Prediction of Radiation-induced Lymphopenia following Exposure of the Thoracic Region and Associated Risk of Infections and Mortality.

AIMS: Large blood volumes are irradiated when the heart is exposed to radiation. The mean heart dose (MHD) may be a good surrogate for circulating lymphocytes exposure. We investigated the association between MHD and radiation-induced lymphopenia and explored the impact of the end-of-radiation-therapy (EoRT) lymphocyte count on clinical outcomes. MATERIALS AND METHODS: In total, 915 patients were analysed: 303 patients with breast cancer and 612 with intrathoracic tumours: oesophageal cancer (291), non-small cell lung cancer (265) and small cell lung cancer (56). Heart contours were generated using an interactive deep learning delineation process and an individual dose volume histogram for each heart was obtained. A dose volume histogram for the body was extracted from the clinical systems. We compared different models analysing the effect of heart dosimetry on the EoRT lymphocyte count using multivariable linear regression and assessed goodness of fit. We published interactive nomograms for the best models. The association of the degree of EoRT lymphopenia with clinical outcomes (overall survival, cancer treatment failure and infection) was investigated. RESULTS: An increasing low dose bath to the body and MHD were associated with a low EoRT lymphocyte count. The best models for intrathoracic tumours included dosimetric parameters, age, gender, number of fractions, concomitant chemotherapy and pre-treatment lymphocyte count. Models for patients with breast cancer showed no improvement when adding dosimetric variables to the clinical predictors. EoRT lymphopenia grade ≥3 was associated with decreased survival and increased risk of infections among patients with intrathoracic tumours. CONCLUSION: Among patients with intrathoracic tumours, radiation exposure to the heart contributes to lymphopenia and low levels of peripheral lymphocytes after radiotherapy are associated with worse clinical outcomes.

OHSU Employees' Opinions of Receipt of Clinical Care and Participation in Clinical Research at Place of Employment.

Academic medical centers conduct clinical research and provide patient care to the community and their workforce. Conflict may exist, as employees might expect benefits or feel pressured or coerced to participate in research studies or receive clinical care. Without evidence, some universities consider employees to be part of a vulnerable population for research consent at their institution, potentially restricting opportunities for employees to participate in clinical trials. At the same time, these universities encourage employees to receive health care at the same institution. We hypothesized that attitudes toward voluntary research participation and receipt of health care services at the site of employment are similar and favorable. To study this, we conducted a survey of employees at Oregon Health & Science University (OHSU) that asked parallel questions focusing on attitudes regarding concerns with participation in research and receipt of clinical care. We found the majority of respondents reported favorable and similar attitudes regarding employee participation in clinical care 596/688 (87%) or research 605/639 (95%) and personally comfortable with the idea (614/688 (90%) for clinical care, 582/639 (92%) for research participation). Our findings support efforts to remove barriers that restrict participation in clinical research by employees at academic medical centers.

Klippel-Trenaunay syndrome / Síndrome de Klippel-Trenaunay

Klippel-Trenaunay syndrome (KTS) is a rare congenital, vascular disorder affecting one or more limbs. The syndrome is characterized by capillary malformations, soft tissue or bony hypertrophy and varicose veins or venous malformations. We present a case of this disorder in a twelveyear old boy who had an enlarged right lower limb with varicosities. Investigations revealed extensive superficial and deep venous varices, with dilatation of the right common iliac and external iliac veins. Klippel-Trenaunay syndrome should be suspected in a child presenting with capillary haemangioma and an enlarged limb.

El síndrome de Klippel-Trenaunay (KTS) es un raro trastorno congénito vascular que afecta a una o más extremidades. El síndrome se caracteriza por malformaciones capilares, hipertrofia ósea o del tejido suave, y várices o malformaciones venosas. Presentamos un caso de este trastorno en un muchacho de doce años que tenía una extremidad inferior derecha agrandada con varicocidades. Las investigaciones revelaron varices superficiales y várices venosas profundas, con dilatación de las venas ilíacas comunes derecha y las venas ilíacas externas. El síndrome de Klippel-Trenaunay se debe sospechar en un niño que se presenta con hemangioma capilar y agrandamiento de un miembro.

Klippel-Trenaunay syndrome.

Klippel-Trenaunay syndrome (KTS) is a rare congenital, vascular disorder affecting one or more limbs. The syndrome is characterized by capillary malformations, soft tissue or bony hypertrophy and varicose veins or venous malformations. We present a case of this disorder in a twelve-year old boy who had an enlarged right lower limb with varicosities. Investigations revealed extensive superficial and deep venous varices, with dilatation of the right common iliac and external iliac veins. Klippel-Trenaunay syndrome should be suspected in a child presenting with capillary haemangioma and an enlarged limb.

In tumors Salmonella migrate away from vasculature toward the transition zone and induce apoptosis.

Motile bacteria can overcome diffusion resistances that substantially reduce the efficacy of standard cancer therapies. Many reports have also recently described the ability of Salmonella to deliver therapeutic molecules to tumors. Despite this potential, little is known about the spatiotemporal dynamics of bacterial accumulation in solid tumors. Ultimately this timing will affect how these microbes are used therapeutically. To determine how bacteria localize, we intravenously injected Salmonella typhimurium into BALB/c mice with 4T1 mammary carcinoma and measured the average bacterial content as a function of time. Immunohistochemistry was used to measure the extent of apoptosis, the average distance of bacteria from tumor vasculature and the location of bacteria in four different regions: the core, transition, body and edge. Bacteria accumulation was also measured in pulmonary and hepatic metastases. The doubling time of bacterial colonies in tumors was measured to be 16.8 h, and colonization was determined to delay tumor growth by 48 h. From 12 and 48 h after injection, the average distance between bacterial colonies and functional vasculature significantly increased from 130 to 310 µm. After 48 h, bacteria migrated away from the tumor edge toward the central core and induced apoptosis. After 96 h, bacteria began to marginate to the tumor transition zone. All observed metastases contained Salmonella and the extent of bacterial colocalization with metastatic tissue was 44% compared with 0.5% with normal liver parenchyma. These results demonstrate that Salmonella can penetrate tumor tissue and can selectively target metastases, two critical characteristics of a targeted cancer therapeutic.

Mechanistic modelling of dynamic MRI data predicts that tumour heterogeneity decreases therapeutic response.

BACKGROUND: Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) contains crucial information about tumour heterogeneity and the transport limitations that reduce drug efficacy. Mathematical modelling of drug delivery and cellular responsiveness based on underutilised DCE-MRI data has the unique potential to predict therapeutic responsiveness for individual patients. METHODS: To interpret DCE-MRI data, we created a modelling framework that operates over multiple time and length scales and incorporates intracellular metabolism, nutrient and drug diffusion, trans-vascular permeability, and angiogenesis. The computational methodology was used to analyse DCE-MR images collected from eight breast cancer patients at Baystate Medical Center in Springfield, MA. RESULTS: Computer simulations showed that trans-vascular transport was correlated with tumour aggressiveness because increased vessel growth and permeability provided more nutrients for cell proliferation. Model simulations also indicate that vessel density minimally affects tissue growth and drug response, and nutrient availability promotes growth. Finally, the simulations indicate that increased transport heterogeneity is coupled with increased tumour growth and poor drug response. CONCLUSION: Mathematical modelling based on DCE-MRI has the potential to aid treatment decisions and improve overall cancer care. This model is the critical first step in the creation of a comprehensive and predictive computational method.

Tumour-targeted delivery of TRAIL using Salmonella typhimurium enhances breast cancer survival in mice.

BACKGROUND: An effective cancer therapeutic must selectively target tumours with minimal systemic toxicity. Expression of a cytotoxic protein using Salmonella typhimurium would enable spatial and temporal control of delivery because these bacteria preferentially target tumours over normal tissue. METHODS: We engineered non-pathogenic S. typhimurium to secrete murine TNF-related apoptosis-inducing ligand (TRAIL) under the control of the prokaryotic radiation-inducible RecA promoter. The response of the RecA promoter to radiation was measured using fluorometry and immunoblotting. TRAIL toxicity was determined using flow cytometry and by measuring caspase-3 activation. A syngeneic murine tumour model was used to determine bacterial accumulation and the response to expressed TRAIL. RESULTS: After irradiation, engineered S. typhimurium secreted TRAIL, which caused caspase-3-mediated apoptosis and death in 4T1 mammary carcinoma cells in culture. Systemic injection of Salmonella and induction of TRAIL expression using 2 Gy gamma-irradiation caused a significant delay in mammary tumour growth and reduced the risk of death by 76% when compared with irradiated controls. Repeated dosing with TRAIL-bearing Salmonella in conjunction with radiation improved the 30-day survival from 0 to 100%. CONCLUSION: These results show the pre-clinical utility of S. typhimurium as a TRAIL expression vector that effectively reduces tumour growth and extends host survival.

Working memory in schizophrenia: a meta-analysis.

BACKGROUND: Memory impairment is being recognized increasingly as an important feature of the neuropsychology of schizophrenia. Dysfunction of working memory, a system for the short-term storage and manipulation of information, may relate to a number of core symptoms of schizophrenia. Many studies have examined working memory function in schizophrenia but a clear understanding of the nature and extent of any deficit has been elusive. METHOD: A systematic review and meta-analysis of studies comparing working memory function in subjects with schizophrenia and healthy controls was performed. Following a comprehensive literature search, meta-analyses were conducted on 36 measures of phonological, visuospatial and central executive working memory functioning, encompassing 441 separate results from 187 different studies. RESULTS: Statistically significant effect sizes were found for all working memory measures, indicating deficits in schizophrenia groups. Some of these were robust findings in the absence of evidence of significant heterogeneity or publication bias. Meta-regression analyses showed that the working memory deficit was not simply explained by discrepancies in current IQ between schizophrenia and control groups. CONCLUSIONS: Large deficits in working memory were demonstrated in schizophrenia groups across all three working memory domains. There were, however, no clear differences across subdomains or between particular working memory tasks. There was substantial heterogeneity across results that could only be partly explained.

Ixodes frontalis and avian tick-related syndrome in the United Kingdom.

OBJECTIVES: This study aimed to characterise tick species responsible for avian tick infestations in the UK, to analyse various risk factors for tick-related syndrome in tick-infested birds and to test samples for the presence of certain tick-transmitted pathogens. METHODS: Ticks, blood, splenic tissue and tick attachment site tissue from birds with attached ticks were requested from veterinarians and wildlife sanctuaries around the UK. Ticks were identified according to standard keys, and samples were analysed via DNA PCR test for Borrelia burgdorferi sensu lato, Babesia species, Bartonella species and Ehrlichia species. RESULTS: Ixodes frontalis was the most commonly identified tick, and an association of adult female I frontalis with tick-related syndrome in birds was demonstrated. Tick infestation was markedly seasonal. I frontalis was found on 32 species of birds. DNA PCR testing was uniformly negative. Of the birds known to have been treated, 75 per cent (nine of 12) survived. CLINICAL SIGNIFICANCE: Tick-related syndrome is a poorly understood syndrome, with sporadic distribution, both geographically and seasonally. This study confirms I frontalis as the most common cause of this syndrome in the UK and identifies some features of the tick life cycle in this country. The benefit of treatment in affected birds is highlighted. Risk factors for tick-related syndrome are examined and preventive strategies discussed.

Field trial of a Caryospora species vaccine for controlling clinical coccidiosis in falcons.

A Caryospora species vaccine was prepared and used in an attempt to prevent infection and associated morbidity in falcons. A blind field trial was conducted, involving a vaccinated group of 20 birds and two control groups of seven and four birds, which were subsequently challenged with a live mixed-species vaccine. There was a statistically significant reduction in morbidity and shedding of oocysts in the vaccinated group compared with the control groups.

Effect of handling-induced stress on the results of spectral Doppler echocardiography in falcons.

In order to evaluate the effects of habituation to handling on the Doppler-derived velocity of diastolic ventricular inflow and systolic aortic outflow, falcons that were accustomed to regular handling were compared with falcons that had been handled very little. The mean heart rate of the frequently handled birds was 111 beats per minute less than the non-habituated birds. All the mean blood flow velocities recorded were much higher in the non-habituated birds than those accustomed to handling. Taking into account the difficulty of objectively quantifying the level of stress suffered by any individual bird, the question is, if meaningful clinical or reference values for Doppler-derived blood flow velocities may be obtained in unsedated or non-anaesthetized birds?

Pulsed-wave Doppler echocardiography in birds of prey.

Pulsed-wave spectral Doppler echocardiography was applied to 111 diurnal and nocturnal raptors of both sexes weighing between 190 and 4200 g. In the first stage, 40 birds were examined without special preparation; in the second stage, 15 birds were examined first when they were not anaesthetised and then when they were anaesthetised; in the third stage, 41 birds were examined after they had been fasted for different periods of time; and finally 15 birds, in which echocardiography had not been possible by using standard (dorsal) restraint and positioning, were examined after being placed in lateral and ventral recumbency. Doppler-derived diastolic inflow into the ventricles was detectable in approximately 80 per cent of the birds weighing between 190 and 2300 g independently of their weight, heart rate and whether they had been anaesthetised or fasted, and aortic blood flow was detected in about 50 per cent of them. It was possible to apply the technique under standard conditions of dorsal recumbency to only one of the birds weighing more than 3000 g and to about 80 per cent of those weighing between 190 and 2300 g. In 11 of 15 birds in which the technique could not be applied under standard conditions, blood flow could be detected in the ventricles and/or the aorta after the birds had been repositioned. No systolic blood flow through the pulmonary artery was detectable in any of the birds.

Attitudes to menopause and hormone replacement therapy among Asian and Caucasian women general practitioners.

OBJECTIVE: To look for any differences in attitudes to menopause and hormone replacement therapy (HRT) between Asian and Caucasian women standardised for educational background, socio-economic status and access to medical information. METHOD: Self administered postal questionnaire sent to 144 women doctors (general practitioners) in defined geographical areas. RESULTS: The overall response rate was 61%. Both Asian and Caucasian women responded in a similar manner for most aspects. A high proportion of these women doctors (over 75%) would seek HRT at the climacteric. More Asian respondents reported a fear of breast cancer (P=0.001), and that a woman feels less of a woman after the menopause (P=0.02). More Caucasian respondents felt positively about the potential for HRT to enhance enjoyment of life (P=0.01). CONCLUSIONS: The lack of major differences between the ethnic groups in our sample suggests that variations reported elsewhere may be due to lack of knowledge and/or differences in socio-economic status.

Using isotopomer path tracing to quantify metabolic fluxes in pathway models containing reversible reactions.

As a more complete picture of the genetic and enzymatic composition of cells becomes available, there is a growing need to describe how cellular regulatory elements interact with the cellular environment to affect cell physiology. One means for describing intracellular regulatory mechanisms is concurrent measurement of multiple metabolic pathways and their interactions by metabolic flux analysis. Flux of carbon through a metabolic pathway responds to all cellular regulatory systems, including changes in enzyme and substrate concentrations, enzyme activation or inhibition, and ultimately genetic control. The extent to which metabolic flux analysis can describe cellular physiology depends on the number of pathways in the model and the quality of the data. Intracellular information is obtainable from isotopic tracer experiments, the most extensive being the determination of the isotopomer distribution, or specific labeling pattern, of intracellular metabolites. We present a rapid and novel solution method that determines the flux of carbon through complex pathway models using isotopomer data. This time-consuming problem was solved with the introduction of isotopomer path tracing, which drastically reduces the number of isotopomer variables to the number of isotopomers observed experimentally. We propose a partitioned solution method that takes advantage of the nearly linear relationship between fluxes and isotopomers. Whereas the stoichiometric matrix and the isotopomer matrix are invertible, simulated annealing and the Newton-Raphson method are used for the nonlinear components. Reversible reactions are described by a new parameter, the association factor, which scales hyperbolically with the rate of metabolite exchange. Automating the solution method permits a variety of models to be compared, thus enhancing the accuracy of results. A simplified example that contains all of the complexities of a comprehensive pathway model is presented.

Necrotizing fasciitis and non steroidal anti-inflammatory drugs: a case series and review of the literature.

AIMS: To assess two years experience of necrotizing fasciitis in the Department of Intensive Care Medicine (DICM), Middlemore Hospital, and to investigate a possible link with non steroidal antiinflammatory drugs (NSAID's). METHODS: A retrospective chart review of patients with soft tissue infections admitted to the DICM between January 1998 and December 1999. RESULTS: There were 24 cases of soft tissue infection, of which thirteen had necrotizing fasciitis. In the latter group, nine were diabetics, and three had elevated glycosylated haemoglobin. Seven were obese and twelve had two or more comorbities. Five were taking NSAID's. Wound swabs and/or tissue biopsies were positive in eleven patients, but only three had positive blood cultures. Mortality was 6/13 (46%). The seven survivors had a mean of 5.7 operations and a mean hospital stay of 39 days. CONCLUSIONS: The literature contains scattered anecdotal case reports linking NSAID's and necrotizing fasciitis. Plausible biological mechanisms exist to explain how these drugs might predispose to serious infection and how they may mask signs and symptoms, therefore delaying diagnosis. In this series, less than half the patients were taking NSAID'S Diabetes and other co-morbidities were frequently found. The role of NSAIDS remains unclear.