Spatial Attentional Selection Modulates Early Visual Stimulus Processing Independently of Visual Alpha Modulations.

The capacity-limited human brain is constantly confronted with a huge amount of sensory information. Selective attention is needed for biasing neural processing towards relevant information and consequently allows meaningful interaction with the environment. Activity in the alpha-band has been proposed to be related to top-down modulation of neural inhibition and could thus represent a viable candidate to control the priority of stimulus processing. It is, however, unknown whether modulations in the alpha-band directly relate to changes in the sensory gain control of the early visual cortex. Here, we used a spatial cueing paradigm while simultaneously measuring ongoing alpha-band oscillations and steady-state visual evoked potentials (SSVEPs) as a marker of continuous early sensory processing in the human visual cortex. Thereby, the effects of spatial attention for both of these signals and their potential interactions were assessed. As expected, spatial attention modulated both alpha-band and SSVEP responses. However, their modulations were independent of each other and the corresponding activity profiles differed across task demands. Thus, our results challenge the view that modulations of alpha-band activity represent a mechanism that directly alters or controls sensory gain. The potential role of alpha-band oscillations beyond sensory processing will be discussed in light of the present results.

Identification of Inhibitors of Integrin Cytoplasmic Domain Interactions With Syk.

Leukocyte inflammatory responses require integrin cell-adhesion molecule signaling through spleen tyrosine kinase (Syk), a non-receptor kinase that binds directly to integrin ß-chain cytoplasmic domains. Here, we developed a high-throughput screen to identify small molecule inhibitors of the Syk-integrin cytoplasmic domain interactions. Screening small molecule compound libraries identified the ß-lactam antibiotics cefsulodin and ceftazidime, which inhibited integrin ß-subunit cytoplasmic domain binding to the tandem SH2 domains of Syk (IC50 range, 1.02-4.9 µM). Modeling suggested antagonist binding to Syk outside the pITAM binding site. Ceftazidime inhibited integrin signaling via Syk, including inhibition of adhesion-dependent upregulation of interleukin-1ß and monocyte chemoattractant protein-1, but did not inhibit ITAM-dependent phosphorylation of Syk mediated by FcγRI signaling. Our results demonstrate a novel means to target Syk independent of its kinase and pITAM binding sites such that integrin signaling via this kinase is abrogated but ITAM-dependent signaling remains intact. As integrin signaling through Syk is essential for leukocyte activation, this may represent a novel approach to target inflammation.

Incorporation of monovalent cations in sulfate green rust.

Green rust is a naturally occurring layered mixed-valent ferrous-ferric hydroxide, which can react with a range of redox-active compounds. Sulfate-bearing green rust is generally thought to have interlayers composed of sulfate and water. Here, we provide evidence that the interlayers also contain monovalent cations, using X-ray photoelectron spectroscopy and synchrotron X-ray scattering. For material synthesized with Na(+), K(+), Rb(+), or Cs(+), interlayer thickness derived from basal plane spacings correlates with the radius of the monovalent cation. In addition, sequential washing of the materials with water showed that Na(+) and K(+) were structurally fixed in the interlayer, whereas Rb(+) and Cs(+) could be removed, resulting in a decrease in the basal layer spacing. The incorporation of cations in the interlayer opens up new possibilities for the use of sulfate green rust for exchange reactions with both anions and cations: e.g., radioactive Cs.

Small molecule agonist of very late antigen-4 (VLA-4) integrin induces progenitor cell adhesion.

Activation of the integrin family of cell adhesion receptors on progenitor cells may be a viable approach to enhance the effects of stem cell-based therapies by improving cell retention and engraftment. Here, we describe the synthesis and characterization of the first small molecule agonist identified for the integrin α4ß1 (also known as very late antigen-4 or VLA-4). The agonist, THI0019, was generated via two structural modifications to a previously identified α4ß1 antagonist. THI0019 greatly enhanced the adhesion of cultured cell lines and primary progenitor cells to α4ß1 ligands VCAM-1 and CS1 under both static and flow conditions. Furthermore, THI0019 facilitated the rolling and spreading of cells on VCAM-1 and the migration of cells toward SDF-1α. Molecular modeling predicted that the compound binds at the α/ß subunit interface overlapping the ligand-binding site thus indicating that the compound must be displaced upon ligand binding. In support of this model, an analog of THI0019 modified to contain a photoreactive group was used to demonstrate that when cross-linked to the integrin, the compound behaves as an antagonist instead of an agonist. In addition, THI0019 showed cross-reactivity with the related integrin α4ß7 as well as α5ß1 and αLß2. When cross-linked to αLß2, the photoreactive analog of THI0019 remained an agonist, consistent with it binding at the α/ß subunit interface and not at the ligand-binding site in the inserted ("I") domain of the αL subunit. Co-administering progenitor cells with a compound such as THI0019 may provide a mechanism for enhancing stem cell therapy.

Synthesis and evaluation of an anti-MLC1 × anti-CD90 bispecific antibody for targeting and retaining bone-marrow-derived multipotent stromal cells in infarcted myocardium.

A key issue regarding the use of stem cells in cardiovascular regenerative medicine is their retention in target tissues. Here, we have generated and assessed a bispecific antibody heterodimer designed to improve the retention of bone-marrow-derived multipotent stromal cells (BMMSC) in cardiac tissue damaged by myocardial infarction. The heterodimer comprises an anti-human CD90 monoclonal antibody (mAb) (clone 5E10) and an anti-myosin light chain 1 (MLC1) mAb (clone MLM508) covalently cross-linked by a bis-arylhydrazone. We modified the anti-CD90 antibody with a pegylated-4-formylbenzamide moiety to a molar substitution ratio (MSR) of 2.6 and the anti-MLC1 antibody with a 6-hydrazinonicotinamide moiety to a MSR of 0.9. The covalent modifications had no significant deleterious effect on mAb epitope binding. Furthermore, the binding of anti-CD90 antibody to BMMSCs did not prevent their differentiation into adipo-, chondro-, or osteogenic lineages. Modified antibodies were combined under mild conditions (room temperature, pH 6, 1 h) in the presence of a catalyst (aniline) to allow for rapid generation of the covalent bis-arylhydrazone, which was monitored at A(354). We evaluated epitope immunoreactivity for each mAb in the construct. Flow cytometry demonstrated binding of the bispecific construct to BMMSCs that was competed by free anti-CD90 mAb, verifying that modification and cross-linking were not detrimental to the anti-CD90 complementarity-determining region. Similarly, ELISA-based assays demonstrated bispecific antibody binding to plastic-immobilized recombinant MLC1. Excess anti-MLC1 mAb competed for bispecific antibody binding. Finally, the anti-CD90 × anti-MLC1 bispecific antibody construct induced BMMSC adhesion to plastic-immobilized MLC1 that was resistant to shear stress, as measured in parallel-plate flow chamber assays. We used mAbs that bind both human antigens and the respective pig homologues. Thus, the anti-CD90 × anti-MLC1 bispecific antibody may be used in large animal studies of acute myocardial infarction and may provide a starting point for clinical studies.

Watching the growth of bulk grains during recrystallization of deformed metals.

We observed the in situ growth of a grain during recrystallization in the bulk of a deformed sample. We used the three-dimensional x-ray diffraction microscope located at the European Synchrotron Radiation Facility in Grenoble, France. The results showed a very heterogeneous growth pattern, contradicting the classical assumption of smooth and spherical growth of new grains during recrystallization. This type of in situ bulk measurement opens up the possibility of obtaining experimental data on scientific topics that before could only be analyzed theoretically on the basis of the statistical characterization of microstructures. For recrystallization, the in situ method includes direct measurements of nucleation and boundary migration through a deformed matrix.

Paclitaxel formulation as a cause of ethanol intoxication.

OBJECTIVE: To report a case of ethyl alcohol intoxication associated with paclitaxel administration. CASE SUMMARY: A patient who received a 3-hour paclitaxel infusion for metastatic breast carcinoma and developed symptoms of acute alcohol intoxication. A blood ethanol concentration drawn at the end of the paclitaxel infusion was 97.8 mg/dL (0.098%). DISCUSSION: The amount of alcohol contained in paclitaxel is discussed. A review of the literature revealed one patient series where the highest blood alcohol concentration was one-third that seen in our patient. CONCLUSIONS: Clinicians should recognize the potential for alcohol intoxication with paclitaxel administration. This is especially pertinent when higher doses are given over a short period of time.

Charge and reimbursement analysis for intensive care unit patients in a large tertiary teaching hospital.

Hospital charge and reimbursement data were analyzed for 115 patients admitted to the surgical intensive care and burn-trauma units at Brigham and Women's Hospital over a two-month study period. A skewed distribution of hospital charges resulted in mean and median charges of $43,068 and $29,081, respectively. Major differences were observed in total charges among major diagnostic groups. The median charge was highest in orthopedic trauma and neurosurgery patients. The median charge across major diagnostic groups correlated with the length of stay in the unit and in the hospital, and the number of drugs used. The median percent reimbursement from private providers, Medicaid, Medicare, and health maintenance organizations was 93, 55, 40, and 30 percent, respectively, and 55 percent overall. Reimbursement was high from private providers regardless of major diagnostic group. Medicare reimbursement through the diagnostic reference group system was considerably higher in cardiothoracic patients (77 percent) than in other major diagnostic groups. The discrepancy between charge and Medicare reimbursement in these patients was consistent with that reported for intensive care units in other hospitals, thereby underscoring the need for cost containment and more realistic reimbursement methods.

Drug usage patterns in the ICU: profile of a major metropolitan hospital and comparison with other ICUs.

Drug use patterns observed in an intensive care unit (ICU) at a large tertiary teaching hospital (Brigham & Women's Hospital [BWH], Boston) were documented and compared with patterns reported from ICUs of hospitals at two other sites. Antibiotics, analgesics, and H2 antagonists were the most frequently prescribed classes of drugs. Despite the variability in ICU populations studied, similar patterns of drug use (drug classes and frequency of use) were seen at all three institutions. Pharmacy charges for ICU care at BWH were calculated with respect to total hospitalization charges and were found to account for 10% of total charges. Identifying drug use patterns in ICUs--an area of potentially high drug use, risk, and cost--provides valuable information for P & T Committees as well as for medical staff quality assurance and usage evaluation functions.

Clinical pharmacy education in new England: a report of the Whispering Pines Conference.

Clinical pharmacy practice as it relates to the future of the pharmacy profession has been examined at Hilton Head in 1985 and at regional conferences throughout the U.S. between 1986 and 1988. However, clinical pharmacy education and its role in the future of the profession had not been the focus of this type of "futuristic" conference. In 1988, the clinical pharmacy faculties from the four colleges of pharmacy in New England met to discuss the "Directions for Clinical Pharmacy Education in New England." Through a series of workshops, and stimulated by challenges from keynote speakers, the participants focused on the current status of clinical pharmacy education in New England, the barriers to change, and the strategies required to accomplish these changes. Consensus on prioritization of changes and their strategies was reached, and those that could be implemented in the near future were identified. Since the conference, changes have occurred and the professional networking that began at the conference has continued. This paper is a summary of the proceedings of this conference.