Process parameter dependent growth phenomena of naproxen nanosuspension manufactured by wet media milling.

The production of nanosuspensions has proved to be an effective method for overcoming bioavailability challenges of poorly water soluble drugs. Wet milling in stirred media mills and planetary ball mills has become an established top-down-method for producing such drug nanosuspensions. The quality of the resulting nanosuspension is determined by the stability against agglomeration on the one hand, and the process parameters of the mill on the other hand. In order to understand the occurring dependencies, a detailed screening study, not only on adequate stabilizers, but also on their optimum concentration was carried out for the active pharmaceutical ingredient (API) naproxen in a planetary ball mill. The type and concentration of the stabilizer had a pronounced influence on the minimum particle size obtained. With the best formulation the influence of the relevant process parameters on product quality was investigated to determine the grinding limit of naproxen. Besides the well known phenomenon of particle agglomeration, actual naproxen crystal growth and morphology alterations occurred during the process which has not been observed before. It was shown that, by adjusting the process parameters, those effects could be reduced or eliminated. Thus, besides real grinding and agglomeration a process parameter dependent ripening of the naproxen particles was identified to be a concurrent effect during the naproxen fine grinding process.

Discrepant NOXA (PMAIP1) transcript and NOXA protein levels: a potential Achilles' heel in mantle cell lymphoma.

Mantle cell lymphoma (MCL) is an aggressive lymphoid neoplasm with transient response to conventional chemotherapy. We here investigated the role of the Bcl-2 homology domain 3-only protein NOXA for life-death decision in MCL. Surprisingly, NOXA (PMAIP1) mRNA and NOXA protein levels were extremely discrepant in MCL cells: NOXA mRNA was found to be highly expressed whereas NOXA protein levels were low. Chronic active B-cell receptor signaling and to a minor degree cyclin D1 overexpression contributed to high NOXA mRNA expression levels in MCL cells. The phoshatidyl-inositol-3 kinase/AKT/mammalian target of rapamycin pathway was identified as the major downstream signaling pathway involved in the maintenance of NOXA gene expression. Interestingly, MCL cells adapt to this constitutive pro-apoptotic signal by extensive ubiquitination and rapid proteasomal degradation of NOXA protein (T½âˆ¼15-30 min). In addition to the proteasome inhibitor Bortezomib, we identified the neddylation inhibitor MLN4924 and the fatty acid synthase inhibitor Orlistat as potent inducers of NOXA protein expression leading to apoptosis in MCL. All inhibitors targeted NOXA protein turnover. In contrast to Bortezomib, MLN4924 and Orlistat interfered with the ubiquitination process of NOXA protein thereby offering new strategies to kill Bortezomib-resistant MCL cells. Our data, therefore, highlight a critical role of NOXA in the balance between life and death in MCL. The discrepancy between NOXA transcript and protein levels is essential for sensitivity of MCL to ubiquitin-proteasome system inhibitors and could therefore provide a druggable Achilles' heel of MCL cells.

Break-up of the Atlantic deep western boundary current into eddies at 8 degrees S.

The existence in the ocean of deep western boundary currents, which connect the high-latitude regions where deep water is formed with upwelling regions as part of the global ocean circulation, was postulated more than 40 years ago. These ocean currents have been found adjacent to the continental slopes of all ocean basins, and have core depths between 1,500 and 4,000 m. In the Atlantic Ocean, the deep western boundary current is estimated to carry (10-40) x 10(6) m3 s(-1) of water, transporting North Atlantic Deep Water--from the overflow regions between Greenland and Scotland and from the Labrador Sea--into the South Atlantic and the Antarctic circumpolar current. Here we present direct velocity and water mass observations obtained in the period 2000 to 2003, as well as results from a numerical ocean circulation model, showing that the Atlantic deep western boundary current breaks up at 8 degrees S. Southward of this latitude, the transport of North Atlantic Deep Water into the South Atlantic Ocean is accomplished by migrating eddies, rather than by a continuous flow. Our model simulation indicates that the deep western boundary current breaks up into eddies at the present intensity of meridional overturning circulation. For weaker overturning, continuation as a stable, laminar boundary flow seems possible.

[Tissue harmonic imaging (THI) and contrast harmonic imaging (CHI) for sonographically guided vacuum-assisted biopsy of mammographically occult breast tumors]. / Tissue Harmonic Imaging (THI) und Contrast Harmonic Imaging (CHI) zur sonographisch gezielten Vakuumstanzbiopsie mammographisch okkulter Brusttumoren.

PURPOSE: To assess the guidance of tissue harmonic imaging (THI) and contrast harmonic imaging (CHI) for vacuum assisted biopsies of suspicious breast lesions compared to fundamental B-mode ultrasound-guided biopsies. MATERIAL AND METHODS: In 550 patients, ultrasound examinations of the breast were performed prospectively using fundamental B-scan, THI, and CHI. Focal lesions were documented in comparable projections for all three ultrasound modes. As contrast agent, a dose of 0.5 milliliters of Perflutren Protein-Type A microspheres ( Optison) was injected. An ultrasound-guided biopsy was performed in 38 focal lesions. Three radiologists experienced in breast imaging retrospectively assessed the lesions on the ultrasound images. RESULTS: Thirty-eight suspicious focal lesions [size 4 - 15 mm; median 8 mm] were detected by ultrasound. Of these, 29 were detected by fundamental B-scan images, 34 by THI, and 38 by CHI. Ultrasound-guided biopsy was performed on all of these lesions. No complications related to the biopsy were observed. In 25/38 cases, invasive carcinomas were found; in 6/38 ductal carcinomas in situ; in 3 cases metastases of already known invasive ductal carcinomas; and in 4 cases fibroadenomas. The size of the lesion was best identified using THI, smaller lesions (< 10 mm) using CHI. CONCLUSION: THI and CHI can help to detect focal lesions in dense breasts. Both modes can make it easier to perform ultrasound-guided biopsies of focal breast lesions.

Color stereopsis: a model for depth reversals based on border contrast.

Color stereopsis refers to the effect of stimulus color on perceived depth of stimuli viewed binocularly. It is well established and well understood that the wavelength of a stimulus affects its perceived depth in color stereopsis by prismatic effects in human optics, with long-wavelength stimuli normally seen in front of short-wavelength stimuli. It is less well known, and not well understood, that the background of the stimulus affects depth order as well. We demonstrate experimentally, using a long-wavelength orange stimulus and a short-wavelength blue stimulus, that a change from black to white in the background at the border (a change in border contrast) of the stimulus changes the perceived depth order from orange in front of blue to blue in front of orange (a color reversal). We present a descriptive model to explain reversals in color stereopsis when stimuli are displayed on a white background and suggest that it may account for instances of color reversals that are currently unexplained or questionably explained by other models.