Glycosylation in Indolent,Significant and Aggressive Prostate Cancer by Automated High-Throughput N-Glycan Profiling

The diagnosis and treatment of prostate cancer (PCa) is a major health-care concern worldwide. This cancer can manifest itself in many distinct forms and the transition from clinically indolent PCa to the more invasive aggressive form remains poorly understood. It is now universally accepted that glycan expression patterns change with the cellular modifications that accompany the onset of tumorigenesis. The aim of this study was to investigate if differential glycosylation patterns could distinguish between indolent, significant, and aggressive PCa. Whole serum N-glycan profiling was carried out on 117 prostate cancer patients’ serum using our automated, high-throughput analysis platform for glycan-profiling which utilizes ultra-performance liquid chromatography (UPLC) to obtain high resolution separation of N-linked glycans released from the serum glycoproteins. We observed increases in hybrid, oligomannose, and biantennary digalactosylated monosialylated glycans (M5A1G1S1, M8, and A2G2S1), bisecting glycans (A2B, A2(6)BG1) and monoantennary glycans (A1), and decreases in triantennary trigalactosylated trisialylated glycans with and without core fucose (A3G3S3 and FA3G3S3) with PCa progression from indolent through significant and aggressive disease. These changes give us an insight into the disease pathogenesis and identify potential biomarkers for monitoring the PCa progression, however these need further confirmation studies.     

Failure to cure Mycobacterium gordonae peritonitis associated with continuous ambulatory peritoneal dialysis

Nontuberculous mycobacteria are increasingly recognized as important pathogens in peritonitis associated with continuous ambulatory peritoneal dialysis (CAPD). Mycobacterium gordonae rarely causes human infection and is the least likely mycobacterium to produce clinical infection in CAPD patients. We describe a patient with persistent M. gordonae peritonitis acquired while undergoing CAPD. During 18 months of treatment, clinical improvement occurred but a microbiological cure could not be achieved. Principles of therapy for mycobacterial peritonitis developing during CAPD are reviewed, and potential explanations for our patient's failure to respond to therapy are discussed.     

A phase I-II study of paclitaxel, ifosfamide, and vinorelbine with filgrastim (rhG-CSF) support in advanced non-small-cell lung cancer

PURPOSE: We designed a phase I-II trial of three active agents, paclitaxel, ifosfamide, and vinorelbine, in advanced non-small-cell lung cancer (NSCLC) to: 1) define the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) of paclitaxel with filgrastim (G-CSF) support; and 2) determine the overall response rate and median survival of patients treated on this regimen. PATIENTS AND METHODS: We treated cohorts of patients with stage IIIB or IV NSCLC with ifosfamide 1.2-1.6 g/m2/day x 3 and vinorelbine 20-25 mg/m2/day x 3 and escalating doses of paclitaxel at 100-175 mg/m2 on day 2 with G-CSF support on a 21-day cycle. One prior experimental single-agent chemotherapy regimen was allowed. RESULTS: Fifty-six patients, were enrolled on this trial: 27 on the phase I portion of the study and an additional 29 at the recommended phase II dose (RPTD). Thirteen patients had received prior chemotherapy. Paclitaxel doses of 175 mg/m2 and 150 mg/m2 produced dose-limiting myelosuppression, and the RPTD was determined to be paclitaxel 135 mg/m2 with ifosfamide 1.2 g/m2/day on days 1-3 and vinorelbine 20 mg/m2/ day on days 1-3 with G-CSF support. The overall response rate was 18%, with a median survival of 6.1 months. Six of 35 patients (17%) treated at the RPTD achieved a partial response to therapy. Grade IV neutropenia was observed in 19 of 35 patients at this dose, with eight patients suffering febrile neutropenia. CONCLUSIONS: This non-cisplatin-containing three-drug regimen has substantial toxicity and low activity in advanced NSCLC, and does not seem to improve on prior regimens. It is unclear whether the lack of efficacy relates to an antagonistic reaction between the specific drugs, administration schedule, or to subtherapeutic doses of the individual agents.     

Blood pressure estimation and beliefs among normotensives and hypertensives.

14 medicated hypertensive, 15 nonmedicated mild hypertensive, 39 normotensive, and 13 hypotensive adults participated in a 1–2 hr laboratory experiment that assessed each S's symptoms, moods, and estimates of systolic blood pressure (SBP) relative to actual SBP levels. Several self-reports and autonomic measures were collected during and after each of 22 tasks. Within-S correlations indicated that all Ss could estimate SBP at levels greater than chance. Further, 68% of the Ss evidenced at least 1 significant symptom–SBP correlation. Although medicated hypertensives believed they could estimate their BP more accurately than other groups, they were actually no more accurate than the other Ss. They also evidenced far fewer empirically derived symptom–SBP and emotion–SBP correlations than any other group. Overall, blood pressure (BP) beliefs were largely inaccurate. If these erroneous beliefs can be eliminated, Ss may be able to estimate BP fluctuations more accurately. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Anti-D in a D-positive renal transplant patient

PURPOSE: We report a case of postoperative reparalysis in the recovery room, following nebulized epinephrine. The patient was pharmacologically reversed with edrophonium after paralysis with rocuronium. CLINICAL FINDINGS: A 12-yr-old girl developed postoperative reparalysis following the intraoperative administration of rocuronium. A total of 0.92 mg.kg-1 rocuronium was administered. After surgery, pharmacological reversal was achieved with 20 mg edrophonium with 0.15 mg atropine sulfate iv 35 min after the last administration of rocuronium. Muscular relaxation was monitored using an ulnar peripheral nerve stimulator (PNS). After reversal, a full train-of-four and sustained tetanus at 50 Hz were present. In the recovery room, following nebulized epinephrine, the patient became apneic. The patient was paralyzed and an ulnar PNS demonstrated only one faint twitch. The paralysis was reversed with 1.5 mg neostigmine with 0.3 mg glycopyrrolate. CONCLUSION: Postoperative reparalysis following rocuronium may be a cause of postoperative respiratory distress. The definitive diagnosis is made using PNS and observing the response to pharmacological reversal. Nebulized epinephrine may have a previously undescribed role in the development of postoperative reparalysis.     

Autoimmunity caused by disruption of central T cell tolerance. A murine model of drug-induced lupus

A side effect of therapy with procainamide and numerous other medications is a lupus-like syndrome characterized by autoantibodies directed against denatured DNA and the (H2A-H2B)-DNA subunit of chromatin. We tested the possibility that an effect of lupus-inducing drugs on central T cell tolerance underlies these phenomena. Two intrathymic injections of procainamide-hydroxylamine (PAHA), a reactive metabolite of procainamide, resulted in prompt production of IgM antidenatured DNA antibodies in C57BL/6xDBA/2 F1 mice. Subsequently, IgG antichromatin antibodies began to appear in the serum 3 wk after the second injection and were sustained for several months. Specificity, inhibition and blocking studies demonstrated that the PAHA-induced antibodies showed remarkable specificity to the (H2A-H2B)-DNA complex. No evidence for polyclonal B cell activation could be detected based on enumeration of Ig-secreting B cells and serum Ig levels, suggesting that a clonally restricted autoimmune response was induced by intrathymic PAHA. The IgG isotype of the antichromatin antibodies indicated involvement of T cell help, and proliferative responses of splenocytes to oligonucleosomes increased up to 100-fold. As little as 5 microM PAHA led to a 10-fold T cell proliferative response to chromatin in short term organ culture of neonatal thymi. We suggest that PAHA interferes with self-tolerance mechanisms accompanying T cell maturation in the thymus, resulting in the emergence of chromatin-reactive T cells followed by humoral autoimmunity.     

Scarring trachoma is associated with polymorphism in the tumor necrosis factor alpha (TNF-alpha) gene promoter and with elevated TNF-alpha levels in tear fluid

Tumor necrosis factor alpha (TNF-alpha) may play a central role in the disease pathogenesis which occurs as a consequence of chlamydial infection. To investigate the importance of TNF-alpha gene promoter polymorphisms and TNF-alpha levels in tear fluid in scarring trachoma, a large matched-pair case-control study was performed in The Gambia. The -308A allele was present in a higher proportion of patients (28.4%) than controls (18.4%), with an increasing association for homozygotes (chi2 for trend, P = 0.032; allele frequency, 0.163 in patients and 0.099 in controls; chi2, P = 0.025). For the -238A allele, the association was similar but not significant. The disease association was highly significant when the number of either -308A or -238A sites in an individual was considered (P = 0.003). TNF-alpha promoter alleles are tightly linked to some HLA class I and II alleles, but multivariate analysis confirmed that the disease associations were independent of HLA, although a class I allele, A*6802, is also associated with disease. TNF-alpha was more frequently detected in tear samples from patients (27.6%) than from controls (15.9%), increasingly so for higher levels of detectable TNF-alpha (P = 0.015). Among patients, detectable TNF-alpha in tears was highly associated with the presence of ocular chlamydial infection (P < 0.001). The results indicate that TNF-alpha plays a major role in the tissue damage and scarring which occurs as a consequence of Chlamydia trachomatis infection.     

Antibody against synthetic rat PTH peptide (1-34) blocks PTH-mediated cAMP formation and phosphate transport in opossum kidney cells

The expression of the NMDA subtype of glutamate receptors was investigated by Western blot analysis and RT-PCR in cultured chick Bergmann and Müller glial cells. Using subunit-specific antibodies directed to the carboxy terminus of the rat NMDAR2A/B we detected the expression of the NMDAR2 subunit in both kinds of culture. The functional subunit of the NMDA receptor, NMDAR1, was detected by means of RT-PCR. These results, together with our previous functional characterization of NMDA receptors in radial glia, provide conclusive evidence for the expression of functional NMDA receptor/channels in Bergmann and Muller glia cells. Our findings strengthen the notion of a modulatory role of glial cells in synaptic transmission.     

GUIDELINES FOR DESIGNING EIS INTERFACES Meeting Executives' Information Needs

For users of an executive information system (EIS), the EIS interface is the system and is crucial to the EIS's success. These guidelines for designing EIS interfaces are based on studies of actual EIS interfaces that meet the unique information needs of executives.