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.

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.

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.

Optimization of cytochrome P4502D6 (CYP2D6) phenotype assignment using a genotyping algorithm based on allele frequency data.

Cytochrome P4502D6 (CYP2D6) is a highly polymorphic gene locus with > 50 variant alleles which lead to a wide range in enzymatic activity. So called poor metabolizers are carriers of any two non-functional alleles of the CYP2D6 gene. CYP2D6 genotyping is cumbersome and the question of how much genotyping is necessary for an accurate phenotype prediction is still debated. The goal of this study was to determine the optimum amount of genotyping required to accurately predict the phenotype at a reasonable cost in a white North American population. To address this issue, we designed a polymerase chain reaction (PCR)/restriction fragment length polymorphism-based genotyping strategy to detect 'key' mutations linked to extensive metabolizer or poor metabolizer associated alleles in combination with extra-long PCR (XL-PCR). All mutations with the exception of gene deletions and duplications are detectable by simple restriction digestion analysis and agarose gel electrophoresis. In addition, we utilized a genotyping algorithm based on our own and published allele frequency data and phenotype analysis to calculate the probability of a correct genotype (and thus, phenotype) assignment. As little as one XL-PCR reaction followed by a maximum of six reamplification reactions allows an accurate prediction of an individual's genotype to 99.15%. As few as four reamplification reactions identify 97.9% of poor metabolizer individuals. We evaluated our model in 208 white North Americans by testing for the presence of 'key' mutations linked to CYP2D6*2, *3, *4, *6, *7, *8, *9, *10, *11, *12, *15, *17 and *18 alleles and the *5, *13 and *16 gene deletions. For all individuals, the correct phenotype has been predicted. Discordant phenotype assignment occurred in only two individuals which subsequently was attributed to CYP2D6 inhibition by concomitant drug therapy.

Adrenal weight and morphology in victims of completed suicide.

Several lines of evidence have implicated hypothalamic-pituitary-adrenal (HPA) axis dysfunction in major depression and suicidal behavior. In the present study, the weight and morphology of postmortem adrenal glands were compared between suicide victims and sudden death, nonpsychiatric controls. The mean adrenal weight of the combined left and right glands was significantly higher in the suicide group; this difference was accounted for specifically by increases in left adrenal weight of suicides compared with the control group. There was a positive correlation between adrenal weight and total cortical thickness in both left and right glands, providing direct evidence that increased adrenal weight in suicide victims is due to cortical hypertrophy. The finding of left-right adrenal weight asymmetry in suicides is consistent with the hypothesis of abnormal lateralized input from higher control centers of the HPA axis.

Suicide and Alzheimer's pathology in the elderly: a case-control study.

BACKGROUND: The single most important risk factor for Alzheimer's pathology is age. Elderly individuals are also at increased risk for suicide, but comprehensive studies of the association between Alzheimer's pathology and suicide are lacking. We designed the current study to determine if Alzheimer's disease changes are overrepresented in elderly people committing suicide. METHODS: The design is a case-control study. Cases (n = 28) were subjects older than 60 years of age who completed suicide. For each case, two age- and gender-matched individuals who died naturally were selected as control subjects (n = 56). Neuropathologic examination of hippocampal sections was performed blindly and included a modified Braak scoring system and semiquantitative assessment of neurofibrillary tangles, amyloid deposition, Lewy bodies, and Lewy-associated neurites. Data were analyzed by conditional logistic regression. RESULTS: The brains of individuals who committed suicide had higher modified Braak scores than those of matching control subjects (p =.0028). The number of neurofibrillary tangles in CA1 was not an independent predictor of suicide status in the statistical analysis (p =.16), although the distribution was more highly skewed among the cases (75th percentile of 10.5 for cases, vs. 2 for control subjects). CONCLUSIONS: Severe Alzheimer's disease pathology is overrepresented in elderly patients who complete suicide.

Relationships of age and axis I diagnoses in victims of completed suicide: a psychological autopsy study.

OBJECTIVE: Psychiatric illness is a potent risk factor for suicide, rates of which differ markedly with age. The purpose of this study was to examine whether the psychiatric diagnoses of suicide victims vary predictably with age. METHOD: DSM-III-R axis I diagnoses of 141 persons aged 21 to 92 years who had completed suicide were established by the psychological autopsy method. Multiple logistic regression analyses were used to determine whether age, gender, or their interaction predicted the presence of specific disorders. RESULTS: One or more axis I conditions were diagnosable in 90.1% of the suicide victims. Substance use disorders were most frequent, followed by mood disorders and primary psychotic illness. Younger age at death was a significant predictor of substance abuse or dependence and primary psychoses, while older age predicted major mood disorders. Comorbidity of substance use and mood disorders was common. Among victims with substance abuse or dependence, older age at death predicted major depression; among victims with mood disorders, younger age at death predicted comorbid substance abuse or dependence. CONCLUSIONS: The distribution of psychiatric illnesses in suicide victims differs across the life course. Age-related patterns of addictive and psychotic disorders echo their prevalence in the general population. In contrast, the relationship between age and mood disorders among suicide victims is distinctly different from that of the general population. These findings suggest that risk for suicide increases with age in individuals with major affective illness. Depressed elderly men are particular targets for suicide prevention strategies.

Validation of a measure of physical illness burden at autopsy: the Cumulative Illness Rating Scale.

OBJECTIVE: To further validate an objective measure of physical illness burden, the Cumulative Illness Rating Scale (CIRS). DESIGN: Survey with correlation of CIRS ratings made from physician interviews and review of medical records with post-mortem ratings made independently at tissue autopsy. SUBJECTS: Victims of completed suicide investigated by both psychological and tissue autopsy (n = 72). RESULTS: CIRS ratings made by examination of tissue at autopsy were highly predictive of analogous ratings based on historical data, accounting for 75% of the variance in CIRS scores. Taking autopsy findings as the gold standard of objective health assessment, historical ratings tend to underestimate physical illness at high levels of tissue pathology and to overestimate burden at lower levels. CONCLUSIONS: The CIRS score, when derived from all available sources of medical information, is a valid objective measure of physical illness burden and has broad applicability to research in geriatrics.

Rhabdomyoma of the heart: a diagnostic and therapeutic challenge.

The sector scan was decisive in establishing the diagnosis of multiple rhabdomyomas of the heart in a newborn infant. Successful resection of the tumors was performed with profound hypothermia and limited cardiopulmonary bypass. Nine months later, the infant died of the complications of tuberous sclerosis. This case report documents the diagnostic accuracy of the sector scan and the potential benefit of aggressive surgical management of this condition.

Sucrose consumption as an hedonic measure following chronic unpredictable mild stress.

The consumption of, and preference for, a rewarding 0.9% sucrose solution was examined in rats subjected chronically (8 wk) to a regimen of unpredictable mild stressors. Intake of sucrose was reduced in stressed animals compared to controls after 3 wk. However, correction for body weight changes revealed no significant difference in sucrose consumption between the groups. A comparison of the mean sucrose intakes of matched low-weight rats, with low weight a function of either immaturity or stress, failed to differentiate between the groups. Total sucrose consumption and total fluid intake correlated significantly with body weight of stressed animals and controls. Percentage preference for sucrose solution did not differ between controls and stressed animals. It is concluded that the validity and reliability of sucrose consumption as an hedonic measure within the context of exposure to chronic unpredictable mild stress must be questioned.

Chronic mild stress and sucrose consumption: validity as a model of depression.

Sucrose consumption and preference were examined in rats subjected to a 6-week regimen of unpredictable mild stressors, after Willner et al. (11). These subjects were compared with groups exposed to: 1. only the food deprivation element of the stress protocol; or 2. the stress protocol without the food deprivation element. A control group was not exposed to stressors. Body weight and sucrose consumption were significantly reduced in stressed and food-deprived animals compared to the other 2 groups. These variables therefore appeared dependent on food deprivation and independent of other elements of the stress protocol. Neither sucrose consumption per gram body weight nor sucrose preference differed significantly among the 4 groups. These results indicate that food deprivation is not only necessary, but sufficient, to produce sucrose consumption deficits in rats. It is, therefore, likely that reduced sucrose consumption in stressed rats results solely from diminished body weight rather than exposure to the series of stressors. We conclude that sucrose consumption is not a valid index of reward responsiveness. Other measures (such as place-preference conditioning or intracranial self-stimulation threshold) should be evaluated also with respect to body weight change when considering the validity of stressor-based models of depressive disorder.

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.

Comparative mutagenicity of alkylsulfate and alkanesulfonate derivatives in Chinese hamster ovary cells.

Mutation induction and cell killing produced by selected alkylsulfates and alkanesulfonates have been quantitated using the Chinese hamster ovary/hypoxanthine--guanine phosphoribosyl transferase (CHO/HGPRT) system. Dose--response relationships of cytotoxicity and mutagenicity are presented for two alkylsulfates [dimethylsulfate (DMS), diethylsulfate (DES)] and three alkyl alkanesulfonates [methyl methanesulfonate (MMS), ethyl methanesulfonate (EMS), and isopropyl methanesulfonate (iPMS)]. Under the experimental conditions employed, cytotoxicity decreased with the size of the alkyl group. DMS was more toxic than DES, and MMS was more toxic than EMS and iPMS. All agents produced linear dose--response of mutation induction: DMS was more mutagenic than DES, and MMS was more mutagenic than EMS and iPMS based on mutants induced per unit mutagen concentration. However, the following relative mutagenic potency was observed when comparisons were made at 10% survival: DES greater than DMS; EMS greater than MMS greater than iPMS.

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?

Heat stroke and fluphenazine therapy: report of a case.

A fatal case of heat stroke in a 21-year-old man with chronic schizophrenia is reported. Phenothiazine therapy is thought to have been a factor of major importance in the induction of this syndrome. These cases may become the responsibility of the medical examiner, and the importance of obtaining a complete drug history is stressed.