Hemispheric specialization for nonverbal gestures depicting motion and space.

INTRODUCTION: The right hemispheric specialisation for mental rotation suggests a left hand preference for nonverbal gestures that depict spatial information. We therefore hypothesized that nonverbal depictions of spatial information are preferentially demonstrated by the left hand, i.e., are grounded in right hemispheric functions. METHODS: Right-handed participants were asked in two experiments to nonverbally demonstrate how to move tachistoscopically presented (in the left or right visual hemifields) geometric objects of different rotations into an identical final position. Two independent blind raters evaluated the videotaped hand gestures employing the Neuropsychological Gesture (NEUROGES) Coding System. RESULTS: Pantomime gestures increase in order to rotate gravitationally unstable objects whereas spatial relation presentation gestures increase when to nonverbally demonstrate a gravitationally stable object. Individuals preferred the right hand for pantomime gestures but the left hand for spatial relation presentation gestures. DISCUSSION: Individuals increase their pantomime gestures to nonverbally depict motion particularly with the right hand, i.e. the left hemisphere. In contrast, increased left hand spatial relation presentations gestures indicate that those gestures are of right hemispheric origin. Thus, the hemispherical lateralization of nonverbal gestures seems to depend on the hands' functional depiction.

Sample preparation with sucrose cryoprotection dramatically alters Zn distribution in the rodent hippocampus, as revealed by elemental mapping.

Transition metal ions (Fe, Mn, Cu, Zn) are essential for healthy brain function, but altered concentration, distribution, or chemical form of the metal ions has been implicated in numerous brain pathologies. Currently, it is not possible to image the cellular or sub-cellular distribution of metal ions in vivo and therefore, studying brain-metal homeostasis largely relies on ex vivo in situ elemental mapping. Sample preparation methods that accurately preserve the in vivo elemental distribution are essential if one wishes to translate the knowledge of elemental distributions measured ex vivo toward increased understanding of chemical and physiological pathways of brain disease. The choice of sample preparation is particularly important for metal ions that exist in a labile or mobile form, for which the in vivo distribution could be easily distorted by inappropriate sample preparation. One of the most widely studied brain structures, the hippocampus, contains a large pool of labile and mobile Zn. Herein, we describe how sucrose cryoprotection, the gold standard method of preparing tissues for immuno-histochemistry or immuno-fluorescence, which is also often used as a sample preparation method for elemental mapping studies, drastically alters hippocampal Zn distribution. Based on the results of this study, in combination with a comparison against the strong body of published literature that has used either rapid plunge freezing of brain tissue, or sucrose cryo-protection, we strongly urge investigators in the future to cease using sucrose cryoprotection as a method of sample preparation for elemental mapping, especially if Zn is an analyte of interest.

Contrasting patterns of X-chromosome divergence underlie multiple sex-ratio polymorphisms in stalk-eyed flies.

Sex-linked segregation distorters cause offspring sex ratios to differ from equality. Theory predicts that such selfish alleles may either go to fixation and cause extinction, reach a stable polymorphism or initiate an evolutionary arms race with genetic modifiers. The extent to which a sex ratio distorter follows any of these trajectories in nature is poorly known. Here, we used X-linked sequence and simple tandem repeat data for three sympatric species of stalk-eyed flies (Teleopsis whitei and two cryptic species of T. dalmanni) to infer the evolution of distorting X chromosomes. By screening large numbers of field and recently laboratory-bred flies, we found no evidence of males with strongly female-biased sex ratio phenotypes (SR) in one species but high frequencies of SR males in the other two species. In the two species with SR males, we find contrasting patterns of X-chromosome evolution. T. dalmanni-1 shows chromosome-wide differences between sex-ratio (XSR ) and standard (XST ) X chromosomes consistent with a relatively old sex-ratio haplotype based on evidence including genetic divergence, an inversion polymorphism and reduced recombination among XSR chromosomes relative to XST chromosomes. In contrast, we found no evidence of genetic divergence on the X between males with female-biased and nonbiased sex ratios in T. whitei. Taken with previous studies that found evidence of genetic suppression of sex ratio distortion in this clade, our results illustrate that sex ratio modification in these flies is undergoing recurrent evolution with diverse genomic consequences.

Towards a Common Understanding of the Health Sciences.

OBJECTIVE: The aim of health sciences is to maintain and improve the health of individuals and populations and to limit disability. Health research has expanded astoundingly over the last century and a variety of scientific disciplines rooted in very different scientific and intellectual traditions has contributed to these goals. To allow health scientists to fully contextualize their work and engage in interdisciplinary research, a common understanding of the health sciences is needed. The aim of this paper is to respond to the call of the 1986 Ottawa Charter to improve health care by looking both within and beyond health and health care, and to use the opportunity offered by WHO's International Classification of Functioning, Disability and Health (ICF) for a universal operationalization of health, in order to develop a common understanding and conceptualization of the field of health sciences that account for its richness and vitality. METHODS: A critical analysis of health sciences based on WHO's ICF, on WHO's definition of health systems and on the content and methodological approaches promoted by the biological, clinical and socio-humanistic traditions engaged in health research. RESULTS: The field of health sciences is presented according to: 1) a specification of the content of the field in terms of people's health needs and the societal response to them, 2) a meta-level framework to exhaustively represent the range of mutually recognizable scientific disciplines engaged in health research and 3) a heuristic framework for the specification of a set of shared methodological approaches relevant across the range of these disciplines. CONCLUSION: This conceptualization of health sciences is offered to contextualize the work of health researchers, thereby fostering interdisciplinarity.

The relative merits of cord blood as a cell source for autologous T regulatory cell therapy in type 1 diabetes.

Cord blood has been used as a cell source for therapeutic purposes in children with type 1 diabetes and other disorders. Here, we explore the benefits of cord blood as an autologous source of T regulatory cells for immune cell therapy in patients. CD4(+)CD25(+) T regulatory cells were isolated from cord blood and adult peripheral blood of healthy donors and compared during and after expansion in a 14-day protocol incorporating anti-CD3/anti-CD28 beads, and IL-2 with or without rapamycin. Cord blood T regulatory cells were largely naïve (89±7 vs. 31±10% in young adults, p<0.0001), and had higher expansion yields (median 5,968-fold) than adult T regulatory cells (median 516-fold, p=0.001) and adult naïve T regulatory cells (median 820-fold, p=0.003). Rapamycin reduced expansion yields, but was not necessary to obtain pure expanded cord blood T regulatory cells as judged by FOXP3 staining (94±3%), methylation status of FOXP3 (97%), and intracellular effector cytokine staining (< 6%). Expanded adult T regulatory cells were much less pure in the absence of rapamycin (72±19% FOXP3; 76% by methylation status, <13% INF-γ, <16% IL-4, <5% IL-17 positive), but purity was achieved by inclusion of rapamycin during expansion. Despite differences in purity, all preparations of expanded T regulatory from all sources were able to strongly suppress proliferation of T effector cells in vitro. Our findings suggest that cord blood is an excellent source of T regulatory cells for expansion and autologous cell therapy that may be considered as a strategy to prevent immune-mediated destruction of beta cells in type 1 diabetes.

Magnetic resonance imaging correlates of physical disability in relapse onset multiple sclerosis of long disease duration.

BACKGROUND: Understanding long-term disability in multiple sclerosis (MS) is a key goal of research; it is relevant to how we monitor and treat the disease. OBJECTIVES: The Magnetic Imaging in MS (MAGNIMS) collaborative group sought to determine the relationship of brain lesion load, and brain and spinal cord atrophy, with physical disability in patients with long-established MS. METHODS: Patients had a magnetic resonance imaging (MRI) scan of their brain and spinal cord, from which we determined brain grey (GMF) and white matter (WMF) fractional volumes, upper cervical spinal cord cross-sectional area (UCCA) and brain T2-lesion volume (T2LV). We assessed patient disability using the Expanded Disability Status Scale (EDSS). We analysed associations between EDSS and MRI measures, using two regression models (dividing cohort by EDSS into two and four sub-groups). RESULTS: In the binary model, UCCA (p < 0.01) and T2LV (p = 0.02) were independently associated with the requirement of a walking aid. In the four-category model UCCA (p < 0.01), T2LV (p = 0.02) and GMF (p = 0.04) were independently associated with disability. CONCLUSIONS: Long-term physical disability was independently linked with atrophy of the spinal cord and brain T2 lesion load, and less consistently, with brain grey matter atrophy. Combinations of spinal cord and brain MRI measures may be required to capture clinically-relevant information in people with MS of long disease duration.

Microrheology close to an equilibrium phase transition.

We investigate the microstructural and microrheological response to a tracer particle of a two-dimensional colloidal suspension under thermodynamic conditions close to a liquid-gas phase boundary. On the liquid side of the binodal, increasing the velocity of the (repulsive) tracer leads to the development of a pronounced cavitation bubble, within which the concentration of colloidal particles is strongly depleted. The tendency of the liquid to cavitate is characterized by a dimensionless "colloidal cavitation" number. On the gas side of the binodal, a pulled (attractive) tracer leaves behind it an extended trail of colloidal liquid, arising from downstream advection of a wetting layer on its surface. For both situations the velocity dependent friction is calculated.

Spinal cord injury-related chronic pain in victims of the 2008 Sichuan earthquake: a prospective cohort study.

STUDY DESIGN: Prospective cohort. OBJECTIVES: To characterize spinal cord injury (SCI)-related pain and treatment in victims of the 2008 Sichuan earthquake. SETTING: Mianzhu County, China. METHODS: Twenty-six patients who sustained SCI in the 2008 Sichuan earthquake and who were treated in the same hospital were enrolled. Data was collected on pain severity with a visual analog scale, depression with Patient Health Questionnaire-9, quality of life (QoL) with World Health Organization Quality of Life-BREF and social participation with the Craig Hospital Handicap Assessment and Reporting Technique Short Form at three assessment points. Detailed pain descriptions including therapeutic interventions were elicited at the fourth assessment. Pain determinants were analyzed with a longitudinal Tobit regression, and Pearson's correlations of pain severity with depression, QoL and social participation stratified by measurement point were calculated. RESULTS: SCI-related pain was highly prevalent and prevalence of neuropathic pain was nearly twice that of nociceptive pain. Most patients reported pain since the onset and severity was not significantly reduced over time. Cervical injury, complete lesions and education level were significant pain determinants. Depression and QoL scores were highly correlated with pain at the first two assessments points but not at the third measurement. Most patients did not seek treatment because they regarded pain as either a normal condition after SCI or were afraid of drug dependency. CONCLUSION: This initial longitudinal assessment and characterization of SCI-related pain in earthquake victims provides a foundation for further exploration of the biological and psychosocial determinants of pain severity and of the correlation of chronic pain with other outcomes of interest in this population. Patient pain-treatment-seeking behavior and therapeutic interventions should be evaluated concurrently.

Medical rehabilitation of spinal cord injury following earthquakes in rehabilitation resource-scarce settings: implications for disaster research.

STUDY DESIGN: Narrative literature review. OBJECTIVES: To (1) summarize epidemiological and scientific research on spinal cord injury (SCI) populations from three severe earthquakes (EQs) in rehabilitation resource-scarce settings; (2) summarize SCI rehabilitation services by local and foreign providers in response to these EQs and (3) provide implications including research gaps for a supporting global scientific research agenda. SETTING: International. METHODS: A literature review was conducted using PubMed to identify epidemiological studies reporting data on SCI survivors of the 2005 Kashmir EQ in Pakistan, the Sichuan EQ of 2008 in China and the 2010 Haiti EQ. A follow-up review on the SCI rehabilitation services provided by local and foreign providers in response to these EQs was also performed. RESULTS: Review of the scientific literature revealed the qualitative trends in focused EQ victim epidemiological data, including SCI classification and types of medical complications. Selected EQ country narratives showed that post-disaster SCI rehabilitation services were expanded by adapting local resources with international assistance to manage the significant numbers of SCI survivors. The resulting SCI research was limited. CONCLUSION: A global disaster research agenda for SCI in EQs in rehabilitation resource-scarce settings is needed to strengthen the evidence base for improvement of clinical management and outcomes for SCI EQ survivors. Expansion of this limited narrative review into a systematic review to identify additional research gaps is a proposed next step. Effective disaster setting data management and research collaborations of foreign and local SCI disability and rehabilitation stakeholders will be required for agenda implementation.

To work or not to work: labour market participation of people with spinal cord injury living in Switzerland.

STUDY DESIGN: Cross-sectional survey. OBJECTIVES: To establish labour market participation figures of persons with spinal cord injury (SCI) living in Switzerland and to investigate determinants and consequences of having paid work. SETTING: Community. METHODS: A survey among members of the Swiss Paraplegic Association was performed in 2008. Inclusion criteria were: SCI of traumatic or non-traumatic origin, minimum age of 18 years, and living in the community for at least 1 year. A total of 559 persons with SCI returned the questionnaire (response rate 27%), of which 495 (24%) fulfilled the eligibility criteria. Bivariate and logistic regression analyses were performed based on theoretical considerations and relevant determinants found in the literature. RESULTS: Of the respondents of working age, 63.8% were involved in gainful employment. No significant difference between persons with para- and tetraplegia was observed. Logistic regression showed that employment was associated with age, time since onset of SCI, having worked at 2 years after initial rehabilitation, having received vocational counselling, having less pain, more years of education and more perceived importance of work. Working persons achieved a significantly higher total income. The most important reasons to work were not financial, but rather of social nature. Barriers to work were primarily health-related. CONCLUSIONS: We found a relatively high employment rate among the studied persons with SCI living in Switzerland. However, because of the low response, it is difficult to generalise this finding.

Post-traumatic stress disorder in a population of 2008 Wenchuan earthquake survivors with disabilities: the role of environmental barriers.

PURPOSE: Earthquake survivors whose physical injuries result in disability may be at increased risk for prolonged and severe post-traumatic stress disorder. We estimated the prevalence of post-traumatic stress disorder, functional limitations, and environmental barriers in 289 survivors with disabilities induced by the 2008 Wenchuan earthquake eight years after the disaster. We also investigated the relationship of post-traumatic stress disorder symptom severity with function, considering a mediating role of environmental barriers. METHODS: Post-traumatic stress disorder was measured with post-traumatic stress disorder checklist-civilian version. Physical and mental functioning was assessed with Medical Outcomes Short Form-36 and perceived environmental barriers were evaluated with Nottwil Environmental Factors Inventory-Short Form. Path analysis was employed to examine the relationship of exposures, post-traumatic stress disorder symptom severity, environmental barriers, and physical and mental function. RESULTS: Prevalence of probable post-traumatic stress disorder was 18.68% (95% CI: 14.19-23.18%). Earthquake survivors with lower physical and mental functioning perceived more environmental barriers, and those who perceived more barriers demonstrated more severe post-traumatic stress disorder symptoms, confirming a mediating role of environmental barriers. CONCLUSIONS: Long-term community-based health services for earthquake survivors with disabilities should combine both mental and physical rehabilitation and focus on creating disability-inclusive environments.Implications for rehabilitationEarthquake survivors whose physical injuries result in permanent disability may experience two different types of psychological trauma. The first originates from the initial psychological impact of the disaster and their injuries and the second arises from the added difficulty of coping with environmental barriers given the limitations imposed by their impairments.Even years after the disaster, prevalence of post-traumatic stress disorder is likely high in earthquake survivors with acquired musculoskeletal or neurological impairments and needs to be considered in the rehabilitation process.Physical and mental functioning, as well as environmental barriers, are important intervention targets to reduce post-traumatic stress disorder symptoms.Long-term community-based health services for earthquake survivors with disabilities are needed that combine both mental health and physical rehabilitation components with advocating for disability-inclusive environments.

[Requirements for long-term follow-up on efficacy and safety of advanced therapy medicinal products. Risk management and traceability]. / Regelungen zur Uberwachung von Wirksamkeit und Sicherheit nach der Zulassung. Risikomanagement und Rückverfolgbarkeit von Arzneimitteln für Neuartige Therapien.

Advanced therapy medicinal products (ATMPs) are an innovative treatment option. To promote timely access of the innovative medicinal product and to safeguard public health, new elements have been introduced into legislation. A key element of the ATMP regulation is the requirement for long-term follow-up on safety and efficacy of patients enrolled in clinical trials with ATMPs, which is beyond the routine requirements on pharmacovigilance. For gene therapy medicinal products, a guideline on long-term follow-up, which lays down the technical requirements, is available. A further key element of the ATMP regulation is the traceability of the starting materials used to manufacture the ATMP. A common European coding system is imperative to ensure the traceability of starting materials, especially across the borders of European Member States.

Regulatory requirements for clinical trial and marketing authorisation application for cell-based medicinal products.

The new era of regenerative medicine has led to rapid development of new innovative therapies especially for diseases and tissue/organ defects for which traditional therapies and medicinal products have not provided satisfactory outcome. Although the clinical use and developments of cell-based medicinal products (CBMPs) could be witnessed already for a decade, robust scientific and regulatory provisions for these products have only recently been enacted. The new Regulation for Advanced Therapies (EC) 1394/2007 together with the revised Annex I, Part IV of Directive 2001/83/EC provides the new legal framework for CBMPs. The wide variety of cell-based products and the foreseen limitations (small sample sizes, short shelf life) vs. particular risks (microbiological purity, variability, immunogenicity, tumourigenicity) associated with CBMPs have called for a flexible, case-by-case regulatory approach for these products. Consequently, a risk-based approach has been developed to allow definition of the amount of scientific data needed for a Marketing Authorisation Application (MAA) of each CBMP. The article provides further insight into the initial risk evaluation, as well as to the quality, non-clinical, and clinical requirements of CBMPs. Special somatic cell therapies designed for active immunotherapy are also addressed.

Immunomodulatory effects of some Namibian plants traditionally used for treating inflammatory diseases.

ETHNOPHARMACOLOGICAL RELEVANCE: Acanthosicyos naudininus, Gomphocarpus fruticosus, and Cryptolepis decidua are, according to the knowledge of traditional healers, used in Namibia to treat inflammatory disorders such as pain, fever and skin rashes. AIM OF THE STUDY: The present study was conducted to evaluate the immunomodulatory effects and the possible underlying mechanisms of action of the plant extracts on peripheral blood mononuclear cells (PBMCs) such as T-lymphocytes. MATERIALS AND METHODS: Methanolic and EtOAc extracts of A. naudinianus, G. fruticosus and C. decidua were analysed for their immunomodulatory potential. PBMCs were isolated from the blood of healthy donors and incubated with the plant extracts at concentrations 100, 30, 10, 3, 1 and 0.3 µg/mL. Effects on proliferation and viability of activated human lymphocytes were assessed in comparison to ciclosporin A by flow cytometry using carboxyfluorescein succinimidyl ester (CFSE) and WST-1 assay. Flow cytometry by annexin V/propidium iodide (PI) staining was performed to investigate the necrotic/apoptotic effect of the plant extracts on mitogen-activated human lymphocytes. In addition, analysis of the influence of plant extracts on the regulatory mechanisms of T-lymphocytes was performed using activation marker and cytokine production assays. An HPLC-PDA-ELSD-ESIMS profile was recorded for each of the extracts. RESULTS: T-lymphocyte proliferation was inhibited in a dose-dependent manner by the extracts of A. naudinianus, G. fruticosus, and C. decidua in concentrations not causing apoptosis or necrosis. This effect was mediated by inhibition of lymphocyte activation, specifically the suppression of CD25 and CD69 surface receptor expression. Moreover, the extracts suppressed effector functions, as indicated by reduced production of IFN-γ and IL-2. Based on the HPLC profile, possible responsible compound classes could be identified for the extracts of A. naudinianus (cucurbitacins) and C. decidua (indole alkaloids), but not for G. fruticosus. CONCLUSIONS: The data show that the extracts of A. naudinianus, G. fruticosus and C. decidua have in vitro immunomodulatory activity and they interfere with the function of immunocompetent cells, suggesting an anti-inflammatory mode-of-action. The present chemical determination and pattern recognition results explain the therapeutic potency. However, further studies to investigate the therapeutic potential of the plants in inflammatory disorders should be done.

Hyperalgesia, synovitis and multiple biomarkers of inflammation are suppressed by interleukin 1 inhibition in a novel animal model of gouty arthritis.

BACKGROUND: Monosodium urate (MSU) and calcium pyrophosphate dihydrate (CPPD) crystal-induced interleukin 1 beta (IL1beta) release contributes to inflammation in subcutaneous air pouch and peritoneal models of acute gout and pseudogout. However, consequences of IL1 inhibition have not been explored in more clinically relevant models of crystal-induced arthritis. OBJECTIVE: To develop a novel mouse model of acute gouty ankle arthritis and use it to assess the effects of genetic deletion of IL1 receptor type (IL1R1) and of exogenous mIL1 Trap (a high-affinity blocker of mouse IL1alpha and IL1beta) on pain, synovitis and systemic inflammatory biomarkers. METHODS: MSU crystals were injected into the mouse ankle joint and pain and ankle swelling were measured over 4 days. The effects of IL1 inhibition were determined in this model, and in the comparator models of crystal-induced peritonitis and subcutaneous air pouch inflammation. RESULTS: Both IL1R1-null mice and mice pretreated with mIL1 Trap showed reduced neutrophil influx in MSU and CPPD crystal-induced peritonitis and air pouch models (p<0.05). In the ankle joint model, both IL1R1 knockout mice and pretreatment with mIL1 Trap were associated with significant reductions in MSU crystal-induced elevations in hyperalgesia, inflammation, serum amyloid A and the levels of multiple inflammatory cytokines and chemokines (p<0.05). Additionally, it was found that administration of mIL1 Trap after MSU crystal injection reduced established hyperalgesia and ankle swelling. CONCLUSIONS: IL1 inhibition both prevented and relieved pain and ankle joint inflammation in response to intra-articular MSU crystals in mice. Results suggested that IL1 Trap has the potential to both prevent and treat gouty arthritis.

Effect of Tooth-Whitening Procedures on Stained Composite Resins.

In this laboratory study, a composite resin was stained to a visibly discernible level using both coffee and red wine over 14 days (change was considered clinically noticeable and significant when ΔEab*≥2.7). Color change was measured at one, three, seven, and 14 days of staining. Although the nature of color change was different for the two staining solutions, the overall degree of staining (ΔEab*) rendered by either coffee or wine at each time interval was not significantly different ( p≥0.05). Four whitening protocols were applied to stained composites. Treatment included applications of distilled water (control), Crest Pro-Health [HD] toothpaste, Crest Whitestrips, Opalescence PF bleach (15%), and application of a fine pumice polishing (Preppies). HD toothpaste and Whitestrips were applied daily for 21 days, Opalescence was applied daily for 10 days, and polishing was applied once. Each of the whitening products, applied in a manner simulating at-home or in-office treatment, was effective in producing color improvements (lightening) over controls ( p<0.05), but none of the four treatments produced lightening that was significantly different from the other treatments ( p≥0.05). A comparison of final composite color with that measured at baseline showed that Opalescence returned composite color to an acceptable level following exposure to both staining solutions (ΔEab*<2.7), Whitestrips returned color close to baseline for wine-stained composites, and HD paste and polishing permitted residual stain to remain (ΔEab*≥2.7).

[Impact of technical and morphological factors on the precision of software-based MR tumor volumetry: a phantom study]. / Einfluss messtechnischer und morphologischer Faktoren auf die Genauigkeit der softwarebasierten MR-Tumorvolumetrie: eine Phantomstudie.

PURPOSE: To investigate the impact of technical and morphological parameters on the precision of software-based MR tumor volumetry (SBV) in an in-vitro experimental setting. MATERIALS AND METHODS: Tumor models were formed from a silicone compound in three different sizes with a max. diameter < 2 cm (small), 2 - 4 cm (middle), and > 4 cm (large). For each size a spherical, an elliptic and an irregular shaped model was produced. The true volume of the tumor models was established by water displacement. Tumor models were examined with a high-field MRI (TRIO, 3 Tesla, Siemens) with T 2-weighted sequences under optimized contrast conditions. Slice thickness was 1, 3 and 5 mm. The volume of the tumor models was then calculated using (1). manually driven volumetric software (SBVmanual) and (2). automatic volumetric software (SBVauto). The influence of the following parameters on the precision of SBV was analyzed: Size and shape of the tumor models, manual/automatic SBV, segmentation technique and slice thickness. RESULTS: In general, SBVauto measurements showed less deviation than measurements with SBVmanual (p < 0.01). However, both methods depended significantly on morphologic factors, especially on tumor size. In small tumor models, the volume was strongly underestimated by -36.2 +/- 27.8 % (SBVmanual) and -33.1 +/- 8.6 % (SBVauto), whereas the deviation for large tumor models was only 2.0 +/- 14.7 % (SBVmanual) and 3.0 +/- 2.3 % (SBVauto; p < 0.01). The deviation of measurements increased from the "spherical" to the "irregular" shape by 9.5 % (SBVmanual) and 10.7 % (SBVauto). In addition, SBVmanual depended on technical factors. Using a "minimal" segmentation technique (e. g. excluding partial volume effects), volumes were underestimated in all cases, whereas volumes of middle and large tumor models were slightly overestimated when using a "maximum" segmentation technique (e. g. including partial volume effects; p = 0.01). Deviation of SBVmanual increased with slice thickness from 15.9 +/- 12.7 % (1 mm slices) to 27.1 +/- 21.3 % (5 mm-slices). CONCLUSION: In general, SBVauto measurements yielded smaller deviations than SBVmanual. However, both methods showed major inaccuracy in the volumetric estimation of small and irregular shaped tumor models, thus the tumor volumetry of these tumors has to be considered inappropriate for clinical practice. Moreover, the exactness of SBVmanual depended significantly on segmentation technique and slice thickness.

Immuno-driven and Mechano-mediated Neotissue Formation in Tissue Engineered Vascular Grafts.

In vivo development of a neovessel from an implanted biodegradable polymeric scaffold depends on a delicate balance between polymer degradation and native matrix deposition. Studies in mice suggest that this balance is dictated by immuno-driven and mechanotransduction-mediated processes, with neotissue increasingly balancing the hemodynamically induced loads as the polymer degrades. Computational models of neovessel development can help delineate relative time-dependent contributions of the immunobiological and mechanobiological processes that determine graft success or failure. In this paper, we compare computational results informed by long-term studies of neovessel development in immuno-compromised and immuno-competent mice. Simulations suggest that an early exuberant inflammatory response can limit subsequent mechano-sensing by synthetic intramural cells and thereby attenuate the desired long-term mechano-mediated production of matrix. Simulations also highlight key inflammatory differences in the two mouse models, which allow grafts in the immuno-compromised mouse to better match the biomechanical properties of the native vessel. Finally, the predicted inflammatory time courses revealed critical periods of graft remodeling. We submit that computational modeling can help uncover mechanisms of observed neovessel development and improve the design of the scaffold or its clinical use.

Genotoxicity and carcinogenicity in rats and mice of 2-amino-3,6-dihydro-3-methyl-7H-imidazolo[4,5-f]quinolin-7- one: an intestinal bacterial metabolite of 2-amino-3-methyl-3H-imidazo[4,5-f]quinoline.

BACKGROUND: Compounds formed on the surface of fried or grilled meat and fish may be associated with increased risk of colon cancer. Normal intestinal bacteria can convert one of these compounds, 2-amino-3-methyl-3H-imidazo[4,5-f]quinoline (IQ), to the 7-hydroxy metabolite, 2-amino-3,6-dihydro-3-methyl-7H-imidazolo[4,5-f]quinolin-7-o ne (7-OHIQ), a direct-acting mutagen. PURPOSE: We studied the genotoxicity and carcinogenicity of 7-OHIQ to determine if it is responsible for the colon-specific activity of IQ. METHODS: The effects of pure, synthetic 7-OHIQ on DNA were evaluated in the Ames Salmonella typhimurium TA98 test, with and without an induced rat liver S9 fraction, and in the Williams DNA repair test using freshly explanted rat hepatocytes. 7-OHIQ was also subjected to an in vivo bioassay for 21 months by long-term intrarectal infusion in male F344 rats, using IQ and N-nitrosomethylurea (NMU) given intrarectally as positive tumor-producing controls. The standard NIH-07 rodent diet was supplemented with 15% corn oil to maximize any effect of the infused materials on the colon. A parallel bioassay involved intraperitoneal injection of 7-OHIQ in newborn mice, followed by dietary administration from week 11 to week 67. Again, IQ and NMU were used as positive controls. RESULTS: We confirmed that 7-OHIQ is a direct-acting mutagen in the Ames test, with added S9 liver fraction giving higher mutagenicity. 7-OHIQ was negative in the Williams test, whereas IQ was positive. 7-OHIQ did not induce colon cancer in rats, and in the newborn mouse test it produced only a low incidence of liver neoplasms. CONCLUSIONS: 7-OHIQ is not genotoxic, for to be so classified it must be definitely positive in both the Ames and Williams tests; moreover, it is not carcinogenic, in marked contrast to IQ and NMU.

Effects of chronic ethanol consumption on the metabolism and carcinogenicity of N'-nitrosonornicotine in F344 rats.

The effects of chronic ethanol consumption on the carcinogenicity and metabolism of N'-nitrosonornicotine (NNN) in male F344 rats have been investigated. Groups of 26 to 30 rats were maintained on either a control liquid diet (Groups 1, 3, and 5) or an ethanol-containing liquid diet (Groups 2, 4, and 6) for 4 weeks prior to and during treatment with NNN. The carcinogen was injected s.c. (10 mg/kg, Groups 3 and 4) three times weekly or added to the liquid diet (17.5 mg/liter, Groups 5 and 6). The total dose was 1 mmol of NNN per rat. Control rats (Groups 1 and 2) received s.c. injections of 0.9% NaCl solution. The nasal mucosa was the main target tissue of NNN in Groups 3 and 4, but both the nasal mucosa and esophagus were major target tissues in Groups 5 and 6. In rats treated s.c. with NNN (Groups 3 and 4), ethanol consumption had no effect on the distribution and incidence of nasal cavity tumors. In rats treated with NNN added to the control liquid diet or to the ethanol-containing liquid diet, the number of tumors of the nasal cavity was 18 in Group 5 and 26 in Group 6 (p less than 0.05). In contrast, the number of rats with esophageal tumors was 25 in Group 5 and 20 in Group 6 (p less than 0.05). The effects of ethanol on the enzyme system which activates NNN were studied in rats which had been maintained on an ethanol-containing liquid diet for 4 weeks. Explants of nasal mucosae, lingual mucosae, esophagi , and livers were cultured in vitro with NNN. Nasal mucosae of ethanol-consuming rats had a 1.5-fold higher (p less than 0.05) alpha-carbon-hydroxylating activity than did those of control rats. Activating enzymes in the lingual mucosae, esophagi , and livers were not induced by ethanol. The results show that the increased susceptibility of the rat nasal mucosa to the carcinogenic effects of NNN added to an ethanol-containing diet could be due in part to an induction of activating enzymes by ethanol. However, since chronic ethanol consumption had no apparent effect on the incidence of nasal cavity tumors in rats treated by s.c. injection of NNN, factors other than enzyme induction are important in determining the effects of ethanol on NNN carcinogenicity.