Search

Bleomycin induces a transient lung fibrosis in mice that has been used to investigate mechanisms related to idiopathic pulmonary fibrosis . Our aim was to determine a sensitive method for assessing lung function in bleomycin treated mice that correlated with the degree of lung fibrosis as measured by collagen immunohistochemistry . Bleomycin (2 U/kg) or saline was intratracheally microsprayed to male C57BL/6 mice under isoflurane anesthesia . Lung function (single compartment model, constant phase model, and work of breathing) was assessed using the flexiVent system, and after euthanasia lungs were inflated with formalin in situ for histological analysis. The lung fibrosis histopathology score for the bleomycin treated animals on day 21 was indicative of mild-to-moderate fibrosis (Saline treated control: 0 ± 0, Bleomycin treated: 4.9 ± 0.4). There were at least three large areas of fibrosis in the peribronchial alveolar regions of the lung, but less than 50% of each lung was affected by fibrosis. Although changes in lung function were less obvious, volume normalized dynamic work of breathing measured at 30 ml/kg tidal volume (Saline treated control: 9.2 ± 0.1 J/l, Bleomycin treated: 10.6 ± 0.3 J/l) and the oscillatory mechanics constant phase model parameter tissue elastance (H; Saline treated control: 31 ± 2 cm H 2O/ml, Bleomycin treated: 38 ± 3 cm H2O/ml) were significantly increased on day 21. The work of breathing (r = 0.83) correlated slightly better with fibrosis histopathology score than H (r = 0.64). Work of breathing can detect decrements in lung function due to pulmonary fibrosis, correlates well with the amount of collagen in the lungs, and may be a more sensitive quantitative measure of efficacy for drugs being developed to treat pulmonary fibrosis.

Background Obesity and inflammation are highly integrated processes in the pathogenesis of insulin resistance, diabetes, dyslipidemia, and non-alcoholic fatty liver disease. Molecular mechanisms underlying inflammatory events during high fat diet-induced obesity are poorly defined in mouse models of obesity. This work investigated gene activation signals integral to the temporal development of obesity. Methods Gene expression analysis in multiple organs from obese mice was done with Taqman Low Density Array (TLDA) using a panel of 92 genes representing cell markers, cytokines, chemokines, metabolic, and activation genes. Mice were monitored for systemic changes characteristic of the disease, including hyperinsulinemia, body weight, and liver enzymes. Liver steatosis and fibrosis as well as cellular infiltrates in liver and adipose tissues were analyzed by histology and immunohistochemistry. Results Obese C57BL/6 mice were fed with high fat and cholesterol diet (HFC) for 6, 16 and 26 weeks. Here we report that the mRNA levels of macrophage and inflammation associated genes were strongly upregulated at different time points in adipose tissues (6-16 weeks) and liver (16-26 weeks), after the start of HFC feeding. CD11b+ and CD11c+ macrophages highly infiltrated HFC liver at 16 and 26 weeks. We found clear evidence that signals for IL-1β, IL1RN, TNF-α and TGFβ-1 are present in both adipose and liver tissues and that these are linked to the development of inflammation and insulin resistance in the HFC-fed mice. Conclusions Macrophage infiltration accompanied by severe inflammation and metabolic changes occurred in both adipose and liver tissues with a temporal shift in these signals depending upon the duration of HFC feeding. The evidences of gene expression profile, elevated serum alanine aminotransferase, and histological data support a progression towards nonalcoholic fatty liver disease and steatohepatitis in these HFC-fed mice within the time frame of 26 weeks.

Arcanobacterium haemolyticum causes pharyngitis as well as skin and other wound infections. Although it is a beta-hemolytic organism, the hemolysis is less well defined than that of beta-hemolytic streptococci and may be overlooked in cultures with heavy growth of commensal throat flora. To determine whether routine throat culture conditions are sufficient to produce recognizable colonies of A. haemolyticum, the morphology of six distinct strains was studied after various combinations of incubation time, medium, and atmosphere. The agar media, containing 5% sheep blood, were Trypticase soy agar, Columbia agar, and heart infusion agar. Cultures were incubated in ambient air, 6 to 8% CO2, or an anaerobic atmosphere. Cultures were compared after 24, 48, and 72 h of incubation for colony size, clarity and size of hemolytic zone, and macroscopic evidence of agar pitting. A minimum of 48 h was needed for expression of beta-hemolysis and pitting. Trypticase soy agar was the superior medium and CO2 was the superior atmosphere for beta-hemolysis. Agar pitting was not significantly affected by variations in medium or atmosphere. Strains differed in their expression of hemolysis and production of pits at 48 h. After 72 h of incubation, beta-hemolysis and pitting were visible in over 96% of culture observations.

Increased activity against colorectal cancer by 5-fluorouracil (5-Fu) modulation with leucovorin (LV) and/or interferon (IFN) has been reported. In this study 22 patients with measurable advanced pancreatic cancer received 5-Fu 375 mg/m2 and LV 20 mg/m2 by i.v. bolus daily x 5 every 28 days plus IFN-alpha 3 million units/m2 s.c. There were three out of 21 (14%) responses lasting from 4 to 8 months. Sixteen patients (73%) had one or more episodes of grade 3 or greater toxicity (stomatitis, diarrhea or fatigue). While this combination has some activity against pancreatic cancer, its toxicity limits its potential as a palliative treatment.

We observe the ([ital r],[theta]) drift motion of two nearly identical magnetized electron columns bounded by a cylindrical wall. In the 2D [bold E][times][bold B] drift approximation, these columns are vortices evolving according to the Euler equation. We observe stable and unstable equilibria in which the vortices orbit about the center of the cylinder. The equilibrium positions, oscillation frequencies, and instability rates for these spatially extended vortices agree well with the predictions of integrable point vortex theory, apparently because surface waves and shape distortions do not couple to the center-of-mass motion.

Objective. On January 25, 1990, a jetliner crashed on Long Island, New York. Twenty-two children survived the crash. The purpose of this study was to evaluate the emergency medical system's response to these pediatric survivors. Methods. A questionnaire was sent to all local, acute care hospitals to determine their specific pediatric capabilities and to rank them as level I, II, or III pediatric centers; level I centers are tertiary care facilities. A second questionnaire was sent to all hospitals that received pediatric survivors to collect specific clinical information for each patient. Based on this clinical information a Pediatric Trauma Score (PTS) was assigned to each patient. Children with a PTS ≤8 are considered to be at increased risk of trauma-related mortality. The assigned PTS was compared to the level of the pediatric center to which each patient was transported. Results. Of 25 children on board the plane, 22 (88%) survived the crash; of 135 adults on board, 70 (52%) survived (χ2 = 9.9, P = .002). Seven children had a PTS ≤8; only 1 of these high-risk patients was transported directly to a level I pediatric center, and only 2 of the 5 high-risk children initially transported to level III facilities were transferred to higher level pediatric centers. Conclusions. Pediatric survivors were neither adequately triaged nor transported to appropriate facilities which could optimize their care. Possible explanations for this include (1) unique features of the rescue operation, (2) limited pediatric training of prehospital personnel, and (3) deficiencies of the regional disaster plan. Emergency medical services systems and disaster plans can be made more responsive to children's needs by (1) acknowledging that children have special needs requiring referral, (2) improving the training of prehospital personnel in pediatric emergency care, (3) classifying ill and injured children according to appropriate triage criteria, (4) recognizing existing tertiary care pediatric centers as the optimal location for the treatment of critically ill and injured children, and (5) designating these centers as the appropriate transport destination for critically ill and injured children.

Field development in the Danish chalk fields using horizontal wells has increased productivity in low-permeability reservoirs, maximized fracture intersection with the wellbore and optimized oil rim development. Horizontal drilling requires extraordinary planning in order to achieve proper well placement. Unfortunately, the available data from logs, shows and field mapping does not always give consistent results and adjustments to the planned well trajectory must be made. A review from Maersk Oil experience indicates that despite uncertainties related to such factors as structural dip, fluid levels and faults, objectives can nevertheless be satisfactorily attained. Several techniques incorporating 3D seismic, pilot holes, wellsite biostratigraphy, wellsite geology and logging while drilling are utilized. They have proven crucial for recognizing and implementing rapid changes in the prognosed well trajectory where necessary. Our experience further emphasizes the absolute necessity of ongoing communication between qualified wellsite and office personnel during both the planning and operational phases of drilling a well.

CXCR3 is a chemokine receptor, upregulated upon activation of T cells and expressed on nearly 100% of T cells in sites of inflammation. SCH 900875 is a selective CXCR3 receptor antagonist. Thrombocytopenia and severe hemolytic anemia with acanthocytosis occurred in rats at doses of 75, 100, and 150 mg/kg/day. Massively enlarged spleens corresponded histologically to extramedullary hematopoiesis, macrophages, and hemosiderin pigment and sinus congestion. Phagocytosed erythrocytes and platelets were within splenic macrophages. IgG and/or IgM were not detected on erythrocyte and platelet membranes. Ex vivo increased osmotic fragility of RBCs was observed. Lipid analysis of the RBC membrane revealed modifications in phosphatidylcholine, overall cholesterol, and/or sphingomyelin. Platelets exhibited slender filiform processes on their plasma membranes, analogous to those of acanthocytes. The presence of similar morphological abnormalities in acanthocytes and platelets suggests that possibly similar alterations in the lipid composition of the plasma membrane have taken place in both cell types. This phenotype correlated with alterations in plasma lipids (hypercholesterolemia and low triglycerides) that occurred after SCH 900875 administration, although other factors cannot be excluded. The increased cell destruction was considered triggered by alterations in the lipid profile of the plasma membranes of erythrocytes and platelets, as reflected morphologically.

A Q-switched ruby laser was used to irradiate excised biological tissues. An isolated narrow band emission line was observed at 347 nm on irradiation of collagenous tissues. Temporal pulses at 347 nm were narrower than the laser pulses at 694 nm. Reduced crystalline glutathione yielded narrow band emission at 347 nm that was similar to that for the collagenous tissues. The observed narrow band emission at 347 nm is thought to be due to optical second harmonic generation.

Worst-case conditions for threshold injury on direct viewing of a cw He-Ne laser are defined. A transpupillary power of 50-1OC microW for threshold injury to the eye is calculated on the basis of a heat conduction model and experimental observations.

Two models for retinal threshold injury on exposure to intense light (laser) pulses ranging from 0.1 see to 10(-8) sec, are discussed. In both models, the melanin granules in the retina are considered as the primary absorption site-the site of greatest energy absorption per unit volume in the retina. The single mechanism granule model considers that a specific temperature must be reached in the perigranular region to produce injury. The two-mechanism model assumes that production of steam is not required for injury at long pulse durations-that is, injury at long pulse durations is essentially thermal-but that once steam is produced, injury is related to steam production. The models agree with experimental observations that indicate that the energy for threshold injury decreases as the pulse duration is shortened to the Q-switched range.

The kinetics of metabolic and inflammatory parameters associated with obesity were evaluated in a murine diet-induced obesity (DIO) model using a diet high in fat and cholesterol. Cellular infiltration and mediator production were assessed and shown to be therapeutically modulated by the PPARgamma agonist rosiglitazone. C57BL/6 mice were maintained on a 45% fat/0.12% cholesterol (HF/CH) or Chow diet for 3, 6, 16, or 27 weeks. Flow cytometry was employed to monitor peripheral blood monocytes and adipose tissue macrophages (ATM). Gene expression and protein analysis methods were used to evaluate mediator production from total epididymal fat (EF), stromal vascular fraction (SVF), and sorted SVF cells. To investigate therapeutic intervention, mice were fed a HF/CH diet for 12 weeks and then a diet formulated with rosiglitazone (5 mg/kg) for an additional 6 weeks. A HF/CH diet correlated with obesity and a dramatic proinflammatory state. Therapeutic intervention with rosiglitazone attenuated the HF/CH induced inflammation. In addition, a novel population was found that expressed the highest levels of the pro-inflammatory mediators CCL2 and IL-6.

A simple perturbation theory of the frequencies and density distortions of the l=1 diocotron mode on pure electron plasma columns is presented. This mode is the dynamical state of an off‐axis electron column which is orbiting around the containment axis at the E×B drift velocity. The theory predicts shifts in the orbit frequency and quadrupole distortions of the plasma surface, both varying as the offset squared, in good agreement with experiments. The results also apply to a two‐dimensional vortex patch in an inviscid fluid with circular boundaries.

This article examines some current issues in toxicologic care. First there is a review of the scope of pediatric poisonings and some aspects of initial management. Then there is a discussion of the decision-making process required to properly use gastric decontamination in the management of poisonings. Each of the common methods available--emesis, gastric lavage, activated charcoal, catharsis, and whole bowel irrigation--is discussed. Finally, several new and old antidotes are reviewed, namely naloxone, glucagon, bicarbonate, dimercaptosuccinic acid, digoxin-specific fab fragments, and flumazenil.

Serpentinised plagioclase-olivine clinopyroxenite and dolerite fragments were dredged from the western Jan Mayen Fracture Zone, near its intersection with the Kolbeinsey Ridge. According to major and trace element analyses of the rocks and minerals (a) the clinopyroxenite represents cumulates which crystallised from a Jan Mayen-like alkaline magma at an intermediate basaltic stage in the uppermost mantle or lower crust, and (b) the dolerite fragments constitute an oceanic, within-plate tholeiitic series with alkaline affinities. These rocks have been subjected to serpentinization, low-medium grade metamorphism, metasomatism, brecciation and veining, part of which probably took place during fracture zone tectonism. By analogy with the geological development of the Canary Islands, they are considered to form part of a layered basal complex to the alkaline Jan Mayen volcanic province.

We have reported that 5-fluorouracil (5-FU) and folinic acid increased response rate and survival in patients with metastatic colorectal cancer. Now we have analysed prognostic factors for response, toxicity, survival and time to progression. The variables used for survival and response were treatment centre, treatment, age, sex, Eastern Cooperative Oncology Group (ECOG) performance status (PS), site of disease, previous radiotherapy, site of primary, disease-free interval, initial alkaline phosphatase (AP), albumin (A), lactate dehydrogenase (LDH) and aspartate aminotransferase (SGOT). The significant independent variables for survival were PS of 2 or more, initial albumin and SGOT, and treatment received, in order of importance. The relative risk of death when patients received 5-FU/folinic acid was 60% of that of patients receiving 5-FU alone. The variables predictive of response were treatment and PS. The variables used for analysis of toxicity were age, treatment centre, treatment, sex, tumour response, PS, number of courses, SGOT, AP and albumin. Treatment was found to be predictive of toxicity. Thus, baseline albumin and SGOT, and 5-FU/folinic acid treatment are significant determinats of survival, 5-FU/folinic acid and PS of 2 or more are major determinants of response and no clinical parameter could be identified as a predictor of toxicity.

We examined the records of 105 patients with advanced ovarian cancer who had been treated with cisplatin combination chemotherapy followed by abdominopelvic radiotherapy. The purpose was to define the morbidity of this approach, and identify those factors predictive of toxicity. Acute toxicity resulting in delay or failure to complete treatment was most commonly due to myelosuppression. Nine of 105 patients (8.6%) required surgery for bowel obstruction that was not due to recurrent disease, 3 had an episode of bowel obstruction that settled conservatively, and a further 5 underwent surgery for obstruction due to recurrent tumor. The presence of both a dose of abdominopelvic radiotherapy over 2250 cGy, as well as a second-look laparotomy prior to radiotherapy, was associated with an increased risk of serious bowel complications. The increased frequency of late bowel morbidity seen in the combined modality group is likely explained by the presence of these two factors, rather than the exposure to chemotherapeutic agents per se. These observations are supported by the published literature.

Background CCR2 plays a key role in regulating monocyte trafficking to sites of inflammation and therefore has been the focus of much interest as a target for inflammatory disease. Methods Here we examined the effects of CCR2 blockade with a potent small molecule antagonist to determine the pharmacodynamic consequences on the peripheral blood monocyte compartment in the context of acute and chronic inflammatory processes. Results We demonstrate that CCR2 antagonism in vivo led to a rapid decrease in the number of circulating Ly6Chi monocytes and that this decrease was largely due to the CXCR4-dependent sequestration of these cells in the bone marrow, providing pharmacological evidence for a mechanism by which monocyte dynamics are regulated in vivo. CCR2 antagonism led to an accumulation of circulating CCL2 and CCL7 levels in the blood, indicating a role for CCR2 in regulating the levels of its ligands under homeostatic conditions. Finally, we show that the pharmacodynamic changes due to CCR2 antagonism were apparent after chronic dosing in mouse experimental autoimmune encephalomyelitis, a model in which CCR2 blockade demonstrated a dramatic reduction in disease severity, manifest in a reduced accumulation of monocytes and other cells in the CNS. Conclusion CCR2 antagonism in vivo has tractable pharmacodynamic effects that can be used to align target engagement with biologic effects on disease activity.

Many studies of bottom-up visual attention have focused on identifying which features of a visual stimulus render it salient--i.e., make it "pop out" from its background--and on characterizing the extent to which salience predicts eye movements under certain task conditions. However, few studies have examined the relationship between salience and other cognitive functions, such as memory. We examined the impact of visual salience in an object-place working memory task, in which participants memorized the position of 3-5 distinct objects (icons) on a two-dimensional map. We found that their ability to recall an object's spatial location was positively correlated with the object's salience, as quantified using a previously published computational model (Itti et al., 1998). Moreover, the strength of this relationship increased with increasing task difficulty. The correlation between salience and error could not be explained by a biasing of overt attention in favor of more salient icons during memorization, since eye-tracking data revealed no relationship between an icon's salience and fixation time. Our findings show that the influence of bottom-up attention extends beyond oculomotor behavior to include the encoding of information into memory.

Epileptic seizures were experimentally induced in the CA3 region of rat hippocampus in vivo. Recordings of seizure activity were made in both hippocampi as well as anteromedial region of the thalamus in order to analyze the instantaneous activity for synchronous oscillators. A new method is introduced for detecting this synchrony which combines empirical mode decomposition, the Hilbert analytic signal method and eigenvalue decomposition.

In psoriasis, leukocytes that infiltrate skin lesions have been shown to be involved in the pathogenesis of this disease. Previous investigations reporting the presence of CXCR3(+) T lymphocytes in psoriatic lesional skin have suggested a role of this receptor in the recruitment of T cells into the lesion. The purpose of this study was to quantify the mRNA levels of CXCR3 and to perform a systematic analysis of the cell populations that express CXCR3 in human lesional and non-lesional psoriatic biopsies. We showed by real-time reverse transcriptase-polymerase chain reaction that the mRNA levels of CXCR3 and its ligands, CXCL9-11, were significantly elevated in psoriatic lesions, as compared to non-lesional samples. Serial cryostat sections of psoriasis skin biopsies were evaluated by immunohistochemistry. The number of CXCR3(+) cells was low in non-lesional tissues. Quantitative image analysis demonstrated significant increases in the number of both epidermal and dermal CXCR3(+) cells in lesional compared with non-lesional biopsies. The majority of CXCR3(+) cells were located in the dermis of the lesional skin and 74% were demonstrated to be CD3(+) T lymphocytes. A small number of CXCR3(+) cells were CD68(+) myeloid cells. In addition, we found that nearly all BDCA-2(+) plasmacytoid dendritic cells in the psoriatic biopsies were CXCR3(+). These findings support and extend prior reports suggesting the potential role for CXCR3 in the pathophysiology of plaque psoriasis, by mediating the recruitment of plasmacytoid dendritic cells and T cells into the developing lesions.

We have examined the expression and function of the cell adhesion molecules LFA-1 (CD11a/CD18), ICAM-1 (CD54), and ICAM-2 in murine fetal thymic ontogeny and in the adult thymus. On fetal days 14 and 15, 40 to 50% of thymocytes coexpress high levels of LFA-1 and ICAM-1, as determined by flow cytometry. By day 16, more than 90% of fetal thymocytes are LFA-1+ ICAM-1hi, and all IL-2R+ cells are located in this population. Although LFA-1 expression remains unchanged thereafter, ICAM-1 expression appears to be differentially regulated in different thymocyte subpopulations, with CD4+8+ cells being ICAM-1lo and CD4-8- thymocytes remaining ICAM-1hi. ICAM-2 surface expression is dull on both fetal and adult thymocytes. Surprisingly, the expression of ICAM-1 is differentially up-regulated on T cells having a mature phenotype in thymus and in peripheral lymphoid organs, with CD8+ T cells bearing the highest amount of surface ICAM-1. Addition of anti-ICAM-1 or anti-LFA-1 antibodies to fetal thymic organ cultures results in the impaired generation of CD4+8+ cells. These results indicate that LFA-1/ICAM-1 interactions facilitate murine thymic development and suggest that cell adhesion molecules mediate important events in T cell differentiation.

Molecular and cellular assessment of dermal delayed-type hypersensitivity (DTH) responses is a useful approach for evaluating the mechanism of action (MOA) of immunomodulatory agents. In the present report, we characterized the delayed-type hypersensitivity response induced by keyhole limpet hemocyanin (KLH), and validated its utility by evaluating an immunomodulator, BIRB-796. Intradermal KLH challenge of the ear pinna following subcutaneous antigen sensitization resulted in a pronounced skin inflammation that peaked at 24-48h. At the molecular level, there was an activation of 3 mitogen-activated protein kinases (MAPKs: p38, JNK and ERK), an induction of the chemokines CCL2/JE, CXCL2/Mip-2, CXCL1/KC, CCL3/Mip-1alpha CCL4/Mip-1beta and CXCL10/IP-10, and expression of the cytokines IL-1beta and IL-10 in the ear parenchyma. Modulation of TNFalpha protein level was only detected in ex-vivo ear whole organ cultures (EWOC). Consistent with this inflammatory profile there was an infiltration of neutrophils and mononuclear cells into the ear parenchyma. BIRB-796, a potent allosteric p38 MAPK inhibitor attenuated the ear swelling response, which correlated with a reduced inflammatory profile. BIRB-796 inhibited p38 but not JNK or ERK kinase activation, decreased multiple chemokines which correlated with a decrease in the infiltration of neutrophils and macrophages; CD4 T cells were modesty reduced. Similarly, there was a decrease of levels of cytokines including IL-1beta, IL-10 and TNFalpha. These data support the utility of this model for evaluating immunomodulators on skin inflammation and suggest that modulation of p38 kinase may be of therapeutic value for the treatment of inflammatory skin conditions.

We measure the width of the MgII $\lambda2799$ line in quasar spectra from the SDSS, 2QZ and 2SLAQ surveys and, by invoking an unnormalised virial mass estimator, relate the scatter in line width to the scatter in mass in the underlying black hole population. We find conclusive evidence for a trend such that there is less scatter in line width, and hence black hole mass, in more luminous objects. However, the most luminous objects in our sample show such a low degree of scatter in line width that, when combined with measures for the intrinsic scatter in the radius-luminosity relation for the broad-line region in active galaxies, an inconsistency arises in the virial technique for estimating black hole masses. This analysis implies that, at least for the most luminous quasars, either there is little-to-no intrinsic scatter in the radius-luminosity relation or the MgII broad emission line region is not totally dominated by virial velocities. Finally we exploit the measured scatter in line widths to constrain models for the velocity field of the broad-line region. We show that the lack of scatter in broad line-widths for luminous quasars is inconsistent with a pure planar/disk-like geometry for the broad-line region... (abridged), Comment: 19 pages 16 figures, accepted MNRAS. High res version available at: http://www.physics.usyd.edu.au/~sfine/qso_bl_scatter.ps

Publisher Summary This chapter provides an overview of how health-care organizations (HCOs) are structured in the United States, mapping the evolution of HCOs to more complex and integrated systems and describing the information technology (IT) decisions faced by the organizations, the components of a leadership team, and the stakeholders within the organization. The approach of an HCO to the integration of diverse health-care delivery systems is a strategic issue with far-reaching implications for the financing and management of care. The benefits of integration include improvements in the coordination of care and economies of scale for operational functions. Following this, the study turns its attention to exploring what makes for effective leadership and management within the organization, shedding light on qualities of effective leadership, barriers to implementation of a health-care information system (HCIS) within the organization, and project management strategies for implementation. To develop strategy that is consonant with the organizational goals, the leaders must see the larger context of the organization highlighting the economic, political, and social forces shaping it. Within the leadership team, there must be technical competence and a solid understanding of the hardware and software needs for the system. This chapter indicates that management guidelines for organizational change are part of a larger discussion of how to formulate and implement an organizational strategy. Finally, it addresses the social aspects of implementation.

We present the final spectroscopic QSO catalogue from the 2dF-SDSS LRG and QSO (2SLAQ) Survey. This is a deep, 18, Comment: 28 pages, 23 figures. Accepted for publication in MNRAS. Survey data, including catalogue and spectra available from http://www.2slaq.info/

A statistical pattern recognition technique called IREW is described. IREW has several strengths, such as fast execution, small storage requirements, and increments learning, that may make the technique useful for many meteorological pattern recognition problems. A weakness of IREW is that it may not recognize complex patterns as well as more sophisticated pattern recognition techniques do. IREW analyzes data by using a derivative of Bayes' rule to multiplicatively combine the influence of predictors. The weight assigned to each predictor is determined empirically from a training dataset containing the data and verifications for multiple cases. IREW uses several methods to select useful subsets of a large set of predictors. The objective identification of surface fronts in Nested Grid Model forecasts is described to illustrate how IREW can be applied to a typical pattern recognition problem. The work consisted of identifying factors related to fronts and using some of those factors to make analys...

Magnetically confined columns of electrons are excellent experimental manifestations of two‐dimensional (2‐D) vortices in an inviscid fluid. Surface charge perturbations on the electron column (diocotron modes) are equivalent to surface ripples on extended vortices; and unstable diocotron modes on hollow electron columns are examples of the Kelvin–Helmholtz instability. Experiments demonstrate that the stable and unstable modes are distinct and may coexist, having different frequencies and radial eigenfunctions. For azimuthal mode number l=1, an exponentially unstable mode is observed on hollow columns, in apparent contradiction to 2‐D fluid theory. For l=2, a similar unstable mode is observed, consistent with fluid theory. These diocotron instabilities on hollow columns saturate with the formation of smaller vortex structures, and radial transport is determined by the nonlinear interaction of these secondary vortices. The vortex pairing instability has been observed for isolated, well‐controlled vortices, and the instability is found to depend critically on the vortex separation distance.

Exposure of experimental animals to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) results in severe thymic atrophy and suppression of cell-mediated and humoral immune functions. However, despite much effort the mechanism by which TCDD produces these responses, particularly thymic atrophy, remains unclear. In this report, we have examined the effect of acute TCDD exposure on lymphocyte stem cells in young adult BALB/c mice to determine whether alterations to events early in T lymphopoiesis contribute to TCDD-induced thymic atrophy. TCDD produced a dose-dependent reduction in thymic weight and cellularity following a single dose of 5 to 120 micrograms TCDD/kg. This thymic atrophy correlated with a dose-dependent suppression of the biosynthesis and mRNA levels of the lymphocyte stem cell-specific DNA polymerase terminal deoxynucleotidyl transferase in bone marrow and thymus. However, the reduction in thymic terminal deoxynucleotidyl nucleotidyl transferase synthesis, on a per cell basis, was less than that observed in bone marrow. Intrathymic CD4/CD8 and IL-2R expression demonstrated only mild alterations after exposure to 30 micrograms TCDD/kg. These data suggest that thymocytes are more refractory to TCDD than are pre-T cells. To assess this possibility directly, bone marrow prothymocytes from TCDD-treated donor mice were examined for their capacity to reconstitute the thymuses of adoptive, irradiated recipients. Our results indicate that prothymocyte activity was severely impaired by TCDD exposure and that this effect occurred at low tissue levels of TCDD. In contrast, we observed no reduction in the number of colony-forming unit-granulocyte macrophage and a moderate decrease in colony-forming unit-spleen. These data suggest that TCDD-induced thymic atrophy is the result, at least in part, of impaired thymic seeding by prothymocytes.

A new class of antiemetic agents, the 5-hydroxytryptamine (5-HT3) antagonists, have been shown to possess potent antiemetic properties in the ferret model. We conducted a phase I/II trial of the 5-HT3 antagonist BRL43694 (granisetron) in 24 chemotherapy-naïve patients who were receiving any combination of doxorubicin and/or cisplatin. The first 12 patients received 40 micrograms/kg and the second 12 received 80 micrograms/kg of granisetron intravenously before beginning chemotherapy. Nausea was assessed by a patient-completed visual analogue scale and episodes of retching recorded by the patient and an independent observer. Fifty-two percent of the 22 evaluable patients had no retching or vomiting and 32% had no nausea during the first 24 hours after chemotherapy. Pharmacokinetic measurements were performed. The disposition of granisetron was best described using a two-compartment model. The area under the plasma concentration curve (AUC) was 277 +/- 226 ng.h/mL and 359 +/- 282 ng.h/mL at 40 and 80 micrograms/kg, respectively. The total body clearance was 0.319 +/- 0.315 L/kg/hr and 0.483 +/- 0.504 L/kg/hr at the 40 and 80 micrograms/kg doses. Wide interpatient variation in model independent parameters was observed. There was no suggestion of dose-dependent efficacy at the two dose levels studied. We conclude that granisetron shows promise as a well-tolerated and effective antiemetic. Randomized trials comparing this drug with standard regimens are currently underway.

Cells were isolated by sequential collagenase digestion from the parietal segments of one day old mice (Swiss albino BNL strain) and characterized for osteoblast parameters by alkaline phosphatase histochemistry and bovine parathyroid hormone (bPTH- (1–34)) induced cAMP activity (protein binding assay). Phenytoin (DPH) reduced PTH stimulated cAMP activity nearly 3-fold in the presence and nearly 1.5-fold in the absence of added calcium. In the absence of PTH, DPH exerted no significant effect. Bay-K-8644, a calcium channel activator, appeared to approximate the PTH stimulation of cAMP activity, even in the presence of DPH. This study demonstrates that DPH has a direct effect on PTH stimulated cAMP activity in cultured murine osteoblasts.

Work to improve the therapeutic properties of cannabinoid CB(2) receptor-selective inverse agonists has led to the development of Sch.036, an aryl substituted triaryl bis-sulfone with improved oral pharmacokinetic parameters. In this report, we show that this compound blocks in vivo trafficking of various leukocyte populations, a property consistent with other members of this chemical series. This CB(2)-selective compound also shows efficacy in leukocyte recruitment models when added in concert with suboptimal doses of selected anti-inflammatory agents, consistent with its unique function and indicative of its potential therapeutic utility. Finally, studies with Sch.036 show that this cannabinoid CB(2)-specific inverse agonist can ameliorate bone damage in a rat model of relapsing-remitting arthritis. This result suggests that a cannabinoid CB(2)-selective inverse agonist may help ameliorate a particularly harmful property of this inflammatory joint disease.

How does the brain compute? To address this question, mathematical modelers, neurophysiologists, and psychophysicists have sought behaviors that provide evidence of specific neural computations. Human motor behavior consists of several such computations [Shadmehr, R., Wise, S.P. (2005). MIT Press: Cambridge, MA], such as the transformation of a sensory input to a motor output. The motor system is also capable of learning new transformations to produce novel outputs; humans have the remarkable ability to alter their motor output to adapt to changes in their own bodies and the environment [Wolpert, D.M., Ghahramani, Z. (2000). Nat. Neurosci., 3: 1212-1217]. These changes can be long term, through growth and changing body proportions, or short term, through changes in the external environment. Here we focus on trial-by-trial adaptation, the transformation of individually sensed movements into incremental updates of adaptive control. These investigations have the promise of revealing important basic principles of motor control and ultimately guiding a new understanding of the neuronal correlates of motor behaviors.

A series of novel and potent 3,4-diamino-2,5-thiadiazole-1-oxides were prepared and found to show excellent binding affinities for CXCR2 and CXCR1 receptors and excellent inhibitory activity of Gro-α and IL-8 mediated in vitro hPMN MPO release of CXCR2 and CXCR1 expressing cell lines. On the other hand, a closely related 3,4-diamino-2,5-thiadiazole-dioxide did not show functional activity despite its excellent binding affinities for CXCR2 and CXCR1 in membrane binding assays. A detailed SAR has been discussed in these two closely related structures.

Humans can rapidly change their motor output to make goal-directed reaching movements in a new environment. Theories that describe this adaptive process have long presumed that adaptive steps scale proportionally with error. Here we show that while performing a novel reaching task, participants did not adopt a fixed learning rule, but instead modified their adaptive response based on the statistical properties of the movement environment. We found that as the directional bias of the force distribution shifted from strongly biased to unbiased, participants transitioned from an adaptive process that scaled proportionally with error to one that adapted to the direction, but not magnitude, of error. Participants also modified their response as the likelihood of the perturbation changed; as the likelihood decreased from 80 to 20% of trials, participants adopted an increasingly disproportional strategy. We propose that people can rapidly switch between learning processes within minutes of experiencing a novel environment.

A novel series of cyclobutenedione centered C(4)-alkyl substituted furanyl analogs was developed as potent CXCR2 and CXCR1 antagonists. Compound 16 exhibits potent inhibitory activities against IL-8 binding to the receptors (CXCR2 Ki=1 nM, IC(50)=1.3 nM; CXCR1 Ki=3 nM, IC(50)=7.3 nM), and demonstrates potent inhibition against both Gro-alpha and IL-8 induced hPMN migration (chemotaxis: CXCR2 IC(50)=0.5 nM, CXCR1 IC(50)=37 nM). In addition, 16 has shown good oral pharmacokinetic profiles in rat, mouse, monkey, and dog.

How does the brain compute? To address this question, mathematical modelers, neurophysiologists, and psychophysicists have sought behaviors that provide evidence of specific neural computations. Human motor behavior consists of several such computations [Shadmehr, R., Wise, S.P. (2005). MIT Press: Cambridge, MA], such as the transformation of a sensory input to a motor output. The motor system is also capable of learning new transformations to produce novel outputs; humans have the remarkable ability to alter their motor output to adapt to changes in their own bodies and the environment [Wolpert, D.M., Ghahramani, Z. (2000). Nat. Neurosci., 3: 1212-1217]. These changes can be long term, through growth and changing body proportions, or short term, through changes in the external environment. Here we focus on trial-by-trial adaptation, the transformation of individually sensed movements into incremental updates of adaptive control. These investigations have the promise of revealing important basic principles of motor control and ultimately guiding a new understanding of the neuronal correlates of motor behaviors.

Although previous experiments have identified that errors in movement induce adaptation, the precise manner in which errors determine subsequent control is poorly understood. Here we used transient pulses of force, distributed pseudo-randomly throughout a movement set, to study how the timing of feedback within a movement influenced subsequent predictive control. Human subjects generated a robust adaptive response in postpulse movements that opposed the pulse direction. Regardless of the location or magnitude of the pulse, all pulses yielded similar changes in predictive control. All current supervised and unsupervised theories of motor learning presume that adaptation is proportional to error. Current neural models that broadly encode movement velocity and adapt proportionally to motor error can mimic human insensitivity to pulse location, but cannot mimic human insensitivity to pulse magnitude. We conclude that single trial adaptation to force pulses reveals a categorical strategy that humans adopt to counter the direction, rather than the magnitude, of movement error.

We present a spectroscopic survey of almost 15,000 candidate intermediate-redshift Luminous Red Galaxies (LRGs) brighter than i=19.8, observed with 2dF on the Anglo-Australian Telescope. The targets were selected photometrically from the Sloan Digital Sky Survey (SDSS) and lie along two narrow equatorial strips covering 180 sq deg. Reliable redshifts were obtained for 92% of the targets and the selection is very efficient: over 90% have redshifts between 0.45 and 0.8. More than 80% of the ~11,000 red galaxies have pure absorption-line spectra consistent with a passively-evolving old stellar population. The redshift, photometric and spatial distributions of the LRGs are described. The 2SLAQ data will be released publicly from mid-2006, providing a powerful resource for observational cosmology and the study of galaxy evolution., Accepted for publication in MNRAS. 21 pages. The 2SLAQ LRG data discussed in this paper will become public when the paper appears in the journal. See http://www.2slaq.info for more information on the survey and data release, and a higher resolution version of the paper

The expression of the cannabinoid peripheral cannabinoid receptor (CB(2)) receptor on peripheral immune cells suggests that compounds specific for CB(2) might be effective anti-inflammatory agents. In this report, we present the initial biological profiling of a novel triaryl bis-sulfone, Sch.336 (N-[1(S)-[4-[[4-methoxy-2-[(4-methoxyphenyl)sulfonyl]phenyl]-sulfonyl]phenyl]ethyl]methanesulfonamide), which is selective for the human cannabinoid CB(2) receptor (hCB(2)). Sch.336 is an inverse agonist at hCB(2), as shown by its ability to decrease guanosine 5'-3-O-(thio)triphosphate (GTPgammaS) binding to membranes containing hCB(2), by the ability of GTPgammaS to left-shift Sch.336 binding to hCB(2) in these membranes, and by the compound's ability to increase forskolin-stimulated cAMP levels in CHO cells expressing hCB(2). In these systems, Sch.336 displays a greater potency than that reported for the CB(2)-selective dihydropyrazole, SR144528 (N-[(1S)-endo-1,3,3-trimethylbicyclo [2.2.1]heptan2-yl]-5-(4-chloro-3-methylphenyl)-1-[(4-methylphenyl)methyl]-1H-pyrazole-3-carboxamide). In vitro, Sch.336 impairs the migration of CB(2)-expressing recombinant cell lines to the cannabinoid agonist 2-arachidonylglycerol. In vivo, the compound impairs migration of cells to cannabinoid agonist HU210 [(6aR)-trans-3-(1,1-dimethylheptyl)-6a,7,10,10a-tetrahydro-1-hydroxy-6,6-dimethyl-6H-dibenzo [b,d] pyran-9-methanol]. Oral administration of the Sch.336 significantly inhibited leukocyte trafficking in several rodent in vivo models, induced either by specific chemokines or by antigen challenge. Finally, oral administration of Sch.336 blocked ovalbumin-induced lung eosinophilia in mice, a disease model for allergic asthma. We conclude that selective cannabinoid CB(2) inverse agonists may serve as novel immunomodulatory agents in the treatment of a broad range of acute and chronic inflammatory disorders in which leukocyte recruitment is a hallmark of disease pathology.