OSETI with STACEE: a search for nanosecond optical transients from nearby stars.

We have used the Solar Tower Atmospheric Cherenkov Effect Experiment (STACEE) high-energy gamma-ray detector to look for fast blue-green laser pulses from the vicinity of 187 stars. The STACEE detector offers unprecedented light-collecting capability for the detection of nanosecond pulses from such lasers. We estimate STACEE's sensitivity to be approximately 10 photons/m(2) at a wavelength of 420 nm. The stars have been chosen because their characteristics are such that they may harbor habitable planets, and they are relatively close to Earth. Each star was observed for 10 minutes, and we found no evidence for laser pulses in any of the data sets. Key Words: Search for extraterrestrial intelligence-Optical search for extraterrestrial intelligence-Interstellar communication-Laser.

Development of vascular endothelial growth factor receptor (VEGFR) kinase inhibitors as anti-angiogenic agents in cancer therapy.

Among the known angiogenic growth factors and cytokines implicated in the modulation of normal and pathological angiogenesis, the VEGF family (VEGF-A, VEGF-B, VEGF-C, VEGF-D) and their corresponding receptor tyrosine kinases [VEGFR-1 (Flt-1), VEGFR-2 (Flk-1, KDR), and VEGFR-3 (Flt-4)] play a paramount and indispensable role in regulating the multiple facets of the angiogenic and lymphangiogenic processes, as well as the induction of vascular permeability and inflammation. The receptor VEGFR-2/KDR is the principal one through which VEGFs exert their mitogenic, chemotactic, and vascular permeabilizing effects on the host vasculature. Increased expression of VEGFs by tumor cells and VEGFR-2/KDR and VEGFR-1/Flt-1 by the tumor-associated vasculature are a hallmark of a variety of human and rodent tumors in vivo and correlates with tumor growth rate, micro-vessel density/proliferation, tumor metastatic potential, and poorer patient prognosis in a variety of malignancies. Approaches to disrupting the VEGF/VEGFR signaling cascade range from biological agents (soluble receptors, anti-VEGF and anti-VEGFR-2 antibodies, and VEGF transcription inhibitors) to small molecule ATP competitive VEGFR inhibitors. Examples from this latter class that are currently in clinical development include compounds from distinct chemical classes such as: indolin-2-ones, anilinoquinazolines, anilinophthalazines, isothiazoles, indolo- and indenocarbazoles. The structure activity relationships, biochemical and pharmacological profile of optimized representatives from each of these classes constitute the subject matter of this review.

Recruiting and selecting generalist-oriented students at Pennsylvania State University College of Medicine.

The authors describe the strategies developed at the Pennsylvania State University College of Medicine, as part of The Robert Wood Johnson Foundation's Generalist Physician Initiative, to increase the proportion of graduating medical students entering generalist disciplines. These strategies included modifying the admission process to involve more primary care faculty so that students with identified potential for primary care would make up at least half of each entering class, and partnering with selected colleges and universities in Pennsylvania to increase the number of applicants with the potential for primary care. They describe partnering and outreach programs--Primary Care Day, off-campus cluster meetings, and the Primary Care Scholars Program for college seniors--and present promising information about the results.

Histopathologic and flow-cytometric analysis of neoplastic and benign "background" tissue in breast carcinoma resections.

Two-color, multiparametric synthesis phase fraction (SPF) analysis of cytokeratin-labeled epithelial cells was flow cytometrically performed on both benign (SPFb) and malignant tissue samples (if available, SPFt) from 132 mastectomy/lumpectomy specimens. These data were then correlated with clinicopathologic features, including (1) tumor differentiation, (2) the proportion of tumor comprised of duct carcinoma-in situ (DCIS), and (3) the histology of accompanying benign breast tissue, classified by predominant microscopic pattern as intact, normal terminal duct lobular units (NTDLU, 34% of cases), atrophic (AT, 33% of cases), proliferative fibrocystic (PFC, 26% of cases), and non-proliferative fibrocystic (NPFC, 7% of cases). SPFt was inversely correlated with extent of DCIS (DCIS = 0-20% tumor volume - 12.7% mean SPFt, vs. DCIS >20% tumor volume - 6.4% mean SPFt, p = 0.001). SPFt also correlated with the histology of background benign breast tissue (NTDLU - 14.8% mean SPFt vs. AT - 6.9% mean SPFt vs. PFC - 12.7% mean SPFt, p = 0.05) but it did not correlate with patient age or SPFb (overall mean = 0.73%). SPFb was correlated with patient age (>56 yr - 0.59% mean SPFb vs. <56 yr - 0.84% mean SPFb, p = 0.02), with background histology (NTDLU - 1.1% mean SPFb vs. AT - 0.43% mean SPFb vs. PFC - 0.70% mean SPFb, p < 0.02) and with the grade of the neoplasm (well/moderate - 0.58% mean vs. poorly differentiated - 0.85% mean, p = 0.04). Patients having a background of PFC were significantly older than patients with a background of NTDLU (45.2 yr vs. 60.2 yr, p = 0.01). We conclude: (1) breast carcinomas arising from a background of more actively cycling pre-involutional or proliferative fibrocystic epithelium have a greater proliferative fraction than tumors arising from atrophic epithelium, implying that the differentiation status of target cells may impact the effect(s) of tumorigenic events; (2) PFC may represent delayed, abnormal or interrupted involution rather than a hyperproliferative state relative to NTDLU, suggesting that it facilitates neoplasia by extending the period of exposure to promoter agents such as endogenous hormones, and (3) lower SPFt in breast neoplasia with more abundant "residual" DCIS may reflect a lengthier pre-invasive disease interval due to intrinsically less aggressive phenotype.

Excess coffee consumption in simulated complex work settings: detriment or facilitation of performance?

Twenty-four managers who normally consume between 400 and 1,000 mg of caffeine per day participated in all-day quasi-experimental simulations. In a crossover, doubleblind design, they made complex managerial decisions either on treatment with their typical daily dose of caffeine or on treatment with 400 mg of caffeine in excess of daily consumption. The effect of caffeine treatment on various validated performance indicators was investigated. The impact of excess caffeine consumption was mild. Increased caffeine facilitated speed of response to incoming information but decreased utilization of opportunity. No significance was obtained for other measures of managerial effectiveness (such as activity, breadth, strategy, and emergency response).

Cell cycle analysis of normal, atrophic, and hyperplastic breast epithelium using two-color multiparametric flow cytometry.

We performed two-color flow cytometric synthesis phase fraction (SPF) determinations on cytokeratin-labeled benign epithelial populations from 142 breast specimens (41 mastectomy, 70 diagnostic biopsy, 31 reduction mammoplasty). There was wide variability of SPF, ranging from 0.1 to 3.5%, with a frequency distribution skewed to higher values (mean 0.75%, median 0.5%). The mean SPE for women less than 29 years was 0.91%, vs. 0.89% for 30-42 years, 0.66% for 43-49 years, and 0.56% for > or = 50 years (P = 0.05). Histologically atrophic tissue samples exhibited a mean SPF approximately half that of morphologically normal tissue from premenopausal age women (0.79% vs. 0.36%, P = 0.02). Tissues showing histologically proliferative fibrocystic features had a greater mean SPF than non-proliferative fibrocystic tissues (0.59% vs. 0.92%); however, due to the wide spread of values within each of these categories, this difference was not statistically significant and neither group was significantly different from 'normal' tissue samples. Patients with histologically normal breast tissue, though, were significantly younger (mean = 34.6 years) than those with fibrocystic changes (non-proliferative mean = 53.4 years vs. proliferative mean = 42.8 years, P = 0.005). Synchronous right- and left-sided specimens obtained from reduction mammoplasty demonstrated significantly correlated SPF determinations (R = 0.77). We conclude that selective analysis of epithelial populations using two-color flow cytometry provides cell cycle information in benign breast tissue which is analogous to that obtained by labor-intensive nucleotide labeling studies. This study also confirms the biologic variability and age-dependence of breast epithelial proliferation. Finally, the data imply that derangements of cell proliferation in fibrocystic conditions are heterogeneous, complex and incompletely correlated with histologic parameters such as hyperplasia.

Alcohol hangover and managerial effectiveness.

Twenty-one male managers who normally drink moderate amounts of alcohol participated in a placebo-controlled, double-blind, cross-over experiment. Subjects consumed either placebo or alcoholic drinks to attain a breath alcohol level of 0.10 during the evening before participation in Strategic Management Simulations. By the time of arrival at the simultaion laboratory on the following morning, breath alcohol levels were measured at 0.00. Questionnaire responses indicated considerable hangover discomfort. Responses to semantic differential evaluative scales suggested that research participants evaluated their own managerial performance in the simulation setting as impaired. However, multiple (validated) measures of decision-making performance obtained in the simulation task did not show any deterioration of functioning. Previous research had shown considerable performance decrements in the same task setting, while blood/breath alcohol levels ranged from 0.05 through 0.10%. Apparently, complex decision-making competence by persons who normally consume moderate amounts of alcohol may not be impaired by hangover caused by intoxication during the previous evening that remains at or below a blood alcohol level of 0.10.

Effects of caffeine deprivation on complex human functioning.

Twenty-five managers who reported an average daily caffeine consumption of 575 mg participated in two complex simulations. A double-blind cross-over design was employed to assess the effects of normal caffeine consumption versus caffeine deprivation upon seven validated measures of managerial effectiveness. Data from a Caffeine Withdrawal Questionnaire indicated discomfort upon deprivation. Systolic blood pressure increased during "normal" caffeine consumption levels but fell quickly and remained lower during deprivation. Several measures of managerial performance indicated decreased effectiveness upon caffeine deprivation. In contrast to prior research from simpler task settings, cognitive effectiveness (during complex task performance) was diminished. However, a measure of strategic performance which requires a relatively high level of cognitive effort showed no impact of caffeine deprivation.

Alcohol and managerial performance.

Effects of alcohol intoxication at .05 and .10 breath alcohol concentration upon a number of validated indicators of managerial performance were investigated in a double-blind crossover placebo-controlled simulation design. Managers (N = 48) spent 2 days handling quasi-experimental (partially event-controlled) tasks that permitted realistic managerial decision making under both "normal" and "emergency" conditions. The data showed that speed and frequency of managerial action were affected by alcohol at the .10 but not the .05 level. Strategy and planning deteriorated at both levels. Limited improvement of performance was observed for one simpler component of managerial functioning at the lower intoxication level, possibly due to myopia and/or a motivated "strain" toward better performance induced by the perception of impairment.

Effects of alcohol intoxication on risk taking, strategy, and error rate in visuomotor performance.

Adult men (N = 44) participated for 2 days (alcohol vs. placebo treatment) in a double-blind, crossover experiment. Performance on the Digit Symbol Substitution Task (DSST) and a visuomotor (VM) task was measured 4 times each day. On the alcohol-treatment day, data were obtained once during ascending breath alcohol levels (BALs), once during maximal BALs (0.05 or 0.10), and twice during descending BALs. Data were collected at the same time points on the placebo-treatment day. Limited evidence for acute tolerance was obtained with the DSST, but error rates on the VM task were higher during maximal and descending BALs. Error rates remained near placebo values, and participants displayed slightly greater caution, while BALs were ascending. Strategy scores on the VM task exceeded placebo scores during maximal intoxication. Data interpretation is focused on individuals in higher level (e.g., professional) positions.

Linkage between cooperative oxygenation and subunit assembly of cobaltous human hemoglobin.

The thermodynamic linkage between cooperative oxygenation and dimer-tetramer subunit assembly has been determined for cobaltous human hemoglobin in which iron(II) protoporphyrin IX is replaced by cobalt(II) protoporphyrin IX. The equilibrium parameters of the linkage system were determined by global nonlinear least-squares regression of oxygenation isotherms measured over a range of hemoglobin concentrations together with the deoxygenated dimer-tetramer assembly free energy determined independently from forward and reverse reaction rates. The total cooperative free energy of tetrameric cobalt hemoglobin (over all four binding steps) is found to be 1.84 (+/- 0.13) kcal, compared with the native ferrous hemoglobin value of 6.30 (+/- 0.14) kcal. Detailed investigation of stepwise cooperativity effects shows the following: (1) The largest change occurs at the first ligation step and is determined on model-independent grounds by knowledge of the intermediate subunit assembly free energies. (2) Cooperativity in the shape of the tetrameric isotherm occurs mainly during the middle two steps and is concomitant with the release of quaternary constraints. (3) Although evaluation of the pure tetrameric isotherm portrays identical binding affinity between the last two steps, this apparent noncooperativity is the result of a "hidden" oxygen affinity enhancement at the last step of 0.48 (+/- 0.12) kcal. This quaternary enhancement energy is revealed by the difference in subunit assembly free energies of the triply and fully ligated species and is manifested visually by the oxygenation isotherms at high versus low hemoglobin concentration. (4) Cobaltous hemoglobin dimers exhibit apparent anticooperativity of 0.49 (+/- 0.16) kcal (presumed to arise from heterogeneity of subunit affinities).(ABSTRACT TRUNCATED AT 250 WORDS)

Managing prostatitis in the elderly.

Bacterial prostatitis is primarily a disease of elderly men, and it is the most common urinary tract infection seen in this age group. Urosepsis from prostatitis or prostatic abscess occurs less frequently than with urological manipulation, but must always be considered in elderly men with prostatitis. This article focuses on the diagnosis and antibiotic treatment of bacterial prostatitis in the elderly.

Pneumonia syndromes: a clinical approach in the elderly.

Important in the pathogenesis of pneumonia in the elderly patient are chronic diseases, including diabetes mellitus, coronary artery disease, congestive heart failure, chronic obstructive pulmonary disease, and cerebrovascular disease. Also vital are the changes that take place in the immune system and mucociliary clearance mechanisms of the lung. The clinician should be aware of these risk factors, especially since the mortality rate of lower respiratory infections approaches 40% in these elderly patients. Treatment guidelines are included.

Infections in the hospitalized elderly.

Nosocomial infections are a particular problem among the elderly. Their cost is high mortality and a bill of $4 billion annually. The routine observation of a few simple aseptic practices will significantly blunt the impact of this health-care concern in our hospitals and nursing homes.

Three-state combinatorial switching in hemoglobin tetramers: comparison between functional energetics and molecular structures.

In a previous study on cyanomethemoglobin the 10 tetrameric species (each with a unique combination of ligated and unligated subunits) were found to exhibit three distinct free energies of cooperative interaction. The distribution of these free energies among the partially ligated species is incompatible with a two-state mechanism of molecular switching and requires a minimum of three molecular structures with distinctly different free energies of heme-heme interaction. Ligand-linked transitions between the three cooperativity states were found to be "combinatorial"--i.e., dependent upon changes in both the number and specific configuration of bound ligands. Here we present results from two other chemical systems that mimic intermediate oxygenation states. In these systems the heme iron is replaced by manganese in certain of the subunits. We find the same distribution of cooperative free energies as reported for the cyanomethemoglobin system. These results demonstrate that the three-state combinatorial nature of cooperative switching is neither a special feature of the cyanomet reactions nor of the substitution of manganese for iron, but reflects a fundamental property of hemoglobin. These findings are compared with crystallographic structural results on partially ligated hemoglobins.

Characterization of a highly negative and labile binding protein induced in Euglena gracilis by cadmium.

The physiochemical properties and physiological significance of the cadmium-binding protein (CdBP) of the algae Euglena gracilis have been studied. Following in vivo exposure of cells to 0.4 or 1.3 micrograms/mL of Cd2+, all the cytosolic Cd is bound to high molecular weight species. At 4.7 micrograms/mL, appreciable CdBP has formed in cells grown under illumination or in the dark. An analogous ZnBP could not be isolated from control or Zn-exposed (20 micrograms/mL) cells, but zinc and a trace of copper were bound to the CdBP when 2-mercaptoethanol (2-ME) is added to the homogenates of Cd-treated cells and the buffers used during isolation. The large pool of very low molecular weight zinc species previously reported is increased when cells are exposed to high cadmium levels. Two distinct species, BP-1 and BP-2 are resolved by ion-exchange chromatography on DEAE-Sephadex. Unusually high conductivities (25 and 40 mSiemen) are required to displace them, indicating that they are very negatively charged proteins at pH 8.6. The pH for half-titration of bound Cd2+ is between 5 and 6. EDTA (0.4 M) and the CdBP isolated by gel-exclusion chromatography react biphasically with pseudo-first-order rate constants of 4 +/- 3 X 10(-4) sec-1 and 7 +/- 2 X 10(-5) sec-1. Neither form of the CdBP cross-reacts with antibodies to rat liver metallothionein (MT) antibodies. The structural, chemical, and functional differences between the Euglena CdBPs and mammalian MTs are discussed.(ABSTRACT TRUNCATED AT 250 WORDS)

Accumulation of cadmium by the fourth instar larva of the fly Chironomus thummi.

Accumulation and effects of cadmium were investigated in Chironomus thummi larvae exposed to 10, 100 and 250 mug radiolabeled Cd/1 for up to 4 days. (1) After 4 days, average cadmium accumulation was 6.6 ng Cd/mg dry weight (10 mug Cd/1 exposure) and 177 ng Cd/mg dry weight (250 mug Cd/1 exposure). (2) Dissection studies showed that by 32 hr of exposure to both cadmium concentrations, 63.5-81.4% of accumulated cadmium was confined to the posterior midgut epithelium. Light microscope autoradiography similarly showed accumulations of cadmium in posterior midgut epithelium and smaller amounts in fat body and muscle. Little cadmium was associated with Malphigian tubules, haemocoel, anterior midgut or exoskeleton. (3) After exposure to 10 or 250 mug Cd/1, 60-75% of cadmium in ultracentrifuged homogenates of whole animals or dissected guts was associated with the resulting supernatant. When supernatants were further analyzed by gel chromatography, cadmium eluted with both a high and low molecular weight peak. The relative proportions of cadmium in the two peaks varied with concentration and length of exposure. (4) Transmission electron microscopy of posterior midgut cells from animals exposed to cadmium demonstrated frequent mitochondrial lesions. Exposure to high cadmium concentrations caused some posterior midgut cells to undergo generalized structural degeneration.

The binding of Gold(I) to metallothionein.

The binding of gold(I) to metallothionein, MT, has been unambiguously established by the reaction of Na2AuTM with purified horse kidney MT. Zinc was displaced more readily than cadmium although the latter could be displaced using large Au/Cd ratios. The metal exchange reactions were complete within 2 hr of mixing. Further evidence that such reactions might be physiologically significant were obtained by studying in vitro metal displacements in the liver cytol of in vivo metal treated rats: When Na2AuTM was added to the cytosol of rats administered CdCl2 in vivo, zinc, copper and cadmium were displaced in 2/1/1 ratios from the metallothionein fraction. The zinc and cadmium displacement provide direct evidence that the gold was binding to MT. Addition of Cd+2 to liver cytosol of gold-treated rats resulted in displacement of copper and zinc, but not gold, from the MT fractions. When liver MT is prepared from rats exposed to Au or Cd, the Cd/protein ratio increased during the preparation, but the Au/protein ratio decreased. The Mt-bound metals account for 95% of the cytosolic Cd but only 15%-30% of the cytosolic gold in these studies. Thus, the nonspecific binding of gold to MT in vivo should be considered as one aspect in its equilibration among protein binding sites, which include, inter alia, metallothionein. Gold was found to coelute with zinc and cadmium in the MT fraction of rat kidney cytosol, when both Cd and Na2AuTM were administered to the rats. The possible significance of gold binding to MT in the treatment of rheumatoid arthritis--chrysotherapy--is briefly discussed.