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PubMedDate not supplied

Issues in deep space radiation protection.

The exposures in deep space are largely from the Galactic Cosmic Rays (GCR) for which there is as yet little biological experience. Mounting evidence indicates that conventional linear energy transfer (LET) defined protection quantities (quality factors) may not be appropriate for GCR ions. The available biological data indicates that aluminum alloy structures may generate inherently unhealthy internal spacecraft environments in the thickness range for space applications. Methods for optimization of spacecraft shielding and the associated role of materials selection are discussed. One material which may prove to be an important radiation protection material is hydrogenated carbon nanofibers.

Aluminum↗

PubMed1997

Estimating Y chromosome specific microsatellite mutation frequencies using deep rooting pedigrees.

Recently, a set of highly polymorphic chromosome Y specific microsatellites became available for forensic, population genetic and evolutionary studies. However, the lack of a mutation frequency estimate for these loci prevents a reliable application. We therefore used seven chromosome Y tetranucleotide repeat loci to screen 42 males who are descendants from 12 'founding fathers' by a total number of 213 generations. As a result, we were able to estimate an average chromosome Y tetranucleotide mutation frequency of 0.20% (95% CIL 0.05-0.55). This closely matches the often cited Weber and Wong estimate of 0.21% for a set of autosomal tetranucleotide repeats. Expanding the set of microsatellites with two more loci (a tri- and a penta-nucleotide repeat locus) an average chromosome Y microsatellite mutation frequency of 0.21% (95% CIL 0.06-0.49) was found. These estimates suggest that microsatellites on the Y chromosome have mutation frequencies comparable to those on the autosomes. This supports the hypothesis that slippage-generated growth is the driving force behind the microsatellite variability.

Gene Frequency↗

PubMed2001

Experimental measurements of deep directional columnar heating by laser-generated relativistic electrons at near-solid density.

In our experiments, we irradiated solid CH targets with a 400 J, 5 ps, 3 x 10(19) W/cm(2) laser, and we used x-ray imaging and spectroscopic diagnostics to monitor the keV x-ray emission from thin Al or Au tracer layers buried within the targets. The experiments were designed to quantify the spatial distribution of the thermal electron temperature and density as a function of buried layer depth; these data provide insights into the behavior of relativistic electron currents which flow within the solid target and are directly and indirectly responsible for the heating. We measured approximately 200-350 eV temperatures and near-solid densities at depths ranging from 5 to 100 microm beneath the target surface. Time-resolved x-ray spectra from Al tracers indicate that the tracers emit thermal x rays and cool slowly compared to the time scale of the laser pulse. Most intriguingly, we consistently observe annular x-ray images in all buried tracer-layer experiments, and these data show that the temperature distribution is columnar, with enhanced heating along the edges of the column. The ring diameters are much greater than the laser focal spot diameter and do not vary significantly with the depth of the tracer layer for depths greater than 30 microm. The local temperatures are 200-350 eV for all tracer depths. We discuss recent simulations of the evolution of electron currents deep within solid targets irradiated by ultra-high-intensity lasers, and we discuss how modeling and analytical results suggest that the annular patterns we observe may be related to locally strong growth of the Weibel instability. We also suggest avenues for future research in order to further illuminate the complex physics of relativistic electron transport and energy deposition inside ultra-high-intensity laser-irradiated solid targets.

Journal Article↗

PubMed1990

Intracortical processes regulating the integration of sensory information.

The mechanisms that link sensory inputs in spatially separated regions of cortex can be elucidated by analyzing the mechanisms that generate receptive field properties in cortical neurons under conditions that mimic the waking state; a state when learning, memory and the modification of synaptic strength can be most readily demonstrated. Important advances in understanding receptive field mechanisms in sensory cortex have arisen from studying the precise relationship between the mystacial vibrissae or "whiskers" and their neural representation in separate cortical domains or "barrels". The anatomical precision of whisker projections to barrels permits a unique delineation of thalamocortical and intracortical components of cortical cell responses based on latency and security of response to peripheral receptor stimulation. When recorded in awake animals or even under very light anesthesia, cortical neurons show two components to their response to whisker movement. Neurons in layer IV of a whisker's primary projection zone respond with short latency (7-10 msec) and a high response magnitude (two or more action potentials (spikes) per stimulus). This "Center Receptive Field" (CRF) for layer IV cells is generated in large part by sensory fiber inputs from the thalamus. The CRF is restricted to 1.4 whiskers on average and is the only response detectable when cortical responses are depressed by deep anesthesia. In the "waking state" the same neuron often will respond to deflection of 4-6 surrounding whiskers, but only at longer latency (15-40 msec) and with fewer spikes per stimulus. These more labile responses form an excitatory surround receptive field (SRF). Sensory information that is transduced by individual whiskers and that generates the SRF of a cortical neuron achieves this added response complexity through intracortical mechanisms. The control of the mechanisms that determine the dissemination of sensory information within cortex include: (1) regulating the level of GABAergic inhibition; and (2) potentiation or depression of the response level generated by repeated sensory experience. State-dependent "modulatory" inputs to cortex, such as the noradrenergic and cholinergic fiber system, could regulate the degree of horizontal spread of a sensory input, in part through global changes in the level of inhibition and/or regulating the amplitude of cortical responses, thereby determining the level of associative interactions between sensory inputs.

Animals↗

PubMed2026

Rapidly evolving aphid gall effector proteins exhibit saposin-like folds.

Many insects manipulate plants by injecting effector proteins. In one extreme example of this molecular "hijacking," Hormaphis cornu aphids inject bicycle proteins into Hamamelis virginiana, contributing to the development of novel organs called galls. Bicycle proteins share no amino acid sequence similarity with proteins of known function. Here, we report the crystal structures of two divergent bicycle proteins. Both proteins contain saposin-like folds: one with multiple disulfide bonds exhibits a swapped domain topology; the other has no disulfide bonds and possesses two distinct, tandem domains. To explore the structural evolution of bicycle proteins, we attempted to predict bicycle protein structures with Alphafold2 (AF2) and other deep learning programs. While AF2 did not recover the two experimental structures using existing databases, it succeeded when provided with multiple sequence alignments (MSAs) of protein sequences from newly sequenced closely related species. Using this approach, we generated 2,400 high-confidence bicycle protein predictions from seven aphid species. While all aphid bicycle proteins contain predicted saposin-like folds, they display a vast diversity of structural and physicochemical properties. While this diversity thwarts prediction of conserved functions encoded in structure, it suggests that bicycle proteins have evolved to target diverse plant processes and/or to evade plant immune surveillance. Our extension of AF2 with custom MSAs of proteins from closely related species provides a generalizable, powerful approach for predicting structures of rapidly evolving protein families.

Animals↗

PubMed1995

Temporal fluctuations in coherence of brain waves.

As a measure of dynamical structure, short-term fluctuations of coherence between 0.3 and 100 Hz in the electroencephalogram (EEG) of humans were studied from recordings made by chronic subdural macroelectrodes 5-10 mm apart, on temporal, frontal, and parietal lobes, and from intracranial probes deep in the temporal lobe, including the hippocampus, during sleep, alert, and seizure states. The time series of coherence between adjacent sites calculated every second or less often varies widely in stability over time; sometimes it is stable for half a minute or more. Within 2-min samples, coherence commonly fluctuates by a factor up to 2-3, in all bands, within the time scale of seconds to tens of seconds. The power spectrum of the time series of these fluctuations is broad, extending to 0.02 Hz or slower, and is weighted toward the slower frequencies; little power is faster than 0.5 Hz. Some records show conspicuous swings with a preferred duration of 5-15s, either irregularly or quasirhythmically with a broad peak around 0.1 Hz. Periodicity is not statistically significant in most records. In our sampling, we have not found a consistent difference between lobes of the brain, subdural and depth electrodes, or sleeping and waking states. Seizures generally raise the mean coherence in all frequencies and may reduce the fluctuations by a ceiling effect. The coherence time series of different bands is positively correlated (0.45 overall); significant nonindependence extends for at least two octaves. Coherence fluctuations are quite local; the time series of adjacent electrodes is correlated with that of the nearest neighbor pairs (10 mm) to a coefficient averaging approximately 0.4, falling to approximately 0.2 for neighbors-but-one (20 mm) and to < 0.1 for neighbors-but-two (30 mm). The evidence indicates fine structure in time and space, a dynamic and local determination of this measure of cooperativity. Widely separated frequencies tending to fluctuate together exclude independent oscillators as the general or usual basis of the EEG, although a few rhythms are well known under special conditions. Broad-band events may be the more usual generators. Loci only a few millimeters apart can fluctuate widely in seconds, either in parallel or independently. Scalp EEG coherence cannot be predicted from subdural or deep recordings, or vice versa, and intracortical microelectrodes show still greater coherence fluctuation in space and time. Widely used computations of chaos and dimensionality made upon data from scalp or even subdural or depth electrodes, even when reproducible in successive samples, cannot be considered representative of the brain or the given structure or brain state but only of the scale or view (receptive field) of the electrodes used. Relevant to the evolution of more complex brains, which is an outstanding fact of animal evolution, we believe that measures of cooperativity are likely to be among the dynamic features by which major evolutionary grades of brains differ.

Brain↗

PubMed2005

Crystal structure of human pFGE, the paralog of the Calpha-formylglycine-generating enzyme.

In eukaryotes, sulfate esters are degraded by sulfatases, which possess a unique Calpha-formylglycine residue in their active site. The defect in post-translational formation of the Calpha-formylglycine residue causes a severe lysosomal storage disorder in humans. Recently, FGE (formylglycine-generating enzyme) has been identified as the protein required for this specific modification. Using sequence comparisons, a protein homologous to FGE was found and denoted pFGE (paralog of FGE). pFGE binds a sulfatase-derived peptide bearing the FGE recognition motif, but it lacks formylglycine-generating activity. Both proteins belong to a large family of pro- and eukaryotic proteins containing the DUF323 domain, a formylglycine-generating enzyme domain of unknown three-dimensional structure. We have crystallized the glycosylated human pFGE and determined its crystal structure at a resolution of 1.86 A. The structure reveals a novel fold, which we denote the FGE fold and which therefore serves as a paradigm for the DUF323 domain. It is characterized by an asymmetric partitioning of secondary structure elements and is stabilized by two calcium cations. A deep cleft on the surface of pFGE most likely represents the sulfatase polypeptide binding site. The asymmetric unit of the pFGE crystal contains a homodimer. The putative peptide binding site is buried between the monomers, indicating a biological significance of the dimer. The structure suggests the capability of pFGE to form a heterodimer with FGE.

Amino Acid Motifs↗

PubMed2004

Mapping drug resistance genes in Plasmodium falciparum by genome-wide association.

When alleles conferring drug resistance spread through a population of malaria parasites, they leave characteristic "scars" in the parasite genome. Flanking neutral polymorphisms "hitchhike" to high frequency with the resistance mutation, generating deep valleys of reduced variation and broad swathes of elevated linkage disequilibrium around the resistance locus. We can systematically search the genome for these scars by genotyping polymorphic marker loci at intervals throughout the genome of P. falciparum, and use them as signposts for locating drug resistance genes. In this review I outline the rational behind this approach to genetic mapping. I describe key features of P. falciparum population biology, such as recombination rate, inbreeding, and selection intensity that influence the size of genomic regions affected by selection and the choice of study population. I discuss suitable genetic markers, study designs, and statistical approaches to data analysis. Finally, to demonstrate the utility of the approach I describe two proof-of-principle studies documenting patterns of genetic variability around known drug resistance genes.

Animals↗

PubMed2006

Measurement of the clinical and cost-effectiveness of non-invasive diagnostic testing strategies for deep vein thrombosis.

OBJECTIVES: To estimate the diagnostic accuracy of non-invasive tests for proximal deep vein thrombosis (DVT) and isolated calf DVT, in patients with clinically suspected DVT or high-risk asymptomatic patients, and identify factors associated with variation in diagnostic performance. Also to identify practical diagnostic algorithms for DVT, and estimate the diagnostic accuracy, clinical effectiveness and cost-effectiveness of each. DATA SOURCES: Electronic databases (to April 2004). A postal survey of hospitals in the UK. REVIEW METHODS: Selected studies were assessed against validated criteria. A postal survey of hospitals in the UK was undertaken to describe current practice and availability of tests, and identify additional diagnostic algorithms. Pooled estimates of sensitivity, specificity and likelihood ratios were obtained for each test using random effects meta-analysis. The effect of study-level covariates was explored using random effects metaregression. A decision-analytic model was used to combine estimates from the meta-analysis and estimate the diagnostic performance of each algorithm in a theoretical population of outpatients with suspected DVT. The net benefit of using each algorithm was estimated from a health service perspective, using cost--utility analysis, assuming thresholds of willingness to pay of pound 20,000 and pound 30,000 per quality-adjusted life-year (QALY). The model was analysed probabilistically and cost-effectiveness acceptability curves were generated to reflect uncertainty in estimated cost-effectiveness. RESULTS: Individual clinical features are of limited diagnostic value, with most likelihood ratios being close to 1. Wells clinical probability score stratifies proximal, but not distal, DVT into high-, intermediate- and low-risk categories. Unstructured clinical assessment by experienced clinicians may have similar performance to Wells score. In patients with clinically suspected DVT, D-dimer has 91% sensitivity and 55% specificity for DVT, although performance varies substantially between assays and populations. D-dimer specificity is dependent on pretest clinical probability, being higher in patients with a low clinical probability of DVT. Plethysmography and rheography techniques have modest sensitivity for proximal DVT, poor sensitivity for distal DVT, and modest specificity. Ultrasound has 94% sensitivity for proximal DVT, 64% sensitivity for distal DVT and 94% specificity. Computed tomography scanning has 95% sensitivity for all DVT (proximal and distal combined) and 97% specificity. Magnetic resonance imaging has 92% sensitivity for all DVT and 95% specificity. The diagnostic performance of all tests is worse in asymptomatic patients. The most cost-effective algorithm discharged patients with a low Wells score and negative D-dimer without further testing, and then used plethysmography alongside ultrasound, with venography in selected cases, to diagnose the remaining patients. However, the cost-effectiveness of this algorithm was dependent on assumptions of test independence being met and the ability to provide plethysmography at relatively low cost. Availability of plethysmography and venography is currently limited at most UK hospitals, so implementation would involve considerable reorganisation of services. Two algorithms were identified that offered high net benefit and would be feasible in most hospitals without substantial reorganisation of services. Both involved using a combination of Wells score, D-dimer and above-knee ultrasound. For thresholds of willingness to pay of pound 10,000 or pound 20,000 per QALY the optimal strategy involved discharging patients with a low or intermediate Wells score and negative D-dimer, ultrasound for those with a high score or positive D-dimer, and repeat scanning for those with positive D-dimer and a high Wells score, but negative initial scan. For thresholds of pound 30,000 or more a similar strategy, but involving repeat ultrasound for all those with a negative initial scan, was optimal. CONCLUSIONS: Diagnostic algorithms based on a combination of Wells score, D-dimer and ultrasound (with repeat if negative) are feasible at most UK hospitals and are among the most cost-effective. Use of repeat scanning depends on the threshold for willingness to pay for health gain. Further diagnostic testing for patients with a low Wells score and negative D-dimer is unlikely to represent a cost-effective use of resources. Recommendations for research include the evaluation of the costs and outcomes of using the optimal diagnostic algorithms in routine practice, the development and evaluation of algorithms appropriate for specific groups of patients with suspected DVT, such as intravenous drug abusers, pregnant patients and those with previous DVT, the evaluation of the role of plethysmography: interaction with other diagnostic tests, outcome of low-risk patients with negative plethysmography and measurement of the costs of providing plethysmography, and methodological research into the incorporation of meta-analytic data into decision-analytic modelling.

Adult↗

PubMed2004

Characterization of a linear streak artifact with pulse inversion tissue harmonics in musculoskeletal sonography.

OBJECTIVE: To understand a linear artifact that projects deep to reflective structures that move rapidly while using tissue harmonic imaging with pulse inversion (PI) sonography. We hypothesize that this artifact is due to a cancellation error between firings in PI imaging, and it is, therefore, similar in generation to the twinkling artifact in color Doppler sonography. This artifact could be studied with the use of surfaces of different roughness to represent different rates of motion, in which roughness corresponds to spatial fluctuations in surface height. Given very slight variations in beam focusing as occurs with sonographic imaging arrays, these spatial fluctuations translate into temporal fluctuations in the received signal as would occur with tissue motion. METHODS: We scanned 4 different sandpaper grits and a smooth surface through a water path using fundamental and PI mode, 1- and 2-pulse techniques, respectively. The sandpaper and the smooth surface were scanned through a water path at mechanical indices of 0.1 to 0.7. Four independent images were subtracted pairwise to remove nonfluctuating signals. These noise pixels were counted and analyzed. RESULTS: Analysis of variance showed that the noise generated behind the different surfaces was highly significantly different. Two-tailed t tests generally showed significant differences in the quantity of noise between fundamental and harmonic imaging behind the roughest 3 grades of sandpaper. A multiple regression model showed significantly greater slopes for harmonic imaging for all grades of sandpaper and the smooth surface. CONCLUSIONS: The noise and, by extension, the linear streak artifact in musculoskeletal imaging are dependent on the mechanical index and are functions of sandpaper roughness. This would be equivalent to a subtraction error between 2 firings due to soft tissue motion, and the artifact may be a way to identify rapid soft tissue motion in PI images.

Acoustics↗

PubMed2003

Antibodies to a cell surface histone-like protein protect against Histoplasma capsulatum.

A protective role for antibodies has not previously been described for host defense against the pathogenic fungus Histoplasma capsulatum (Hc). Mouse mAb's were generated from mice immunized with Hc yeast that binds the cell surface of Hc. Administration of mAb's before Hc infection reduced fungal burden, decreased pulmonary inflammation, and prolonged survival in a murine infection model. Protection mediated by mAb's was associated with enhanced levels of IL-4, IL-6, and IFN-gamma in the lungs of infected mice. The mAb's increased phagocytosis of yeast by J774.16 cells through a CR3-dependent process. Ingestion of mAb-opsonized Hc by J774.16 macrophage-like cells was associated with yeast cell growth inhibition and killing. The mAb's bound to a 17-kDa antigen expressed on the surface of Hc. The antigen was identified as a histone H2B-like protein. This study establishes that mAb's to a cell surface protein of Hc alter the intracellular fate of the fungus and mediate protection in a murine model of lethal histoplasmosis, and it suggests a new candidate antigen for vaccine development.

Amino Acid Sequence↗

PubMed2004

Use of inferior vena caval filters and survival in patients with malignancy.

BACKGROUND: Inferior vena cava (IVC) filters have proven to be a viable alternative to anticoagulation therapy for the prevention of life-threatening pulmonary emboli (PE) for patients who have contraindications to anticoagulation therapy. The clinical benefit of placing IVC filters in patients with advanced-stage cancer is controversial. The current study reported the authors' experience with IVC filters in patients with cancer. METHODS: Between January 2000 and May 2003, IVC filters were placed in 308 patients with venous thromboembolic (VTE) disease. Of these patients, 267 had solid tumors and 41 had liquid tumors. Outcome was reviewed retrospectively with regards to patient survival as well as procedural and filter-related complications. Patients with solid and liquid tumors were used to generate Kaplan-Meier estimates for survival and the probability of surviving 30, 90, and 365 days was also calculated. The prognostic effect of age, primary malignancy, gender, extent of disease, indication, admission to the intensive care unit, and IVC thrombus on overall survival was also evaluated using univariate and multivariate Cox models for patients with solid tumors. RESULTS: The median survival periods for patients with solid and liquid tumors were 145 days and 207 days, respectively. The probability of survival at 30, 90, and 365 days was 0.81, 0.60, and 0.35, respectively, for patients with solid tumors and 0.85, 0.67, and 0.48, respectively, for patients with liquid tumors. There was no statistically significant difference in survival based on primary malignancy for solid tumors (P = 0.628) or between solid and liquid tumors (P = 0.16). For patients with solid tumors, a statistically significant difference in survival was found by extent of disease (P = 0.002). Patients with solid tumors classified as local disease (n = 15), locally advanced disease (n = 95), and widely metastatic or disseminated disease (n = 153) had a probability of survival at 30 days of 0.93, 0.87, and 0.76, respectively. Compared with patients with local disease, patients with metastatic or disseminated disease were 3.7 times more likely to die (P = 0.013). Patients with a history of deep venous thrombosis (DVT) and hemorrhage were 2 times more likely to die than patients with DVT and no history of hemorrhage (P = 0.0057). Documented complications occurred in 22 of 308 (7.1%) patients and included PE (n = 4), new caval thrombosis (n = 14), retroperitoneal hemorrhage (n = 2), and maldeployed filters (n = 2). CONCLUSIONS: IVC filters were shown to be safe and highly effective in preventing PE-related deaths in patients with cancer with VTE disease. Patients with a history of DVT and bleeding or metastatic/disseminated stage of disease had the lowest survival after IVC filter placement.

Adult↗

PubMed1992

Chondrodysplasia in transgenic mice harboring a 15-amino acid deletion in the triple helical domain of pro alpha 1(II) collagen chain.

We have generated transgenic mice by microinjection of a 39-kb mouse pro alpha 1(II) collagen gene construct containing a deletion of exon 7 and intron 7. This mutation was expected to disturb the assembly and processing of the homotrimeric type II collagen molecule in cartilage. Expression of transgene mRNA at levels equivalent or higher than the endogenous mRNA in the offspring of two founder animals resulted in a severe chondrodysplastic phenotype with short limbs, hypoplastic thorax, abnormal craniofacial development, and other skeletal deformities. The affected pups died at birth due to respiratory distress. Light microscopy of epiphyseal growth plates of transgenic pups demonstrated a marked reduction in cartilaginous extracellular matrix and disruption of the normal organization of the growth plate. The zone of proliferating chondrocytes was greatly reduced whereas the zone of hypertrophic chondrocytes was markedly increased extending deep into the diaphysis suggestive of a defect in endochondral ossification. Electron microscopic examination revealed chondrocytes with extended RER, a very severe reduction in the amount of cartilage collagen fibrils, and abnormalities in their structure. We postulate that the deletion in the alpha 1(II) collagen acts as a dominant negative mutation disrupting the assembly and secretion of type II collagen molecules. The consequences of the mutation include interference with normal endochondral ossification. These mice constitute a valuable model to study the mechanisms underlying human chondrodysplasias and normal bone formation.

Animals↗

PubMed2006

Fuzzy theory approach for temporal model-based diagnosis: An application to medical domains.

OBJECTIVE: The aim of this work is to provide a theoretical framework which is sufficiently expressive to describe temporal evolution of diseases, and also to propose a diagnostic process for building explanations of patient's observed temporal evolution based on these disease descriptions. BACKGROUND: Model-based diagnosis (MBD) tackles the problem of troubleshooting systems by starting from a description of their structure and function (or behaviour). It is in this area where the use of deep causal models, as part of MBD systems, has shown its greater efficiency over classical rule based systems. From its beginnings, the temporal dimension was considered as an important component in MBD, since it makes it possible to define the dynamic behaviour. Several approaches have been proposed to represent time in MBD, enabling the representation of temporal concepts and relations, as well as the use of temporal reasoning mechanisms. METHODOLOGY: We first propose a temporal behavioural model (TBM), which allows us to capture the dynamics underlying temporal evolution of diseases and to include contextual information. Contextual information is required to model how contextual factors change the temporal evolution of diseases. The temporal component is modelled by fuzzy temporal constraints networks (FTCN), which makes the representation of quantitative and qualitative imprecise temporal information possible. We also provide a diagnostic process, which is based on a temporal adaptation of classical cover and differentiate method. RESULTS: The TBM and diagnostic process proposed provides a unique framework which addresses three problems not dealt with together so far: (a) the inclusion of contextual information, (b) the expressivity of the solution provided, and (c) the evaluation of the diagnostic hypotheses. This proposal demonstrates that the FTCN formalism provides mechanisms sufficiently expressive to cope with the intrinsic imprecision in the description of diseases' temporal evolution. The explanation generated provides the user with a complete picture of the temporal evolution of diseases and its causal links, thus allowing the appearance of repeated instances of the same disease through time. Mechanisms are provided which evaluate the credibility of alternative hypotheses, based on possibility theory. A prototype is presented along with a knowledge acquisition tool that guides medical experts in the model building process. CONCLUSIONS: In this paper, we propose a model that tightly couples methods from MBD area with constraint-based temporal reasoning techniques. The proposed model allows us to model complex contextual relationships in a compact way as well as providing solutions expressive enough to be used for decision support purposes. The solution provided conforms a causal network entailing the abnormal observations, including pathophysiological and etiological states. Furthermore, different instances of the same diagnostic hypotheses, located at different time instants, are also possible in the final solution. Finally, we provide an analysis of related and future works.

Artificial Intelligence↗

PubMedDate not supplied

Intratumoral dendritic cell vaccination elicits potent tumoricidal immunity against malignant glioma in rats.

Dendritic cells (DC) are attractive candidates for innovative cancer immunotherapy by virtue of their ability to function as powerful antigen presenting cells and elicit potent antitumor cytotoxic immune responses. With the aim of generating antitumor immunity, the authors sought to enhance in vivo tumor antigen presentation by using an intratumoral DC vaccination strategy in the setting of partially irradiated intracranial brain tumors. Fisher rats, implanted with 9L gliomas in the right corpus striatum, were treated with freshly cultured, unpulsed syngeneic DC inoculated directly into the tumor bed. Intracranially inoculated DCs were found to drain to ipsilateral deep cervical lymph nodes. This was associated with increased local and systemic antitumor cytoxicity, as evidenced by robust infiltration of treated tumors with CD4 and CD8 T cells as well as by increased IFN-gamma protein and message levels in in vitro restimulated splenic lymphocytes. DC therapy resulted in prolonged survival and immunity to subsequent intracranial tumor re-challenge. These results demonstrate the viability of intratumoral DC vaccination as an effective therapeutic strategy for intracranial glioma.

Animals↗

PubMed2002

Regional differences in distribution volume of I-123 IMP in the human brain: effect on CBF calculated by ARG method.

OBJECTIVE: Two methods of quantitating cerebral blood flow (CBF) with iodine-123-labeled N-isopropyl-p-iodoamphetamine (I-123 IMP) and a two-compartment model had been proposed; one is the table look-up (TLU) method and the other is the autoradiographic (ARG) method. The TLU method provides values of the cerebral blood flow (CBF) values and distribution volume of I-123 IMP (Vd) independently. In the ARG method, a fixed Vd is applied for the entire brain to calculate CBF. Our purpose was to evaluate regional differences in Vd in the human brain, or possible effects of regional differences in Vd on CBF calculated by the ARG method. METHODS: In the present study, two SPECT scans were acquired from each of eight normal subjects (aged 44.0 +/- 16.7) at 40 min and 180 min of mid-scan-time after intravenous 1 min infusion of 111 MBq IMP. A single arterial blood sampling was performed 10 min after the IMP infusion. All images were anatomically normalized and analyzed with SPM99 and Matlab. We generated CBF and Vd images for each subject by the TLU method and evaluated differences in Vd among brain structures. We subsequently generated another set of CBF images by the ARG method and examined differences between CBF calculated by the TLU method and that by the ARG method. RESULTS: Significant main effects of subject and brain structure in Vd were observed (two-way ANOVA). Vd values were higher in the deep gray matter than in the cerebral cortical regions. Among the cerebral cortical regions, no significant difference in Vd was observed. In spite of the significant differences in Vd among the brain structures, the voxel-by-voxel analyses as well as the ROI analyses revealed no statistically significant difference between CBF calculated by the TLU method and that by the ARG method. CONCLUSIONS: Although regional differences in Vd were observed, the present results support the assumption that a fixed Vd does not cause significant error in the calculation of CBF by the ARG method.

Adult↗

PubMed1999

Imaging of spontaneous canine mammary tumors using fluorescent contrast agents.

We present near-infrared frequency-domain photon migration imaging for the lifetime sensitive detection and localization of exogenous fluorescent contrast agents within tissue-simulating phantoms and actual tissues. We employ intensity-modulated excitation light that is expanded and delivered to the surface of a tissue or tissue-simulating phantom. The intensity-modulated fluorescence generated from within the volume propagates to the surface and is collected using a gain-modulated image-intensified charge-coupled device camera. From the spatial values of modulation amplitude and phase of the detected fluorescent light, micromolar volumes of diethylthiatricarbocyanine iodide (tau = 1.17 ns) and indocyanine green (ICG) (tau = 0.58 ns) embedded 1.0 cm deep in a tissue phantom are localized and discriminated on the basis of their lifetime differences. To demonstrate the utility of frequency-domain fluorescent measurements for imaging disease, we image the fluorescence emitted from the surface of in vivo and ex vivo canine mammary gland tissues containing lesions with preferential uptake of ICG. Pathology confirms the ability to detect spontaneous mammary tumors and regional lymph nodes amidst normal mammary tissue and fat as deep as 1.5 cm from the tissue surface.

Animals↗

PubMed1989

Microscopic correlates of adaptive cytoprotection in an ethanol injury model.

The present study histologically investigated the efficacy of pretreating rat gastric mucosa with the mild irritants, 10% and 25% ethanol (EtOH), against the known damaging effects of 100% EtOH. Fasted rats received 1 ml of either water, 10% EtOH, or 25% EtOH by orogastric intubation. Fifteen minutes later, a portion of these animals was sacrificed and tissue samples of the oxyntic region of the stomach were excised and processed for quantitative histologic analysis. Remaining animals received a 1 ml oral bolus of the necrotizing agent, 100% EtOH. Five minutes later, these animals were sacrificed and tissues were prepared in a like manner. In a separate series of experiments, the aforementioned protocols were repeated, except that all animals received the prostaglandin synthetase inhibitor, indomethacin (5.0 mg/kg intraperitoneally), 30 min before administration of the mild irritant. Microscopically, the administration of water or 10% EtOH alone caused a small and comparable amount of superficial injury to the gastric mucosa. Moreover, both substances failed to induce protection in stomachs subsequently exposed to 100% EtOH. Indomethacin pretreatment did not significantly alter any of these findings. In marked contrast, 25% EtOH alone elicited a substantial degree of superficial damage to the gastric mucosa. Nevertheless it significantly reduced the depth of injury in animals subsequently challenged by 100% EtOH. Indomethacin failed to aggravate the effects of 25% EtOH alone, but partially inhibited the protective effect of this mild irritant against 100% EtOH induced damage. Our findings indicate that adaptive cytoprotection is a real phenomenon that can be demonstrated microscopically. Such protection is limited primarily to the deep mucosal layers (i.e. gastric glands), appears in part to be prostaglandin mediated and seems to require the generation of moderate surface cell damage (as occurred with 25% EtOH, but not 10% EtOH) to induce its initiation.

Animals↗