A three step supercritical process to improve the dissolution rate of eflucimibe.

The aim of this study is to improve the dissolution properties of a poorly-soluble active substance, Eflucimibe by associating it with gamma-cyclodextrin. To achieve this objective, a new three-step process based on supercritical fluid technology has been proposed. First, Eflucimibe and cyclodextrin are co-crystallized using an anti-solvent process, dimethylsulfoxide being the solvent and supercritical carbon dioxide being the anti-solvent. Second, the co-crystallized powder is held in a static mode under supercritical conditions for several hours. This is the maturing step. Third, in a final stripping step, supercritical CO(2) is flowed through the matured powder to extract the residual solvent. The coupling of the first two steps brings about a significant synergistic effect to improve the dissolution rate of the drug. The nature of the entity obtained at the end of each step is discussed and some suggestions are made as to what happens in these operations. It is shown the co-crystallization ensures a good dispersion of both compounds and is rather insensitive to the operating parameters tested. The maturing step allows some dissolution-recrystallization to occur thus intensifying the intimate contact between the two compounds. Addition of water is necessary to make maturing effective as this is governed by the transfer properties of the medium. The stripping step allows extraction of the residual solvent but also removes some of the Eflucimibe which is the main drawback of this final stage.     

Light scattering from normal and dysplastic cervical cells at different epithelial depths: finite-difference time-domain modeling with a perfectly matched layer boundary condition

The finite-difference time-domain (FDTD) method provides a flexible approach to studying the scattering that arises from arbitrarily inhomogeneous structures. We implemented a three-dimensional FDTD program code to model light scattering from biological cells. The perfectly matched layer (PML) boundary condition has been used to terminate the FDTD computational grid. We investigated differences in angle-dependent scattering properties of normal and dysplastic cervical cells. Specifically, the scattering patterns and phase functions have been computed for normal and dysplastic cervical cells at three different epithelial depths, namely, basal/parabasal, intermediate, and superficial. Construction of cervical cells within the FDTD computational grid is based on morphological and chromatin texture features obtained from quantitative histopathology. The results show that angle-dependent scattering characteristics are different not only for normal and dysplastic cells but also for cells at different epithelial depths. The calculated scattering cross-sections are significantly greater for dysplastic cells. The scattering cross-sections of cells at different depths indicate that scattering decreases in going from the superficial layer to the intermediate layer, but then increases in the basal/parabasal layer. This trend for epithelial cell scattering has also been observed in confocal images of ex vivo cervical tissue.     

Light scattering from cervical cells throughout neoplastic progression: influence of nuclear morphology,DNA content,and chromatin texture

A number of noninvasive fiber optic optical technologies are under development for real-time diagnosis of neoplasia. We investigate how the light scattering properties of cervical cells are affected by changes in nuclear morphology, DNA content, and chromatin texture, which occur during neoplastic progression. We used a Cyto-Savant computer-assisted image analysis system to acquire quantitative nuclear features measurements from 122 Feulgen-thionin-stained histopathologic sections of cervical tissue. A subset of the measured nuclear features was incorporated into a finite-difference time-domain (FDTD) model of cellular light scattering. The magnitude and angular distribution of scattered light was calculated for cervical cells as a function of pathologic grade. The nuclear atypia strongly affected light scattering properties. The increased size and elevated DNA content of nuclei in high-grade lesions caused the most significant changes in scattering intensity. The spatial dimensions of chromatin texture features and the amplitude of refractive index fluctuations within the nucleus impacted both the angular distribution of scattering angles and the total amount of scattered light. Cellular scattering is sensitive to changes in nuclear morphology that accompany neoplastic progression. Understanding the quantitative relationships between nuclear features and scattering properties will aid in the development of noninvasive optical technologies for detection of precancerous conditions.     

Allele variations in the OCA2 gene (pink-eyed-dilution locus) are associated with genetic susceptibility to melanoma

The occuloalbinism 2 (OCA2) gene, localized at 15q11, encodes a melanosomal transmembrane protein that is involved in the most common form of human occulo-cutaneous albinism, a human genetic disorder characterized by fair pigmentation and susceptibility to skin cancer. We wondered whether allele variations at this locus could influence susceptibility to malignant melanoma (MM). In all, 10 intragenic single-nucleotide polymorphisms (SNPs) were genotyped in 113 patients with melanomas and in 105 Caucasian control subjects with no personal or family history of skin cancer. By comparing allelic distribution between cases and controls, we show that MM and OCA2 are associated (p value=0.030 after correction for multiple testing). Then, a recently developed strategy, the 'combination test' enabled us to show that a combination formed by two SNPs was most strongly associated to MM, suggesting a possible interaction between intragenic SNPs. In addition, the role of OCA2 on MM risk was also detected using a logistic model taking into account the presence of variants of the melanocortin 1 receptor gene (MC1R, a key pigmentation gene) and all pigmentation characteristics as melanoma risk factors. Our data demonstrate that a second pigmentation gene, in addition to MC1R, is involved in genetic susceptibility to melanoma.     

牛磺酸对染铅大鼠海马一氧化氮合酶活力的影响

目的　探讨牛磺酸拮抗铅损害学习记忆能力的作用。方法　采用NADPH d组织化学法 ,研究饮用含不同剂量铅 (0 .0 11、0 .110g L)的水和含不同剂量牛磺酸 (5、10g kg)的饲料喂养的大鼠海马一氧化氮合酶 (NOS)阳性神经元数量的变化。结果　 10g kg的牛磺酸饲料能明显增加染铅大鼠海马CA1区和齿状回NOS阳性神经元的数量。低铅水高牛磺酸饲料组NADPH d阳性神经数量在CA1区为 5 1.80± 4 .6 8,在齿状回为 4 7.4 0± 4 .2 0 ,较低铅水普通饲料组的CA1区 (4 1.2 0± 5 .32 )和齿状回 (39.87± 3.81)明显增多 ,差异有显著性 (P <0 .0 5 )。结论　牛磺酸对铅损害学习记忆能力有较明显的拮抗作用。     

Comparing the Impact of Artemisinin-Based Combination Therapies on Malaria Transmission in Sub-Saharan Africa

Artemisinin-based combination therapies (ACTs) are currently considered the first-line treatments for uncomplicated Plasmodium falciparum malaria. Among these, artemether-lumefantrine (AL) has been the most widely prescribed ACT in sub-Saharan Africa. Recent clinical trials conducted in sub-Saharan Africa have shown that dihydroartemisinin-piperaquine (DP), a most recent ACT, may have a longer post-treatment prophylactic period and post-treatment infection period (duration of gametocyte carriage) than AL. Using epidemiological and clinical data on the efficacy of AL and DP, we developed and parameterized a mathematical transmission model that we used to compare the population-level impact of AL and DP for reducing P. falciparum malaria transmission in sub-Saharan Africa. Our results showed that DP is likely to more effectively reduce malaria incidence of clinical episodes than AL. However in low P. falciparum transmission areas, DP and AL are likely to be equally effective in reducing malaria prevalence. The predictions of our model were shown to be robust to the empirical uncertainty summarizing the epidemiological parameters. DP should be considered as a replacement for AL as first-line treatment of uncomplicated malaria in highly endemic P. falciparum communities. To optimize the effectiveness of ACTs, it is necessary to tailor treatment policies to the transmission intensity in different settings.     

Assessment of Nociception and Pain in Participants in an Unresponsive or Minimally Conscious State After Acquired Brain Injury: The Relation Between the Coma Recovery Scale–Revised and the Nociception Coma Scale–Revised

Objectives

To investigate the relation between consciousness and nociceptive responsiveness (ie, Nociception Coma Scale–Revised [NCS-R]), to examine the suitability of the NCS-R for assessing nociception in participants with disorders of consciousness (DOC), and to replicate previous findings on psychometric properties of the scale.