Temporal integration at 6 kHz as a function of masker bandwidth

Thresholds were measured for a 6-kHz sinusoidal signal presented within a 500-ms masker. The masker was either a bandpass Gaussian noise of varying bandwidth, or a sinusoid of the same frequency as the signal. The spectrum level of the noise masker was kept constant at 20 dB SPL, and the level of the sinusoidal masker was 40 dB SPL. Thresholds for signal durations between 2 and 300 ms were measured for masker bandwidths ranging from 60 to 12,000 Hz. The masker was spectrally centered around 6 kHz. For masker bandwidths less than 600 Hz, the slope of the temporal integration function decreased with decreasing masker bandwidth. The results are not consistent with current models of temporal integration or temporal resolution. It is suggested that the results at narrow bandwidths can be understood in terms of changes in the power spectrum of the stimulus envelope or modulation spectrum. According to this view, the onset and offset ramps of the signal introduce detectable high-frequency components into the modulation spectrum, which provide a salient cue in narrowband maskers. For broadband maskers, these high-frequency components are masked by the inherent rapid fluctuations in the masker envelope. Additionally, for signal durations between 7 and 80 ms, signal thresholds decreased by up to 5 dB as the masker bandwidth increased from 1200 to 12,000 Hz. The mechanisms underlying this effect are not yet fully understood.     

Treatment algorithm use to optimize management of symptomatic patients with a history of mania

BACKGROUND: While monotherapy has significant limitations in bipolar disorder, few published data addressing alternatives exist. Treatment algorithms have been proposed, but none have undergone empirical evaluation. This study provides a systematic prospective, open evaluation of the effectiveness and tolerability of a treatment algorithm for patients with histories of mania. METHOD: Twenty-eight symptomatic outpatients from a public mental health facility who were diagnosed as having either bipolar I or schizoaffective illness, bipolar type, entered the study. Minimum blood levels of lithium and divalproex sodium were defined. Medications were pushed to predetermined levels (as tolerated) before proceeding to the next algorithm step. Clinical symptoms were assessed monthly using the Brief Psychiatric Rating Scale (BPRS, 27 item) and Clinical Global Impressions scale. RESULTS: Pretreatment and posttreatment clinical symptoms were compared. Over 50% of patients attained 30% improvement from baseline BPRS after 4 months. Thirty-six percent of patients (N = 10) became mood stable, 46% (N = 13) remained mood unstable, and 18% (N = 5) dropped out before completing the algorithm. Although patients who finished the algorithm were taking more medication, either dosage and/or drugs, somatic complaints did not increase. CONCLUSION: The potential benefit of a defined treatment algorithm was demonstrated for these complex and persistently ill patients. Despite long treatment histories, patients improved with more frequent visits and addition of medication(s). A randomized controlled trial comparing a similar treatment algorithm with treatment-as-usual is warranted.     

Potent and selective bicyclic lactam inhibitors of thrombin: Part 2: P1 modifications

The synthesis and antithrombotic activity of a series of nonpeptide bicyclic thrombin inhibitors is described. We have explored the SAR with modifications to the P1 site. The introduction of arginine mimetics at the P1 site led to potent and selective thrombin inhibitors.     

Clinical outcome of patients infected with hepatitis C virus infection on survival after primary liver transplantation under tacrolimus

In 1994, as a result of both programme evaluations which identified students' fears and apprehensions about their practical ability, and a review of the literature on skill acquisition, experiential skills teaching was resumed within the faculty. Having invested considerable finance into the reconstruction of a skills centre to teach skills, it is now imperative that its use be formally evaluated. Part of the evaluative process includes a review of the empirical literature on the acquisition of psychomotor skills in nursing. This paper summarizes this review.     

Transgenic mice secreting coronavirus neutralizing antibodies into the milk

Ten lines of transgenic mice secreting transmissible gastroenteritis coronavirus (TGEV) neutralizing recombinant monoclonal antibodies (rMAbs) into the milk were generated. The rMAb light- and heavy-chain genes were assembled by fusing the genes encoding the variable modules of the murine MAb 6A.C3, which binds an interspecies conserved coronavirus epitope essential for virus infectivity, and a constant module from a porcine myeloma with the immunoglobulin A (IgA) isotype. The chimeric antibody led to dimer formation in the presence of J chain. The neutralization specific activity of the recombinant antibody produced in transiently or stably transformed cells was 50-fold higher than that of a monomeric rMAb with the IgG1 isotype and an identical binding site. This rMAb had titers of up to 10(4) by radioimmunoassay (RIA) and neutralized virus infectivity up to 10(4)-fold. Of 23 transgenic mice, 17 integrated both light and heavy chains, and at least 10 of them transmitted both genes to the progeny, leading to 100% of animals secreting functional TGEV neutralizing antibody during lactation. Selected mice produced milk with TGEV-specific antibody titers higher than 10(6) as determined by RIA, neutralized virus infectivity by 10(6)-fold, and produced up to 6 mg of antibody per ml. Antibody expression levels were transgene copy number independent and integration site dependent. Comicroinjection of the genomic beta-lactoglobulin gene with rMAb light- and heavy-chain genes led to the generation of transgenic mice carrying the three transgenes. The highest antibody titers were produced by transgenic mice that had integrated the antibody and beta-lactoglobulin genes, although the number of transgenic animals generated does not allow a definitive conclusion on the enhancing effect of beta-lactoglobulin cointegration. This approach may lead to the generation of transgenic animals providing lactogenic immunity to their progeny against enteric pathogens.     

cDNA sequence and gene locus of the human retinal phosphoinositide-specific phospholipase-C beta 4 (PLCB4)

Defects in the Drosophila norpA (no receptor potential A) gene encoding a phosphoinositide-specific phospholipase C (PLC) block invertebrate phototransduction and lead to retinal degeneration. The mammalian homolog, PLCB4, is expressed in rat brain, bovine cerebellum, and the bovine retina in several splice variants. To determine a possible role of PLCB4 gene defects in human disease, we isolated several overlapping cDNA clones from a human retina library. The composite cDNA sequence predicts a human PLC beta 4 polypeptide of 1022 amino acid residues (MW 117,000). This PLC beta 4 variant lacks a 165-amino-acid N-terminal domain characteristic for the rat brain isoforms, but has a distinct putative exon 1 unique for human and bovine retina isoforms. A PLC beta 4 monospecific antibody detected a major (130 kDa) and a minor (160 kDa) isoform in retina homogenates. Somatic cell hybrids and deletion panels were used to localize the PCLB4 gene to the short arm of chromosome 20. The gene was further sublocalized to 20p12 by fluorescence in situ hybridization.     

Expression of type 2 11beta-hydroxysteroid dehydrogenase and corticosteroid hormone receptors in early human fetal life

In adult life, the type 2 isozyme of 11beta-hydroxysteroid dehydrogenase (11betaHSD2) protects the mineralocorticoid receptor (MR) from glucocorticoid by inactivating cortisol to cortisone. 11betaHSD2 activity has been reported in human fetal tissues, where glucocorticoids may impair fetal growth yet are also required for normal fetal development. Using digoxigenin-labeled complementary ribonucleic acid (RNA) probes and an in-house 11betaHSD2 antiserum, we have analyzed the expression of 11betaHSD2, MR, and glucocorticoid receptor (GR) in human fetal tissues of gestational age 6-17 weeks (n=15). 11BetaHSD2 expression was absent at gestational age 6+ weeks, but was expressed in abundance in many fetal tissues between 8-12 weeks. At this time, 11betaHSD2 colocalized with GR messenger RNA (mRNA) expression in metanephros, gut, muscle, spinal cord and dorsal root ganglia, periderm, sex chords of testis, and adrenal. In particular within fetal kidney, intense expression of 11betaHSD2 and GR mRNA was observed over Bowman's capsule and the vascular tufts of developing glomeruli as they migrated from the surface of the kidney to the inner cortex. Only lung and adrenal medullary rests demonstrated high levels of GR mRNA but low levels of 11betaHSD2. 11BetaHSD2 mRNA and immunoreactivity staining patterns were similar, with the exception of the fetal adrenal, where mRNA was localized to the outer definitive zone but immunoreactivity was localized to the inner fetal zone. Colocalization of 11betaHSD2 (and GR mRNA) with MR mRNA was observed principally within epithelial cells of collecting ducts, particularly after 16 weeks gestation when the pattern of distribution of 11betaHSD2 became more adult in nature. High levels of MR mRNA were observed within developing bone. The data indicate that 11betaHSD2 in fetal life principally modulates ligand access to the GR in most fetal tissues, notably glomeruli and tubules in the developing kidney, testis, and periderm, and this may be have ramifications for fetal sodium homeostasis and differentiation. The development of tissues previously shown to have a critical requirement for glucocorticoids, such as lung and adrenal medulla, is facilitated by the expression of GR mRNA, but not 11betaHSD2. The expression of MR mRNA in high abundance in bone suggests a role for corticosteroids in human bone development, and the low/absent expression of 11betaHSD2 at this site suggests that it is functionally acting as a GR.