Multipath artifacts enable angular contrast in multimodal endoscopic optical coherence tomography.

Multipath artifacts are inherent to double-clad fiber based optical coherence tomography (OCT), appearing as ghost images blurred in the A-line direction. They result from the excitation of higher-order inner-cladding modes in the OCT sample arm which cross-couple into the fundamental mode at discontinuities and thus are detected in single-mode fiber-based interferometers. Historically, multipath artifacts have been regarded as a drawback in single fiber endoscopic multimodal OCT systems as they degrade OCT quality. In this work, we reveal that multipath artifacts can be projected into high-quality two-dimensional en face images which encode high angle backscattering features. Using a combination of experiment and simulation, we characterize the coupling of Mie-range scatterers into the fundamental image (LP01 mode) and higher-order image (multipath artifact). This is validated experimentally through imaging of microspheres with an endoscopic multimodal OCT system. The angular dependence of the fundamental image and higher order image generated by the multipath artifact lays the basis for multipath contrast, a ratiometric measurement of differential coupling which provides information regarding the angular diversity of a sample. Multipath contrast images can be generated from OCT data where multipath artifacts are present, meaning that a wealth of clinical data can be retrospectively examined.

Triple-clad W-type fiber mitigates multipath artifacts in multimodal optical coherence tomography.

Multimodal endoscopic optical coherence tomography (OCT) can be implemented with double-clad fiber by using the presumed single-mode core for OCT and the higher numerical aperture cladding for a secondary modality. However, the quality of OCT in double-clad fiber (DCF) based systems is compromised by the introduction of multipath artifacts that are nt present in single-mode fiber OCT systems. Herein, the mechanisms for multipath artifacts in DCF are linked to its modal contents using a commercial software package and experimental measurement. A triple-clad W-type fiber is proposed as a method for achieving multimodal imaging with single-mode quality OCT in an endoscopic system. Simulations of the modal contents of a W-type fiber are compared to DCF and single-mode fiber. Finally, a W-Type fiber rotary catheter is used in a DCF-based endoscopic OCT and autofluorescence imaging (AFI) system to demonstrate multipath artifact free OCT and AFI of a human fingertip.

The effect of the menstrual cycle and hyperglycaemia on hormonal and metabolic responses during exercise.

PURPOSE: Variations in substrate metabolism have been identified in women during continuous steady-state aerobic exercise performed at the same relative intensity throughout discrete phases of the menstrual cycle, although some evidence exists that this is abolished when carbohydrate is ingested. This investigation examined the effects of a supraphysiologic exogenous glucose infusion protocol, administered during two phases of the menstrual cycle (follicular and luteal) in eumenorrheic women to identify differences between metabolic, hormonal and substrate oxidative responses. METHODS: During the experimental conditions, blood glucose was infused intravenously at rates to "clamp" blood glucose at 10 mM in seven healthy females (age 20 ± 1 y, mass 55.0 ± 4.1 kg, [Formula: see text] 40.0 ± 1.8 ml/kg/min). Following 30 min of seated rest, participants exercised on a cycle ergometer for 90 min at 60% [Formula: see text]. During the rest period and throughout exercise, blood metabolites and hormones were collected at regular intervals, in addition to expired air for the measurement of substrate oxidation. RESULTS: Significant differences between ovarian hormones and menstrual phase were identified, with estrogen significantly higher during the luteal phase compared to the follicular phase (213.28 ± 30.70 pmol/l vs 103.86 ± 13.85 pmol/l; p = 0.016), and for progesterone (14.23 ± 4.88 vs 2.11 ± 0.36 nmol/l; p = 0.042). However, no further significance was identified in any of the hormonal, metabolite or substrate utilisation patterns between phases. CONCLUSION: These data demonstrate that the infusion of a supraphysiological glucose dose curtails any likely metabolic influence employed by the fluctuation of ovarian hormones in eumenorrheic women during moderate exercise.

Eli Lilly and Company Insulins - A Century of Innovation.

Eli Lilly and Company has played a pivotal role in the development of insulin products since its discovery in 1921. Through their dedication to pharmaceutical innovation, Josiah K. Lilly Sr. and George HA Clowes, in close collaborations with the University of Toronto, made insulin commercially available in 1923. Other innovations include the development and commercialization of the first biosynthetic human insulin, a rapid-acting insulin analog and analog mixtures. Lilly has advanced the field of knowledge with significant efforts toward developing a hepatic preferential basal insulin. Other important insulin projects include the first concentrated rapid-acting insulin analog, clinical studies supporting the use of highly concentrated human insulin, and an advanced clinical development program for an ultra-rapid insulin analog. Lilly's commitment to people affected with diabetes remains strong and will continue into the future through collaborative research, innovative product development and investing in advanced technologies.

The generation of consensus guidelines for carrying out process evaluations in rehabilitation research.

BACKGROUND: Although in recent years there has been a strong increase in published research on theories (e.g. realist evaluation, normalization process theory) driving and guiding process evaluations of complex interventions, there is limited guidance to help rehabilitation researchers design and carry out process evaluations. This can lead to the risk of process evaluations being unsystematic. This paper reports on the development of new consensus guidelines that address the specific challenges of conducting process evaluations alongside clinical trials of rehabilitation interventions. METHODS: A formal consensus process was carried out based on a modified nominal group technique, which comprised two phases. Phase I was informed by the findings of a systematic review, and included a nominal group meeting with an expert panel of participants to rate and discuss the proposed statements. Phase II was an in depth semi-structured telephone interviews with expert panel participants in order to further discuss the structure and contents of the revised guidelines. Frequency of rating responses to each statement was calculated and thematic analysis was carried out on all qualitative data. RESULTS: The guidelines for carrying out process evaluations within complex intervention rehabilitation research were produced by combining findings from Phase I and Phase II. The consensus guidelines include recommendations that are grouped in seven sections. These sections are theoretical work, design and methods, context, recruitment and retention, intervention staff, delivery of the intervention and results. These sections represent different aspects or stages of the evaluation process. CONCLUSION: The consensus guidelines here presented can play a role at assisting rehabilitation researchers at the time of designing and conducting process evaluations alongside trials of complex interventions. The guidelines break new ground in terms of concepts and theory and works towards a consensus in regards to how rehabilitation researchers should go about carrying out process evaluations and how this evaluation should be linked into the proposed trials. These guidelines may be used, adapted and tested by rehabilitation researchers depending on the research stage or study design (e.g. feasibility trial, pilot trial, etc.).

An analysis of Pseudomonas genomic diversity in take-all infected wheat fields reveals the lasting impact of wheat cultivars on the soil microbiota.

Manipulation of the soil microbiota associated with crop plants has huge promise for the control of crop pathogens. However, to fully realize this potential we need a better understanding of the relationship between the soil environment and the genes and phenotypes that enable microbes to colonize plants and contribute to biocontrol. A recent 2 years of investigation into the effect of wheat variety on second year crop yield in the context of take-all fungal infection presented the opportunity to examine soil microbiomes under closely defined field conditions. Amplicon sequencing of second year soil samples showed that Pseudomonas spp. were particularly affected by the wheat cultivar grown in year one. Consequently, 318 rhizosphere-associated Pseudomonas fluorescens strains were isolated and characterized across a variety of genetic and phenotypic traits. Again, the wheat variety grown in the first year of the study was shown to exert considerable selective pressure on both the extent and nature of Pseudomonas genomic diversity. Furthermore, multiple significant correlations were identified within the phenotypic/genetic structure of the Pseudomonas population, and between individual genotypes and the external wheat field environment. The approach outlined here has considerable future potential for our understanding of plant-microbe interactions, and for the broader analysis of complex microbial communities.

The physiological effects of low-intensity neuromuscular electrical stimulation (NMES) on short-term recovery from supra-maximal exercise bouts in male triathletes.

This study investigated the acute effects of NMES on blood lactate (BLa) and performance parameters in trained male triathletes. On three separate days, 13 trained male triathletes performed six 30 s Wingate tests (30 WanT) on a cycle ergometer. Each session consisted of performing 3 × 30 WanT (bouts 1-3) followed by a randomly assigned 30 min recovery intervention of either: (i) passive (seated), (ii) active (cycling at 30% VO(2 max)) or (iii) NMES (1 Hz/500 µs-ON:OFF 2:6 s). The 3 × 30 WanT bouts were then repeated (bouts 4-6) and compared to bouts 1-3 for peak power (PP), mean power (MP) and fatigue index (FI). BLa and heart rate (HR) were recorded at designated time points throughout. Data were analyzed using repeated measures ANOVA with Tukey's honestly significant difference post hoc test. BLa decreased significantly faster during the active recovery intervention (P < 0.001), however, there were no significant differences between interventions for PP (P = 0.217), MP (P = 0.477) and FI (P = 0.234) when the post intervention bouts (4-6) where compared to the pre intervention bouts (1-3). NMES during recovery was not more effective than active or passive recovery for improving subsequent performance. Despite BLa clearing at a significantly faster rate for the active recovery intervention, PP, MP or FI did not improve significantly compared to NMES and passive. In conclusion, NMES does not appear to be more effective than traditional methods for enhancing short-term recovery from supra-maximal exercise bouts in trained male triathletes.

Yoga for reducing perceived stress and back pain at work.

BACKGROUND: Stress and back pain are two key factors leading to sickness absence at work. Recent research indicates that yoga can be effective for reducing perceived stress, alleviating back pain, and improving psychological well-being. AIMS: To determine the effectiveness of a yoga-based intervention for reducing perceived stress and back pain at work. METHODS: Participants were recruited from a British local government authority and randomized into a yoga group who received one 50 min Dru Yoga session each week for 8 weeks and a 20 min DVD for home practice and a control group who received no intervention. Baseline and end-programme measurements of self-reported stress, back pain and psychological well-being were assessed with the Perceived Stress Scale, Roland Morris Disability Questionnaire and the Positive and Negative Affect Scale. RESULTS: There were 37 participants in each group. Analysis of variance and multiple linear regression showed that in comparison to the control group, the yoga group reported significant reductions in perceived stress and back pain, and a substantial improvement in psychological well-being. When compared with the control group at the end of the programme, the yoga group scores were significantly lower for perceived stress, back pain, sadness and hostility, and substantially higher for feeling self-assured, attentive and serene. CONCLUSIONS: The results indicate that a workplace yoga intervention can reduce perceived stress and back pain and improve psychological well-being. Larger randomized controlled trials are needed to determine the broader efficacy of yoga for improving workplace productivity and reducing sickness absence.

Association of Baseline Patient-reported Health-related Quality of Life Metrics with Outcome in Localised Prostate Cancer.

AIMS: Although health-related quality of life (HR-QoL) outcomes are pivotal in oncology, the prognostic significance of patient-reported HR-QoL metrics is largely undefined in localised prostate cancer. We report the association of baseline HR-QoL metrics with overall survival and toxicity in localised prostate cancer. MATERIALS AND METHODS: This was a secondary analysis of a phase III randomised controlled study conducted in a single-payer health system. Patients with Gleason score ≤7, clinical stage T1b-T3a and prostate-specific antigen <30 ng/ml were randomised to neoadjuvant and concurrent androgen deprivation therapy (ADT) for 6 months starting 4 months before prostate radiotherapy or concurrent and adjuvant ADT for 6 months starting simultaneously with prostate radiotherapy. HR-QoL scores were estimated using the European Organisation for Research and Treatment of Cancer QoL questionnaire. A multistate Markov model was used to determine the association of baseline HR-QoL metrics with overall survival and a multilevel multivariable Cox regression was used to determine the association with the incidence of delayed-onset grade ≥3 radiotherapy-related toxicities. To adjust for multiple analyses, P < 0.025 was considered as statistically significant. RESULTS: Overall, 393 patients with baseline HR-QoL data were included in this analysis: 194 in the neoadjuvant arm and 199 in the adjuvant arm. Baseline financial difficulty (hazard ratio 1.020, 95% confidence interval 1.010-1.030, P = 0.02) and dyspnoea (hazard ratio 1.020, 95% confidence interval 1.003-1.030, P = 0.01) were associated with inferior overall survival. Baseline dyspnoea was associated with a higher incidence of grade ≥3 toxicity (hazard ratio 1.020, 95% confidence interval 1.010-1.030, P = 0.023). CONCLUSION: In a cohort of localised prostate cancer patients treated with radiotherapy and short-term ADT, a 10-point higher baseline financial difficulty or dyspnoea was associated with a 20% increased risk of death. With each 10-point increase in baseline dyspnoea, we noted a 20% increase in the associated risk of grade ≥3 delayed-onset radiotherapy-related toxicity.

DURATION-2: efficacy and safety of switching from maximum daily sitagliptin or pioglitazone to once-weekly exenatide.

AIMS: In the initial 26-week, double-blind, double-dummy assessment period of the DURATION-2 trial in patients with Type 2 diabetes on metformin, the once-weekly glucagon-like peptide 1 (GLP-1) receptor agonist exenatide once-weekly resulted in greater HbA(1c) improvement and weight reduction compared with maximum approved daily doses of sitagliptin or pioglitazone. This subsequent, 26-week, open-label, uncontrolled assessment period evaluated the safety and efficacy of (i) continued exenatide once-weekly treatment and (ii) switching from sitagliptin or pioglitazone to exenatide once-weekly. METHODS: Randomised oral medications were discontinued and all patients received exenatide once-weekly. Of the 364 patients [original baseline HbA(1c) 8.5 ± 1.1% (70 mmol/mol), fasting plasma glucose 9.0 ± 2.5 mmol/l, weight 88 ± 20 kg) who continued into the open-label period, 319 patients (88%) completed 52 weeks. RESULTS: Evaluable patients who received only exenatide once-weekly demonstrated significant 52-week improvements (least square mean ± se) in HbA(1c) (-1.6 ± 0.1%), fasting plasma glucose (-1.8 ± 0.3 mmol/l) and weight (-1.8 ± 0.5 kg). Evaluable patients who switched from sitagliptin to exenatide once-weekly demonstrated significant incremental improvements in HbA(1c) (-0.3 ± 0.1%), fasting plasma glucose (-0.7 ± 0.2 mmol/l) and weight (-1.1 ± 0.3 kg). Patients who switched from pioglitazone to exenatide once-weekly maintained HbA(1c) and fasting plasma glucose improvements (week 52: -1.6 ± 0.1%, -1.7 ± 0.3 mmol/l), with significant weight reduction (-3.0 ± 0.3 kg). Exenatide once-weekly was generally well tolerated and adverse events were predominantly mild or moderate in intensity. Nausea was the most frequent adverse event in this assessment period (intent-to-treat: exenatide once-weekly-only 5%; sitagliptin→exenatide once-weekly 11%; pioglitazone→exenatide once-weekly 10%). No major hypoglycaemia was observed. CONCLUSIONS: Patients who switched to once-weekly exenatide from daily sitagliptin or pioglitazone had improved or sustained glycaemic control, with weight loss.

Airway proteins involved in bacterial clearance susceptible to cathepsin G proteolysis.

Serine proteases released from neutrophils are central to the pathogenesis of cystic fibrosis lung disease and are considered to be obvious therapeutic targets. Neutrophil elastase digests key opsonins present in the lung and disrupts phagocytosis, allowing bacteria to persist despite established pulmonary inflammation. We have found that cathepsin G, an abundant serine protease found in human and murine neutrophils, has other roles in the development of suppurative lung diseases. Murine models of endobronchial inflammation indicate that cathepsin G inhibits airway defences and interferes with the host's ability to clear Pseudomonas aeruginosa from the lung with effects distinct from neutrophil elastase. We hypothesise that differences in bacterial killing are due to defects in innate defences created by proteolysis. Protein profiles of bronchoalveolar lavage of infected wild-type and cathepsin G-deficient mice were compared using two-dimensional polyacrylamide gel electrophoresis and tandem mass spectrometry. Four proteins in bronchoalveolar lavage were cleaved by cathepsin G. Serum amyloid P component leaked into the lung during acute infection and was digested by cathepsin G. Its cleavage products had greater binding to lipopolysaccharide and interfered with phagocytosis. These results indicate that cleaved serum amyloid P component acts as an anti-opsonin and interferes with bacterial clearance from the lung.

Chemoenzymatic synthesis of chiral 2,2'-bipyridine ligands and their N-oxide derivatives: applications in the asymmetric aminolysis of epoxides and asymmetric allylation of aldehydes.

A series of enantiopure 2,2'-bipyridines have been synthesised from the corresponding cis-dihydrodiol metabolites of 2-chloroquinolines. Several of the resulting hydroxylated 2,2'-bipyridines were found to be useful chiral ligands for the asymmetric aminolysis of meso-epoxides leading to the formation of enantioenriched amino alcohols (-->84% ee). N-oxide and N,N'-dioxide derivatives of these 2,2'-bipyridines, including separable atropisomers, have been synthesised and used as enantioselective organocatalysts in the asymmetric allylation of aldehydes to give allylic alcohols (-->86% ee).

Oestrogen-mediated phosphorylation and stabilization of BRCA2 protein in breast.

Disease-associated BRCA2 mutations typically result in protein truncations that delete the phosphorylation-regulated S3291 BRCA2 domain that interacts with Rad51. BRCA2 hereditary breast cancers are usually ER(+), differing from BRCA1 hereditary cancers, which are usually ER(-). We studied BRCA2 protein expression and S3291 phosphorylation in normal breast tissues and in sporadic breast cancers and observed that BRCA2 is expressed and phosphorylated in normal breast and 10 ER(+) breast cancers but not in 10 ER(-) breast cancers. In order to study this correlation between ER and BRCA2 expression, we studied ER(+) breast cancer cell lines. We found that a rapid increase in BRCA2 S3291 phosphorylation occurs following 17-beta-oestradiol (E2) treatment. This increase seen in BRCA2 total and phospho-S3291 protein levels was found to be unaffected with cycloheximide pre-treatment, but decreased following tamoxifen, ICI 182,780 or roscovitine treatment. This suggests a requirement for ER and cdk (cyclin-dependent kinase) in mediating the increased protein levels. MCF7 cell cycle distribution analysis following E2, in both the presence and absence of roscovitine (a cdk inhibitor), did not demonstrate any changes during an 8 h period, which further supports our hypothesis that mitogenic effects of E2 are not predominant at early time points. Studies with MG132 proteasome inhibitor and siRNA to skp2 support a model in which skp2-mediated proteasomal degradation of BRCA2 rapidly degrades BRCA2 protein in the absence of hormone treatment, which likely inhibits this pathway. E2 was shown to improve survival of MCF7 cells upon radiation treatment and roscovitine partially reversed this effect. We have demonstrated that BRCA2 protein is specifically expressed in ER(+) breast cancers and are investigating a pathway that may show a link between E2 action and BRCA2 protein function in breast cancer.

Ethical aspects in the use of radiation in medicine: update from ICRP Task Group 109.

Whereas scientific evidence is the basis for recommendations and guidance on radiological protection, professional ethics is critically important and should always guide professional behaviour. The International Commission on Radiological Protection (ICRP) established Task Group 109 to advise medical professionals, patients, families, carers, the public, and authorities about the ethical aspects of radiological protection of patients in the diagnostic and therapeutic use of radiation in medicine. Occupational exposures and research-related exposures are not within the scope of this task group. Task Group 109 will produce a report that will be available to the different interested parties for consultation before publication. Presently, the report is at the stage of a working document that has benefitted from an international workshop organised on the topic by the World Health Organization. It presents the history of ethics in medicine in ICRP, and explains why this subject is important, and the benefits it can bring to the standard biomedical ethics. As risk is an essential part in decision-making and communication, a summary is included on what is known about the dose-effect relationship, with emphasis on the associated uncertainties. Once this theoretical framework has been presented, the report becomes resolutely more practical. First, it proposes an evaluation method to analyse specific situations from an ethical point of view. This method allows stakeholders to review a set of six ethical values and provides hints on how they could be balanced. Next, various situations (e.g. pregnancy, elderly, paediatric, end of life) are considered in two steps: first within a realistic, ethically challenging scenario on which the evaluation method is applied; and second within a more general context. Scenarios are presented and discussed with attention to specific patient circumstances, and on how and which reflections on ethical values can be of help in the decision-making process. Finally, two important related aspects are considered: how should we communicate with patients, family, and other stakeholders; and how should we incorporate ethics into the education and training of medical professionals?

Recruitment of osteoclast precursors by purified bone matrix constituents.

The osteoclast, the multinucleated giant cell of bone, is derived from circulating blood cells, most likely monocytes. Evidence has accrued that is consistent with the hypothesis that the recruitment of monocytes for osteoclast development occurs by chemotaxis. In the present study, we have examined the chemotactic response of human peripheral blood monocytes and related polymorphonuclear leucocytes to three constituents of bone matrix: peptides from Type I collagen, alpha 2-HS glycoprotein, and osteocalcin (bone gla protein). The latter two substances are among the major noncollagenous proteins of bone and are uniquely associated with calcified connective tissue. In chemotaxis assays using modified Boyden chambers, Type I collagen peptides, alpha 2HS glycoprotein, and osteocalcin evoke a dose-dependent chemotactic response in human monocytes. No chemotaxis is observed on PMNs despite their ontogenetic relationship to monocytes and their documented sensitivity to a broad range of other chemical substances. Our observations are consistent with the view that osteoclast precursors (monocytes) are mobilized by chemotaxis, and suggest that the chemoattractants responsible for this activity are derived from the bone matrix or, in the case of collagen and osteocalcin; directly from the osteoblasts which produce them.

Galactose toxicity in the chick: hyperosmolality.

Galactose-fed chicks have been found to develop severe hyperosmolar dehydration. Although biochemical abnormalities have been observed in the brain of the galactose-toxic chick, the observed physiologic alteration of serum osmolality could be the major factor responsible for the galactose toxicity syndrome in the chick.

Hexokinase isoenzymes in human erythrocytes: association of type II with fetal hemoglobin.

Hexokinase activity in human erythrocytes is associated with three electrophoretically distinct bands. Normal adult erythrocytes contain hexokinases Types I and III. Type II hexokinase is present in the erythrocytes of newborn infants and absent from those of normal adults; it is, however, present in erythrocytes of adults with hereditary persistence of fetal hemoglobin. Type II hexokinase and fetal hemtoglobin appear to be associated.

An essential need: creating opportunities for veterinary students and graduates to gain an appreciation of responsibilities and opportunities in global veterinary issues.

Globalisation trends and bioterrorism issues have led to new concerns relating to public health, animal health, international trade and food security. There is an imperative to internationalise and strengthen global public health capacity by renewed emphasis on veterinary public health in veterinary education and increasing opportunities for elective experiential learning in public practice programmes for veterinary students. Recent experience with a US-Brazil Higher Education Consortia Program is used as an example of potential ways in which veterinary students can gain an appreciation for global veterinary issues.

New ethical issues for radiation protection in diagnostic radiology.

The ethical basis for many medical practices has been challenged over the last two decades. Radiology has seen enormous growth during the same period. Many practices and equipment types, now commonplace, did not exist a generation ago. Yet the fundamental ethical basis for these practices has not seen a corresponding level of development. This is possibly an oversight, and may be particularly important given that these innovations have taken place over a period of changing social attitudes. Areas of concern include, for example, issues around justification, consent/authorisation, inadvertent irradiation of the foetus/embryo during pregnancy and the place of paternalism/individual autonomy in the structure of practice. This paper provides the background to a workshop on these issues held in late-2006 and presents a summary of its findings.

Ethical issues in medico-legal exposures.

The Medical Exposure Directive (MED) 97/43/Euratom defines medico-legal procedures as 'procedures performed for insurance or legal purposes without a medical indication'. The term 'medico-legal exposures' covers a wide range of possible types of exposures, very different in nature, for which the only feature in common is the fact that the main reason for performing them does not relate directly to the health of the individual being exposed to ionising radiation. The key issue in medico-legal exposures is justification. Balancing the advantages and disadvantages of such exposures is complex because not only can these be difficult to quantify and hence compare, but often the advantage may be to society whereas the disadvantage is usually to an individual. This adds an additional layer of ethical complexity to the problem and one, which requires input from a number of sources beyond the established radiation protection community. Because medico-legal exposures are considered to be medical exposures, they are not subject to dose limits. In medico-legal exposures where the benefit is not necessarily to the individual undergoing the exposure, the question must be asked as to whether or not this is an appropriate framework within which to conduct such exposures. This paper looks at the current situation in Europe, highlighting some of the particular problems that have arisen, and tries to identify the areas, which require further clarification and guidance.