secondary outcomes. Outcomes were measured at baseline and following a six-week home based exercise program including weekly sessions of real-time ultrasound imaging. Results Within group comparisons revealed clinically meaningful reductions in pain for both groups. The MC exercise only (N= 40, xˉ =-20.9mm, 95%CI -25.7, -16.1) and the combined MC and hip exercise (N= 40, xˉ = -24.9mm, 95%CI -30.8, -19.0). There was no statistical difference in the change of pain (xˉ =-4.0mm, t= -1.07, p=0.29, 95%CI -11.5, 3.5) or disability (xˉ =-0.3%, t=-0.19, p=0.85, 95%CI -11.5, 3.5) between groups. Conclusion Both exercise programs had similar and positive effects on NSLBP which support the use of the home based exercise programs with weekly supervised visits. However, the addition of specific hip strengthening exercises to a MC based exercise program did not result in significantly greater reductions in pain or disability. Trial Registration NCTO1567566 Funding: Worker’s Compensation Board Alberta Research Grant.

The use of penumbrae to define and analyse non-standard fields

Aim A new method of penumbral analysis is implemented which allows an unambiguous determination of field size and penumbra size and quality for small fields and other non-standard fields. Both source occlusion and lateral electronic disequilibrium will affect the size and shape of cross-axis profile penumbrae; each is examined in detail. Method A new method of penumbral analysis is implemented where the square of the derivative of the cross-axis profile is plotted. The resultant graph displays two peaks in the place of the two penumbrae. This allows a strong visualisation of the quality of a field penumbra, as well as a mathematically consistent method of determining field size (distance between the two peak’s maxima), and penumbra (full-widthtenth-maximum of peak). Cross-axis profiles were simulated in a water phantom at a depth of 5 cm using Monte Carlo modelling, for field sizes between 5 and 30 mm. The field size and penumbra size of each field was calculated using the method above, as well as traditional definitions set out in IEC976. The effect of source occlusion and lateral electronic disequilibrium on the penumbrae was isolated by repeating the simulations removing electron transport and using an electron spot size of 0 mm, respectively. Results All field sizes calculated using the traditional and proposed methods agreed within 0.2 mm. The penumbra size measured using the proposed method was systematically 1.8 mm larger than the traditional method at all field sizes. The size of the source had a larger effect on the size of the penumbra than did lateral electronic disequilibrium, particularly at very small field sizes. Conclusion Traditional methods of calculating field size and penumbra are proved to be mathematically adequate for small fields. However, the field size definition proposed in this study would be more robust amongst other nonstandard fields, such as flattening filter free. Source occlusion plays a bigger role than lateral electronic disequilibrium in small field penumbra size.

The complete genome sequence of Escherichia coli EC958: a high quality reference sequence for the globally disseminated multidrug resistant E. coli O25b:H4-ST131 clone

Escherichia coli ST131 is now recognised as a leading contributor to urinary tract and bloodstream infections in both community and clinical settings. Here we present the complete, annotated genome of E. coli EC958, which was isolated from the urine of a patient presenting with a urinary tract infection in the Northwest region of England and represents the most well characterised ST131 strain. Sequencing was carried out using the Pacific Biosciences platform, which provided sufficient depth and read-length to produce a complete genome without the need for other technologies. The discovery of spurious contigs within the assembly that correspond to site-specific inversions in the tail fibre regions of prophages demonstrates the potential for this technology to reveal dynamic evolutionary mechanisms. E. coli EC958 belongs to the major subgroup of ST131 strains that produce the CTX-M-15 extended spectrum β-lactamase, are fluoroquinolone resistant and encode the fimH30 type 1 fimbrial adhesin. This subgroup includes the Indian strain NA114 and the North American strain JJ1886. A comparison of the genomes of EC958, JJ1886 and NA114 revealed that differences in the arrangement of genomic islands, prophages and other repetitive elements in the NA114 genome are not biologically relevant and are due to misassembly. The availability of a high quality uropathogenic E. coli ST131 genome provides a reference for understanding this multidrug resistant pathogen and will facilitate novel functional, comparative and clinical studies of the E. coli ST131 clonal lineage.

Demonstration of regulatory cross-talk between P fimbriae and type 1 fimbriae in uropathogenic Escherichia coli

The majority of Escherichia coli strains isolated from urinary tract infections have the potential to express multiple fimbriae. Two of the most common fimbrial adhesins are type 1 fimbriae and pyelonephritis-associated pili (Pap). Previous research has shown that induced, plasmid-based expression of a Pap regulator, papB, and its close homologues can prevent inversion of the fim switch controlling the expression of type 1 fimbriae. The aim of the present study was to determine if this cross-regulation occurs when PapB is expressed from its native promoter in the chromosome of E. coli K-12 and clinical isolates. The regulation was examined in three ways: (1) mutated alleles of the pap regulatory region, including papB and papI, that maintain the pap promoter in either the off or the on phase were exchanged into the chromosome of both E. coli K-12 and the clinical isolate E. coli CFT073, and the effect on type 1 fimbrial expression was measured; (2) type 1 fimbrial expression was determined using a novel fimS : : gfp+ reporter system in mutants of the clinical isolate E. coli 536 in which combinations of complete fimbrial clusters had been deleted; (3) type 1 fimbrial expression was determined in a range of clinical isolates and compared with both the number of P clusters and their expression. All three approaches demonstrated that P expression represses type 1 fimbrial expression. Using a number of novel genetic approaches, this work extends the initial finding that PapB inhibits FimB recombination to the impact of this regulation in clinical isolates.

Biological monitoring in workers in a nitrobenzene reduction plant : Haemoglobin versus serum albumin adducts

The high priority of monitoring workers exposed to nitrobenzene is a consequence of clear findings of experimental carcinogenicity of nitrobenzene and the associated evaluations by the International Agency for Research on Cancer. Eighty male employees of a nitrobenzene reduction plant, with potential skin contact with nitrobenzene and aniline, participated in a current medical surveillance programme. Blood samples were routinely taken and analysed for aniline, 4-aminodiphenyl (4-ADP) and benzidine adducts of haemoglobin (Hb) and human serum albumin (HSA). Also, levels of methaemoglobin (Met-Hb) and of carbon monoxide haemoglobin (CO-Hb) were monitored. Effects of smoking were straightforward. Using the rank sum test of Wilcoxon, we found that very clear-cut and statistically significant smoking effects (about 3-fold increases) were apparent on CO-Hb (P = 0.00085) and on the Hb adduct of 4-ADP (P = 0.0006). The mean aniline-Hb adduct level in smokers was 1.5 times higher than in non-smokers; the significance (P = 0.05375) was close to the 5% level. The strongest correlation was evident between the Hb and HSA adducts of aniline (rs = 0.846). Less pronounced correlations (but with P values < 0.02) appeared between aniline-Hb and 4-ADP-Hb adducts (rs = 0.388), between 4-ADP and 4-ADP-HSA adducts (rs = 0.373), and between 4-ADP-Hb and aniline-HSA adducts (rs = 0.275). In view of the proposal for additional use of the aniline-HSA adduct for biological monitoring, particularly in cases of acute overexposures or poisonings, the strong correlation of the Hb and HSA conjugates is noteworthy; the ratio aniline-HSA:aniline-Hb was 1:42 for the entire cohort.

Increased sensitivity to tryptophan bioavailability is a positive adaptation by the human strains of Chlamydia pneumoniae

One of the most significant activities induced by interferon-gamma against intracellular pathogens is the induction of IDO (indoleamine 2,3-dioxygenase) expression, which subsequently results in the depletion of tryptophan. We tested the hypothesis that human strains of Chlamydia pneumoniae are more sensitive to tryptophan limitation than animal C. pneumoniae strains. The human strains were significantly more sensitive to IFN-γ than the animal strains in a lung epithelia cell model (BEAS-2B), with exposure to 1 U ml(-1) IFN-γ resulting in complete loss of infectious yield of human strains, compared to the animal strains where reductions in infectious progeny were around 3.5-4.0 log. Strikingly, the IFN-γ induced loss of ability to form infectious progeny production was completely rescued by removal of the IFN-γ and addition of exogenous tryptophan for the human strains, but not the animal strains. In fact, a human heart strain was more capable of entering a non-infectious, viable persistent stage when exposed to IFN-γ and was also more effectively rescued, compared to a human respiratory strain. Exquisite susceptibility to IFN-γ, specifically due to tryptophan availability appears to be a core adaptation of the human C. pneumoniae strains, which may reflect the chronic nature of their infections in this host.

Dalby Shopping Precinct Survey Report : Consumer Attitudes towards Proposed Extended Trading Hours at Dalby

Data was collected to measure shopper’s attitudes toward the proposed Sunday and limited public holiday trading in Dalby. Survey questionnaires were conducted between 29th August to 31st August at Coles Dalby and Dalby Shoppingtown Plaza. In total, 150 respondents participated in the survey. Overall, the findings suggest that most respondents, especially males, couples with children, fulltime workers and those under the age of 49 years, embrace the proposed Sunday and limited holiday trading in Dalby. While there are concerns over increasing competition for smaller retailers who already trade on Sundays, a majority of respondents indicated it would suit their lifestyle, be convenient, provide more jobs, increase trade for smaller retailers within the area, reduce queues and congestion observed on Saturdays. The majority of those shoppers that indicated they currently did some shopping on a Sunday reported they would continue to support smaller retailers who currently trade on Sundays and some public holidays, if changes came about. Those opposed to changes to trading hours indicated a belief that existing trading hours were sufficient. Most people indicated the proposed extension of trading hours would not harm the community or have a negative, detrimental effect on themselves or their family. The main findings presented in the report are as follows: - 96.8% of respondents surveyed reported to be local, permanent residents of Dalby. - Residents of Dalby visited shopping centres and stores on average 2.8 times per week. This frequency is proportionately higher than the average Australian shopping behaviour at 2.5 times per week (Roy Morgan Supermarket Monitor). - It was determined that weekday evenings (after 5 pm) were the busiest times for shopping, with Saturday the next most popular day to shop. - 68% of respondents support the proposal of the extended trading hours at supermarkets, department stores and the shopping centre in Dalby, 26% oppose and 6% are unsure. - 90% of the respondents agreed that residents of Dalby should be allowed the same choice as other regional towns and cities in supporting/opposing changes to trading hours. The remaining 10% expressed a disagreement. - A larger percentage of males supported the proposal for Sunday and limited holiday trading. Of all the males surveyed, 80% were in support, 15% were opposed and 5% unsure. 60% of female respondents support the proposal, while 33% oppose it and 5% were unsure. - The highest percentage of support exists in fulltime workers with 90% of those respondents supporting the proposal. - In contrast, the lowest percentage of support was found in the non-working (retired/unemployed) respondents, where 67% opposed the application. - It was noted that 71% of respondents employed casually also indicated opposition against proposed changes. Further questioning identified an underlying concern from casually employed persons that Sunday trade would force them onto Sunday work rosters. - 92% of shared households expressed support for Sunday and limited public holiday trading, while 83% of both couples with children and single parent with children at home also supported the application. - 72% of the respondents often find it necessary to do some grocery shopping in Dalby on a Sunday. 76% of shoppers who indicated they already undertook some shopping on Sunday, indicated would continue to shop and support smaller retailers. - Of the respondents surveyed, 44% have travelled outside of Dalby on a Sunday to shop. This indicates that such residents find it necessary to undertake some shopping on a Sunday and in order to do so, drive an hour to Toowoomba in order to access a range of retailers. - The most cited reasons for supporting Sunday and limited public holiday trade were; ‘More choice about when I shop and that is convenient’ (69%), ‘Sunday trade will create job opportunities’ (71%), ‘Sunday trade will be helpful when preparing school lunches and getting ready for the working week’ (62%), and ‘Sunday trade will reduce shopping congestion during peak shopping periods’ (62%) - The most cited reasons for opposing the proposed changes are that ‘Sunday trade may increase competition for small retailers who already trade on Sunday’ (41%), ‘Shops are already open 6 days a week which is enough’ (31%), and ‘Sunday is a day of rest or a religious day and shopping should not be allowed’ (23%). - 97% of respondents indicated they would not change their sporting or social commitment if changes to trading hours were implemented.

Mt Isa Shopping Precinct Survey Report : Consumer Attitudes towards Proposed Extended Trading Hours at Mt Isa

Data was collected to measure shopper’s attitudes toward the proposed Sunday and limited public holiday trading in Mt Isa. Survey questionnaires were conducted between 15th August to 17th August at Kmart Plaza, Woolworths, Miles St. and Mt Isa Plaza. In total, 300 respondents participated in the survey. Overall, the findings suggest that most respondents, especially males, couples with children and fulltime workers, embrace the proposed Sunday and limited holiday trading in Mt Isa. While there are concerns over increasing competition for smaller retailers who already trade on Sundays, a majority of respondents indicated it would suit their lifestyle, be convenient, provide more jobs, increase trade for smaller retailers within the area, reduce queues and congestion, and offer a less expensive grocery shopping. The majority of those shoppers that indicated they currently did some shopping on a Sunday reported they would continue to support smaller retailers who currently trade on Sundays and some public holidays, if changes came about. Those opposed to changes to trading hours also indicated a belief that existing trading hours were sufficient. Most people indicated the proposed extension of trading hours would not harm the community or have a negative, detrimental effect on themselves or their family. The main findings presented in the report are as follows: - 96% of respondents surveyed reported to be local, permanent residents of Mt Isa. - Residents of Mt Isa visited shopping centres and stores on average 2.4 times per week. This mirrors the average Australian shopping behaviour at 2.5 times per week (Roy Morgan Supermarket Monitor) - It was determined that Saturday was the busiest day for shopping with a majority of respondents indicating they visited stores on that day of the week. - 71% of respondents support the proposal of extended trading hours at shopping centres in Mt Isa, 25% oppose and 4% are unsure. - 87% of the respondents agreed that residents of Mt Isa should be allowed the same choice as other regional towns and cities in supporting/opposing changes to trading hours. The remaining 13% expressed a disagreement. - A larger percentage of males supported the proposal for Sunday and limited holiday trading. Of all the males surveyed, 81% were in support, 17% were opposed and 2% unsure. By contrast, 64% of female respondents support the proposal, while 31% oppose it and 5% are unsure. - The highest percentage of support exists in fulltime workers with 85% of those respondents supporting the proposal. In contrast, the lowest percentage of support was found in the non-working respondents, where 62% opposed the application. - 78% of couples living with children at home expressed support for Sunday and limited public holiday trading, while 60% of couples without children also supported the application. - Of the respondents surveyed, virtually none (less than 1%) have travelled outside of Mt Isa on a Sunday to shop. This indicates that due to the remote and isolated location of this town, residents do not have the option to travel reasonable distances in order to access a range of retailers. - 70% of the respondents often find it necessary to do some grocery shopping in Mt Isa on a Sunday. - Convenience is cited as the major reason for support (79%) followed by lifestyle (75%). - The most cited reasons for supporting ‘it would be convenient’ (81%), ‘It may create more jobs’ (77%), ‘It may reduce congestion during busy shopping periods’ (74%, and ‘It would make it easier for working families with kids’ (74%). - The most cited reasons for opposing the proposed changes are that ‘It will disadvantage smaller businesses’ (44%), ‘It is unnecessary’ (29%). - 72% of shoppers who indicated they already undertook some shopping on Sunday, indicated would continue to shop and support smaller retailers. - 98% of respondents indicated they would not change their sporting or social commitment if changes to trading hours were implemented.

Incidence of paediatric fatal and non-fatal low speed vehicle run over events in Queensland, Australia : eleven year analysis

Background The purpose of this study was to estimate the incidence of fatal and non-fatal Low Speed Vehicle Run Over (LSVRO) events among children aged 0–15 years in Queensland, Australia, at a population level. Methods Fatal and non-fatal LSVRO events that occurred in children resident in Queensland over eleven calendar years (1999-2009) were identified using ICD codes, text description, word searches and medical notes clarification, obtained from five health related data bases across the continuum of care (pre-hospital to fatality). Data were manually linked. Population data provided by the Australian Bureau of Statistics were used to calculate crude incidence rates for fatal and non-fatal LSVRO events. Results There were 1611 LSVROs between 1999–2009 (IR = 16.87/100,000/annum). Incidence of non-fatal events (IR = 16.60/100,000/annum) was 61.5 times higher than fatal events (IR = 0.27/100,000/annum). LSVRO events were more common in boys (IR = 20.97/100,000/annum) than girls (IR = 12.55/100,000/annum), and among younger children aged 0–4 years (IR = 21.45/100000/annum; 39% or all events) than older children (5–9 years: IR = 16.47/100,000/annum; 10–15 years IR = 13.59/100,000/annum). A total of 896 (56.8%) children were admitted to hospital for 24 hours of more following an LSVRO event (IR = 9.38/100,000/annum). Total LSVROs increased from 1999 (IR = 14.79/100,000) to 2009 (IR = 18.56/100,000), but not significantly. Over the 11 year period, there was a slight (non –significant) increase in fatalities (IR = 0.37-0.42/100,000/annum); a significant decrease in admissions (IR = 12.39–5.36/100,000/annum), and significant increase in non-admissions (IR = 2.02-12.77/100,000/annum). Trends over time differed by age, gender and severity. Conclusion This is the most comprehensive, population-based epidemiological study on fatal and non-fatal LSVRO events to date. Results from this study indicate that LSVROs incur a substantial burden. Further research is required on the characteristics and risk factors associated with these events, in order to adequately inform injury prevention. Strategies are urgently required in order to prevent these events, especially among young children aged 0-4 years.

2nd ESMO consensus conference on lung cancer : early-stage non-small-cell lung cancer consensus on diagnosis, treatment and follow-up

To complement the existing treatment guidelines for all tumour types, ESMO organises consensus conferences to focus on specific issues in each type of tumour. The 2nd ESMO Consensus Conference on Lung Cancer was held on 11-12 May 2013 in Lugano. A total of 35 experts met to address several questions on non-small-cell lung cancer (NSCLC) in each of four areas: pathology and molecular biomarkers, first-line/second and further lines in advanced disease, earlystage disease and locally advanced disease. For each question, recommendations were made including reference to the grade of recommendation and level of evidence. This consensus paper focuses on early-stage disease. © The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

2nd ESMO Consensus Conference on Lung Cancer : non-small-cell lung cancer first-line/second and further lines in advanced disease

To complement the existing treatment guidelines for all tumour types, ESMO organises consensus conferences to focus on specific issues in each type of tumour. The 2nd ESMO Consensus Conference on Lung Cancer was held on 11-12 May 2013 in Lugano. A total of 35 experts met to address several questions on non-small-cell lung cancer (NSCLC) in each of four areas: pathology and molecular biomarkers, first-line/second and further lines in advanced disease, early stage disease and locally-advanced disease. For each question, recommendations were made including reference to the grade of recommendation and level of evidence. This consensus paper focuses on 1st line / 2nd and further lines of treatment in advanced disease. © The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

Second ESMO consensus conference on lung cancer : pathology and molecular biomarkers for non-small-cell lung cancer

To complement the existing treatment guidelines for all tumour types, ESMO organises consensus conferences to focus on specific issues in each type of tumour. The Second ESMO Consensus Conference on Lung Cancer was held on 11-12 May 2013 in Lugano. A total of 35 experts met to address several questions on management of patients with nonsmall- cell lung cancer (NSCLC) in each of four areas: pathology and molecular biomarkers, early stage disease, locally advanced disease and advanced (metastatic) disease. For each question, recommendations were made including reference to the grade of recommendation and level of evidence. This consensus paper focuses on recommendations for pathology and molecular biomarkers in relation to the diagnosis of lung cancer, primarily non-small-cell carcinomas.