A 12-month phase 3 study of pasireotide in cushing's disease

BACKGROUND: Cushing's disease is associated with high morbidity and mortality. Pasireotide, a potential therapy, has a unique, broad somatostatin-receptor-binding profile, with high binding affinity for somatostatin-receptor subtype 5. METHODS: In this double-blind, phase 3 study, we randomly assigned 162 adults with Cushing's disease and a urinary free cortisol level of at least 1.5 times the upper limit of the normal range to receive subcutaneous pasireotide at a dose of 600 ??g (82 patients) or 900 ??g (80 patients) twice daily. Patients with urinary free cortisol not exceeding 2 times the upper limit of the normal range and not exceeding the baseline level at month 3 continued to receive their randomly assigned dose; all others received an additional 300 ??g twice daily. The primary end point was a urinary free cortisol level at or below the upper limit of the normal range at month 6 without an increased dose. Open-label treatment continued through month 12. RESULTS: Twelve of the 82 patients in the 600-??g group and 21 of the 80 patients in the 900-??g group met the primary end point. The median urinary free cortisol level decreased by approximately 50% by month 2 and remained stable in both groups. A normal urinary free cortisol level was achieved more frequently in patients with baseline levels not exceeding 5 times the upper limit of the normal range than in patients with higher baseline levels. Serum and salivary cortisol and plasma corticotropin levels decreased, and clinical signs and symptoms of Cushing's disease diminished. Pasireotide was associated with hyperglycemia-related adverse events in 118 of 162 patients; other adverse events were similar to those associated with other somatostatin analogues. Despite declines in cortisol levels, blood glucose and glycated hemoglobin levels increased soon after treatment initiation and then stabilized; treatment with a glucose-lowering medication was initiated in 74 of 162 patients. CONCLUSIONS: The significant decrease in cortisol levels in patients with Cushing's disease who received pasireotide supports its potential use as a targeted treatment for corticotropin-secreting pituitary adenomas. (Funded by Novartis Pharma; ClinicalTrials.gov number, NCT00434148.) Copyright © 2012 Massachusetts Medical Society

Urbanization and seasonality strengthens the CO2 capacity of the Red River Delta, Vietnam

Tropical rivers are dynamic CO2 sources. Regional patterns in the partial pressure of CO2 (pCO2) and relationships with other a/biotic factors in densely populated and rapidly developing river delta regions of Southeast Asia are still poorly constrained. Over one year, at 21 sites across the river system in the Red River Delta (RRD), Vietnam, we calculated pCO2 levels from temperature, pH, and total alkalinity and inter-linkages between pCO2 and phytoplankton, water chemistry and seasonality were then assessed. The smaller, more urbanized, and polluted Day River had an annual median pCO2 of 5000 ± 3300 µatm and the larger Red River of 2675 ± 2271 µatm. pCO2 was 1.6 and 3.2 times higher during the dry season in the Day and Red rivers respectively than the rainy season. Elevated pCO2 levels in the Day River during the dry season were also 2.4-fold higher than the median value (2811 ± 3577 µatm) of calculated and direct pCO2 measurements in >20 sub/tropical rivers. By further categorizing the river data into Hanoi City vs. other less urban-populated provinces, we found significantly higher nutrients, organic matter content, and riverine cyanobacteria during the dry season in the Day River across Hanoi City. Forward selection also identified riverine cyanobacteria and river discharge as the main predictors explaining pCO2 variation in the RRD. After accounting for the shared effects (14%), river discharge alone significantly explained 12% of the pCO2 variation, cyanobacteria uniquely a further 21%, while 53% of the pCO2 variance was unexplained by either. We show that the urbanization of rivers deltas could result in increased sources of riverine pCO2, water pollution, and harmful cyanobacterial blooms. Such risks could be mitigated through water management to increase water flows in problem areas during the dry season

New method to characterize a machining system: application in turning

Many studies simulates the machining process by using a single degree of freedom spring-mass sytem to model the tool stiffness, or the workpiece stiffness, or the unit tool-workpiece stiffness in modelings 2D. Others impose the tool action, or use more or less complex modelings of the efforts applied by the tool taking account the tool geometry. Thus, all these models remain two-dimensional or sometimes partially three-dimensional. This paper aims at developing an experimental method allowing to determine accurately the real three-dimensional behaviour of a machining system (machine tool, cutting tool, tool-holder and associated system of force metrology six-component dynamometer). In the work-space model of machining, a new experimental procedure is implemented to determine the machining system elastic behaviour. An experimental study of machining system is presented. We propose a machining system static characterization. A decomposition in two distinct blocks of the system "Workpiece-Tool-Machine" is realized. The block Tool and the block Workpiece are studied and characterized separately by matrix stiffness and displacement (three translations and three rotations). The Castigliano's theory allows us to calculate the total stiffness matrix and the total displacement matrix. A stiffness center point and a plan of tool tip static displacement are presented in agreement with the turning machining dynamic model and especially during the self induced vibration. These results are necessary to have a good three-dimensional machining system dynamic characterization

Triad pattern algorithm for predicting strong promoter candidates in bacterial genomes

Abstract Background Bacterial promoters, which increase the efficiency of gene expression, differ from other promoters by several characteristics. This difference, not yet widely exploited in bioinformatics, looks promising for the development of relevant computational tools to search for strong promoters in bacterial genomes. Results We describe a new triad pattern algorithm that predicts strong promoter candidates in annotated bacterial genomes by matching specific patterns for the group I σ70 factors of Escherichia coli RNA polymerase. It detects promoter-specific motifs by consecutively matching three patterns, consisting of an UP-element, required for interaction with the α subunit, and then optimally-separated patterns of -35 and -10 boxes, required for interaction with the σ70 subunit of RNA polymerase. Analysis of 43 bacterial genomes revealed that the frequency of candidate sequences depends on the A+T content of the DNA under examination. The accuracy of in silico prediction was experimentally validated for the genome of a hyperthermophilic bacterium, Thermotoga maritima, by applying a cell-free expression assay using the predicted strong promoters. In this organism, the strong promoters govern genes for translation, energy metabolism, transport, cell movement, and other as-yet unidentified functions. Conclusion The triad pattern algorithm developed for predicting strong bacterial promoters is well suited for analyzing bacterial genomes with an A+T content of less than 62%. This computational tool opens new prospects for investigating global gene expression, and individual strong promoters in bacteria of medical and/or economic significance.</p

Comparative Genomic Analysis of Human Fungal Pathogens Causing Paracoccidioidomycosis

Paracoccidioides is a fungal pathogen and the cause of paracoccidioidomycosis, a health-threatening human systemic mycosis endemic to Latin America. Infection by Paracoccidioides, a dimorphic fungus in the order Onygenales, is coupled with a thermally regulated transition from a soil-dwelling filamentous form to a yeast-like pathogenic form. To better understand the genetic basis of growth and pathogenicity in Paracoccidioides, we sequenced the genomes of two strains of Paracoccidioides brasiliensis (Pb03 and Pb18) and one strain of Paracoccidioides lutzii (Pb01). These genomes range in size from 29.1 Mb to 32.9 Mb and encode 7,610 to 8,130 genes. To enable genetic studies, we mapped 94% of the P. brasiliensis Pb18 assembly onto five chromosomes. We characterized gene family content across Onygenales and related fungi, and within Paracoccidioides we found expansions of the fungal-specific kinase family FunK1. Additionally, the Onygenales have lost many genes involved in carbohydrate metabolism and fewer genes involved in protein metabolism, resulting in a higher ratio of proteases to carbohydrate active enzymes in the Onygenales than their relatives. To determine if gene content correlated with growth on different substrates, we screened the non-pathogenic onygenale Uncinocarpus reesii, which has orthologs for 91% of Paracoccidioides metabolic genes, for growth on 190 carbon sources. U. reesii showed growth on a limited range of carbohydrates, primarily basic plant sugars and cell wall components; this suggests that Onygenales, including dimorphic fungi, can degrade cellulosic plant material in the soil. In addition, U. reesii grew on gelatin and a wide range of dipeptides and amino acids, indicating a preference for proteinaceous growth substrates over carbohydrates, which may enable these fungi to also degrade animal biomass. These capabilities for degrading plant and animal substrates suggest a duality in lifestyle that could enable pathogenic species of Onygenales to transfer from soil to animal hosts.National Institute of Allergy and Infectious Diseases (U.S.)National Institutes of Health. Department of Health and Human Services (contract HHSN266200400001C)National Institutes of Health. Department of Health and Human Services(contract HHSN2722009000018C)Brazil. National Council for Scientific and Technological Developmen