Galaxy Harassment and the Evolution of Clusters of Galaxies

Disturbed spiral galaxies with high rates of star formation pervaded clusters of galaxies just a few billion years ago, but nearby clusters exclude spirals in favor of ellipticals. ``Galaxy harassment" (frequent high speed galaxy encounters) drives the morphological transformation of galaxies in clusters, provides fuel for quasars in subluminous hosts and leaves detectable debris arcs. Simulated images of harassed galaxies are strikingly similar to the distorted spirals in clusters at $z \sim 0.4$ observed by the Hubble Space Telescope.Comment: Submitted to Nature. Latex file, 7 pages, 10 photographs in gif and jpeg format included. 10 compressed postscript figures and text available using anonymous ftp from ftp://ftp-hpcc.astro.washington.edu/pub/hpcc/moore/ (mget *) Also available at http://www-hpcc.astro.washington.edu/papers

The incidence of total hip arthroplasty after hip arthroscopy in osteoarthritic patients

<p>Abstract</p> <p>Objective</p> <p>To assess the incidence of total hip arthroplasty (THA) in osteoarthritic patients who were treated by arthroscopic debridement and to evaluate factors that might influence the time interval from the first hip arthroscopy to THA.</p> <p>Design</p> <p>Retrospective clinical series</p> <p>Methods</p> <p>Follow-up data and surgical reports were retrieved from 564 records of osteoarthritic patients that have had hip arthroscopy between the years 2002 to 2009 with a mean follow-up time of 3.2 years (range, 1-6.4 years). The time interval between the first hip arthroscopy to THA was modelled as a function of patient age; level of cartilage damage; procedures performed and repeated arthroscopies with the use of multivariate regression analysis.</p> <p>Results</p> <p>Ninety (16%) of all participants eventually required THA. The awaiting time from the first arthroscopy to a hip replacement was found to be longer in patients younger than 55 years and in a milder osteoarthritic stage. Patients that experienced repeated hip scopes had a longer time to THA than those with only a single procedure. Procedures performed concomitant with debridement and lavage did not affect the time interval to THA.</p> <p>Conclusions</p> <p>In our series of arthroscopic treatment of hip osteoarthritis, 16% required THA over a period of 7 years. Factors that influence the time to arthroplasty were age, degree of osteoarthritis and recurrent procedures.</p

Safety and tolerability of sitagliptin in patients with type 2 diabetes: a pooled analysis

<p>Abstract</p> <p>Background</p> <p>Sitagliptin, a highly selective dipeptidyl peptidase-4 inhibitor, is the first in a new class of oral antihyperglycemic agents (AHAs) for the treatment of patients with type 2 diabetes. Type 2 diabetes is a life-long disease requiring chronic treatment and management. Therefore, robust assessment of the long-term safety and tolerability of newer therapeutic agents is of importance. The purpose of this analysis was to assess the safety and tolerability of sitagliptin by pooling 12 large, double-blind, Phase IIb and III studies up to 2 years in duration. Methods: This analysis included 6139 patients with type 2 diabetes receiving either sitagliptin 100 mg/day (N = 3415) or a comparator agent (placebo or an active comparator) (N = 2724; non-exposed group). The 12 studies from which this pooled population was drawn represent the double-blind, randomized, Phase IIB and III studies that included patients treated with the clinical dose of sitagliptin (100 mg/day) for at least 18 weeks up to 2 years and that were available in a single safety database as of November 2007. These 12 studies assessed sitagliptin as monotherapy, initial combination therapy with metformin, or add-on combination therapy with other oral AHAs (metformin, pioglitazone, sulfonylurea, sulfonylurea + metformin, or metformin + rosiglitazone). Patients in the non-exposed group were taking placebo, pioglitazone, metformin, sulfonylurea, sulfonylurea + metformin, or metformin + rosiglitazone. This safety analysis used patient-level data from each study to evaluate clinical and laboratory adverse experiences.</p> <p>Results</p> <p>For clinical adverse experiences, the incidence rates of adverse experiences overall, serious adverse experiences, and discontinuations due to adverse experiences were similar in the sitagliptin and non-exposed groups. The incidence rates of specific adverse experiences were also generally similar in the two groups, with the exception of an increased incidence rate of hypoglycemia observed in the non-exposed group. The incidence rates of drug-related adverse experiences overall and discontinuations due to drug-related adverse experiences were higher in the non-exposed group, primarily due to the increased incidence rate of hypoglycemia in this group. For cardiac- and ischemia-related adverse experiences (including serious events), there were no meaningful between-group differences. No meaningful differences between groups in laboratory adverse experiences, either summary measures or specific adverse experiences, were observed.</p> <p>Conclusion</p> <p>In patients with type 2 diabetes, sitagliptin 100 mg/day was well tolerated in clinical trials up to 2 years in duration.</p

Validity and reliability of the semi-quantitative self-report Home Food Availability Inventory Checklist (HFAI-C) in White and South Asian populations.

Despite interest in the importance of the home food environment and its potential influence on children's diets and social norms, there remain few self-report checklist methods that have been validated against the gold standard of researcher-conducted inventories. This study aimed to assess the criterion validity and reliability of the 'Home Food Availability Inventory Checklist' (HFAI-C), a 39-item checklist including categories of fruit, vegetables, snacks and drinks.The HFAI-C was completed by 97 participants of White and Pakistani origin in the UK. Validity was determined by comparing participant-reported HFAI-C responses to data from researcher observations of home food availability using PABAK and weighted kappa statistics. The validity of measuring the amount of items (in addition to presence/absence) available was also determined. Test-retest reliability compared repeated administrations of the HFAI-C using intra-class correlation coefficients.Validity and reliability was fair to moderate overall. For validity, the average category-level PABAK ranged from 0.31 (95 % CI: 0.25, 0.37) for vegetables to 0.44 (95 % CI: 0.40, 0.49) for fruits. Assessment of the presence/absence of items demonstrated higher validity compared to quantity measurements. Reliability was increased when the HFAI-C was repeated close to the time of the first administration. For example, ICCs for reliability of the measurement of fruits were 0.52 (95 %CI: 0.47, 0.56) if re-administered within 5 months, 0.58 (95 % CI: 0.51, 0.64) within 30 days and 0.97 (95 %CI: 0.94, 1.00) if re-administered on the same day.Overall, the HFAI-C demonstrated fair to moderate validity and reliability in a population of White and South Asian participants. This evaluation is consistent with previous work on other checklists in less diverse, more affluent populations. Our research supports the use of the HFAI-C as a useful, albeit imperfect, representation of researcher-conducted inventories. The feasibility of collecting information using the HFAI-C in large, multi-ethnic samples can facilitate examination of home food availability in relation to exposures such as ethnicity and outcomes including behavioural, social and health outcomes. Future work using the HFAI-C could provide important insights into a modifiable influence with potential to impact health

The Novel Deacetylase Inhibitor AR-42 Demonstrates Pre-Clinical Activity in B-Cell Malignancies In Vitro and In Vivo

While deacetylase (DAC) inhibitors show promise for the treatment of B-cell malignancies, those introduced to date are weak inhibitors of class I and II DACs or potent inhibitors of class I DAC only, and have shown suboptimal activity or unacceptable toxicities. We therefore investigated the novel DAC inhibitor AR-42 to determine its efficacy in B-cell malignancies.In mantle cell lymphoma (JeKo-1), Burkitt's lymphoma (Raji), and acute lymphoblastic leukemia (697) cell lines, the 48-hr IC(50) (50% growth inhibitory concentration) of AR-42 is 0.61 microM or less. In chronic lymphocytic leukemia (CLL) patient cells, the 48-hr LC(50) (concentration lethal to 50%) of AR-42 is 0.76 microM. AR-42 produces dose- and time-dependent acetylation both of histones and tubulin, and induces caspase-dependent apoptosis that is not reduced in the presence of stromal cells. AR-42 also sensitizes CLL cells to TNF-Related Apoptosis Inducing Ligand (TRAIL), potentially through reduction of c-FLIP. AR-42 significantly reduced leukocyte counts and/or prolonged survival in three separate mouse models of B-cell malignancy without evidence of toxicity.Together, these data demonstrate that AR-42 has in vitro and in vivo efficacy at tolerable doses. These results strongly support upcoming phase I testing of AR-42 in B-cell malignancies

The landscape of Neandertal ancestry in present-day humans

Analyses of Neandertal genomes have revealed that Neandertals have contributed genetic variants to modern humans1–2. The antiquity of Neandertal gene flow into modern humans means that regions that derive from Neandertals in any one human today are usually less than a hundred kilobases in size. However, Neandertal haplotypes are also distinctive enough that several studies have been able to detect Neandertal ancestry at specific loci1,3–8. Here, we have systematically inferred Neandertal haplotypes in the genomes of 1,004 present-day humans12. Regions that harbor a high frequency of Neandertal alleles in modern humans are enriched for genes affecting keratin filaments suggesting that Neandertal alleles may have helped modern humans adapt to non-African environments. Neandertal alleles also continue to shape human biology, as we identify multiple Neandertal-derived alleles that confer risk for disease. We also identify regions of millions of base pairs that are nearly devoid of Neandertal ancestry and enriched in genes, implying selection to remove genetic material derived from Neandertals. Neandertal ancestry is significantly reduced in genes specifically expressed in testis, and there is an approximately 5-fold reduction of Neandertal ancestry on chromosome X, which is known to harbor a disproportionate fraction of male hybrid sterility genes20–22. These results suggest that part of the reduction in Neandertal ancestry near genes is due to Neandertal alleles that reduced fertility in males when moved to a modern human genetic background

The Fate of Porous Hydroxyapatite Granules Used in Facial Skeletal Augmentation

Facial appearance is largely determined by the morphology of the underlying skeleton. Hydroxyapatite is one of several materials available to enhance projection of the facial skeleton. This study evaluated the long-term maintenance of augmented bony projection when porous hydroxyapatite granules are used on the facial skeleton. Ten female patients aged 28–58 years were studied following aesthetic augmentation of the facial skeleton at 24 sites using porous hydroxyapatite granules. Postoperative CT scans at 3 months served as the baseline measurement and compared with scans taken at 1 and 2 years, with the thickness of the hydroxyapatite measured in axial and coronal planes. Thickness of original bone plus overlay of hydroxyapatite, thickness of the overlying soft tissue, and the overall projection (bone plus soft tissue) were recorded. It was found that 99.7% of the hydroxyapatite was maintained at 2 years, with no statistical difference (t test) from the baseline measurement. The overall projection (bony and soft tissue) was maintained as there was no evidence of native bone resorption or soft tissue atrophy. Radiographic results confirmed that the use of porous hydroxyapatite granules for enhancement of the facial skeleton is not only a predictable procedure, but maintains full bony projection at 2 years

Safety and tolerability of sitagliptin in clinical studies: a pooled analysis of data from 10,246 patients with type 2 diabetes

<p>Abstract</p> <p>Background</p> <p>In a previous pooled analysis of 12 double-blind clinical studies that included data on 6,139 patients with type 2 diabetes, treatment with sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, was shown to be generally well tolerated compared with treatment with control agents. As clinical development of sitagliptin continues, additional studies have been completed, and more patients have been exposed to sitagliptin. The purpose of the present analysis is to update the safety and tolerability assessment of sitagliptin by pooling data from 19 double-blind clinical studies.</p> <p>Methods</p> <p>The present analysis included data from 10,246 patients with type 2 diabetes who received either sitagliptin 100 mg/day (N = 5,429; sitagliptin group) or a comparator agent (placebo or an active comparator) (N = 4,817; non-exposed group). The 19 studies from which this pooled population was drawn represent the double-blind, randomized studies that included patients treated with the usual clinical dose of sitagliptin (100 mg/day) for between 12 weeks and 2 years and for which results were available as of July 2009. These 19 studies assessed sitagliptin taken as monotherapy, initial combination therapy with metformin or pioglitazone, or as add-on combination therapy with other antihyperglycemic agents (metformin, pioglitazone, a sulfonylurea ± metformin, insulin ± metformin, or rosiglitazone + metformin). Patients in the non-exposed group were taking placebo, metformin, pioglitazone, a sulfonylurea ± metformin, insulin ± metformin, or rosiglitazone + metformin. The analysis used patient-level data from each study to evaluate between-group differences in the exposure-adjusted incidence rates of adverse events.</p> <p>Results</p> <p>Summary measures of overall adverse events were similar in the sitagliptin and non-exposed groups, except for an increased incidence of drug-related adverse events in the non-exposed group. Incidence rates of specific adverse events were also generally similar between the two groups, except for increased incidence rates of hypoglycemia, related to the greater use of a sulfonylurea, and diarrhea, related to the greater use of metformin, in the non-exposed group and constipation in the sitagliptin group. Treatment with sitagliptin was not associated with an increased risk of major adverse cardiovascular events.</p> <p>Conclusions</p> <p>In this updated pooled safety analysis of data from 10,246 patients with type 2 diabetes, sitagliptin 100 mg/day was generally well tolerated in clinical trials of up to 2 years in duration.</p

Interaction of galectin-3 with MUC1 on cell surface promotes EGFR dimerization and activation in human epithelial cancer cells

Epidermal growth factor receptor (EGFR) is an important regulator of epithelial cell growth and survival in normal and cancerous tissues and is a principal therapeutic target for cancer treatment. EGFR is associated in epithelial cells with the heavily glycosylated transmembrane mucin protein MUC1, a natural ligand of galectin-3 that is overexpressed in cancer. This study reveals that the expression of cell surface MUC1 is a critical enhancer of EGF-induced EGFR activation in human breast and colon cancer cells. Both the MUC1 extracellular and intracellular domains are involved in EGFR activation but the predominant influence comes from its extracellular domain. Binding of galectin-3 to the MUC1 extracellular domain induces MUC1 cell surface polarization and increases MUC1–EGFR association. This leads to a rapid increase of EGFR homo-/hetero-dimerization and subsequently increased, and also prolonged, EGFR activation and signalling. This effect requires both the galectin-3 C-terminal carbohydrate recognition domain and its N-terminal ligand multi-merization domain. Thus, interaction of galectin-3 with MUC1 on cell surface promotes EGFR dimerization and activation in epithelial cancer cells. As MUC1 and galectin-3 are both commonly overexpressed in most types of epithelial cancers, their interaction and impact on EGFR activation likely makes important contribution to EGFR-associated tumorigenesis and cancer progression and may also influence the effectiveness of EGFR-targeted cancer therapy