Antigen depot is not required for alum adjuvanticity

Alum adjuvants have been in continuous clinical use for more than 80 yr. While the prevailing theory has been that depot formation and the associated slow release of antigen and/or inflammation are responsible for alum enhancement of antigen presentation and subsequent T- and B-cell responses, this has never been formally proven. To examine antigen persistence, we used the chimeric fluorescent protein EαGFP, which allows assessment of antigen presentation in situ, using the Y-Ae antibody. We demonstrate that alum and/or CpG adjuvants induced similar uptake of antigen, and in all cases, GFP signal did not persist beyond 24 h in draining lymph node antigen-presenting cells. Antigen presentation was first detectable on B cells within 6–12 h of antigen administration, followed by conventional dendritic cells (DCs) at 12–24 h, then finally plasmacytoid DCs at 48 h or later. Again, alum and/or CpG adjuvants did not have an effect on the magnitude or sequence of this response; furthermore, they induced similar antigen-specific T-cell activation in vivo. Notably, removal of the injection site and associated alum depot, as early as 2 h after administration, had no appreciable effect on antigen-specific T- and B-cell responses. This study clearly rules out a role for depot formation in alum adjuvant activity

Book Reviews

Die hartJou Harl en Lewe. Deur A. J. Brink. Bl. 248. Gemustreer. RI6,95. Pretoria: Femina. 1982.The physiology of digestionExperiments and Observations on the Gastric Juice and the Physiology of Digestion. By William Beaumonr. 1st ed. 1&33. Reprinted in facsimile for the Classics ofMedicine Library, Division of Gryphon Editions Ltd, Birmingham, Alabama, 1980.Bone in Clinical Orthopaedics: A Study in ComparativeOsteology. Ed. by G. Sumner-Smith. Pp. xvi + 435. Illustrated. R94,25. Philadelphia: W. B. Saunders. 1982.Tamoxifen in breast cancerThe Role of Tamoxifen in Breast Cancer. Ed. by S. Iacobelli, M. E. Lippman and G. R. Della Cuna. Pp. xii + 124. Illustrated. 523,12. New York: Raven Press. 1982.Under the Influence. A History ofNitrous Oxide and OxygenAnaesthesia. By W. D. A. Smith. Pp. xxviii + 188. Illustrated. R33,50. London: Macmillan. 1982.Clinical internal medicine in the agedClinical Internal Medicine in the Aged. By R. W. Schrier. Pp. vii + 324. Illustrated. R61,-. Philadelphia: W. B. Saunders. 1982.Genital Infection by Chlamydia Trachomatis (Current Topicsin Infection, No. 2). By J. D. Oriel and G. L. Ridgway. Pp. viii + 144. Illustrated. R32,20. London: Edward Arnold. 1982.Placental Function Tests. By T. Chard and A. Klopper. Pp. viii + 94. Illustrated. DM42,-. Berlin: Springer-Verlag. 1982.Therapeutic Heat and Cold. 3rd ed. Ed. by J. F. Lehmann. Pp. xiv + 641. Illustrated. Baltimore: Williams & Wilkins. 1982

Cerebellar c9RAN proteins associate with clinical and neuropathological characteristics of C9ORF72 repeat expansion carriers.

Clinical and neuropathological characteristics associated with G4C2 repeat expansions in chromosome 9 open reading frame 72 (C9ORF72), the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, are highly variable. To gain insight on the molecular basis for the heterogeneity among C9ORF72 mutation carriers, we evaluated associations between features of disease and levels of two abundantly expressed "c9RAN proteins" produced by repeat-associated non-ATG (RAN) translation of the expanded repeat. For these studies, we took a departure from traditional immunohistochemical approaches and instead employed immunoassays to quantitatively measure poly(GP) and poly(GA) levels in cerebellum, frontal cortex, motor cortex, and/or hippocampus from 55 C9ORF72 mutation carriers [12 patients with ALS, 24 with frontotemporal lobar degeneration (FTLD) and 19 with FTLD with motor neuron disease (FTLD-MND)]. We additionally investigated associations between levels of poly(GP) or poly(GA) and cognitive impairment in 15 C9ORF72 ALS patients for whom neuropsychological data were available. Among the neuroanatomical regions investigated, poly(GP) levels were highest in the cerebellum. In this same region, associations between poly(GP) and both neuropathological and clinical features were detected. Specifically, cerebellar poly(GP) levels were significantly lower in patients with ALS compared to patients with FTLD or FTLD-MND. Furthermore, cerebellar poly(GP) associated with cognitive score in our cohort of 15 patients. In the cerebellum, poly(GA) levels similarly trended lower in the ALS subgroup compared to FTLD or FTLD-MND subgroups, but no association between cerebellar poly(GA) and cognitive score was detected. Both cerebellar poly(GP) and poly(GA) associated with C9ORF72 variant 3 mRNA expression, but not variant 1 expression, repeat size, disease onset, or survival after onset. Overall, these data indicate that cerebellar abnormalities, as evidenced by poly(GP) accumulation, associate with neuropathological and clinical phenotypes, in particular cognitive impairment, of C9ORF72 mutation carriers

A local infrared perspective to deeper ISO surveys

We present new techniques to produce IRAS 12 micron samples of galaxies andstars. We show that previous IRAS 12 micron samples are incompatible fordetailed comparison with ISO surveys and review their problems. We provide astellar infrared diagnostic diagram to distinguish galaxies from stars withoutusing longer wavelength IRAS colour criteria and produce complete 12 micronsamples of galaxies and stars. This new technique allows us to estimate thecontribution of non-dusty galaxies to the IRAS 12 micron counts and produce atrue local mid-infrared extragalactic sample compatible with ISO surveys. Wepresent our initial analysis and results

Effect of Pimobendan in Dogs with Preclinical Myxomatous Mitral Valve Disease and Cardiomegaly: The EPIC Study - A Randomized Clinical Trial

Background: Pimobendan is effective in treatment of dogs with congestive heart failure (CHF) secondary to myxomatous mitral valve disease (MMVD). Its effect on dogs before the onset of CHF is unknown. Hypothesis/Objectives: Administration of pimobendan (0.4-0.6 mg/kg/d in divided doses) to dogs with increased heart size secondary to preclinical MMVD, not receiving other cardiovascular medications, will delay the onset of signs of CHF, cardiac-related death, or euthanasia. Animals: 360 client-owned dogs with MMVD with left atrial-to-aortic ratio >= 1.6, normalized left ventricular internal diameter in diastole >= 1.7, and vertebral heart sum >10.5. Methods: Prospective, randomized, placebo-controlled, blinded, multicenter clinical trial. Primary outcome variable was time to a composite of the onset of CHF, cardiac-related death, or euthanasia. Results: Median time to primary endpoint was 1228 days (95% CI: 856-NA) in the pimobendan group and 766 days (95% CI: 667-875) in the placebo group (P = .0038). Hazard ratio for the pimobendan group was 0.64 (95% CI: 0.47-0.87) compared with the placebo group. The benefit persisted after adjustment for other variables. Adverse events were not different between treatment groups. Dogs in the pimobendan group lived longer (median survival time was 1059 days (95% CI: 952-NA) in the pimobendan group and 902 days (95% CI: 747-1061) in the placebo group) (P = .012). Conclusions and Clinical Importance: Administration of pimobendan to dogs with MMVD and echocardiographic and radiographic evidence of cardiomegaly results in prolongation of preclinical period and is safe and well tolerated. Prolongation of preclinical period by approximately 15 months represents substantial clinical benefit

Psychometric properties of the IDS-SR30 for the assessment of depressive symptoms in spanish population

<p>Abstract</p> <p>Background</p> <p>Due to the high prevalence of depression, it is clinically relevant to improve the early identification and assessment of depressive episodes. The main objective of the present study was to examine the psychometric properties of the IDS-SR₃₀(Self-rated Inventory of Depressive Symptomatology) in a large Spanish sample of depressive patients.</p> <p>Methods</p> <p>This prospective, naturalistic, multicenter, nationwide epidemiological study conducted in Spain included 1595 adult patients (65.3% females) with a DSM-IV Major Depressive Disorder (MDD. IDS-SR₃₀and the Hamilton Depression Rating Scale (HDRS, 21 items)were administered to the sample. Data was collected during 2 routine visits. The second assessment was carried out after 10 ± 2 weeks after first assessment.</p> <p>Results</p> <p>The IDS-SR₃₀showed good internal consistency (α = 0.94) and high item total correlations (≥ 0.50) were found in 70% of the items. The convergent validity was 0.85. Results of the principal component analysis (PCA) and confirmatory factor analyses (CFA) showed that a three factor model (labelled mood/cognition, anxiety/somatic and sleep) is adequate for the current sample.</p> <p>Conclusions</p> <p>The Spanish version of the IDS-SR₃₀seems a reliable, valid and useful tool for measuring depression symptomatology in Spanish population.</p

Receptor Tyrosine Kinase (RTK) Mediated Tyrosine Phosphor-Proteome from Drosophila S2 (ErbB1) Cells Reveals Novel Signaling Networks

Protein phosphorylation mediates many critical cellular responses and is essential for many biological functions during development. About one-third of cellular proteins are phosphorylated, representing the phosphor-proteome, and phosphorylation can alter a protein's function, activity, localization and stability. Tyrosine phosphorylation events mediated by aberrant activation of Receptor Tyrosine Kinase (RTK) pathways have been proven to be involved in the development of several diseases including cancer. To understand the systems biology of RTK activation, we have developed a phosphor-proteome focused on tyrosine phosphorylation events under insulin and EGF signaling pathways using the PhosphoScan® technique coupled with high-throughput mass spectrometry analysis. Comparative proteomic analyses of all these tyrosine phosphorylation events revealed that around 70% of these pY events are conserved in human orthologs and paralogs. A careful analysis of published in vivo tyrosine phosphorylation events from literature and patents revealed that around 38% of pY events from Drosophila proteins conserved on 185 human proteins are confirmed in vivo tyrosine phosphorylation events. Hence the data are validated partially based on available reports, and the credibility of the remaining 62% of novel conserved sites that are unpublished so far is very high but requires further follow-up studies. The novel pY events found in this study that are conserved on human proteins could potentially lead to the discovery of drug targets and biomarkers for the detection of various cancers and neurodegenerative diseases

An ISOCAM survey through gravitationally lensing galaxy clusters

ISOCAM was used to perform a deep survey through three gravitationally lensing clusters of galaxies. Nearly seventy sq. arcmin were covered over the clusters A370, A2218 and A2390. We present maps and photometry at 6.7 & 14.3 microns, showing a total of 145 mid-IR sources and the associated source counts. The 15 micron counts reach the faintest level yet recorded. All sources have counterparts in the optical or near-IR. Models of the clusters were used to correct for the effects of lensing, which increases the sensitivity of the survey. Seven of fifteen SCUBA sources were detected at 15 microns. Five have redshift between 0.23 & 2.8, with a median of 0.9. The field sources were counted to a lensing-corrected sensitivity of 30 microJy at 15 microns, and 14 microJy at 7 microns. The counts, corrected for completeness, contamination by cluster sources and lensing, confirm and extend findings of an excess by a factor of ten in the 15 micron population with respect to source models with no evolution. Source redshifts are mostly between 0.4 and 1.5. For the counts at 7 microns, integrating from 14 microJy to 460 microJy, we resolve 0.49+/-0.2 nW.m^(-2).sr^(-1) of the infrared background light (IBL) into discrete sources. At 15 microns we include the counts from other ISOCAM surveys to integrate from 30 microJy to 50 mJy, two to three times deeper than unlensed surveys, to resolve 2.7+/-0.62 nW.m^(-2).sr^(-1) of the IBL. These values are 10% and 55%, respectively, of the upper limit to the IBL, derived from photon-photon pair production of the TeV gamma rays from BL-Lac sources on the IBL photons. However, recent detections of TeV gamma rays from the z=0.129 BL Lac H1426+428 suggest that the 15 micron background reported implies substantial absorption of TeV photons from that source.Comment: 35 pages, 17 figures, to appear in Astronomy and Astrophysics, full paper with high-resolution figures available at http://www.iso.vilspa.esa.es/science/pub/2003

Reducing recurrent stroke: methodology of the motivational interviewing in stroke (MIST) randomized clinical trial

Recurrent stroke is prevalent in both developed and developing countries, contributing significantly to disability and death. Recurrent stroke rates can be reduced by adequate risk factor management. However, adherence to prescribed medications and lifestyle changes recommended by physicians at discharge after stroke is poor, leading to a large number of preventable recurrent strokes. Using behavior change methods such as Motivational Interviewing early after stroke occurrence has the potential to prevent recurrent stroke