Chiral separation of β-blockers after derivatization with (−)-menthyl chloroformate by reversed-phase high performance liquid chromatography

Optimum conditions of chiral derivatization reaction of beta-blockers acebutolol, arotinolol, beta-xolol, bisoprolol, celiprolol, metoprolol and pindolol) with (-)-menthyl chloroformate were investigated for the resolution by HPLC. With more than 30 times molar excess of (-)-menthyl chloroformate chiral derivatization reactions were completed within one hour at room temperature except arotinolol and celiprolol. Diastereomeric derivatives of beta-blockers were well resolved on the ODS column using acetonitrile-methanol-water as a mobile phase.     

Intracellular JNK, p38 MAPK and NF-kappaB regulate IL-25 induced release of cytokines and chemokines from costimulated T helper lymphocytes

Novel Th2 cytokine IL-25 has been shown to be elevated in allergic inflammation. We investigated the intracellular mechanisms regulating IL-25-induced Th2 cytokines and chemokines from human Th lymphocytes upon costimulation by anti-CD3 and anti-CD28 antibodies. Cytokines, chemokines, and phosphorylated p38 mitogen activated protein kinases (MAPK), c-Jun amino-terminal kinase (JNK) and extracellular signal-regulated protein kinase were analyzed by bead-based array using flow cytometry. Nuclear factor (NF)-kappaB and total MAPK were assessed by electrophoretic mobility shift assay and Western blot, respectively. IL-25 could synergistically induce the release of Th2 cytokines IL-4, IL-5 and IL-10, inflammatory cytokine IL-6, Th1 related chemokines CXCL9 and CXCL10, and chemokine CCL5 from anti-CD3 and anti-CD28 antibodies costimulated Th cells, especially memory Th cells. Costimulation could also upregulate the cell surface expression of IL-25 receptor on Th cells. Costimulation with or without IL-25 treatment could activate JNK, p38 MAPK and NF-kappaB. The upregulation of costimulation-induced IL-25 receptors and release of cytokines and chemokines from IL-25 treated costimulated Th cells were differentially regulated by intracellular JNK, p38 MAPK and NF-kappaB activity. Therefore, the optimal activation of Th cells by IL-25 for the release of Th2 cytokines and chemokines requires the CD3 and CD28 mediated costimulation of Th cells via the upregulation of IL-25 receptors and the activation of intracellular signaling pathways. This mechanistic study shows that IL-25 and CD28 costimulation can play pathophysiological roles by inducing inflammation and hyperresponsiveness through the production of both Th2 cytokines and chemokines from memory Th cells.     

Cochlear implantation with preservation of residual deep frequency hearing

BACKGROUND: The aim of the present paper is to evaluate the clinical parameters in patients implanted for combined, ipsilateral electric-acoustic stimulation of the auditory system. METHODS: A total of 18 patients with residual deep frequency hearing were implanted with a Combi 40+cochlear implant (MED-EL, Austria). Insertion depths ranged from 18 to 22 mm (360 degrees ). A modified surgical technique should contribute to hearing preservation in low frequency regions of the cochlea. Pure-tone audiometric thresholds were measured pre- and postoperatively. A speech audiometric evaluation was performed on two subjects. RESULTS: Utilizing adapted surgical procedures, the preservation of low frequency hearing was accomplished in 16 of 18 subjects (88.9%). Seven (38.9%) patients had complete and nine (50.0%) partial preservation of residual hearing. The speech discrimination scores of two patients documented an increase in sentence intelligibility when compared with only the cochlear implant. CONCLUSIONS: Hearing preservation in cochlear implant surgery is possible. Insertions of 360 degrees provide a full functioning cochlear implant to stimulate sufficient neural structures for above average discrimination scores with the implant alone. A synergistic effect of the electric and the acoustic stimulation modes leads to high discrimination scores in background noise.     

The role of age in pediatric cochlear implantation

OBJECTIVE: To document progress, benefit and importance of age in paediatric cochlear implantation. DESIGN: The EARS (Evaluation of Auditory Responses to Speech) test battery was performed on 33 prelingually deaf children at regular intervals up to 36 months following implantation. All children participated in individually tailored intensive audiological rehabilitation programs after receiving their implants. In this respect, it was attempted to evaluate speech perception scores in children implanted before and after the age of 3 in a homogenous group. RESULTS: All children demonstrated encouraging improvements over time in their speech recognition abilities. Furthermore, it was observed that the children who were implanted under the age of 3 achieved higher levels of speech perception performance. CONCLUSION: In order to shorten the process of central maturation of the auditory system, it is desirable to implant the children as young as possible. Early intervention seems to be the ideal strategy in enabling prelingually deaf children to derive maximum benefit from cochlear implantation.     

p21/Cyclin E pathway modulates anticlastogenic function of Bmi‐1 in cancer cells

Apart from regulating stem cell self‐renewal, embryonic development and proliferation, Bmi‐1 has been recently reported to be critical in the maintenance of genome integrity. In searching for novel mechanisms underlying the anticlastogenic function of Bmi‐1, we observed, for the first time, that Bmi‐1 positively regulates p21 expression. We extended the finding that Bmi‐1 deficiency induced chromosome breaks in multiple cancer cell models. Interestingly, we further demonstrated that knockdown of cyclin E or ectopic overexpression of p21 rescued Bmi‐1 deficiency‐induced chromosome breaks. We therefore conclude that p21/cyclin E pathway is crucial in modulating the anticlastogenic function of Bmi‐1. As it is well established that the overexpression of cyclin E potently induces genome instability and p21 suppresses the function of cyclin E, the novel and important implication from our findings is that Bmi‐1 plays an important role in limiting genomic instability in cylin E‐overexpressing cancer cells by positive regulation of p21.     

Coupled column chromatography in chiral separation of salmeterol

A coupled achiral-chiral high-performance liquid chromatographic system has been developed for the determination of the enantiomers of salmeterol, S-(+)-salmeterol and R-(-)-salmeterol in urine. The salmeterol was separated from the interfering components in urine and quantified on the silica column, and the enantiomeric composition was determined on a Sumichiral OA-4700 chiral stationary phase. The two columns were connected by a switching valve equipped with a silica precolumn. The precolumn was used to concentrate the salmeterol in the eluent from the achiral column before backflushing onto the chiral phase. The coupled system was validated.