Previous studies have reported that the spontaneous, resting-state time course of the default-mode network is negatively correlated with that of the "task-positive network", a collection of regions commonly recruited in demanding cognitive tasks. However, all studies of negative correlations between the default-mode and task-positive networks have employed some form of normalization or regression of the whole-brain average signal ("global signal"); these processing steps alter the time series of voxels in an uninterpretable manner as well as introduce spurious negative correlations. Thus, the extent of negative correlations with the default mode network without global signal removal has not been well characterized, and it is has recently been hypothesized that the apparent negative correlations in many of the task-positive regions could be artifactually induced by global signal pre-processing. The present study aimed to examine negative and positive correlations with the default-mode network when model-based corrections for respiratory and cardiac noise are applied in lieu of global signal removal. Physiological noise correction consisted of (1) removal of time-locked cardiac and respiratory artifacts using RETROICOR (Glover, G.H., Li, T.Q., Ress, D., 2000. Image-based method for retrospective correction of physiological motion effects in fMRI: RETROICOR. Magn. Reson. Med. 44, 162-167), and (2) removal of low-frequency respiratory and heart rate variations by convolving these waveforms with pre-determined transfer functions (Birn et al., 2008; Chang et al., 2009) and projecting the resulting two signals out of the data. It is demonstrated that negative correlations between the default-mode network and regions of the task-positive network are present in the majority of individual subjects both with and without physiological noise correction. Physiological noise correction increased the spatial extent and magnitude of negative correlations, yielding negative correlations within task-positive regions at the group-level (p<0.05, uncorrected; no regions at the group level were significant at FDR=0.05). Furthermore, physiological noise correction caused region-specific decreases in positive correlations within the default-mode network, reducing apparent false positives. It was observed that the low-frequency respiratory volume and cardiac rate regressors used within the physiological noise correction algorithm displayed significant (but not total) shared variance with the global signal, and constitute a model-based alternative to correcting for non-neural global noise.

Echo planar (EP) diffusion tensor imaging (DTI) permits in vivo identification of the orientation and coherence of brain white matter tracts but suffers from field inhomogeneity-induced geometric distortion. To reduce spatial distortion, polynomial warping corrections were applied and the effects tested on measures of fractional anisotropy (FA) in the genu and splenium of corpus callosum. Implementation entailed spatially warping EP images obtained without diffusion weighting (b = 0) to long-echo T(2)-weighted fast spin echo images, collected for anatomical delineation, tissue segmentation, and coregistration with the diffusion images. Using the optimal warping procedure (third-order polynomial), the effects of age on FA and a quantitative measure of intervoxel coherence (C) in the genu, splenium, centrum semiovale, and frontal and parietal pericallosal white matter were examined in 31 healthy men (23-76 years). FA declined significantly with age in all regions except the splenium, whereas intervoxel coherence positively correlated with age in the genu. Magn Reson Med 44:259-268, 2000.

OBJECTIVE

Circulatory shock is a life-threatening syndrome resulting in multiorgan failure and a high mortality rate. The aim of this consensus is to provide support to the bedside clinician regarding the diagnosis, management and monitoring of shock.

METHODS

The European Society of Intensive Care Medicine invited 12 experts to form a Task Force to update a previous consensus (Antonelli et al.: Intensive Care Med 33:575-590, 2007). The same five questions addressed in the earlier consensus were used as the outline for the literature search and review, with the aim of the Task Force to produce statements based on the available literature and evidence. These questions were: (1) What are the epidemiologic and pathophysiologic features of shock in the intensive care unit? (2) Should we monitor preload and fluid responsiveness in shock? (3) How and when should we monitor stroke volume or cardiac output in shock? (4) What markers of the regional and microcirculation can be monitored, and how can cellular function be assessed in shock? (5) What is the evidence for using hemodynamic monitoring to direct therapy in shock? Four types of statements were used: definition, recommendation, best practice and statement of fact.

RESULTS

Forty-four statements were made. The main new statements include: (1) statements on individualizing blood pressure targets; (2) statements on the assessment and prediction of fluid responsiveness; (3) statements on the use of echocardiography and hemodynamic monitoring.

CONCLUSIONS

This consensus provides 44 statements that can be used at the bedside to diagnose, treat and monitor patients with shock.

Kaposi's sarcoma (KS)-associated herpesvirus or human herpesvirus 8 (KSHV/HHV8) is the likely cause of KS and primary effusion lymphomas or body cavity-based lymphomas (BCBLs). A latency-associated nuclear immunofluorescence antigen (LANA) (D. H. Kedes, E. Operskalski, M. Busch, R. Kohn, J. Flood, and D. Ganem, Nat. Med. 2:918-924, 1996; S. J. Gao, L. Kingsley, M. Li, W. Zheng, C. Parravicini, J. Ziegler, R. Newton, C. R. Rinaldo, A. Saah, J. Phair, R. Detels, Y. Chang, and P. S. Moore, Nat. Med. 2:925-928, 1996) and a 222- to 234-kDa nuclear protein (LNA) (S. J. Gao, L. Kingsley, D. R. Hoover, T. J. Spira, C. R. Rinaldo, A. Saah, J. Phair, R. Detels, P. Parry, Y. Chang, and P. S. Moore, N. Engl. J. Med. 335:233-241, 1996) have previously been described in BCBL cell lines by immunofluorescence and Western blotting techniques, respectively. To identify the viral gene(s) encoding this antigen(s) we screened a cDNA library from HBL-6 cells, a B-cell lymphoma cell line persistently infected with KSHV/HHV8, with KS patient sera. One set of positive clones contained the 3' end of orf73, as well as the complete orf72 and orfK13, and another set contained the 5' end of orf73. Comparison of cDNA sequences with the KSHV/HHV8 genomic sequence revealed a splice event, occurring upstream of orf73. Immunoaffinity purified antibodies to a recombinant carboxy-terminal fragment of the orf73-encoded protein showed the characteristic speckled nuclear immunofluorescence pattern of LANA and reacted with the 222- to 234-kDa LNA on Western blots. Expression of full-length orf73 in bacteria and COS7 cells reproduced the LNA banding pattern. Immunohistochemistry on cases of nodular KS revealed that orf73/LNA is expressed in the nucleus of KS spindle cells. These findings demonstrate that orf73 encodes the 222- to 234-kDa LNA, is a component of LANA, and is expressed in KS tumor cells.

We have examined the amino-terminal sequence of the kappa light chains of a set of monoclonal antibodies specific for one of the major antigenic determinants (Sb) on the influenza virus PR8[A/PR/8/34(H1N1)] hemagglutinin molecule. This set was believed to be structurally related from earlier serological analysis that typed these kappa chains as members of the variable (V) region V kappa 21 group [ Staudt , L. M. & Gerhard , W. (1983) J. Exp. Med. 157, 678-704]. Our sequence analysis confirms and extends this conclusion; all examples of this set belong to a subgroup of the V kappa 21 group, V kappa 21C . A special feature of this set of kappa light chains is that all examples were derived from the same mouse (designated H36 ). This sequence analysis along with the characterization of gene rearrangements at the kappa light chain loci of these hybridomas is consistent with the idea that certain members of this set are the progeny of one or two lymphocytes. Because of this potential clonal relationship, we can reach several conclusions about the diversity observed among these kappa light chains: (i) the diversity is due to somatic mutation, (ii) somatic mutations occur sequentially and accumulate in the first complementarity-determining region, and (iii) the extent of somatic variation in this sample is high, suggesting a somatic mutation rate of about 10(-3) per base pair per generation.

Skin color is one of the most conspicuous ways in which humans vary and has been widely used to define human races. Here we present new evidence indicating that variations in skin color are adaptive, and are related to the regulation of ultraviolet (UV) radiation penetration in the integument and its direct and indirect effects on fitness. Using remotely sensed data on UV radiation levels, hypotheses concerning the distribution of the skin colors of indigenous peoples relative to UV levels were tested quantitatively in this study for the first time. The major results of this study are: (1) skin reflectance is strongly correlated with absolute latitude and UV radiation levels. The highest correlation between skin reflectance and UV levels was observed at 545 nm, near the absorption maximum for oxyhemoglobin, suggesting that the main role of melanin pigmentation in humans is regulation of the effects of UV radiation on the contents of cutaneous blood vessels located in the dermis. (2) Predicted skin reflectances deviated little from observed values. (3) In all populations for which skin reflectance data were available for males and females, females were found to be lighter skinned than males. (4) The clinal gradation of skin coloration observed among indigenous peoples is correlated with UV radiation levels and represents a compromise solution to the conflicting physiological requirements of photoprotection and vitamin D synthesis. The earliest members of the hominid lineage probably had a mostly unpigmented or lightly pigmented integument covered with dark black hair, similar to that of the modern chimpanzee. The evolution of a naked, darkly pigmented integument occurred early in the evolution of the genus Homo. A dark epidermis protected sweat glands from UV-induced injury, thus insuring the integrity of somatic thermoregulation. Of greater significance to individual reproductive success was that highly melanized skin protected against UV-induced photolysis of folate (Branda & Eaton, 1978, Science201, 625-626; Jablonski, 1992, Proc. Australas. Soc. Hum. Biol.5, 455-462, 1999, Med. Hypotheses52, 581-582), a metabolite essential for normal development of the embryonic neural tube (Bower & Stanley, 1989, The Medical Journal of Australia150, 613-619; Medical Research Council Vitamin Research Group, 1991, The Lancet338, 31-37) and spermatogenesis (Cosentino et al., 1990, Proc. Natn. Acad. Sci. U.S.A.87, 1431-1435; Mathur et al., 1977, Fertility Sterility28, 1356-1360).As hominids migrated outside of the tropics, varying degrees of depigmentation evolved in order to permit UVB-induced synthesis of previtamin D(3). The lighter color of female skin may be required to permit synthesis of the relatively higher amounts of vitamin D(3)necessary during pregnancy and lactation. Skin coloration in humans is adaptive and labile. Skin pigmentation levels have changed more than once in human evolution. Because of this, skin coloration is of no value in determining phylogenetic relationships among modern human groups.

Since publication of the American Association of Physicists in Medicine (AAPM) Task Group No. 43 Report in 1995 (TG-43), both the utilization of permanent source implantation and the number of low-energy interstitial brachytherapy source models commercially available have dramatically increased. In addition, the National Institute of Standards and Technology has introduced a new primary standard of air-kerma strength, and the brachytherapy dosimetry literature has grown substantially, documenting both improved dosimetry methodologies and dosimetric characterization of particular source models. In response to these advances, the AAPM Low-energy Interstitial Brachytherapy Dosimetry subcommittee (LIBD) herein presents an update of the TG-43 protocol for calculation of dose-rate distributions around photon-emitting brachytherapy sources. The updated protocol (TG-43U1) includes (a) a revised definition of air-kerma strength; (b) elimination of apparent activity for specification of source strength; (c) elimination of the anisotropy constant in favor of the distance-dependent one-dimensional anisotropy function; (d) guidance on extrapolating tabulated TG-43 parameters to longer and shorter distances; and (e) correction for minor inconsistencies and omissions in the original protocol and its implementation. Among the corrections are consistent guidelines for use of point- and line-source geometry functions. In addition, this report recommends a unified approach to comparing reference dose distributions derived from different investigators to develop a single critically evaluated consensus dataset as well as guidelines for performing and describing future theoretical and experimental single-source dosimetry studies. Finally, the report includes consensus datasets, in the form of dose-rate constants, radial dose functions, and one-dimensional (1D) and two-dimensional (2D) anisotropy functions, for all low-energy brachytherapy source models that met the AAPM dosimetric prerequisites [Med. Phys. 25, 2269 (1998)] as of July 15, 2001. These include the following 125I sources: Amersham Health models 6702 and 6711, Best Medical model 2301, North American Scientific Inc. (NASI) model MED3631-A/M, Bebig/Theragenics model I25.S06, and the Imagyn Medical Technologies Inc. isostar model IS-12501. The 103Pd sources included are the Theragenics Corporation model 200 and NASI model MED3633. The AAPM recommends that the revised dose-calculation protocol and revised source-specific dose-rate distributions be adopted by all end users for clinical treatment planning of low energy brachytherapy interstitial sources. Depending upon the dose-calculation protocol and parameters currently used by individual physicists, adoption of this protocol may result in changes to patient dose calculations. These changes should be carefully evaluated and reviewed with the radiation oncologist preceding implementation of the current protocol.

The molecular mechanisms underlying the initiation of innate and adaptive proallergic type 2 responses are not understood. Interleukin (IL) 25, a member of the IL-17 cytokine family, was recently reported (Owyang, A.M., C. Zaph, E.H. Wilson, K.J. Guild, T. McClanahan, H.R. Miller, D.J. Cua, M. Goldschmidt, C.A. Hunter, R.A. Kastelein, and D. Artis. 2006. J. Exp. Med. 203:843-849; Fallon, P.G., S.J. Ballantyne, N.E. Mangan, J.L. Barlow, A. Dasvarma, D.R. Hewett, A. McIlgorm, H.E. Jolin, and A.N. McKenzie. 2006. J. Exp. Med. 203:1105-1116) to be important in Th2 cell-mediated immunity to parasitic infection. However, the cellular source and targets of IL-25 are not well understood. We show that mouse IL-25 is expressed by lung epithelial cells as a result of innate immune responses to allergens. Transgenic overexpression of IL-25 by these cells leads to mucus production and airway infiltration of macrophages and eosinophils, whereas blockade of IL-25 conversely reduces the airway inflammation and Th2 cytokine production in an allergen-induced asthma model. In addition, IL-25, with a receptor more highly expressed in Th2 than other effector T cells, promotes Th2 cell differentiation in an IL-4- and signal transducer and activator of transcription 6-dependent manner. During early T cell activation, IL-25 potentiates expression of the nuclear factor of activated T cells c1 and JunB transcription factors, which possibly results in increased levels of initial IL-4 production, up-regulation of GATA-3 expression, and enhanced Th2 cell differentiation. Thus, IL-25 is a critical factor regulating the initiation of innate and adaptive proallergic responses.

Heart rate fluctuations occur in the low-frequency range (<0.1 Hz) probed in functional magnetic resonance imaging (fMRI) studies of resting-state functional connectivity and most fMRI block paradigms and may be related to low-frequency blood-oxygenation-level-dependent (BOLD) signal fluctuations. To investigate this hypothesis, temporal correlations between cardiac rate and resting-state fMRI signal timecourses were assessed at 3 T. Resting-state BOLD fMRI and accompanying physiological data were acquired and analyzed using cross-correlation and regression. Time-shifted cardiac rate timecourses were included as regressors in addition to established physiological regressors (RETROICOR (Glover, G.H., Li, T.Q., Ress, D., 2000. Image-based method for retrospective correction of physiological motion effects in fMRI: RETROICOR. Magn Reson Med 44, 162-167) and respiration volume per unit time (Birn, R.M., Diamond, J.B., Smith, M.A., Bandettini, P.A., 2006b. Separating respiratory-variation-related fluctuations from neuronal-activity-related fluctuations in fMRI. NeuroImage 31, 1536-1548). Significant correlations between the cardiac rate and BOLD signal timecourses were revealed, particularly negative correlations in gray matter at time shifts of 6-12 s and positive correlations at time shifts of 30-42 s (TR=6 s). Regressors consisting of cardiac rate timecourses shifted by delays of between 0 and 24 s explained an additional 1% of the BOLD signal variance on average over the whole brain across 9 subjects, a similar additional variance to that explained by respiration volume per unit time and RETROICOR regressors, even when used in combination with these other physiological regressors. This suggests that including such time-shifted cardiac rate regressors will be beneficial for explaining physiological noise variance and will thereby improve the statistical power in future task-based and resting-state fMRI studies.

Our forefathers in pathology, on observing cancer tissue under the microscope in the mid-19th century, noticed the similarity between embryonic tissue and cancer, and suggested that tumors arise from embryo-like cells [Recherches dur le Traitement du Cancer, etc. Paris. (1829); Editoral Archiv fuer pathologische Anatomie und Physiologie und fuer klinische Medizin 8 (1855) 23]. The concept that adult tissues contain embryonic remnants that generally lie dormant, but that could be activated to become cancer was later formalized by Cohnheim [Path. Anat. Physiol. Klin. Med. 40 (1867) 1-79; Virchows Arch. 65 (1875) 64] and Durante [Arch. Memori ed Osservazioni di Chirugia Practica 11 (1874) 217-226], as the "embryonal rest" theory of cancer. An updated version of the embryonal rest theory of cancer is that cancers arise from tissue stem cells in adults. Analysis of the cellular origin of carcinomas of different organs indicates that there is, in each instance, a determined stem cell required for normal tissue renewal that is the most likely cell of origin of carcinomas [Lab. Investig. 70 (1994) 6-22]. In the present review, the nature of normal stem cells (embryonal, germinal and somatic) is presented and their relationships to cancer are further expanded. Cell signaling pathways shared by embryonic cells and cancer cells suggest a possible link between embryonic cells and cancer cells. Wilm's tumors (nephroblastomas) and neuroblastomas are presented as possible tumors of embryonic rests in children. Teratocarcinoma is used as the classic example of the totipotent cancer stem cell which can be influenced by its environment to differentiate into a mature adult cell. The observation that "promotion" of an epidermal cancer may be accomplished months or even years after the initial exposure to carcinogen ("initiation"), implies that the original carcinogenic event occurs in a long-lived epithelial stem cell population. The cellular events during hepatocarcinogenesis illustrate that cancers may arise from cells at various stages of differentiation in the hepatocyte lineage. Examples of genetic mutations in epithelial and hematopoietic cancers show how specific alterations in gene expression may be manifested as maturation arrest of a cell lineage at a specific stage of differentiation. Understanding the signals that control normal development may eventually lead us to insights in treating cancer by inducing its differentiation (differentiation therapy). Retinoid acid (RA) induced differentiation therapy has acquired a therapeutic niche in treatment of acute promyelocytic leukemia and the ability of RA to prevent cancer is currently under examination.

This article introduces a new image processing technique for rapid analysis of tagged cardiac magnetic resonance image sequences. The method uses isolated spectral peaks in SPAMM-tagged magnetic resonance images, which contain information about cardiac motion. The inverse Fourier transform of a spectral peak is a complex image whose calculated angle is called a harmonic phase (HARP) image. It is shown how two HARP image sequences can be used to automatically and accurately track material points through time. A rapid, semiautomated procedure to calculate circumferential and radial Lagrangian strain from tracked points is described. This new computational approach permits rapid analysis and visualization of myocardial strain within 5-10 min after the scan is complete. Its performance is demonstrated on MR image sequences reflecting both normal and abnormal cardiac motion. Results from the new method are shown to compare very well with a previously validated tracking algorithm. Magn Reson Med 42:1048-1060, 1999.

METHODS

In 1987 we began a multicenter controlled clinical trial of deprenyl (a monoamine oxidase inhibitor) and tocopherol (a component of vitamin E that traps free radicals) in the treatment of early Parkinson's disease. We randomly assigned 800 patients to one of four treatments: placebo, active tocopherol and deprenyl placebo, active deprenyl and tocopherol placebo, or both active drugs. The primary end point was the onset of disability prompting the clinical decision to begin administering levodopa. An interim analysis showed that deprenyl was beneficial (N Engl J Med 1989;321:1364-71). We report the results of tocopherol treatment after a mean (+/- SD) follow-up of 14 +/- 6 months, as well as the follow-up results for deprenyl.

RESULTS

There was no beneficial effect of tocopherol or any interaction between tocopherol and deprenyl. The beneficial effects of deprenyl, which occurred largely during the first 12 months of treatment, remained strong and significantly delayed the onset of disability requiring levodopa therapy (hazard ratio, 0.50; 95 percent confidence interval, 0.41 to 0.62; P < 0.001). The difference in the estimated median time to the end point was about nine months. The ratings for Parkinson's disease improved during the first three months of deprenyl treatment; the motor performance of deprenyl-treated patients worsened after the treatments were withdrawn.

CONCLUSIONS

Deprenyl (10 mg per day) but not tocopherol (2000 IU per day) delays the onset of disability associated with early, otherwise untreated Parkinson's disease. The action of deprenyl that accounts for its beneficial effects remains unclear.

Voltage-gated sodium channels perform critical roles for electrical signaling in the nervous system by generating action potentials in axons and in dendrites. At least 10 genes encode sodium channels in mammals, but specific physiological roles that distinguish each of these isoforms are not known. One possibility is that each isoform is expressed in a restricted set of cell types or is targeted to a specific domain of a neuron or muscle cell. Using affinity-purified isoform-specific antibodies, we find that Na(v)1.6 is highly concentrated at nodes of Ranvier of both sensory and motor axons in the peripheral nervous system and at nodes in the central nervous system. The specificity of this antibody was also demonstrated with the Na(v)1.6-deficient mouse mutant strain med, whose nodes were negative for Na(v)1.6 immunostaining. Both the intensity of labeling and the failure of other isoform-specific antibodies to label nodes suggest that Na(v)1.6 is the predominant channel type in this structure. In the central nervous system, Na(v)1.6 is localized in unmyelinated axons in the retina and cerebellum and is strongly expressed in dendrites of cortical pyramidal cells and cerebellar Purkinje cells. Ultrastructural studies indicate that labeling in dendrites is both intracellular and on dendritic shaft membranes. Remarkably, Na(v)1.6 labeling was observed at both presynaptic and postsynaptic membranes in the cortex and cerebellum. Thus, a single sodium channel isoform is targeted to different neuronal domains and can influence both axonal conduction and synaptic responses.

The frequencies of low-activity alleles of glucose-6-phosphate dehydrogenase in humans are highly correlated with the prevalence of malaria. These "deficiency" alleles are thought to provide reduced risk from infection by the Plasmodium parasite and are maintained at high frequency despite the hemopathologies that they cause. Haplotype analysis of "A-" and "Med" mutations at this locus indicates that they have evolved independently and have increased in frequency at a rate that is too rapid to be explained by random genetic drift. Statistical modeling indicates that the A- allele arose within the past 3840 to 11,760 years and the Med allele arose within the past 1600 to 6640 years. These results support the hypothesis that malaria has had a major impact on humans only since the introduction of agriculture within the past 10,000 years and provide a striking example of the signature of selection on the human genome.

BACKGROUND

New antiviral drugs are available for the treatment of influenza type A and type B infections. In clinical practice, antiviral use has rarely been guided by antecedent laboratory diagnosis. Defined clinical predictors of an influenza infection can help guide timely therapy and avoid unnecessary antibiotic use.

OBJECTIVE

To examine which clinical signs and symptoms are most predictive of influenza infection in patients with influenza-like illness using a large data set derived from clinical trials of zanamivir.

METHODS

This analysis is a retrospective, pooled analysis of baseline signs and symptoms from phase 2 and 3 clinical trial participants. It was conducted in mainly unvaccinated (mean age, 35 years) adults and adolescents who had influenza-like illness, defined as having fever or feverishness plus at least 2 of the following influenza-like symptoms: headache, myalgia, cough, or sore throat who underwent laboratory testing for influenza. Clinical signs and symptoms were evaluated in statistical models to identify those best predicting laboratory confirmation of influenza.

RESULTS

Of 3744 subjects enrolled with baseline influenza-like symptoms, and included in this analysis, 2470 (66%) were confirmed to have influenza. Individuals with influenza were more likely to have cough (93% vs 80%), fever (68% vs 40%), cough and fever together (64% vs 33%), and/or nasal congestion (91% vs 81%) than those without influenza. The best multivariate predictors of influenza infections were cough and fever with a positive predictive value of 79% (P<. 001). The positive predictive value rose with the increase in the temperature at the time of recruitment.

CONCLUSIONS

When influenza is circulating within the community, patients with an influenza-like illness who have both cough and fever within 48 hours of symptom onset are likely to have influenza and the administration of influenza antiviral therapy may be appropriate to consider. Arch Intern Med. 2000;160:3243-3247.

The study of the expression of alpha-galactosyl epitopes on various mammalian cells is of particular interest, since as much as 1% of circulating IgG antibodies in humans interact with this carbohydrate residue. This natural antibody, designated "anti-Gal," was previously found to bind to terminal Gal alpha 1----3Gal beta 1----4GlcNAc-R on biochemically defined glycolipids (Galili, U., Macher, B. A., Buehler, J., and Shohet, S. B. (1985) J. Exp. Med. 162, 573-582; Galili, U., Buehler, J., Shohet, S. B., and Macher, B. A. (1987) J. Exp. Med. 165, 693-704). The expression of anti-Gal binding epitopes on nucleated cells from various mammalian species was studied by immunostaining with this antibody. The binding of anti-Gal to various cells was correlated with the binding of the lectin Bandeiraea (Griffonia) simplicifolia IB4 (BS lectin). The BS lectin also interacts with alpha-galactosyl residues and particularly with high affinity with Gal alpha 1----3Gal beta 1----4GlcNAc residues. We observed a striking evolutionary pattern in the expression of these epitopes on mammalian nucleated cells. Fibroblasts, epithelial cells, endothelial cells, smooth muscle cells, and lymphoid cells of nonprimate mammals, prosimians, and New World monkeys readily bound both anti-Gal and BS lectin. However, no such binding was detectable on cells of Old World monkeys, apes, and humans. Measurment of the binding of radiolabeled BS lectin to the various nucleated cells suggests that cells binding anti-Gal express 10(6) to 3.5 x 10(7) alpha-galactosyl epitopes, most of which, based on the anti-Gal specificity, seem to have the structure of Gal alpha 1----3Gal beta 1----4GlcNAc-R. The absence of these epitopes from human cells results from diminished activity of the enzyme alpha 1----3 galactosyltransferase, which catalyzes the following reaction. Gal beta 1----4GlcNAc-R + UDP-Gal(alpha 1----3-galactosyltransferase)----Gal alpha 1----3Gal beta 1----4GlcNAc-R + UDP This enzyme, which participates in the glycosylation of cell membrane glycoconjugates in nonprimate mammals, prosimians, and New World monkeys, appears to have been suppressed in Old World primates as a result of evolutionary events which occurred 20-30 million years ago. It is argued that an anomalous activity of this enzyme in man may result in initiation of autoimmune diseases because of the de novo expression of Gal alpha 1----3Gal beta 1----4GlcNAc-R epitopes recognized by anti-Gal.

ACSM Position Stand on Exercise and Physical Activity for Older Adults. Med. Sci. Sports. Exerc., Vol. 30, No. 6, pp. 992-1008, 1998. By the year 2030, the number of individuals 65 yr and over will reach 70 million in the United States alone; persons 85 yr and older will be the fastest growing segment of the population. As more individuals live longer, it is imperative to determine the extent and mechanisms by which exercise and physical activity can improve health, functional capacity, quality of life, and independence in this population. Aging is a complex process involving many variables (e.g., genetics, lifestyle factors, chronic diseases) that interact with one another, greatly influencing the manner in which we age. Participation in regular physical activity (both aerobic and strength exercises) elicits a number of favorable responses that contribute to healthy aging. Much has been learned recently regarding the adaptability of various biological systems, as well as the ways that regular exercise can influence them. Participation in a regular exercise program is an effective intervention/ modality to reduce/prevent a number of functional declines associated with aging. Further, the trainability of older individuals (including octo- and nonagenarians) is evidenced by their ability to adapt and respond to both endurance and strength training. Endurance training can help maintain and improve various aspects of cardiovascular function (as measured by maximal VO2, cardiac output, and arteriovenous O2 difference), as well as enhance submaximal performance. Importantly, reductions in risk factors associated with disease states (heart disease, diabetes, etc.) improve health status and contribute to an increase in life expectancy. Strength training helps offset the loss in muscle mass and strength typically associated with normal aging. Additional benefits from regular exercise include improved bone health and, thus, reduction in risk for osteoporosis; improved postural stability, thereby reducing the risk of falling and associated injuries and fractures; and increased flexibility and range of motion. While not as abundant, the evidence also suggests that involvement in regular exercise can also provide a number of psychological benefits related to preserved cognitive function, alleviation of depression symptoms and behavior, and an improved concept of personal control and self-efficacy. It is important to note that while participation in physical activity may not always elicit increases in the traditional markers of physiological performance and fitness (e.g., VO2max, mitochondrial oxidative capacity, body composition) in older adults, it does improve health (reduction in disease risk factors) and functional capacity. Thus, the benefits associated with regular exercise and physical activity contribute to a more healthy, independent lifestyle, greatly improving the functional capacity and quality of life in this population.

Gliomas are the most common intracranial tumors. In the US, approximately 15,000 patients die with glioblastoma per year (CBTRUS 2002). Despite modern diagnostics and treatments the median survival time does not exceed 15 months. However, it has long been observed that after surgical removal, tumors recur predominantly within 1 cm of the resection cavity. This is mainly due to the fact that at the time of surgery, cells from the bulk tumor have already invaded normal brain tissue. Decades ago Matsukado showed that more than 50% of untreated brain tumors had already reached the contralateral hemisphere (J Neurosurg 18: 636-644, 1961). Therefore one of the most important hallmarks of malignant gliomas is their invasive behavior. Dandy already recognized the highly invasive characteristics of this tumor type and performed hemispherectomy in patients with preoperative hemiplegia (J Am Med Assoc 90: 823-825, 1928). Despite his and others' heroic efforts, recurrence was detected as early as 3 months after surgery (Bell, LJ: J Neurosurg 6: 285-293, 1949), leading to the discontinuation of this radical approach. Diffuse gliomas remain a particularly challenging clinical management problem. Over the last 20 years no significant increase in survival of patients suffering from this disease has been achieved. Even drugs directed against newly identified targets like MMPs or angiogenesis-related targets fail to increase survival duration (Tonn, Goldbrunner: Acta Neurochir Suppl 88: 163-167, 2003) Furthermore, anti-angiogenic drugs have been shown to increase glioma invasiveness, finally leading to gliomatosis cerebri. (Lamszus et al.: Acta Neurochir Suppl 88: 169-177, 2003). In this review we focus on the main features which may underlie the invasive phenotype of human gliomas, and offer a biological basis for optimism towards therapeutic advances to come.

In this study, we have preformed simultaneous near-infrared spectroscopy (NIRS) along with BOLD (blood oxygen level dependent) and ASL (arterial spin labeling)-based fMRI during an event-related motor activity in human subjects in order to compare the temporal dynamics of the hemodynamic responses recorded in each method. These measurements have allowed us to examine the validity of the biophysical models underlying each modality and, as a result, gain greater insight into the hemodynamic responses to neuronal activation. Although prior studies have examined the relationships between these two methodologies through similar experiments, they have produced conflicting results in the literature for a variety of reasons. Here, by employing a short-duration, event-related motor task, we have been able to emphasize the subtle temporal differences between the hemodynamic parameters with a high contrast-to-noise ratio. As a result of this improved experimental design, we are able to report that the fMRI measured BOLD response is more correlated with the NIRS measure of deoxy-hemoglobin (R = 0.98; P < 10(-20)) than with oxy-hemoglobin (R = 0.71), or total hemoglobin (R = 0.53). This result was predicted from the theoretical grounds of the BOLD response and is in agreement with several previous works [Toronov, V.A.W., Choi, J.H., Wolf, M., Michalos, A., Gratton, E., Hueber, D., 2001. "Investigation of human brain hemodynamics by simultaneous near-infrared spectroscopy and functional magnetic resonance imaging." Med. Phys. 28 (4) 521-527.; MacIntosh, B.J., Klassen, L.M., Menon, R.S., 2003. "Transient hemodynamics during a breath hold challenge in a two part functional imaging study with simultaneous near-infrared spectroscopy in adult humans". NeuroImage 20 1246-1252.; Toronov, V.A.W., Walker, S., Gupta, R., Choi, J.H., Gratton, E., Hueber, D., Webb, A., 2003. "The roles of changes in deoxyhemoglobin concentration and regional cerebral blood volume in the fMRI BOLD signal" Neuroimage 19 (4) 1521-1531]. These data have also allowed us to examine more detailed measurement models of the fMRI signal and comment on the roles of the oxygen saturation and blood volume contributions to the BOLD response. In addition, we found high correlation between the NIRS measured total hemoglobin and ASL measured cerebral blood flow (R = 0.91; P < 10(-10)) and oxy-hemoglobin with flow (R = 0.83; P < 10(-05)) as predicted by the biophysical models. Finally, we note a significant amount of cross-modality, correlated, inter-subject variability in amplitude change and time-to-peak of the hemodynamic response. The observed co-variance in these parameters between subjects is in agreement with hemodynamic models and provides further support that fMRI and NIRS have similar vascular sensitivity.

This paper investigates the use of color to represent the directional information contained in the diffusion tensor. Ideally, one wants to take into account both the properties of human color vision and of the given display hardware to produce a representation in which differences in the orientation of anisotropic structures are proportional to the perceived differences in color. It is argued here that such a goal cannot be achieved in general and therefore, empirical or heuristic schemes, which avoid some of the common artifacts of previously proposed approaches, are implemented. Directionally encoded color (DEC) maps of the human brain obtained using these schemes clearly show the main association, projection, and commissural white matter pathways. In the brainstem, motor and sensory pathways are easily identified and can be differentiated from the transverse pontine fibers and the cerebellar peduncles. DEC maps obtained from diffusion tensor imaging data provide a simple and effective way to visualize fiber direction, useful for investigating the structural anatomy of different organs. Magn Reson Med 42:526-540, 1999.

To develop a measure of the burden of comorbid disease from the MED-ECHO data base (Québec), the so-called Charlson index was adapted to International Classification of Disease (ICD-9) codes. The resulting comorbidity index was applied to the study of inpatient death in 33,940 patients with ischemic heart disease. Multiple logistic regression was used to relate inpatient death to its predictors, including gender, principal diagnosis, age, and the comorbidity index. Various transformations of the comorbidity score were performed, and their effect on the predictive accuracy was assessed. The comorbidity index was constantly and strongly associated with death. From a statistical viewpoint, the best results were obtained when the index was transformed into four dummy independent variables (the area under the receiver-operating curve is then 0.87). In a validation analysis performed on 1990-1991 MED-ECHO data (36,012 admissions with ischemic heart disease), the comorbidity index has the same statistical properties. We conclude that the Charlson index may be an efficient approach to risk adjustment from administrative data bases, although it should be tested on other conditions.

Antitumor monoclonal antibodies must bind to tumor antigens with high affinity to achieve durable tumor retention. This has spurred efforts to generate high affinity antibodies for use in cancer therapy. However, it has been hypothesized that very high affinity interactions between antibodies and tumor antigens may impair efficient tumor penetration of the monoclonal antibodies and thus diminish effective in vivo targeting (K. Fujimori et al., J. Nucl. Med., 31: 1191-1198, 1990). Here we show that intrinsic affinity properties regulate the quantitative delivery of antitumor single-chain Fv (scFv) molecules to solid tumors and the penetration of scFv from the vasculature into tumor masses. In biodistribution studies examining a series of radioiodinated scFv mutants with affinities ranging from 10(-7)-10(-11) M, quantitative tumor retention did not significantly increase with enhancements in affinity beyond 10(-9) M. Similar distribution patterns were observed when the scFv were evaluated in the absence of renal clearance in anephric mice, indicating that the rapid renal clearance of the scFv was not responsible for these observations. IHC and IF evaluations of tumor sections after the i.v. administration of scFv affinity mutants revealed that the lowest affinity molecule exhibited diffuse tumor staining whereas the highest affinity scFv was primarily retained in the perivascular regions of the tumor. These results indicate that antibody-based molecules with extremely high affinity have impaired tumor penetration properties that must be considered in the design of antibody-based cancer therapies.

Gradients of ammonium sulfate in liposomes [(NH4)2SO4]lip.>> [(NH4)2SO4]med. were used to obtain 'active' loading of amphipathic weak bases into the aqueous compartment of liposomes. The loading is a result of the base exchange with the ammonium ions. This approach was applied to encapsulate anthracyclines and acridine orange inside the liposomes at very high efficiency >> 90%). Doxorubicin was accumulated in the aqueous phase of the liposomes where it reached a level as high as 100-fold the doxorubicin concentration in the remote loading medium. Most of the intraliposomal doxorubicin was present in an aggregated state. The active entrapment and loading stability were dependent on liposome lipid composition, lipid quality, medium composition and temperature, as well as on the pKa and hydrophobicity of the base. The ammonium sulfate gradient approach differs from most other chemical approaches used for remote loading of liposomes, since it neither requires preparation of the liposomes in acidic pH, nor to alkalinize the extraliposomal aqueous phase. The stability of the ammonium ion gradient is related to the low permeability of its counterion, the sulfate, which also stabilizes anthracycline accumulation for prolonged storage periods >> 6 months) due to the aggregation and gelation of anthracycline sulfate salt.

A method for motion correction, involving both data collection and reconstruction, is presented. The PROPELLER MRI method collects data in concentric rectangular strips rotated about the k-space origin. The central region of k-space is sampled for every strip, which (a) allows one to correct spatial inconsistencies in position, rotation, and phase between strips, (b) allows one to reject data based on a correlation measure indicating through-plane motion, and (c) further decreases motion artifacts through an averaging effect for low spatial frequencies. Results are shown in which PROPELLER MRI is used to correct for bulk motion in head images and respiratory motion in nongated cardiac images. Magn Reson Med 42:963-969, 1999.