Transpupillary collagen photocrosslinking for targeted modulation of ocular biomechanics.

The central vision-threatening event in glaucoma is dysfunction and loss of retinal ganglion cells (RGCs), thought to be promoted by local tissue deformations. Here, we sought to reduce tissue deformation near the optic nerve head by selectively stiffening the peripapillary sclera, i.e. the scleral region immediately adjacent to the optic nerve head. Previous scleral stiffening studies to treat glaucoma or myopia have used either pan-scleral stiffening (not regionally selective) or regionally selective stiffening with limited access to the posterior globe. We present a method for selectively stiffening the peripapillary sclera using a transpupillary annular light beam to activate methylene blue administered by retrobulbar injection. Unlike prior approaches to photocrosslinking in the eye, this approach avoids the damaging effects of ultraviolet light by employing red light. This targeted photocrosslinking approach successfully stiffened the peripapillary sclera at 6 weeks post-treatment, as measured by whole globe inflation testing. Specifically, strain was reduced by 47% when comparing treated vs. untreated sclera within the same eye (n = 7, p=0.0064) and by 54% when comparing the peripapillary sclera of treated vs. untreated eyes (n = 7, p<0.0001). Post-treatment characterization of RGCs (optic nerve axon counts/density, and grading), retinal function (electroretinography), and retinal histology revealed that photocrosslinking was associated with some ocular toxicity. We conclude that a transpupillary photocrosslinking approach enables selective scleral stiffening targeted to the peripapillary region that may be useful in future treatments of glaucoma.

Pain management in patients with malignant mesothelioma: challenges and solutions.

Malignant pleural mesothelioma (MPM) is an aggressive cancer with a considerable symptom burden and poor prognosis. Focus on maintaining patients' quality of life and pain control is therefore paramount. Pain management in MPM is complex due to its multifactorial etiology resulting from direct tumor infiltration of the surrounding soft tissue, bone, and encasement of the intercostal nerves. A variety of treatment modalities, including pharmacological and non-pharmacological options, are often required to achieve adequate pain control in this challenging disease. This review article examines the current challenges and solutions available for pain management in MPM.

Towards the automated identification of Chrysomya blow flies from wing images.

The Old World screwworm fly (OWSF), Chrysomya bezziana (Diptera: Calliphoridae), is an important agent of traumatic myiasis and, as such, a major human and animal health problem. In the implementation of OWSF control operations, it is important to determine the geographical origins of such disease-causing species in order to establish whether they derive from endemic or invading populations. Gross morphological and molecular studies have demonstrated the existence of two distinct lineages of this species, one African and the other Asian. Wing morphometry is known to be of substantial assistance in identifying the geographical origin of individuals because it provides diagnostic markers that complement molecular diagnostics. However, placement of the landmarks used in traditional geometric morphometric analysis can be time-consuming and subject to error caused by operator subjectivity. Here we report results of an image-based approach to geometric morphometric analysis for delivering wing-based identifications. Our results indicate that this approach can produce identifications that are practically indistinguishable from more traditional landmark-based results. In addition, we demonstrate that the direct analysis of digital wing images can be used to discriminate between three Chrysomya species of veterinary and forensic importance and between C. bezziana genders.

SYSTEMS-2: A randomised phase II study of radiotherapy dose escalation for pain control in malignant pleural mesothelioma.

SYSTEMS-2 is a randomised study of radiotherapy dose escalation for pain control in 112 patients with malignant pleural mesothelioma (MPM). Standard palliative (20 Gy/5#) or dose escalated treatment (36 Gy/6#) will be delivered using advanced radiotherapy techniques and pain responses will be compared at week 5. Data will guide optimal palliative radiotherapy in MPM.

A randomised, phase II study of nintedanib or sunitinib in previously untreated patients with advanced renal cell cancer: 3-year results.

BACKGROUND: This exploratory study evaluated the safety/efficacy of nintedanib or sunitinib as first-line therapy in patients with advanced renal cell carcinoma (RCC). METHODS: Ninety-six patients were randomised (2:1) to either nintedanib (200 mg twice daily) or sunitinib (50 mg kg(-1) once daily (4 weeks on treatment; 2 weeks off)). Primary endpoint was progression-free survival (PFS) at 9 months. P-values reported are descriptive only; the study was not powered for such comparisons. RESULTS: Progression-free survival at 9 months was comparable between nintedanib and sunitinib (43.1% vs 45.2%, respectively; P=0.85). Median PFS was 8.4 months in each group (hazard ratio (HR), 1.12; 95% confidence interval (CI): 0.70-1.80; P=0.64). Median overall survival was 20.4 and 21.2 months for nintedanib and sunitinib, respectively (HR, 0.92; 95% CI: 0.54-1.56; P=0.76). Overall incidence of any grade adverse events (AEs) was comparable (90.6% vs 93.8%); AEs grade ⩾ 3 were lower with nintedanib than sunitinib (48.4% vs 59.4%). Nintedanib was associated with lower incidences of some AEs typical of antiangiogenic tyrosine kinase inhibitors (TKIs): hypertension, hypothyroidism, hand-foot syndrome, cardiac disorders and haematological abnormalities. CONCLUSIONS: In patients with advanced RCC, nintedanib has promising efficacy and similar tolerability to sunitinib, and a manageable safety profile with fewer TKI-associated AEs.

Influence of high altitude on cerebral blood flow and fuel utilization during exercise and recovery.

We examined the hypotheses that: (1) during incremental exercise and recovery following 4-6 days at high altitude (HA) global cerebral blood flow (gCBF) increases to preserve cerebral oxygen delivery (CDO2) in excess of that required by an increasing cerebral metabolic rate of oxygen ( CM RO2); (2) the trans-cerebral exchange of oxygen vs. carbohydrates (OCI; carbohydrates = glucose + ½lactate) would be similar during exercise and recovery at HA and sea level (SL). Global CBF, intra-cranial arterial blood velocities, extra-cranial blood flows, and arterial-jugular venous substrate differences were measured during progressive steady-state exercise (20, 40, 60, 80, 100% maximum workload (Wmax)) and through 30 min of recovery. Measurements (n = 8) were made at SL and following partial acclimatization to 5050 m. At HA, absolute Wmax was reduced by ∼50%. During submaximal exercise workloads (20-60% Wmax), despite an elevated absolute gCBF (∼20%, P < 0.05) the relative increases in gCBF were not different at HA and SL. In contrast, gCBF was elevated at HA compared with SL during 80 and 100% Wmax and recovery. Notwithstanding a maintained CDO2 and elevated absolute CM RO2 at HA compared with SL, the relative increase in CM RO2 was similar during 20-80% Wmax but half that of the SL response (i.e. 17 vs. 27%; P < 0.05 vs. SL) at 100% Wmax. The OCI was reduced at HA compared with SL during 20, 40, and 60% Wmax but comparable at 80 and 100% Wmax. At HA, OCI returned almost immediately to baseline values during recovery, whereas at SL it remained below baseline. In conclusion, the elevations in gCBF during exercise and recovery at HA serve to maintain CDO2. Despite adequate CDO2 at HA the brain appears to increase non-oxidative metabolism during exercise and recovery.

Use of wing morphometrics to identify populations of the Old World screwworm fly, Chrysomya bezziana (Diptera: Calliphoridae): a preliminary study of the utility of museum specimens.

The Old World screwworm (OWS) fly, Chrysomya bezziana (Diptera: Calliphoridae), is a major economic and welfare problem for humans and animals in the Old World tropics. Using a bootstrapped log likelihood ratio test of the output of Procrustes principal components and canonical variates analyses for a small sample of museum specimens from which 19 2D wing landmarks had been collected: (1) a consistent and statistically significant difference exists between landmark configurations derived from wings of pinned specimens and those removed from the body and mounted on slides; (2) a highly statistically significant sexual dimorphism in wing morphometry was identified; and (3) a highly statistically significant difference in wing morphometry between populations of the OWS fly from Africa (Tanzania, South Africa Sudan, Zaire, Zimbabwe,) and Asia (Sumba, Indonesia) exists. These results show that wing orientation and gender must be considered when conducting morphometric investigations of OWS fly wings. The latter result is also consistent with results from previous molecular and morphological studies, which indicate there are two distinct genetic lineages within this species. Wing morphometry holds great promise as a practical tool to aid in identification of the geographical origin of introductions of this important pest species, by providing diagnostic markers to distinguish geographical populations and complement molecular diagnostics.

Radiotherapy for the treatment of pain in malignant pleural mesothelioma: a systematic review.

Radiotherapy is commonly used to treat pain in malignant pleural mesothelioma (MPM). The purpose of this systematic review is to examine the evidence for this practice. Medline (1946-2013), Embase (1974-2013) and Central (The Cochrane Library Issue 9, 2012) databases were searched. Eligible studies met the following criteria: MPM (histological or radiological diagnosis), radiotherapy given with the intent of improving pain, response rates to radiotherapy reported, dose and fractionation reported and the relationship between radiotherapy and pain response explored. All studies had independent review and were graded according to evidence level. Eight studies met the eligibility criteria. Two studies were prospective single arm phase II studies while the remainder were retrospective case series. All were graded as either Level 2 or Level 3 evidence. Due to marked heterogeneity among studies, quantitative synthesis of results was not possible. No high quality evidence currently exists to support radiotherapy in treating pain in MPM. Studies focusing on clear pain endpoints and improving target delineation are needed. Such studies should also use modern radiotherapy techniques and concentrate on dose escalation.

What are the minimal standards of radiotherapy planning and dosimetry for "hypofractionated" radiotherapy in breast cancer?

Hypofractionated radiotherapy regimens have become increasingly popular in breast cancer, particularly in the UK and Canada. However, there are some potential problems inherent to providing such regimens, such as the concern of increased toxicity. In this article we discuss the planning and dosimetry and requirements for hypofractionated radiotherapy in breast cancer and make recommendations both for the planning process and for treatment monitoring.

A UK consensus on the management of the bladder in multiple sclerosis.

Bladder symptoms in multiple sclerosis (MS) are common and distressing but also highly amenable to treatment. A meeting of stakeholders involved in patients' continence care, including neurologists, urologists, primary care, MS nurses and nursing groups was recently convened to formulate a UK consensus for management. National Institute for Health and Clinical Excellence (NICE) criteria were used for producing recommendations based on a review of the literature and expert opinion. It was agreed that in the majority of cases, successful management could be based on a simple algorithm which includes using reagent sticks to test for urine infection and measurement of the post micturition residual urine volume. This is in contrast with published guidelines from other countries which recommend cystometry. Throughout the course of their disease, patients should be offered appropriate management options for treatment of incontinence, the mainstay of which is antimuscarinic medications, in combination, if necessary, with clean intermittent self-catheterisation. The evidence for other measures, including physiotherapy, alternative strategies aimed at improving bladder emptying, other medications and detrusor injections of botulinum toxin A was reviewed. The management of urinary tract infections as well as the bladder problems as part of severe disability were discussed and recommendations agreed.

A UK consensus on the management of the bladder in multiple sclerosis.

Bladder symptoms in multiple sclerosis (MS) are common and distressing but also highly amenable to treatment. A meeting of stakeholders involved in patients' continence care, including neurologists, urologists, primary care, MS nurses and nursing groups was recently convened to formulate a UK consensus for management. National Institute for Health and Clinical Excellence (NICE) criteria were used for producing recommendations based on a review of the literature and expert opinion. It was agreed that in the majority of cases, successful management could be based on a simple algorithm which includes using reagent sticks to test for urine infection and measurement of the post micturition residual urine volume. This is in contrast with published guidelines from other countries which recommend cystometry. Throughout the course of their disease, patients should be offered appropriate management options for treatment of incontinence, the mainstay of which is antimuscarinic medications, in combination, if necessary, with clean intermittent self-catheterisation. The evidence for other measures, including physiotherapy, alternative strategies aimed at improving bladder emptying, other medications and detrusor injections of botulinum toxin A was reviewed. The management of urinary tract infections as well as the bladder problems as part of severe disability were discussed and recommendations agreed.

Prediction of sublayer depth in turbid media using spatially offset Raman spectroscopy.

We demonstrate experimentally the feasibility of monitoring the depth of optically thick layers within turbid media using spatially offset Raman spectroscopy (SORS) in combination with multivariate analysis. The method uses the deep penetration capability of SORS to characterize significantly thicker (by at least a factor of 2) layers than possible with conventional Raman spectroscopy. Typical relative accuracies were between 5 and 10%. The incorporation of depth information into a SORS experiment as an additional dimension allows pure spectra of each individual layer to be resolved using three-dimensional multivariate techniques (parallel factor analysis, PARAFAC) to accuracies comparable with the results of a two-dimensional analysis.

Non-invasive detection of cocaine dissolved in beverages using displaced Raman spectroscopy.

We demonstrate the potential of Raman spectroscopy to detect cocaine concealed inside transparent glass bottles containing alcoholic beverages. A clear Raman signature of cocaine with good signal-to-noise was obtained from a approximately 300 g solution of adulterated cocaine (purity 75%) in a 0.7 L authentic brown bottle of rum with 1 s acquisition time. The detection limit was estimated to be of the order of 9 g of pure cocaine per 0.7 L (approximately 0.04 moles L(-1)) with 1 s acquisition time. The technique holds great promise for the fast, non-invasive, detection of concealed illicit compounds inside beverages using portable Raman instruments, thus permitting drug trafficking to be combated more effectively.

Noninvasive detection of concealed liquid explosives using Raman spectroscopy.

We present a Raman spectroscopic method for the noninvasive detection of liquid explosives within bottles, and other packaging, of substantially higher sensitivity and wider applicability than that currently available via conventional Raman spectroscopy. The approach uses a modification of the spatially offset Raman spectroscopy (SORS) concept, which permits the interrogation of a wide range of containers, including transparent, colored, and diffusely scattering plastic and glass beverage, medicine, and cosmetic bottles, with no change in experimental geometry. The enhanced sensitivity is achieved by the technique's inherent ability to effectively suppress fluorescence and Raman contributions originating from the wall of the container. The application is demonstrated on the noninvasive detection of hydrogen peroxide solution, a critical component of a number of liquid explosives. In contrast to conventional Raman spectroscopy, the modified SORS concept enables the detection of concealed hydrogen peroxide solution in all the studied cases.

Microcracks in eggs.

An experimental program of mechanical testing has shown that microcracks initiate in hens' eggs at loads less than that necessary to cause total structural failure. In contact loading, computational modeling and numerical analysis show that very high stress levels develop on the inner surface of the eggshell as it conforms to a hard contact surface. This causes a series of microcracks to initiate at the inner surface of the shell and radiate out from the load site. A series of concentric circumferential microcracks also develop beneath the cuticle from the edge of the contact zone. Calculations relating to the eggshells' dynamic response indicate that microcracks have a little effect on the structural stiffness and resonant frequencies of the egg. As a result, microcracks are unlikely to be detected by online crack detection systems, which rely on mechanical excitation. Eggs in retail outlets are likely to contain microcracks as a result of insults experienced during the collection, grading, and packing processes. Because the eggshell forms the first line of defense against potentially pathogenic microorganisms entering the egg contents, microcracks could potentially compromise egg safety.

Angiotensin-converting enzyme genotype and the ventilatory response to exertional hypoxia.

The "insertion" (I) rather than "deletion" (D) variant of the human angiotensin-converting enzyme (ACE) gene is associated with both lower tissue ACE activity and elite performance at high altitude. Three genotypes, II, ID and DD, are thus represented in the population. The authors examined whether an improved ventilatory response to hypoxic exercise may contribute to this effect. Subjects (n=60; 37 male, mean+/-SEM age 23.6+/-0.6 yrs, 14 II, 30 ID, 16 DD) underwent incremental cardiopulmonary exercise testing to establish maximal oxygen uptake and ventilatory threshold (VT). Four hours later, subjects exercised for 6 mins at 50% of the workload at VT. The protocol was repeated 15 mins later while breathing 12.5+/-0.5% oxygen in nitrogen. All subject characteristics were independent of genotype, as were data during normoxic exercise. However, the hypoxia-induced rise in minute ventilation was significantly greater among those of II genotype (39.6+/-4.1% versus 27.9+/-2.0% versus 28.4+/-2.2% for II versus ID versus DD, respectively). These data are supported by a significantly greater decrease in end tidal carbon dioxide (consistent with an increase in alveolar ventilation) among those homozygous for the I allele (II -18.7+/-1.3%, ID -15.7+/-0.4%, DD -15.1%+/-1.1). The ventilatory response to hypoxic exercise is influenced by angiotensin-converting enzyme genotype. Potential implications concern high altitude performance and the pathogenesis and management of hypoxic lung disease.

Sea level and acute responses to hypoxia: do they predict physiological responses and acute mountain sickness at altitude?

OBJECTIVES: To compare a range of physiological responses to acute sea level hypoxia at simulated altitudes with the same physiological responses and acute mountain sickness (AMS) scores measured at altitude (similar to the simulated altitudes) during a 17 day trek in the Himalayas. METHODS: Twenty men and women aged 18-54 years took part in the study. End tidal CO(2) tension (PETCO(2)) and saturated oxygen (SaO(2)) were measured using a capnograph. Observations made at sea level and some simulated altitudes were compared with those in the Himalayas. Pairwise correlations were used to examine the correlation between variables and regression, with 95% prediction intervals providing information on how well one variable could be predicted from another for a given subject. RESULTS: There was only a significant correlation for a few comparisons. The 95% prediction intervals for individual SaO(2) values at a range of simulated altitudes were fairly wide going from +/- 4% to +/- 5%. All of the correlations between laboratory and Himalayan PETCO(2) values were not statistically significant. There was a significant correlation for the relation between SaO(2)and PETCO(2) at sea level for the laboratory data (r=-0.51; p=0.05). For the Himalayan data, there were significant correlations at Namche Bazaar (3450 m; day 3) (r=-0.56; p=0.01) and Dingboche (4300 m; day 6) (r=-0.48; p=0.03). The correlation between SaO(2) and PETCO(2) and AMS was generally poor. CONCLUSIONS: The results indicate that limited information can be gained on a subject's response to altitude by assessing physiological variables at sea level and a range of simulated altitudes before the subject carries out a trek at altitude.

Synapse loss associated with abnormal PrP precedes neuronal degeneration in the scrapie-infected murine hippocampus.

Numbers of neurones, synapses and axon terminals were quantified in a murine scrapie model with severe hippocampal pyramidal cell loss, in which definite clinical scrapie is evident from 226 days post-infection (dpi) and death occurs around 250 dpi. Disease-specific PrP accumulations were first seen at 70 dpi (28% of the incubation period (IP)) in thalamus and as sparse foci within the stratum pyramidale of CA1. By 98 dpi (39% IP), PrP was seen in the stratum radiatum and was found at later stages throughout all levels of the hippocampus. At the ultrastructural level in the stratum radiatum of CA1, a decrease in the numbers of simple synapses from 84 dpi (34% IP) and in perforated synapses from 98 dpi (42% IP) was found using an unbiased stereological method, the disector analysis. Degeneration of axon terminals was found from 98 dpi (39% IP) onwards. Neuronal loss was detected in CA1 from 180 dpi (72% IP). The results suggest that the fundamental lesion in the hippocampus of ME7-infected mice is associated with PrP release from CA1 pyramidal neurones, which perturbs synaptic function and leads to degeneration of preterminal axons, and that subsequent pathological changes including neurone loss are sequelae to this initial insult.