Self-association of facially amphiphilic methylene bridged glycoluril dimers.

[structure: see text] Facially amphiphilic derivatives of methylene bridged glycoluril dimers are a versatile model system for systematic studies of self-assembly in water. Thorough physical organic characterization, including analytical ultracentrifugation, a technique rarely used in synthetic self-assembly studies, allows us to conclude that this class of molecules undergoes hydrophobically driven self-association to yield tightly associated discrete dimeric assemblies.

A structurally biased combinatorial approach for discovering new anti-picornaviral compounds.

BACKGROUND: Picornaviruses comprise a family of small, non-enveloped RNA viruses. A common feature amongst many picornaviruses is a hydrophobic pocket in the core of VP1, one of the viral capsid proteins. The pocket is normally occupied by a mixture of unidentified, fatty acid-like moieties, which can be competed out by a family of capsid-binding, antiviral compounds. Many members of the Picornaviridae family are pathogenic to both humans and livestock, yet no adequate therapeutics exist despite over a decade's worth of research in the field. To address this challenge, we developed a strategy for rapid identification of capsid-binding anti-picornaviral ligands. The approach we took involved synthesizing structurally biased combinatorial libraries that had been targeted to the VP1 pocket of poliovirus and rhinovirus. The libraries are screened for candidate ligands with a high throughput mass spectrometry assay. RESULTS: Using the mass spectrometry assay, we were able to identify eight compounds from a targeted library of 75 compounds. The antiviral activity of these candidates was assessed by (i) measuring the effect on the kinetics of viral uncoating and (ii) the protective effect of each drug in traditional cell-based assays. All eight of the candidates exhibited antiviral activity, but three of them were particularly effective against poliovirus and rhinovirus. CONCLUSIONS: The results illustrate the utility of combining structure-based design with combinatorial chemistry. The success of our approach suggests that assessment of small, targeted libraries, which query specific chemical properties, may be the best strategy for surveying all of chemical space for ideal anti-picornaviral compounds.

Diastereoselective Formation of Methylene-Bridged Glycoluril Dimers.

The acid-catalyzed formation of methylene-bridged glycoluril dimers yields the C(2)(v)()-diastereomer selectively. Product resubmission experiments establish that the selectivity is the result of thermodynamic control. A modified synthetic route is presented that allows for the preparation of unsymmetrically substituted dimers. We present the X-ray crystal structures of both diastereomers. This class of compounds is useful for studies of self-assembly in aqueous solution.

Evaluation of pancreatic proteolytic enzyme treatment of adenocarcinoma of the pancreas, with nutrition and detoxification support.

Historically, large doses of proteolytic enzymes, along with diet, nutritional supplements, and "detoxification" procedures, have been used in alternative therapies to treat all forms of cancer, without formal clinical studies to support their use. A 2-year, unblinded, 1-treatment arm, 10-patient, pilot prospective case study was used to assess survival in patients suffering inoperable stage II-IV pancreatic adenocarcinoma treated with large doses of orally ingested pancreatic enzymes, nutritional supplements, "detoxification" procedures, and an organic diet. From January 1993 to April 1996 in the authors' private practice, 10 patients with inoperable, biopsy-proven pancreatic adenocarcinoma were entered into the trial. After one patient dropped out, an 11th patient was added to the study (however, all 11 are considered in the data tabulation). Patients followed the treatment at home, under the supervision of the authors. As of 12 January 1999, of 11 patients entered into the study, 9 (81%) survived one year, 5 (45%) survived two years, and at this time, 4 have survived three years. Two patients are alive and doing well: one at three years and the other at four years. These results are far above the 25% survival at one year and 10% survival at two years for all stages of pancreatic adenocarcinoma reported in the National Cancer Data Base from 1995. This pilot study suggests that an aggressive nutritional therapy with large doses of pancreatic enzymes led to significantly increased survival over what would normally be expected for patients with inoperable pancreatic adenocarcinoma.

A strategy for the generation of surfaces presenting ligands for studies of binding based on an active ester as a common reactive intermediate: a surface plasmon resonance study.

This paper describes the immobilization of ten proteins and two low-molecular-weight ligands on mixed self-assembled monolayers (SAMs) of alkanethiolates on gold generated from the tri(ethylene glycol)-terminated thiol 1 (HS(CH2)11(OCH2CH2)3OH) (chi(1) = 1.0-0.0) and the longer, carboxylic acid-terminated thiol2(HS(CH2)11(OCH2-CH2)6OCH2CO2H) (chi(2) = 0.0-1.0). The immobilization was achieved by a two-step procedure: generation of reactive N-hydroxysuccinimidyl esters from the carboxylic acid groups of 2 in the SAM and coupling of these groups with amines on the protein or ligand. Because this method involves a common reactive intermediate that is easily prepared, it provides a convenient method for attaching ligands to SAMs for studies using surface plasmon resonance spectroscopy (and, in principle, other bioanalytical methods that use derivatized SAMs on gold, silver, and other surfaces). These SAMs were resistant to nonspecific adsorption of proteins having a wide range of molecular weights and isoelectric points. The pH of the coupling buffer, the concentration of protein, the ionic strength of the solution of protein, and the molecular weight of the protein all influenced the amount of the protein that was immobilized. For the proteins investigated in detail--carbonic anhydrase and lysozyme--the highest quantities of immobilized proteins were obtained when using a low ionic strength solution at a value of pH approximately one unit below the isoelectric point (pI) of the protein, at a concentration of approximately 0.5 mg mL-1. Comparisons of the kinetic and thermodynamic constants describing binding of carbonic anhydrase and vancomycin to immobilized benzenesulfonamide and N-alpha-Ac-Lys-D-Ala-D-Ala groups, respectively, on mixed SAMs (by methods described in this paper) and in the carboxymethyl dextran matrix of commercially available substrates yielded (for these systems) essentially indistinguishable values of Kd, koff, and kon.

Comparison of the vertec and Just Jump Systems for measuring height of vertical jump by young children.

To assess differences between the Vertec and the Just Jump Systems in measuring height of vertical jump, 248 boys and 232 girls between 7 and 11 years were required to perform four maximal countermovement vertical jumps. A maximum of the four trials recorded was the dependent variable. Each vertical jump was simultaneously evaluated by each measuring device and a paired t test indicated the systems were significantly different; however, the experiment wise difference of .93 in has no practical value. The Just Jump System seems a viable alternative. Advantages and potential pitfalls regarding the use of each system are discussed.

A trivalent system from vancomycin.D-ala-D-Ala with higher affinity than avidin.biotin.

Tris(vancomycin carboxamide) binds a trivalent ligand derived from D-Ala-D-Ala with very high affinity: dissociation constant (Kd) approximately 4 x 10(-17) +/- 1 x 10(-17) M. High-affinity trivalent binding and monovalent binding are fundamentally different. In trivalent (and more generally, polyvalent) binding, dissociation occurs in stages, and its rate can be accelerated by monovalent ligand at sufficiently high concentrations. In monovalent binding, dissociation is determined solely by the rate constant for dissociation and cannot be accelerated by added monomer. Calorimetric measurements for the trivalent system indicate an approximately additive gain in enthalpy relative to the corresponding monomers. This system is one of the most stable organic receptor-ligand pairs involving small molecules that is known. It illustrates the practicality of designing very high-affinity systems based on polyvalency.

[The effect of teaching critical thinking skills in an introductory nursing course]. / El efecto de enseñar las destrezas del pensamiento crítico en un curso introductorio de enfermería.

This almost-experimental study utilized an education model to develop critical thought in a group of first year nursing students having as an objective to determine skills acquisition. Twelve weeks after its implementation the results showed the treatment statistical significance. Therefore, the instruction method utilized to promote critical thought skills produced the intended result in introductory nursing courses.

Preparative purification of phosphorylated and nonphosphorylated bovine prolactins.

Extracts from 12 pituitaries were applied to preparative immunoaffinity chromatography columns containing between 500 mg and 800 mg of clonal antiprolactin IgG1. Extracts were cycled through the column and subsequently washed from the affinity matrix. Total prolactin was eluted from the affinity matrix by a 0.1 M glycine, pH 2.8. The total prolactin was neutralized and dialyzed into 20 mM Bis-Tris (pH 7.0) and applied to a weak anion exchange column. Nonphosphorylated prolactin was eluted with 0.5 M NaCl in Bis-Tris buffer. Phosphorylated prolactin was eluted with 20% acetic acid. Yields averaged 19.6 mg and 11.7 mg for native and phosphorylated prolactin (n = 14 runs), respectively. The molecular weights of the prolactins were similar to prolactin standards. The amino acid compositions of the two prolactin variants were similar. Phosphate was associated predominantly with the phosphorylated prolactin. Native prolactin was biologically active in the Nb2 rat lymphoma bioassay, while the phosphorylated prolactin was without activity in this bioassay.

Fatal mediastinal abscess from upper respiratory infection.

Suppurative mediastinitis following neck infection is an uncommon entity that carries a 40% mortality. It is most commonly associated with esophageal perforation or odontogenic abscess. The rapidity of spread has been attributed to dependent drainage from the neck into the mediastinum, negative intrathoracic pressure, and synergistic necrotizing bacterial growth. Cultures obtained usually grow streptococci and/or Bacteroides. We report the case of a 34-year-old woman with an upper respiratory infection who subsequently was found to have a para-/retropharyngeal and mediastinal abscess. Septic shock, respiratory failure, and death ensued, despite aggressive treatment with broad-spectrum antibiotics (for both aerobes and anaerobes), surgical drainage of the neck and mediastinum, and cardiorespiratory support. The danger of a rapid downhill clinical course with mortality due to suppurative mediastinitis makes early diagnosis of critical importance. All clinicians evaluating a "sore throat" should consider neck edema or gas on neck radiograms as evidence of cervical abscess, and subsequent widening of the mediastinum on chest x-ray as an ominous sign suggesting mediastinal abscess.

The development of children's prejudice against the aged.

Children's prejudice against the aged was studied in terms of their responses to an attitude scale and measures of their social interaction with aged compared to nonaged confederates. Participants were 144 middle-class children, four, six, and eight years of age. Findings from the attitude scale indicated significant levels of ageist prejudice among six- and eight-year-olds but not in four-year-olds. Eight-year-olds had significantly higher prejudice scores than six-year-olds. There were six measures of participant interaction with aged compared to nonaged confederates: proxemic distance, productivity, eye-contact initiation, number of words spoken, number of conversation initiations, and number of verbal appeals. On all of these measures except productivity, participants in each age group showed significant levels of ageist prejudice. Ancillary findings indicated that, in general, participants were more prejudiced against women than against men. Attitude scores correlated significantly with some of the behavioral measures but not with all of them.

Linguistic processing and performance in articulation-disordered subgroups of language-impaired children.

The linguistic and dichotic listening performances of three groups of nine children were studied. The groups were divided as follows: (1) Language-disordered children whose articulatory errors were primarily omissions; (2) language-disordered children whose articulatory errors were primarily substitutions; (3) communicatively normal children. All subjects participated in articulation testing, imitative language tests, analysis of a spontaneous language sample, and a dichotic word task. The articulatory omission group differed significantly from the substitution group on the imitative language test but not on the developmental sentence analysis. All groups demonstrated a right ear advantage, suggesting left hemispheric processing of the dichotic stimuli. The results of the present study and prior research are discussed in terms of possible sources of variability.

Comparative nephrotoxicities of dibekacin, amikacin, and gentamicin in a rat model.

The nephrotoxicity of dibekacin was compared with those of gentamicin and amikacin in a rat model. The doses used were 3, 10, and 30 times the suggested human therapeutic dose on a weight basis. Indices of glomerular and tubular function failed to clearly differentiate the drugs. Dibekacin and gentamicin produced equally severe injury to the renal tissue. Slightly less damage occurred with amikacin.

Effects of ball size, ball color, and preferred color on catching by young children.

45 males and 45 females between 7 and 8 years of age were acquired to catch rubber playground balls which varied in both size and color. Prior to the administration of the criterion catch test, subjects indicated their choice for a preferred color ball. Analysis indicated that the 6-in. balls (diameter) were caught significantly better than were 10-in. balls. Although the main effect of ball color was nonsignificant, the children caught balls of preferred color significantly better than those of non-preferred colors. Males scored significantly higher than the females on the catching task.

Comparative nephrotoxicity of SCH 21420 and amikacin in rats.

The nephrotoxic potentials of the new aminoglycoside SCH 21420 and amikacin were compared in a rat model. Groups of rats received 100, 200, 300, or 600 mg of either drug per kg per day for 14 days. Enzymuria, urine osmolality, protein excretion, and blood urea nitrogen were monitored at periodic intervals, whereas creatinine clearance and pathological changes were determined at sacrifice. Amikacin caused more enzymuria at the two lower doses as well as greater proteinuria and blood urea nitrogen elevations at the highest dose than did SCH 21420 (P less than 0.05). Pathological changes were more severe with amikacin than with SCH 21420 at the three lower doses (P less than 0.05); however, at the 600 mg/kg per day dose, the pathological scores and creatinine clearances of animals receiving either drug were not significantly different (P greater than 0.05).