Uptake of Precursor and Synthesis of Transmitter in a Histaminergic Photoreceptor

As a first step in understanding how the supply of the neurotransmitter histamine is maintained in a photoreceptor, we followed the uptake and metabolism of the immediate precursor of histamine, histidine.

Using serum CA125 to assess the activity of potential cytostatic agents in ovarian cancer

Objective: New strategies are required to rapidly identify novel cytostatic agents before embarking on large randomized trials. This study investigates whether a change in rate of rise (slope) of serum CA125 from before to after starting a novel agent could be used to identify cytostatic agents. Tamoxifen was used to validate this hypothesis. Methods: Asymptomatic patients with relapsed ovarian cancer who had responded to chemotherapy were enrolled and had CA125 measurements taken every 4 weeks, then more frequently when rising. Once levels reached 4 times the upper limit of normal or nadir, they started continuous tamoxifen 20 mg daily, as well as fortnightly CA125 measurements until symptomatic progression. Because of the potentially nonlinear relationship of CA125 over time, it was felt that to enable normal approximations to be utilized a natural logarithmic standard transformation [ln(CA125)] was the most suitable to improve linearity above the common logarithmic transformation to base 10. Results: From 235 recruited patients, 81 started tamoxifen and had at least 4 CA125 measurements taken before and 4 CA125 measurements taken after starting tamoxifen, respectively. The mean regression slopes from using at least 4 1n(CA125) measurements immediately before and after starting tamoxifen were 0I0149 and 0I0093 [ln(CA125)/d], respectively. This difference is statistically significant, P = 0I001. Therefore, in a future trial with a novel agent, at least as effective as tamoxifen, using this effect size, the number of evaluable patients needed, at significance level of 5% and power of 80%, is 56. Conclusions: Further validation of this methodology is required, but there is potential to use comparison of mean regression slopes of ln(CA125) as an interim analysis measure of efficacy for novel cytostatic agents in relapsed ovarian cancer.Peer reviewedFinal Accepted Versio

Cues and knowledge structures used by mental-health professionals when making risk assessments

Background: Research into mental-health risks has tended to focus on epidemiological approaches and to consider pieces of evidence in isolation. Less is known about the particular factors and their patterns of occurrence that influence clinicians’ risk judgements in practice. Aims: To identify the cues used by clinicians to make risk judgements and to explore how these combine within clinicians’ psychological representations of suicide, self-harm, self-neglect, and harm to others. Method: Content analysis was applied to semi-structured interviews conducted with 46 practitioners from various mental-health disciplines, using mind maps to represent the hierarchical relationships of data and concepts. Results: Strong consensus between experts meant their knowledge could be integrated into a single hierarchical structure for each risk. This revealed contrasting emphases between data and concepts underpinning risks, including: reflection and forethought for suicide; motivation for self-harm; situation and context for harm to others; and current presentation for self-neglect. Conclusions: Analysis of experts’ risk-assessment knowledge identified influential cues and their relationships to risks. It can inform development of valid risk-screening decision support systems that combine actuarial evidence with clinical expertise

Analysis of Fcγ receptor haplotypes in rheumatoid arthritis: FCGR3A remains a major susceptibility gene at this locus, with an additional contribution from FCGR3B

The Fcγ receptors play important roles in the initiation and regulation of many immunological and inflammatory processes, and genetic variants (FCGR) have been associated with numerous autoimmune and infectious diseases. The data in rheumatoid arthritis (RA) are conflicting and we previously demonstrated an association between FCGR3A and RA. In view of the close molecular proximity with FCGR2A, FCGR2B and FCGR3B, additional polymorphisms within these genes and FCGR haplotypes were examined to refine the extent of association with RA. Biallelic polymorphisms in FCGR2A, FCGR2B and FCGR3B were examined for association with RA in two well characterized UK Caucasian and North Indian/Pakistani cohorts, in which FCGR3A genotyping had previously been undertaken. Haplotype frequencies and linkage disequilibrium were estimated across the FCGR locus and a model-free analysis was performed to determine association with RA. This was followed by regression analysis, allowing for phase uncertainty, to identify the particular haplotype(s) that influences disease risk. Our results reveal that FCGR2A, FCGR2B and FCGR3B were not associated with RA. The haplotype with the strongest association with RA susceptibility was the FCGR3A–FCGR3B 158V-NA2 haplotype (odds ratio 3.18, 95% confidence interval 1.13–8.92 [P = 0.03] for homozygotes compared with all genotypes). The association was stronger in the presence of nodules (odds ratio 5.03, 95% confidence interval 1.44–17.56; P = 0.01). This haplotype was also more common in North Indian/Pakistani RA patients than in control individuals, but not significantly so. Logistic regression analyses suggested that FCGR3A remained the most significant gene at this locus. The increased association with an FCGR3A–FCGR3B haplotype suggests that other polymorphic variants within FCGR3A or FCGR3B, or in linkage disequilibrium with this haplotype, may additionally contribute to disease pathogenesis

Selective, Activity-Dependent Uptake of Histamine into an Arthropod Photoreceptor

The synapses made by many arthropod photoreceptors are disinhibitory and use histamine as their transmitter. Because decreases and not increases in the cleft concentration of transmitter constitute the important event at these synapses, a transporter to clear the cleft of histamine would seem particularly crucial to signal transfer. We report here tha

The Ursinus Weekly, November 8, 1973

Dr. Pancoast predicts much competition for teachers • Civil service commission announces test dates • Service organization shows true colors • Christmas concert • Campus Chest schedules fund raising activities • Concert cancellation • Editorial: When the life sciences become the death sciences • Letters to the editor: Beef over rhetoric; Physics dept. maintains status quo; A plea for silence; What are we doing here? • Alumni corner • Faculty Portrait: Mr. Ted Xaras • The stage: ProTheatre begins year with three one-act plays in new theatre • A bundle of letters • Film: “Jeremy” • Third team goes undefeated! • Football Bears tie, 21-21 • Once beaten Harriers enter MAC championship • Women’s volleyball team into actionhttps://digitalcommons.ursinus.edu/weekly/1005/thumbnail.jp

Regulation of vascular smooth muscle cell calcification by syndecan-4/FGF-2/PKCα signaling and cross-talk with TGFβ

Aims: Vascular calcification is a major cause of morbidity and mortality. Fibroblast growth factor-2 (FGF-2) plays an instructive role in osteogenesis and bone development, but its role in vascular calcification was unknown. Therefore, we investigated the involvement of FGF-2 in vascular calcification and determined the mechanism by which it regulates this process. Methods and Results: We demonstrate that FGF-2 expression is increased in vascular smooth muscle cells (VSMCs) induced to deposit a mineralized matrix by incubation with β-glycerophosphate. FGF-2 is also localized to sites of calcification within human atherosclerotic plaques. The expression of syndecan-4, a heparan sulfate proteoglycan which regulates FGF-2 signaling, is also increased in mineralizing VSMCs and co-localizes with FGF-2 in human calcified atherosclerotic plaques. Exogenous FGF-2 inhibits VSMC mineralization, and this inhibition is reduced when syndecan-4 expression is knocked-down using siRNA. Biochemical inhibition of FGFR signaling using a pan FGFR inhibitor (BGJ398) or knocking-down syndecan-4 expression in VSMCs using siRNA increases VSMC mineralization. These increases are prevented by inhibiting transforming growth factor-β (TGFβ) signaling with SB431542, suggesting cross-talk between FGF-2 and TGFβ signaling is crucial for the regulation of VSMC mineralization. Syndecan-4 can also regulate FGF-2 signaling directly via protein kinase Cα (PKCα) activation. Biochemical inhibition of PKCα activity using Gö6976, or siRNA-mediated suppression of PKCα expression increases VSMC mineralization; this increase is also prevented with SB431542. Finally, the ability of FGF-2 to inhibit VSMC mineralization is reduced when PKCα expression is knocked-down. Conclusion: This is the first demonstration that syndecan-4 promotes FGF-2 signaling, and in turn, suppresses VSMC mineralization by down-regulating TGFβ signaling. Our discoveries that FGF-2 and syndecan-4 expression is increased in mineralizing VSMCs and that PKCα regulates FGF-2 and TGFβ signaling in VSMCs suggests that the syndecan-4/FGF-2/TGFβ signaling axis could represent a new therapeutic target for vascular calcification

The Ursinus Weekly, February 14, 1974

Week-long festival of arts slated to begin February 22 • Ursinus, at mid-winter, continues coping with problems of energy conservation • Forums set for semester • ProTheatre to present evening of avant-garde • Villanova University to sponsor tenth law review symposium • Editorial: The Myrin follies; Situation wanted: Hero • First semester Dean’s List • Letters to the editor: Union anniversary; Madison Avenue\u27s effect • Student teachers respond to experiences in area schools • SFARC News • Film Review: The Exorcist • Alumni Corner: Mike Hunter: Society drop-in • De-horn the Rams! • Jazz: Thad Jones, Mel Lewis • USGA holds elections, makes amendments and forms committees • 9-5 and still alive!https://digitalcommons.ursinus.edu/weekly/1009/thumbnail.jp

Basophils Produce IL-4 and Accumulate in Tissues after Infection with a Th2-inducing Parasite

Using mice in which the eGfp gene replaced the first exon of the Il4 gene (G4 mice), we examined production of interleukin (IL)-4 during infection by the intestinal nematode Nippostrongylus brasiliensis (Nb). Nb infection induced green fluorescent protein (GFP)pos cells that were FcɛRIpos, CD49bbright, c-kitneg, and Gr1neg. These cells had lobulated nuclei and granules characteristic of basophils. They were found mainly in the liver and lung, to a lesser degree in the spleen, but not in the lymph nodes. Although some liver basophils from naive mice express GFP, Nb infection enhanced GFP expression and increased the number of tissue basophils. Similar basophil GFP expression was found in infected Stat6−/− mice. Basophils did not increase in number in infected Rag2−/− mice; Rag2−/− mice reconstituted with CD4 T cells allowed significant basophil accumulation, indicating that CD4 T cells can direct both tissue migration of basophils and enhanced IL-4 production. IL-4 production was immunoglobulin independent and only partially dependent on IL-3. Thus, infection with a parasite that induces a “Th2-type response” resulted in accumulation of tissue basophils, and these cells, stimulated by a non-FcR cross-linking mechanism, are a principal source of in vivo IL-4 production