Albumin anchored docetaxel lipid nanoemulsion for improved targeting efficiency - preparation, characterization, cytotoxic, antitumor and in vivo imaging studies.
The aim was to develop albumin anchored docetaxel lipid nanoemulsion (ALNE) for improving tumor targeted delivery. The O/W lipid nanoemulsion, LNEs were prepared by homogenization and ultrasonication processes. The size of globules and zeta potential were measured by Malvern Zetasizer. Albumin was coupled to stearylamine containing lipid nanoemulsion (SALNE) globules using water soluble EDC reaction. The drug content and entrapment efficiencies for the LNEs were determined by the high-performance liquid chromatography. The in vitro cytotoxic studies of the delivery systems were performed on MCF-7 and Hela cells. The IC 50 values of ALNE on both the cell lines were statistically significant. The in vivo antitumor activity was tested on solid tumors induced in C57BL/6 mice. This study revealed that the percentage tumor inhibition for the groups treated with DLNE, SALNE and ALNE when compared with untreated control was found to be 55.62 ± 5.41%, 54.27 ± 4.85% and 80.01 ± 2.74%, respectively. Furthermore, in vivo distribution studies were carried out in breast cancer MDA-MB231 xenografted Balb/c mice. The LNEs were loaded with fluorescent DiD oil and the distribution in different organs after 6 h was tracked using Caliper life sciences in vivo imaging system. The studies revealed that ALNE was superior in tumor targeting activity when compared with DLNE and SALNE by 3.04 and 2.26 folds, respectively. The average radiance values of ALNE on the tumor tissue were statistically significant when compared with DLNE, SALNE at p < 0.01. In addition, this strategy can become a platform technology for other lipophilic drugs to target tumors.


Expression of natural cytotoxicity receptors and a2V-ATPase on peripheral blood NK cell subsets in women with recurrent spontaneous abortions and implantation failures.
Natural cytotoxicity receptors (NCRs) are unique markers, which regulate NK cell cytotoxicity and cytokine production. a2V-ATPase is expressed on subsets of PBMC and regulates the extracellular environment, which facilitates NK cytotoxicity or cytokine secretion. In this study, we aim to investigate the expression of NCRs and a2V-ATPase in peripheral blood NK cells of women with recurrent spontaneous abortions (RSA) or implantation failures. Peripheral blood NK cells (CD56(dim) and CD56(bright) were analyzed for the expression of NCRs (NKp46, NKp44 and NKp30) and a2V-ATPase using 3-color flow cytometry in women with RSA (n=24), implantation failures (n=19) or normal healthy women (n=13). CD56+/NKp46+ cells were markedly decreased (P<0.05) and CD56(bright)/a2V-ATPase+ cells were significantly increased (P<0.05) in women with RSA as compared to those of normal controls. In women with RSA or implantation failures, expression of NKp46, NKp44, NKp30, and a2V-ATPase on CD56(bright) NK cells was significantly up-regulated as compared with those of CD56(dim) NK cells. The differential expression of NCRs and a2V-ATPase in NK cell subsets may suggest dysregulation of NK cytotoxicity and cytokine production in women with RSA and implantation failures.


Characterization of the Mycobacterium tuberculosis sigma factor SigM by assessment of virulence and identification of SigM-dependent genes.
Alternate sigma factors have been implicated in the survival of mycobacteria in response to specific stresses. To characterize the role of SigM in Mycobacterium tuberculosis, a sigM deletion mutant was generated by allelic exchange in the virulent CDC1551 strain. Comparing the wild-type and Delta sigM strains by complete genomic microarray, we observed a low level of baseline expression of sigM in wild-type M. tuberculosis and no significant differences in the gene expression patterns between these two strains. Alternatively, a SigM-overexpressing M. tuberculosis strain was constructed and microarray profiling revealed SigM-dependent expression of a relatively small group of genes, which included four esat-6 homologues: esxE, esxF, esxT, and esxU. An assessment of SigM-dependent promoters from the microarray analysis revealed a putative consensus sequence for M. tuberculosis SigM of -35 GGAAC and -10 CGTCR. In vitro expression studies showed that M. tuberculosis sigM transcripts accumulate slightly in stationary phase and following heat shock. To understand the role of SigM in pathogenesis, the M. tuberculosis sigM deletion strain was compared with the isogenic wild-type strain and the complemented mutant strain for survival in murine macrophages and in the mouse model. The mutant was found to have similar abilities to survive in both the resting and activated J774A.1 macrophages. Mouse organ bacterial burdens indicated that the mutant proliferated and persisted at the same level as that of the wild-type and complemented strains in lung and spleen tissues. In time-to-death experiments in the mouse model, the Delta sigM mutant exhibited lethality times comparable to those observed for the wild-type and complemented strains. These data indicate that M. tuberculosis SigM governs the expression of a small set of genes, including four esat-6 homologues, and that the loss of sigM does not confer a detectable virulence defect in the macrophages and mouse models of infection.


Capturing naturally occurring superior performance in the laboratory: translational research on expert performance.
One of the central challenges to studying highly skilled performance in the laboratory is methodological. It is necessary to develop standardized methods that allow investigators to make experts repeatedly reproduce their superior performance in the laboratory. The recent increase in demand for translational research has raised related issues of how everyday phenomena, such as successful clinical treatments and expert achievement, can be reproduced in the laboratory and how laboratory studies of these phenomena can lead to successful interventions in everyday life. The expert-performance approach was developed as a framework for capturing, analyzing, and accounting for complex acquired skills and adaptations. Performance is initially captured and elicited in the laboratory using tasks representative of core activities in the domain. Process-tracing measures are employed to identify the mechanisms that mediate the reproducibly superior performance. Finally, the factors responsible for the development of the mediating mechanisms are studied by a retrospective analysis of training activities, such as deliberate practice, as well as genetic prerequisites. The principles and mechanisms discovered need then be validated using more traditional longitudinal and experimental designs.


Small bowel phytobezoars: detection with radiography.
The authors reviewed the radiographic findings in 19 patients with phytobezoars of the small bowel. The most common predisposing causes were previous gastric outlet surgery and persimmon ingestion. Twelve patients underwent contrast material-enhanced studies of the upper gastrointestinal tract, and one patient underwent a barium enema study. These examinations revealed four gastric, two duodenal, and eight small bowel phytobezoars in 10 patients. The obstruction caused by small bowel phytobezoars frequently occurred in the jejunum or proximal ileum, more proximally than has been reported in previous series. Barium studies are useful in differentiating obstruction due to postoperative adhesions from obstruction caused by bezoars. In addition, barium studies enable the detection of residual gastric bezoars. This information has important implications in patient treatment because bezoar obstruction is unlikely to respond to conservative treatment, and concurrent gastric bezoars must be removed to prevent recurrent bowel obstruction.


Schwann cell expression of PLP1 but not DM20 is necessary to prevent neuropathy.
Proteolipid protein (PLP1) and its alternatively spliced isoform, DM20, are the major myelin proteins in the CNS, but are also expressed in the PNS. The proteins have an identical sequence except for 35 amino acids in PLP1 (the PLP1-specific domain) not present in DM20. Mutations of PLP1/DM20 cause Pelizaeus-Merzbacher Disease (PMD), a leukodystrophy, and in some instances, a peripheral neuropathy. To identify which mutations cause neuropathy, we have evaluated a cohort of patients with PMD and PLP1 mutations for the presence of neuropathy. As shown previously, all patients with PLP1 null mutations had peripheral neuropathy. We also identified 4 new PLP1 point mutations that cause both PMD and peripheral neuropathy, three of which truncate PLP1 expression within the PLP1-specific domain, but do not alter DM20. The fourth, a splicing mutation, alters both PLP1 and DM20, and is probably a null mutation. Six PLP1 point mutations predicted to produce proteins with an intact PLP1-specific domain do not cause peripheral neuropathy. Sixty-one individuals with PLP1 duplications also had normal peripheral nerve function. These data demonstrate that expression of PLP1 but not DMSO is necessary to prevent neuropathy, and suggest that the 35 amino acid PLP1-specific domain plays an important role in normal peripheral nerve function.


Time-dependent density functional theory investigation of the absorption, fluorescence, and phosphorescence spectra of solvated coumarins.
Using time-dependent density functional theory (TD-DFT) and the polarizable continuum model, we have computed the electronic transitions of a large panel of coumarin dyes in their enol, keto, cationic, and anionic forms. Several processes have been studied: absorption, fluorescence, 0-0 phosphorescence, and triplet-triplet excitations. For each process, detailed comparison with experimental data has been carried out. Using the PBE06-31+G(d) scheme, it turns out that for a given electronic transition the experimental shifts resulting from the substitution of the coumarin core are nicely reproduced. Indeed, once a simple statistical correction is applied, the mean absolute errors on the absorption and fluorescence wavelengths are limited to 8 nm (0.09 eV) and 9 nm (0.07 eV), respectively. A valuable correlation between the experimental and theoretical phosphorescence auxochromic displacements has also been unravelled. The differences between the wavelengths of the various electronic processes of a given dye tend to be fairly predicted, especially for the fluorescence-phosphoresence shifts that are strongly overestimated by TD-DFT.


Exploring the Contribution of Autophagy to the Excess-Sucrose Response in Arabidopsis thaliana.
Autophagy is an essential intracellular eukaryotic recycling mechanism, functioning in, among others, carbon starvation. Surprisingly, although autophagy-deficient plants (atg mutants) are hypersensitive to carbon starvation, metabolic analysis revealed that they accumulate sugars under such conditions. In plants, sugars serve as both an energy source and as signaling molecules, affecting many developmental processes, including root and shoot formation. We thus set out to understand the interplay between autophagy and sucrose excess, comparing wild-type and atg mutant seedlings. The presented work showed that autophagy contributes to primary root elongation arrest under conditions of exogenous sucrose and glucose excess but not during fructose or mannitol treatment. Minor or no alterations in starch and primary metabolites were observed between atg mutants and wild-type plants, indicating that the sucrose response relates to its signaling and not its metabolic role. Extensive proteomic analysis of roots performed to further understand the mechanism found an accumulation of proteins essential for ROS reduction and auxin maintenance, which are necessary for root elongation, in atg plants under sucrose excess. The analysis also suggested mitochondrial and peroxisomal involvement in the autophagy-mediated sucrose response. This research increases our knowledge of the complex interplay between autophagy and sugar signaling in plants.


Stuttering as a manifestation of stroke.
Two cases are described of stuttering as a manifestation of cerebral ischaemia in previously stutter-free individuals. In the first case, stuttering suddenly ceased after carotid endarterectomy; the second patient developed stuttering after a period of three days of complete aphasia after which the stutter gradually improved. Aetiological possibilities are discussed in the light of current theories.


Bioequivalence testing for locally acting gastrointestinal products: what role for gamma scintigraphy?
Bioequivalence testing for locally acting gastrointestinal products is a challenging issue for both the pharmaceutical industry and the global regulatory authorities. It is widely accepted that for medicinal products not intended to be delivered into the systemic circulation, pharmacokinetic bioavailability cannot be used. However, it is becoming increasingly accepted that local availability may be assessed, where appropriate, by approaches that qualitatively reflect the presence of the active substance at the site of action. These methods must be specifically chosen for that combination of active substance and route of drug delivery. This paper argues for the use of gamma scintigraphy as a validated measure of local availability and bioequivalence for topically acting products administered to the gastrointestinal tract by the oral and rectal route.


[Family Health Strategy: contributions of health teams in the nutritional care of children].
The scope of this article is to evaluate the structure and work processes of Family Health Strategy teams related to the nutritional care of children. It involved an assessment survey of 136 health teams in 45 municipalities in the State of Paraíba. The data on structure (availability of anthropometric equipment, supplements and technical documents) and processes (management, intersectoriality and activities of the Brazilian Breastfeeding and Feeding Strategy) were summarized in scores and classified as incipient, intermediate or advanced. Analyses were performed according to contextual characteristics of the municipality (population size and human development) and the health team (whether from the Programa Mais Médicos or conventional teams, and whether accompanied by a nutritionist or not). Nutritional care was classified at the intermediate level, with the availability of technical documents, the use of SISVAN or the e-SUS and the implementation of the Brazilian Breastfeeding and Feeding Strategy being the most deficient items. Large municipalities and expanded health teams with nutritionists had better structure and process conditions, respectively. The fragmented implementation of nutritional care calls for improvements in structure and processes for due fitness for purpose.


Secondary Plastids of Euglenids and Chlorarachniophytes Function with a Mix of Genes of Red and Green Algal Ancestry.
Endosymbiosis has been common all along eukaryotic evolution, providing opportunities for genomic and organellar innovation. Plastids are a prominent example. After the primary endosymbiosis of the cyanobacterial plastid ancestor, photosynthesis spread in many eukaryotic lineages via secondary endosymbioses involving red or green algal endosymbionts and diverse heterotrophic hosts. However, the number of secondary endosymbioses and how they occurred remain poorly understood. In particular, contrasting patterns of endosymbiotic gene transfer have been detected and subjected to various interpretations. In this context, accurate detection of endosymbiotic gene transfers is essential to avoid wrong evolutionary conclusions. We have assembled a strictly selected set of markers that provides robust phylogenomic evidence suggesting that nuclear genes involved in the function and maintenance of green secondary plastids in chlorarachniophytes and euglenids have unexpected mixed red and green algal origins. This mixed ancestry contrasts with the clear red algal origin of most nuclear genes carrying similar functions in secondary algae with red plastids.


Evaluation of interaction between histidine binding Cu2+ ion and histidine by atomic force microscopy.
This paper presents a direct interaction force measurement between histidine molecules using AFM force-distance curve measurement. AFM force-distance curves between the histidine-modified cantilever and substrate in the different conditions with or without intercalating Cu2+ ion were measured and interpreted via Gaussian curve fitting analyses. The adhesion force between histidine molecules was shown to be 110 pN under the presence of Cu2+. The result was compareable to the measured adhesion force about 0 pN, which was measured by the removal of Cu2+ ion with the addition of EDTA. The result indicated the direct histidine-histidie interaction was difficult without the role of the bridigible ionic component. From the results, the possibility of direct measurement on chemical affinities between biomolecules was suggested by using AFM force-distance curve analyses. Especially, the current approach showed the possible affinity measurement techniques that elucidate the role of bridge ions.


Focal manipulations of formant trajectories reveal a role of auditory feedback in the online control of both within-syllable and between-syllable speech timing.
Within the human motor repertoire, speech production has a uniquely high level of spatiotemporal complexity. The production of running speech comprises the traversing of spatial positions with precisely coordinated articulator movements to produce 10-15 sounds/s. How does the brain use auditory feedback, namely the self-perception of produced speech sounds, in the online control of spatial and temporal parameters of multisyllabic articulation? This question has important bearings on the organizational principles of sequential actions, yet its answer remains controversial due to the long latency of the auditory feedback pathway and technical challenges involved in manipulating auditory feedback in precisely controlled ways during running speech. In this study, we developed a novel technique for introducing time-varying, focal perturbations in the auditory feedback during multisyllabic, connected speech. Manipulations of spatial and temporal parameters of the formant trajectory were tested separately on two groups of subjects as they uttered "I owe you a yo-yo." Under these perturbations, significant and specific changes were observed in both the spatial and temporal parameters of the produced formant trajectories. Compensations to spatial perturbations were bidirectional and opposed the perturbations. Furthermore, under perturbations that manipulated the timing of auditory feedback trajectory (slow-down or speed-up), significant adjustments in syllable timing were observed in the subjects' productions. These results highlight the systematic roles of auditory feedback in the online control of a highly over-learned action as connected speech articulation and provide a first look at the properties of this type of sensorimotor interaction in sequential movements.


Quantitative culture of bronchoalveolar lavage fluid in community-acquired lower respiratory tract infections.
To evaluate the diagnostic value of quantitative bacterial culture of bronchoalveolar lavage (BAL) fluid obtained by fibreoptic bronchoscopy, 67 consecutive immunocompetent adult patients admitted to hospital with community-acquired lower respiratory tract infections from September 1997 to May 1998 were investigated. Results were compared to the findings in eight healthy control persons investigated in February 1998. There was no difference between study patients and control persons when quantitative culture of total cumulative bacterial findings or bacteria categorized as members of the oropharyngeal normal flora were compared. The culture of normal flora in bronchial washings probably reflects contamination of the lower airways with secretions from upper arways by the fibreoptic procedure itself, as fractionated sampling showed a 10-fold reduct on in quantitative culture results when a primary bronchial washing was compared to a secondary sampling from the same bronchus in the control group. Twenty-four (36%) of 67 patients were cultured as positive in the study group while all control persons were cultured as negative for bacteria categorized as potential pathogens. With a threshold value for positive culture of 10(4) cfu ml(-1) the specificity of lavage culture of potential pathogenic bacteria in relation to actual lower airway infection was 100%. Therefore, quantitative bacterial culture of potential pathogenic bacteria in BAL fluid is very specific but only positive in about one-third of unselected immunocompetent adult patients with a lower respiratory tract infection.


The clustering of four subfamilies of satellite DNA at individual chromosome ends in Silene latifolia.
The satellite DNA (satDNA) on the ends of chromosomes has been isolated and characterized in the dioecious plant Silene latifolia. BAC clones containing large numbers of repeat units of satDNA in a tandem array were isolated to examine the clustering of the repeat units. satDNA repeat units were purified from each isolated BAC clone and sequenced. To investigate pairwise similarities among the repeat units, a phylogenetic tree was constructed using the neighbor-joining algorithm. The repeat units derived from 7 BAC clones were grouped into SacI, KpnI, #11F02, and #16E07 subfamilies. The SacI and KpnI subfamilies have been reported previously. Multicolored fluorescence in situ hybridization (FISH) using SacI or KpnI subfamily probes resulted in different signal intensities and locations at the chromosomal ends, indicating that each chromosomal end has a unique composition of subfamilies of satDNA. For example, the p arm of the X chromosome exhibited signal composition similar to that on the pseudo autosomal region (PAR) of the Y chromosome, but not to that on the q arm of the X chromosome. The satDNA has not been completely homogenized in the S. latifolia genome. Each subfamily is available for a probe of FISH karyotyping.


Cytochrome P450 Mediated Bioactivation of Rutaevin, a Bioactive and Potentially Hepatotoxic Component of Evodia Rutaecarpa.
Rutaevin is one of the major bioactive constituents isolated from Evodia rutaecarpa, a well-known herbal medicine that has been widely prescribed for the treatment of gastrointestinal disorders in China. However, oral administration of rutaevin has been shown to cause hepatotoxicity in mice. Bioactivation was suggested to be involved in rutaevin-induced hepatotoxicity. The aim of this study was to investigate the bioactivation of rutaevin in rat and human liver microsomes fortified with NADPH. Rutaevin was metabolized into the reactive intermediate cis-butene-1,4-dial (BDA) that was dependent on NADPH. The rutaevin-derived BDA intermediate was trapped by nucleophiles such as glutathione (GSH), N-acetyl-lysine (NAL), and methoxylamine (MOA) in the microsomal incubation system. A total of 10 conjugates resulting from the conjugation of the intermediate with GSH, NAL, or MOA were detected and structurally characterized by liquid chromatography combined with high-resolution tandem mass spectrometry. M1, structurally confirmed by NMR spectroscopic analysis, was identified as a cyclic mono(GSH) conjugate of the BDA intermediate, which was also found in the biliary samples of rutaevin-treated rats. Further inhibitory experiments suggested that ketoconazole showed strong inhibitory effect on the formation of the rutaevin-derived BDA intermediate. CYP3A4 was demonstrated to be the major enzyme responsible for rutaevin bioactivation by using cDNA-expressed human recombinant cytochrome P450 enzymes. Additionally, it was found that rutaevin was a mechanism-based inactivator of CYP3A4, with inactivation parameters of KI = 15.98 μM, kinact = 0.032 min-1, and t1/2 inact = 21.65 min. In summary, these findings are of great significance in understanding the bioactivation mechanism of rutaevin, the potential mechanism of rutaevin-caused hepatotoxicity, and the drug-drug interactions associated with rutaevin mainly via CYP3A4 inactivation.


Globoside Is Dispensable for Parvovirus B19 Entry but Essential at a Postentry Step for Productive Infection.
Globoside (Gb4) is considered the primary receptor of parvovirus B19 (B19V); however, its expression does not correlate well with the attachment and restricted tropism of the virus. The N terminus of VP1 (VP1u) of B19V interacts with an as-yet-unknown receptor required for virus internalization. In contrast to Gb4, the VP1u cognate receptor is expressed exclusively in cells that B19V can internalize. With the aim of clarifying the role of Gb4 as a B19V receptor, we knocked out the gene B3GalNT1 coding for the enzyme globoside synthase in UT7/Epo cells. Consequently, B3GalNT1 transcripts and Gb4 became undetectable in the knockout (KO) cells without affecting cell viability and proliferation. Unexpectedly, virus attachment, internalization, and nuclear targeting were not disturbed in the KO cells. However, NS1 transcription failed, and consequently, genome replication and capsid protein expression were abrogated. The block could be circumvented by transfection with a B19V infectious clone, indicating that Gb4 is not required after the generation of viral double-stranded DNA with resolved inverted terminal repeats. While in wild-type (WT) cells, occupation of the VP1u cognate receptor with recombinant VP1u disturbed virus binding and blocked the infection, antibodies against Gb4 had no significant effect. In a mixed population of WT and KO cells, B19V selectively infected WT cells. This study demonstrates that Gb4 does not have the expected receptor function, as it is dispensable for virus entry; however, it is essential for productive infection, explaining the resistance of the rare individuals lacking Gb4 to B19V infection.IMPORTANCE Globoside has long been considered the primary receptor of B19V. However, its expression does not correlate well with B19V binding and uptake and cannot explain the pathogenesis or the remarkable narrow tissue tropism of the virus. By using a knockout cell line, we demonstrate that globoside does not have the expected function as a cell surface receptor required for B19V entry, but it has an essential role at a postentry step for productive infection. This finding explains the natural resistance to infection associated with individuals lacking globoside, contributes to a better understanding of B19V restricted tropism, and offers novel strategies for the development of antiviral therapies.


Effects of vitamin B12 on bright light on cognitive and sleep-wake rhythm in Alzheimer-type dementia.
The present study investigated the effects of vitamin B12 (VB12) on circadian rhythm in Alzheimer-type dementia (ATD). Twenty-eight ATD patients were treated with bright light therapy (BLT) for 8 weeks. For the latter 4 weeks, half were treated with VB12 with BLT (BLT + VB12). We evaluated the cognitive state with Mini-Mental State Examination and the circadian rhythm with actigraphy after the fourth and eighth week. After the first 4 weeks BLT improved the circadian rhythm disturbances and cognitive state especially in the early stage of ATD. Although the latter 4 week-BLT caused no significant effects on the circadian rhythm; BLT + VB12 improved the vigilance level during the daytime. These results suggest that VB12 has some efficiency to enhance vigilance for ATD patients.


Ghosts in the consulting room. An attachment perspective on intergenerational transmission.
Intergenerational transmission of attachment patterns--Selma Fraiberg's classic account of 'ghosts in the nursery'--is one of the basic assumptions of attachment theory, amply confirmed by empirical studies which link narrative style in parents (as measured by the Adult Attachment Interview) with security or insecurity of attachment in infants, as measured by the Strange Situation test. This paper argues that a 'sense of self' and Fonagy's 'reflective function', vital to healthy psychic functioning, arise out of early parental handling, and particularly out of the kind of mirroring experiences hypothesized by Winnicott and elaborated by Gergely and Watson, in which the parent defines her or himself as a 'mirror', by 'marking' (exaggeration of response) and 'contingency' (scrupulously following the child's lead in interactive play). The paper argues that in psychotherapy a similar responsiveness on the part of the therapist is called for. Dealing with 'ghosts in the consulting room' (i.e. transference) is a three phase project comprising (a) calling up the ghosts, through the development of narrative function (b) attempts to expel the ghosts through anger at environmental failure and differentiation of the self from its past (c) coming to terms with ghosts, thus seeing that one's parents were themselves products of intergenerational transmission. An illustrative case is presented.


[Oligonodular hepatocellular carcinoma (HCC): MR-controlled laser-induced thermotherapy].
To prospectively evaluate the therapeutic potential of MR-guided laser-induced thermotherapy (LITT) in patients with oligonodular hepatocellular carcinoma. 39 patients with 61 intrahepatic lesions were treated with LITT. The Nd:YAG laser fiber was introduced with a percutaneously positioned irrigated laser application system. Qualitative and quantitative MR parameters and clinical data were evaluated. All patients tolerated the procedure well under local anesthesia. All observed complications were minor and no further treatment was necessary. Online MR thermometry allowed exact visualization. Lesions up to 2 cm in diameter could be efficiently treated with a single laser application, larger lesions were treated simultaneous multiapplication. In 97.5% we achieved a complete necrosis of the tumor and a 5 mm safety margin, resulting in a complete destruction of the tumor without local recurrences. Mean survival was 4.4 years (95% CI: 3.6-5.2 years) after the time of diagnoses of the HCC (Kaplan-Meier-method). In intrahepatic oligonodular involvement of hepatocellular carcinoma LITT appears to be an effective therapeutic procedure with a high tumor control rate and better survival data.


Epithelial membrane antigen expression by the perineurial cell: further studies of peripheral nerve lesions.
We have previously shown that a range of anti-epithelial membrane antigen monoclonal antibodies show immunoreactivity with the perineurial fibroblast, both in normal nerves and within a range of common peripheral nerve tumours. We have extended these observations by studying a further collection of peripheral nerve lesions, including some which have previously been thought to have an origin from the perineurial cell. The results provide further evidence that these antibodies reliably stain perineurial cells and that in conjunction with antisera to S-100 protein and neurofilaments, the relative contributions of the perineurial fibroblast, Schwann cell and neurone can be assessed within a nerve-related tumour/lesion. The perineurial fibroblast is an important component of some peripheral nerve lesions.


Thoughts on health economics in rheumatoid arthritis.
In this manuscript we discuss the reasons why and how health economics is important, the type of economic studies that are relevant in healthcare to different stakeholders in general, and what analyses can and have been performed in the field of rheumatoid arthritis (RA). We will thus specifically address costs and outcome measurements in RA, as well as the need for modelling in chronic progressive diseases.


Juan Comas's summary history of the American association of physical anthropologists (1928-1968).
This translation of Juan Comas's Summary History of the American Association of Physical Anthropologists was originally published in Spanish by the Instituto Nacional de Antropología e Historia, Mexico, in 1969 (Departamento de Investigaciones Antropológicas, Publication 22). Physical anthropologists from North America and members of the American Association of Physical Anthropologists owe Juan Comas a debt of gratitude for having labored to produce this Summary History of the AAPA. There is much useful and interesting material in this document: extensive endnotes that are helpful to the historian of the profession; an appendix of the Journal issues where the proceedings of annual meetings can be found; a detailed listing of contributors of papers to annual meetings from 1930-1968; a warm acknowledgment and history of the contributions of the Wenner-Gren Foundation to biological anthropology; a history of the Yearbook of Physical Anthropology; and comments on the short-lived PA Newsletter. In addition, there are appendices with the founding AAPA Constitution and By-Laws from 1930 and as they existed in 1968. All of this synoptic information saves the reader with interests in the history of the AAPA considerable effort, especially when few university and college libraries have the full (old and new) series of the AJPA on their shelves. We have tried to provide a translation of Comas's history that is faithful to the original Spanish-language publication. In a few cases, we shortened sentences and applied a slightly more modern usage than was popular in the late 1960s.


Reinekea aestuarii sp. nov., isolated from tidal flat sediment.
Two Gram-negative, non-motile, non-pigmented and curved rod-shaped bacterial strains, designated IMCC4489(T) and IMCC4451, were isolated from a tidal flat sediment of the Yellow Sea. Strains IMCC4489(T) and IMCC4451 shared 99.9 % 16S rRNA gene sequence similarity and 78.5 % DNA-DNA relatedness, which suggested that they belonged to the same species. The isolates were most closely related to Reinekea blandensis MED297(T) (98.7-98.8 % 16S rRNA gene sequence similarity) and Reinekea marinisedimentorum DSM 15388(T) (95.3-95.4 %). DNA-DNA relatedness between the strains and R. blandensis CCUG 52066(T) was 31-34 %. Strains IMCC4489(T) and IMCC4451 could also be differentiated from the type strains of the two recognized Reinekea species by several phenotypic properties. The DNA G+C content was 51.3-51.5 mol% and the major isoprenoid quinone was Q-8. On the basis of the data obtained in this study, it is proposed that strains IMCC4489(T) and IMCC4451 represent a novel species, Reinekea aestuarii sp. nov. The type strain is IMCC4489(T) (=KCTC 22813(T) =KCCM 42938(T) =NBRC 106079(T)).


Standing [111] gold nanotube to nanorod arrays via template growth.
Standing [111]-oriented crystalline gold nanotube (AuNT) and nanorod (AuNR) arrays using electrochemical deposition through template growth are reported. Segments of single crystal and bamboo-like crystalline AuNR arrays with growing direction of [111], having a diameter of 100-150 nm and a length of 10 µm, standing perpendicular to Ti metal foil substrates, are synthesized. The as-synthesized AuNTs and AuNRs are characterized by powder and five circle x-ray diffractometry, UV-visible molecular absorption spectrometry, field emission scanning electron microscopy, and transmission electron microscopy. AuNRs and AuNTs are formed by starting with a tube and the wall of the tube gets progressively thicker and eventually sealed up to form nanorods. Optical absorption at 548 and 578 nm wavelength for gold nanotubes and nanorods, respectively, caused by the transverse (width) mode is identified.


The mean platelet volume is positively correlated with serum thyrotropin concentrations in a population of healthy subjects and subjects with unsuspected subclinical hypothyroidism.
A possible prothrombotic effect of elevated thyrotropin (TSH) has been suggested. The mean platelet volume (MPV), which is used to measure the platelet size, can reflect platelet activity. Although limited and inconsistent data regarding the effects of thyroid function on the MPV are available from small-scale case-control studies, no study has been based on a general population, particularly in euthyroid states. The objective of the present study was to determine whether there is an association between the MPV and serum TSH concentrations in an apparently healthy Korean population without overt thyroid disease, but including subjects with unsuspected subclinical hypothyroidism (SCH). We retrospectively studied 6893 asymptomatic Korean adults who were 20 years of age or older and who underwent voluntary regular health check-ups at the Health Promotion Center of Chosun University Hospital. The subjects who met the inclusion and exclusion criteria were subdivided into four groups, such as tertile groups for the TSH reference range and an SCH (TSH ≥4 μIU/mL with a normal free T4 concentration) group according to the TSH level. We compared the mean values of the MPVs among the groups. Multivariate logistic regression analyses were used to identify associations between the highest tertile of the MPV and the TSH subgroups. The mean level of the MPV in all study subjects was 8.12±0.75 femtoliters (fL), and the mean value of the MPV was significantly different in each group. The mean MPV in SCH was significantly higher compared with those of the first tertile (T1) and second tertile (T2). Moreover, the mean MPV increased statistical significantly by increasing tertiles of the TSH concentration and was highest in SCH (T1, 8.08±0.81 fL; T2, 8.09±0.62 fL; T3, 8.13±0.77 fL; SCH, 8.21±0.81 fL; p for trend=0.012). After adjusting for risk factors associated with increasing MPVs and platelet counts, SCH was independently associated with the highest tertile of the MPV (all subjects, odds radio (OR) 1.58 [95% confidence interval (CI) 1.19-2.09]; men, OR 1.70 [CI 1.10-2.64]; women, OR 1.55 [CI 1.06-2.26]). The MPV was positively correlated with the TSH level. SCH is an independently associated factor with the highest tertile of MPV in a general Korean population. We propose that the MPV may contribute to the prothrombotic condition that is associated with SCH and perhaps even in putative euthyroid states where the TSH level is the higher part of the normal range.


Intestinal spirochete infections of chickens: a review of disease associations, epidemiology and control.
This paper presents an overview of intestinal spirochete infections of chickens. It focuses particularly on studies in Australia, where recent surveys of 136 layer and broiler breeder flocks have revealed a high rate of infection (>40%) with intestinal spirochetes. Infection was not detected in broiler flocks. Approximately 50% of isolates from infected flocks were Brachyspira (Serpulina) intermedia or B. pilosicoli, with the other isolates being B. innocens, B. murdochii or the proposed species 'B. pulli'. No isolates of B. alvinipulli were found. Intestinal spirochetes were significantly associated with wet litter problems and/or reduced egg production. Experimental infection of point-of-lay birds with either B. intermedia or B. pilosicoli caused reduced egg production, and, with B. intermedia, a significant increase in fecal moisture content. Infection with B. innocens caused no significant changes. In-water treatment of a flock with a mixed spirochete infection using lincospectin resulted in a slimy diarrhea lasting for 2-3 weeks, followed by absence of spirochetes for 3 months. Birds treated with tiamulin remained healthy, and had a reduced level of infection with intestinal spirochetes (30%) for 3 months. Trials are under way to test the efficacy of antimicrobials in point-of-lay chickens experimentally infected with either B. intermedia or B. pilosicoli.


[Is the suicidal risk assessment scale RSD of predictive value?].
A part (60% to 70%) of those who are going to act out their suicide consult a doctor the month before. Studies have shown the need to improve the practitioner's capacity to diagnose depression. The assessment of the suicidal risk is crucial. The search for suicidal risk factors helps to define the populations at risk. However, it doesn't provide information concerning the possibility of acting out in the short term. And how does one react when faced with those who do not present any of the risk factors? Psychometric instruments attempt to help the therapist in his/her reasoning. SUICIDAL RISK ASSESSMENT: Among them, the suicidal risk assessment scale RSD should be mentioned. Its objective is to estimate the seriousness of the suicidal risk, with 11 levels. It is built around a possible will to commit suicide rather than a single assessment of the frequency of suicidal ideas. Its construction in hierarchical order permits the progressive assessment of the suicidal risk, in the form of a semi-structured interview. Hence, the suicidal risk assessment scale RSD looks for the existence of death wishes (levels 1-2), of suicide ideations and its frequency (levels 3-4-5), and of a passive desire to die (level 6). Level 7 shows the onset of a decision making process, except that the patient is still inhibited by various important factors in his/her life. More often, the fear of inflicting immense suffering to his/her loved ones or for religious beliefs, is found. From level 8, determination has made way to hesitation. An active death wish exists, and although the plan remains undefined, the act is decided on. At level 9 the methods of application are developed and a plan is established. The ultimate level exists when there is a start in the preparation of the act of suicide (level 10). This hierarchical order has been confirmed by some epidemiological studies. The inclusion of the suicidal risk assessment scale RSD in a double-blind, placebo-controlled study, which tested the efficacy of fluvoxamine in reducing the risk of recurrence of depression over 18 months, appears of particular interest. In this multicentre study, patients of both sexes were included, aged between 18 and 70 years, presenting a major depressive episode with a MADRS equal to a minimum of 25, and having had a minimum of two episodes of major depression within the last five years. The resulting analysis carried out on 103 patients showed a satisfactory concurrent validity between the suicidal risk assessment scale RSD and the items "suicide" of the MADRS (rho=0.79; p=0.0001) and the Hamilton Depression Scale (rho=0.70; p=0.0001), and fairly satisfactory concurrent validity with the depression degree assessed by the MADRS overall score (rho=0.40; p=0.0001). The short-term follow-up under treatment revealed enhanced sensitivity of the RSD versus the MADRS. The improvement in suicidal risk, assessed by the RSD, was faster than the improvement in depression, which is interesting from a clinical point of view. The medium-term follow-up tested the predictive validity of RSD and confirmed a greater level of suicidal risk from a score of 7 on the RSD, with the death by suicide of 2 subjects among the 15 who exhibited a score between 7 and 10 on the RSD on inclusion. On the other hand, no acting out, no attempted suicides, and no suicides were noted in the group of 88 subjects whose RSD was lower or equal to 6 on inclusion (p=0.02 using Fisher's exact test). Thus, the RSD appears of interest, from a clinical point of view, by providing a -diagnostic, or a scientific approach.


[Expression of the voltage-dependent anion channel gene in human ejaculated spermatozoa].
To identify the genes involved in sperm motility. We hybridized asthenospermia and normal motile sperm cDNA samples with the human whole genome Affymetrix chip to screen differentially expressed genes. Then we detected the mRNA expressions of the voltage-dependent anion channel genes (VDACs) in human organs and spermatozoa by RT-PCR and compared their expressions in the poor and normal motility spermatozoa. Differentially expressed genes VDACs were identified by analysis of the hybridization signals, including the 3 subtypes VDAC1, VDAC2 and VDAC3. The expression of VDAC2 mRNA was significantly decreased in the poor motility sperm (0.568 +/- 0.036), as compared with the healthy men (0.803 +/- 0.043, P < 0.01). The decreased expression of VDAC2 in the ejaculated spermatozoa is possibly associated with the reduction of sperm motility.


Six Months of Hybrid Closed-Loop Versus Manual Insulin Delivery With Fingerprick Blood Glucose Monitoring in Adults With Type 1 Diabetes: A Randomized, Controlled Trial.
To investigate glycemic and psychosocial outcomes with hybrid closed-loop (HCL) versus user-determined insulin dosing with multiple daily injections (MDI) or insulin pump (i.e., standard therapy for most adults with type 1 diabetes). Adults with type 1 diabetes using MDI or insulin pump without continuous glucose monitoring (CGM) were randomized to 26 weeks of HCL (Medtronic 670G) or continuation of current therapy. The primary outcome was masked CGM time in range (TIR; 70-180 mg/dL) during the final 3 weeks. Participants were randomized to HCL (n = 61) or control (n = 59). Baseline mean (SD) age was 44.2 (11.7) years, HbA1c was 7.4% (0.9%) (57 [10] mmol/mol), 53% were women, and 51% used MDI. HCL TIR increased from (baseline) 55% (13%) to (26 weeks) 70% (10%) with the control group unchanged: (baseline) 55% (12%) and (26 weeks) 55% (13%) (difference 15% [95% CI 11, 19]; P < 0.0001). For HCL, HbA1c was lower (median [95% CI] difference -0.4% [-0.6, -0.2]; -4 mmol/mol [-7, -2]; P < 0.0001) and diabetes-specific positive well-being was higher (difference 1.2 [95% CI 0.4, 1.9]; P < 0.0048) without a deterioration in diabetes distress, perceived sleep quality, or cognition. Seventeen (9 device-related) versus 13 serious adverse events occurred in the HCL and control groups, respectively. In adults with type 1 diabetes, 26 weeks of HCL improved TIR, HbA1c, and their sense of satisfaction from managing their diabetes compared with those continuing with user-determined insulin dosing and self-monitoring of blood glucose. For most people living with type 1 diabetes globally, this trial demonstrates that HCL is feasible, acceptable, and advantageous.


Predictors of Discontinuation of Subdermal Levonorgestrel Implants (Jadelle) at the Lagos University Teaching Hospital, Lagos, Nigeria: An Analytic Cohort Study.
Uptake and continuation of long acting reversible contraceptives (LARC) such as subdermal levonorgestrel implants are pivotal to the achievement of some sustainable development goals (SDG). We evaluated Jadelle uptake and factors affecting its discontinuation in the first three years of initiation at the Family Planning Clinic of the College of Medicine, University of Lagos (CMUL), Nigeria. A retrospective cohort study was conducted among 517 consecutive new Jadelle acceptors, at the family planning clinic of CMUL, between 1 October 2007 and 30 September 2010, who were followed up till 30 September 2011. Survival life table analysis, Kaplan-Meier plots and multivariable Cox proportional hazard regression were conducted to evaluate factors affecting time to Jadelle discontinuation. Stata version 13 statistical software (StataCorp USA) was used for analysis. The mean age of Jadelle acceptors was 32.9 (S.D: ±5.4) years and uptake rate of Jadelle was 61.8%. The overall discontinuation rate was 19 per 100 women-years while the 1-year, 2-year and 3-year Jadelle discontinuation rates were 7.1%; 27.0% and 58.1% respectively. Increased age, (P=0.047) and previous contraceptive use (P <0.001) were independent predictors of Jadelle discontinuation. Menstrual irregularity (51.4%) and intention to get pregnant (40.3%) were the commonest reasons for discontinuation. The failure rate was low at 0.27 per 100 women-years. This study showed that Jadelle had a high uptake rate complimented by a low failure rate; and is quite suitable for postpartum childbirth spacing as well as ongoing long term contraception.


Genome mining of the biosynthetic gene cluster of the polyene macrolide antibiotic tetramycin and characterization of a P450 monooxygenase involved in the hydroxylation of the tetramycin B polyol segment.
A polyene macrolide antibiotic tetramycin biosynthetic gene cluster was identified by genome mining and isolated from Streptomyces hygrospinosus var. beijingensis. Genetic and in silico analyses gave insights into the mechanism of biosynthesis of tetramycin, and a model of the tetramycin biosynthetic pathway is proposed. Inactivation of a cytochrome P450 monooxygenase gene, tetrK, resulted in the production of a tetramycin B precursor: tetramycin A, which lacks a hydroxy group in its polyol region. TetrK was subsequently overexpressed heterologously in E. coli with a His(6) tag, and purified TetrK efficiently hydroxylated tetramycin A to afford tetramycin B. Kinetic studies revealed no inhibition of TetrK by substrate or product. Surprisingly, sequence-alignment analysis showed that TetrK, as a hydroxylase, has much higher homology with epoxidase PimD than with hydroxylases NysL and AmphL. The 3D structure of TetrK was then constructed by homology modeling with PimD as reference. Although TetrK and PimD catalyzed different chemical reactions, homology modeling indicated that they might share the same catalytic sites, despite also possessing some different sites correlated with substrate binding and substrate specificity. These findings offer good prospects for the production of improved antifungal polyene analogues.


Evaluation of 27Al and 51V electric field gradients and the crystal structure for aluminum orthovanadate (AlVO4) by density functional theory calculations.
Three sets of crystal-structure data reported for AlVO(4) from two powder-XRD studies and a density functional theory (DFT) investigation, employing the Vienna ab initio simulation package (VASP), have been examined and refined using the DFT structure-optimization scheme implemented in the WIEN2k software. The crystal structures are evaluated on the basis of (27)Al and (51)V quadrupole coupling parameters recently reported for AlVO(4), employing the corresponding electric-field gradient (EFG) tensor elements obtained from the DFT calculations. The DFT calculations provide a reliable assignment of the (27)Al/(51)V resonances from three distinct Al and three V environments to the specific crystallographic sites in the asymmetric unit for AlVO(4). An improved agreement between experimental quadrupole tensor elements and calculated EFG tensors is achieved after the DFT structure optimizations and consistent results are obtained using the three different structures as starting points. The improvement of the structural data is also supported by an evaluation of the Al-O and V-O bond lengths before and after DFT structure optimization. The (51)V nuclear quadrupole moment, |Q((51)V)| = 4.8 +/- 0.1 fm(2), derived from the present analysis, represents a value of higher accuracy than earlier reported Q((51)V) values. The origin of the (27)Al and (51)V EFGs are investigated by an evaluation of the orientations of the EFG tensors in the crystal frame and by an examination of the individual contributions from the valence electrons and the surrounding lattice. The latter investigation shows that the magnitude and orientation of the tensors are largely determined by the p-p((27)Al) and p-p, d-d((51)V) orbital contributions to the valence electrons, while the lattice part only gives a minor contribution for both nuclei.


Women, guilt, and home computers.
This paper will discuss, with reference to a field study examining attitudinal, emotional, and physical barriers, some of the ways in which some women are currently restricted in accessing networked computers in their own households. The study was prompted by a concern that current discussions focussing on the potential of computer-supported distance learning do not acknowledge differences in women's experience of family and household which may impinge on access. It will be suggested here that the domestic arrangements of space and time with home computers are crucial factors in supporting women's access to learning and personal development via the Internet.


Formation of atroviridin by Hypocrea atroviridis is conidiation associated and positively regulated by blue light and the G protein GNA3.
Species of the mycoparasitic fungal genus Hypocrea/Trichoderma are prominent producers of peptaibols, a class of small linear peptides of fungal origin. Some of these peptaibols have been shown to act synergistically with cell-wall-degrading enzymes in the inhibition of the growth of other fungi in vitro and in vivo. Here we present the structure of the Hypocrea atroviridis peptaibol synthetase gene (pbs1), deduced from the genome sequence of H. atroviridis. It consists of 19 typical peptide synthetase modules with the required additional modifying domains at the N and C termini. Phylogenetic and similarity analyses of the individual amino acid-activating modules is consistent with its ability to synthesize atroviridins. Matrix-assisted laser desorption ionization-time of flight mass spectrometry of surface-grown cultures of H. atroviridis showed that no peptaibols were formed during vegetative growth, but a microheterogenous mixture of atroviridins accumulated when the colonies started to sporulate. This correlation between sporulation and atroviridin formation was shown to be independent of the pathway inducing sporulation (i.e., light, mechanical injury and carbon starvation, respectively). Atroviridin formation was dependent on the function of the two blue light regulators, BLR1 and BLR2, under some but not all conditions of sporulation and was repressed in a pkr1 (regulatory subunit of protein kinase A) antisense strain with constitutively active protein kinase A. Conversely, however, loss of function of the Galpha-protein GNA3, which is a negative regulator of sporulation and leads to a hypersporulating phenotype, fully impairs atroviridin formation. Our data show that formation of atroviridin by H. atroviridis occurs in a sporulation-associated manner but is uncoupled from it at the stage of GNA3.


Ovomanonychus, a new genus of South American Sericoidini (Coleoptera: Scarabaeidae: Melolonthinae).
Ovomanonychus new genus (Coleoptera: Scarabaeidae: Melolonthinae: Sericoidini) is described based on Ovomanonychus rosettae (Frey, 1976), new combination (type species), Ovomanonychus inajae new species, and Ovomanonychus striatus new species. The genus occurs in Bahia, Mato Grosso, Espírito Santo, Minas Gerais, Paraná, Rio de Janeiro, and São Paulo States, Brazil. Description is provided for the new genus and for its placement in Sericoidini. A key to species is presented along with illustrations, distributional data, and a map for each species.


Common genetic variation and novel loci associated with volumetric mammographic density.
Mammographic density (MD) is a strong and heritable intermediate phenotype of breast cancer, but much of its genetic variation remains unexplained. We conducted a genetic association study of volumetric MD in a Swedish mammography screening cohort (n = 9498) to identify novel MD loci. Associations with volumetric MD phenotypes (percent dense volume, absolute dense volume, and absolute nondense volume) were estimated using linear regression adjusting for age, body mass index, menopausal status, and six principal components. We also estimated the proportion of MD variance explained by additive contributions from single-nucleotide polymorphisms (SNP-based heritability [h2SNP]) in 4948 participants of the cohort. In total, three novel MD loci were identified (at P < 5 × 10- 8): one for percent dense volume (HABP2) and two for the absolute dense volume (INHBB, LINC01483). INHBB is an established locus for ER-negative breast cancer, and HABP2 and LINC01483 represent putative new breast cancer susceptibility loci, because both loci were associated with breast cancer in available meta-analysis data including 122,977 breast cancer cases and 105,974 control subjects (P < 0.05). h2SNP (SE) estimates for percent dense, absolute dense, and nondense volume were 0.29 (0.07), 0.31 (0.07), and 0.25 (0.07), respectively. Corresponding ratios of h2SNP to previously observed narrow-sense h2 estimates in the same cohort were 0.46, 0.72, and 0.41, respectively. These findings provide new insights into the genetic basis of MD and biological mechanisms linking MD to breast cancer risk. Apart from identifying three novel loci, we demonstrate that at least 25% of the MD variance is explained by common genetic variation with h2SNP/h2 ratios varying between dense and nondense MD components.


The Budding Yeast "Saccharomyces cerevisiae" as a Drug Discovery Tool to Identify Plant-Derived Natural Products with Anti-Proliferative Properties.
The budding yeast Saccharomyces cerevisiae is a valuable system to study cell-cycle regulation, which is defective in cancer cells. Due to the highly conserved nature of the cell-cycle machinery between yeast and humans, yeast studies are directly relevant to anticancer-drug discovery. The budding yeast is also an excellent model system for identifying and studying antifungal compounds because of the functional conservation of fungal genes. Moreover, yeast studies have also contributed greatly to our understanding of the biological targets and modes of action of bioactive compounds. Understanding the mechanism of action of clinically relevant compounds is essential for the design of improved second-generation molecules. Here we describe our methodology for screening a library of plant-derived natural products in yeast in order to identify and characterize new compounds with anti-proliferative properties.


[Psychophysiologic particularities in patients with functional syndromes].
Patients with gastroenterological or cardiovascular functional syndromes (n = 109) were examined by means of an extensive psychological standardized diagnostic programme and psychological strain analysis was carried out under psychogenic stress in laboratory. The results were compared with healthy probands (n = 51) likewise examined. Patients with functional syndromes significantly discriminated of healthy probands by more psychosocial risk constellation under strain caused by more distress and in parameters of performance and in psychophysiological field in some strain variables (heart rate, blood pressure, acral vasomotricity) and their dynamics.


Optimization of band-selective homonuclear dipolar recoupling in solid-state NMR by a numerical phase search.
Spin polarization transfers among aliphatic 13C nuclei, especially 13Cα-13Cβ transfers, permit correlations of their nuclear magnetic resonance (NMR) frequencies that are essential for signal assignments in multidimensional solid-state NMR of proteins. We derive and demonstrate a new radio-frequency (RF) excitation sequence for homonuclear dipolar recoupling that enhances spin polarization transfers among aliphatic 13C nuclei at moderate magic-angle spinning (MAS) frequencies. The phase-optimized recoupling sequence with five π pulses per MAS rotation period (denoted as PR5) is derived initially from systematic numerical simulations in which only the RF phases are varied. Subsequent theoretical analysis by average Hamiltonian theory explains the favorable properties of numerically optimized phase schemes. The high efficiency of spin polarization transfers in simulations is preserved in experiments, in part because the RF field amplitude in PR5 is only 2.5 times the MAS frequency so that relatively low 1H decoupling powers are required. Experiments on a microcrystalline sample of the β1 immunoglobulin binding domain of protein G demonstrate an average enhancement factor of 1.6 for 13Cα → 13Cβ polarization transfers, compared to the standard 13C-13C spin-diffusion method, implying a two-fold time saving in relevant 2D and 3D experiments.


Association of Salmonella enterica serovar enteritidis yafD with resistance to chicken egg albumen.
Salmonella enterica serovar Enteritidis is a major cause of food-borne diseases in industrialized countries. The incidence of S. enterica serovar Enteritidis infections has increased substantially in recent decades, and S. enterica serovar Enteritidis is now one of the leading serovars of Salmonella in the United States. A unique epidemiological characteristic of S. enterica serovar Enteritidis is its association with chicken shell eggs, since approximately 80% of all human gastrointestinal diseases can be traced to contaminated egg products. Eggs are contaminated when bacteria from reproductive tissues of infected hens are packaged into the eggs and persist inside the hostile egg albumen environment. Therefore, resistance to egg albumen is an important aspect in the transmission of S. enterica serovar Enteritidis. We identified a gene, yafD from S. enterica serovar Enteritidis, whose overexpression conferred upon S. enterica serovar Typhimurium enhanced resistance to egg albumen, while disruption of this gene in S. enterica serovar Enteritidis rendered the organism more susceptible to egg albumen. YafD is homologous to members of an exonuclease-endonuclease-phosphatase family, including some enzymes involved in DNA repair. Furthermore, we discovered that egg albumen has nuclease activities and uses both circular and linear DNA as substrates. We propose that YafD provides a survival advantage to S. enterica serovar Enteritidis in eggs by repairing DNA damage caused by egg albumen and that it may be one of the biologic determinants that contribute to the epidemiological association of S. enterica serovar Enteritidis with egg products.


Mitochondrial-Localized Versus Cytosolic Intracellular CO-Releasing Organic PhotoCORMs: Evaluation of CO Effects Using Bioenergetics.
While interactions between carbon monoxide (CO) and mitochondria have been previously studied, the methods used to deliver CO (gas or CO-releasing metal carbonyl compounds) lack subcellular targeting and/or controlled delivery. Thus, the effective concentration needed to produce changes in mitochondrial bioenergetics is yet to be fully defined. To evaluate the influence of mitochondrial-targeted versus intracellularly released CO on mitochondrial oxygen consumption rates, we developed and characterized flavonol-based CO donor compounds that differ at their site of release. These molecules are metal-free, visible light triggered CO donors (photoCORMs) that quantitatively release CO and are trackable in cells via confocal microscopy. Our studies indicate that at a concentration of 10 μM, the mitochondrial-localized and cytosolic CO-releasing compounds are similarly effective in terms of decreasing ATP production, maximal respiration, and the reserve capacity of A549 cells. This concentration is the lowest to impart changes in mitochondrial bioenergetics for any CO-releasing molecule (CORM) reported to date. The results reported herein demonstrate the feasibility of using a structurally tunable organic photoCORM framework for comparative intracellular studies of the biological effects of carbon monoxide.


An LRRTM4-HSPG complex mediates excitatory synapse development on dentate gyrus granule cells.
Selective synapse development determines how complex neuronal networks in the brain are formed. Complexes of postsynaptic neuroligins and LRRTMs with presynaptic neurexins contribute widely to excitatory synapse development, and mutations in these gene families increase the risk of developing psychiatric disorders. We find that LRRTM4 has distinct presynaptic binding partners, heparan sulfate proteoglycans (HSPGs). HSPGs are required to mediate the synaptogenic activity of LRRTM4. LRRTM4 shows highly selective expression in the brain. Within the hippocampus, we detected LRRTM4 specifically at excitatory postsynaptic sites on dentate gyrus granule cells. LRRTM4(-/-) dentate gyrus granule cells, but not CA1 pyramidal cells, exhibit reductions in excitatory synapse density and function. Furthermore, LRRTM4(-/-) dentate gyrus granule cells show impaired activity-regulated AMPA receptor trafficking. These results identifying cell-type-specific functions and multiple presynaptic binding partners for different LRRTM family members reveal an unexpected complexity in the design and function of synapse-organizing proteins.


Utilization of an intramolecular hydrogen bond to increase the CNS penetration of an NK(1) receptor antagonist.
This paper describes the synthesis and physical and biological effects of introducing different substituents at the alpha-position of the tryptophan containing neurokinin-1 receptor antagonist [(R)-2-(1H-indol-3-yl)-1-methyl-1-((S)-1-phenyl-ethylcarbamoyl)-ethyl]-carbamic acid benzofuran-2-ylmethyl ester (CI 1021). The described compounds all exhibit less than 5 nM binding affinities for the human neurokinin-1 receptor and selectivity over the tachykinin NK(2) and NK(3) receptor subtypes. Application of variable temperature nuclear magnetic resonance spectroscopy studies of the amide and urethane protons was utilized to determine the existence of an intramolecular hydrogen bond. This intramolecular hydrogen bond increases the apparent lipophilicity to allow increased central nervous system penetration and pharmacological activity (gerbil foot tap test) in the case of the highest affinity compound [(S)-1-dimethylaminomethyl-2-(1H-indol-3-yl)-1-((S)-1-phenyl-ethylcarbamoyl)-ethyl]-carbamic acid benzofuran-2-ylmethyl ester (PD 174424) over those analogues that could not form an intramolecular hydrogen bond.


Designing Motif-Engineered Receptors To Elucidate Signaling Molecules Important for Proliferation of Hematopoietic Stem Cells.
The understanding of signaling events is critical for attaining long-term expansion of hematopoietic stem cells ex vivo. In this study, we aim to analyze the contribution of multiple signaling molecules in proliferation of hematopoietic stem cells. To this end, we design a bottom-up engineered receptor with multiple tyrosine motifs, which can recruit multiple signaling molecules of interest. This is followed by a top-down approach, where one of the multiple tyrosine motifs in the bottom-up engineered receptor is functionally knocked out by tyrosine-to-phenylalanine mutation. The combination of these two approaches demonstrates the importance of Shc in cooperation with STAT3 or STAT5 in the proliferation of hematopoietic stem cells. The platform developed herein may be applied for analyzing other cells and/or other cell fate regulation systems.


MR imaging of the breast for the detection, diagnosis, and staging of breast cancer.
With the introduction of contrast agents, advances in surface coil technology, and development of new imaging protocols, contrast agent-enhanced magnetic resonance (MR) imaging has emerged as a promising modality for detection, diagnosis, and staging of breast cancer. The reported sensitivity of MR imaging for the visualization of invasive cancer has approached 100%. There are many examples in the literature of MR imaging--demonstrated mammographically, sonographically, and clinically occult breast cancer. Often, breast cancer detected on MR images has resulted in a change in patient care. Despite these results, there are many unresolved issues, including no defined standard technique for contrast-enhanced breast MR imaging, no standard interpretation criteria for evaluating such studies, no consensus on what constitutes clinically important enhancement, and no clearly defined clinical indications for the use of MR imaging. Furthermore, this technology remains costly, and issues of cost-effectiveness and cost competition from percutaneous biopsy have yet to be fully addressed. These factors along with the lack of commercially available MR imaging--guided localization and biopsy systems have slowed the transfer of this imaging technology from research centers to clinical breast imaging practices. Technical requirements, potential clinical applications, and potential pitfalls and limitations of contrast-enhanced MR imaging as a method to help detect, diagnose, and stage breast cancer will be described.


Potential flue gas impurities in carbon dioxide streams separated from coal-fired power plants.
For geological sequestration of carbon dioxide (CO2) separated from pulverized coal combustion flue gas, it is necessary to adequately evaluate the potential impacts of flue gas impurities on groundwater aquifers in the case of the CO2 leakage from its storage sites. This study estimated the flue gas impurities to be included in the CO2 stream separated from a CO2 control unit for a different combination of air pollution control devices and different flue gas compositions. Specifically, the levels of acid gases and mercury vapor were estimated for the monoethanolamine (MEA)-based absorption process on the basis of published performance parameters of existing systems. Among the flue gas constituents considered, sulfur dioxide (SO2) is known to have the most adverse impact on MEA absorption. When a flue gas contains 3000 parts per million by volume (ppmv) SO2 and a wet flue gas desulfurization system achieves its 95% removal, approximately 2400 parts per million by weight (ppmw) SO2 could be included in the separated CO2 stream. In addition, the estimated concentration level was reduced to as low as 135 ppmw for the SO2 of less than 10 ppmv in the flue gas entering the MEA unit. Furthermore, heat-stable salt formation could further reduce the SO2 concentration below 40 ppmw in the separated CO2 stream. In this study, it is realized that the formation rates of heat-stable salts in MEA solution are not readily available in the literature and are critical to estimating the levels and compositions of flue gas impurities in sequestered CO2 streams. In addition to SO2, mercury, and other impurities in separated CO2 streams could vary depending on pollutant removal at the power plants and impose potential impacts on groundwater. Such a variation and related process control in the upstream management of carbon separation have implications for groundwater protection at carbon sequestration sites and warrant necessary considerations in overall sequestration planning, engineering, and management.


The clathrin heavy chain isoform CHC22 functions in a novel endosomal sorting step.
Clathrin heavy chain 22 (CHC22) is an isoform of the well-characterized CHC17 clathrin heavy chain, a coat component of vesicles that mediate endocytosis and organelle biogenesis. CHC22 has a distinct role from CHC17 in trafficking glucose transporter 4 (GLUT4) in skeletal muscle and fat, though its transfection into HEK293 cells suggests functional redundancy. Here, we show that CHC22 is eightfold less abundant than CHC17 in muscle, other cell types have variably lower amounts of CHC22, and endogenous CHC22 and CHC17 function independently in nonmuscle and muscle cells. CHC22 was required for retrograde trafficking of certain cargo molecules from endosomes to the trans-Golgi network (TGN), defining a novel endosomal-sorting step distinguishable from that mediated by CHC17 and retromer. In muscle cells, depletion of syntaxin 10 as well as CHC22 affected GLUT4 targeting, establishing retrograde endosome-TGN transport as critical for GLUT4 trafficking. Like CHC22, syntaxin 10 is not expressed in mice but is present in humans and other vertebrates, implicating two species-restricted endosomal traffic proteins in GLUT4 transport.


Determination of phytase activity in feed by a colorimetric enzymatic method: collaborative interlaboratory study.
Fourteen laboratories participated in a collaborative study (coded fyt9404) and 13 laboratories participated in a study (coded fyt9410) to validate a colorimetric assay for determination of microbial phytase activity in feed. For each study, all laboratories received 6 laboratory samples provided by one commercial supplier (phytase activity levels within the range of 200-400 per kg) to be analyzed in duplicate. Method performance was calculated and statistical calculations were executed according to AOAC guidelines. Results from 3 laboratories for study fyt9404 and from one laboratory for study fyt9410 were excluded from statistical analysis because of invalid data determined during initial review by Youden pair, value versus laboratory. For study fyt9404, repeatability relative standard deviation (RSDr) values ranged from 6.2 to 8.6%, and reproducibility relative standard deviation (RSDR) values ranged from 14.1 to 27.6%. No outliers were identified. For study fyt9410, RSDr values ranged from 3.9 to 7.9%, and RSDR values ranged from 14.0 to 20.5%. With outliers excluded, RSDr values ranged from 2.5 to 7.9%, and RSDR values ranged from 14.0 to 20.5%.


Oxytocin does not influence adrenocorticotropin secretion in man.
Recent studies suggest that oxytocin inhibits ACTH secretion in normal men, whereas previous animal studies indicate that oxytocin is a weak secretagogue of ACTH. We studied the effect of oxytocin on plasma ACTH and cortisol in normal men under three conditions. Using four different doses of oxytocin (30, 60, 90, and 120 mU/kg), given by iv bolus injection, we found no difference in the effect of oxytocin on morning ACTH and cortisol levels compared with the effect of a placebo. A prolonged infusion of oxytocin (90 mU/kg . h) given from 0300-0600 h did not suppress basal ACTH or cortisol levels or delay or blunt their normal circadian rise. In addition, pretreatment with oxytocin (50 mU/kg, iv bolus dose, followed by an infusion of 50 mU/kg . h) did not alter the ACTH and cortisol responses to vasopressin. We conclude that oxytocin is not a major regulator of pituitary-adrenal activity in normal men.


Antiretroviral treatment programmes in Nepal: Problems and barriers.
Antiretroviral (ARV) drugs have become the cornerstone of HIV (Human Immunodeficiency Virus) care and treatment. Its use has led to a marked reduction in AIDS (Acquired Immune Deficiency Syndrome) related morbidity and mortality. However, more than fi ve years after their introduction few HIV infected people in Nepal are receiving ARVs. The main aim of this study is to identify barriers and obstacles to providing and expanding ARV programmes in Nepal. A qualitative approach consisting of in-depth interviews with three groups of stakeholders:policy makers, ARV service providers and ARV recipients were carried out. The transcripts were analysed using a thematic approach. The estimated number of people in need was high compared with people currently receiving ARV in Nepal. With regards to the proper distribution of the ARVs, the main problems identified in the interviews were: lack of infrastructure, lack of human resources, financial constraints, programmatic problems, weak leadership and management at national level, poor cooperation between management structures, geographical barriers, lack of awareness and low uptake of counselling and/or testing, stigmatization and discrimination felt by the health workers and the community, lack of coordination and limited access to services. Limited resources and administrative capacity coupled with strong underlying needs for services pose serious challenges to the government. Despite this, better use could be made of existing services and resources to help benefit more people from ARV.


Role of Extracellular Matrix and Inflammation in Abdominal Aortic Aneurysm.
Abdominal aortic aneurysm (AAA) is one of the most dangerous cardiovascular diseases, occurring mainly in men over the age of 55 years. As it is asymptomatic, patients are diagnosed very late, usually when they suffer pain in the abdominal cavity. The late detection of AAA contributes to the high mortality rate. Many environmental, genetic, and molecular factors contribute to the development and subsequent rupture of AAA. Inflammation, apoptosis of smooth muscle cells, and degradation of the extracellular matrix in the AAA wall are believed to be the major molecular processes underlying AAA formation. Until now, no pharmacological treatment has been implemented to prevent the formation of AAA or to cure the disease. Therefore, it is important that patients are diagnosed at a very early stage of the disease. Biomarkers contribute to the assessment of the concentration level, which will help to determine the level and rate of AAA development. The potential biomarkers today include homocysteine, cathepsins, osteopontin, and osteoprotegerin. In this review, we describe the major aspects of molecular processes that take place in the aortic wall during AAA formation. In addition, biomarkers, the monitoring of which will contribute to the prompt diagnosis of AAA patients over the age of 55 years, are described.


Clinical Impact of Revised Cefepime Breakpoint in Patients With Enterobacteriaceae Bacteremia.
The impact of the revised Clinical and Laboratory Standards Institute interpretative criteria for cefepime in Enterobacteriaceae remains unclear. We applied the new breakpoint on 644 previously defined cefepime-susceptible Enterobacteriaceae isolates. We found no differences in mortality or microbiological failure, regardless of isolates being susceptible or cefepime-susceptible dose-dependent by current criteria.


Exosome-carried microRNA-based signature as a cellular trigger for the evolution of chronic lymphocytic leukemia into Richter syndrome.
Even if considered a cumulative and not a proliferative CD5+ B-cell neoplasm, chronic lymphocytic leukemia (CLL) has a proliferation rate higher than that recognized earlier, especially in the lymphoid tissues. Some patients with CLL develop a clinical syndrome entitled Richter syndrome (RS). Understanding CLL genetics and epigenetics may help to elucidate the molecular basics of the clinical heterogeneity of this type of malignancy. In the present project we aimed to identify a microRNA species that can predict the evolution of therapy-resistant CLL towards RS. In the first phase of our study, microRNA-19b was identified as a possible target, and in the second phase, we transfected three different CLL cell lines with microRNA-19b mimic and inhibitor and assessed the potential role on leukemia cells in vitro. The mechanism by which miR-19b acts were identified as the upregulation of Ki67 and downregulation of p53. This was further supported through RT-PCR and western blotting on CLL cell lines, as well as by next generation sequencing on two patients diagnosed with CLL that evolved into RS.


Impact of transport and drug properties on the local pharmacology of drug-eluting stents.
Drugs released from stents are driven by physiological transport forces, principally solvent-driven flow (convection) and random molecular agitation (diffusion). The relative strength of these two forces determines drug penetration and distribution in the arterial wall. Drug physicochemical factors can induce critical modulations to the primary distribution, both transiently and at steady state. Hydrophobic interactions and nonspecific binding, for example, can both result in tissue drug concentrations severalfold above administered concentration. Drug interaction with native proteins may also interfere with drug transfer at the stent-artery interface. These transport forces and tissue interactions can induce local drug concentrations even at steady state to vary by one or more orders of magnitude over the span of a few cells. To account for significant local variations in drug concentrations following stent-based delivery, rational design of vascular delivery systems requires consideration of drug distribution and tissue interactions on a local, continuum basis. Continuum analysis adapts traditional pharmacokinetics to the local environment by supplementing discrete global parameters of drug content with continuous local values of concentration, transport and binding. The interplay of these parameters with local flux conditions and drug and tissue properties defines the local drug distribution in space and over time. This type of analysis may well become increasingly relevant given the trend toward stent-based drug therapy in cardiovascular care.


A randomised trial of placing preterm infants on their back or left side after birth.
Basic life support guidelines recommend placing spontaneously breathing children and adults on their side. Though the majority of preterm newborns breathe spontaneously, they are routinely placed on their back after birth. We hypothesised that they would breathe more effectively when placed on their side. To determine whether preterm newborns placed on their left side at birth, compared with those placed on their back, have higher preductal oxygen saturation (SpO2) at 5 min of life. We randomised infants <32 weeks to be placed on their back or on their left side immediately after birth. Respiratory support was given with a T-piece and face mask with initial fraction of inspired oxygen (FiO2) of 0.3. The FiO2 was increased if SpO2 was <70% at 5 min. We enrolled 87 infants, 41 randomised to back and 46 to left side. The groups were well matched for demographic variables. Fourteen (6 back and 8 left side) infants did not receive respiratory support in the first 5 min. The mean (SD) SpO2 was not different between the groups (back 72 (23) % versus left side 71 (24) %, p=0.956). We observed no adverse effects of placing infants on their side and found no differences in secondary outcomes between the groups. Preterm infants on their left side did not have higher SpO2 at 5 min of life. Placing preterm infants on their side at birth is feasible and appears to be a reasonable alternative to placing them on their back. ISRCTN74486341.


Experimental and time-dependent density functional theory characterization of the UV-visible spectra of monomeric and μ-oxo dimeric ferriprotoporphyrin IX.
Speciation of ferriprotoporphyrin IX, Fe(III)PPIX, in aqueous solution is complex. Despite the use of its characteristic spectroscopic features for identification, the theoretical basis of the unique UV-visible absorbance spectrum of μ-[Fe(III)PPIX](2)O has not been explored. To investigate this and to establish a structural and spectroscopic model for Fe(III)PPIX species, density functional theory (DFT) calculations were undertaken for H(2)O-Fe(III)PPIX and μ-[Fe(III)PPIX](2)O. The models agreed with related Fe(III)porphyrin crystal structures and reproduced vibrational spectra well. The UV-visible absorbance spectra of H(2)O-Fe(III)PPIX and μ-[Fe(III)PPIX](2)O were calculated using time-dependent DFT and reproduced major features of the experimental spectra of both. Transitions contributing to calculated excitations have been identified. The features of the electronic spectrum calculated for μ-[Fe(III)PPIX](2)O were attributed to delocalization of electron density between the two porphyrin rings of the dimer, the weaker ligand field of the axial ligand, and antiferromagnetic coupling of the Fe(III) centers. Room temperature magnetic circular dichroism (MCD) spectra have been recorded and are shown to be useful in distinguishing between these two Fe(III)PPIX species. Bands underlying major spectroscopic features were identified through simultaneous deconvolution of UV-visible and MCD spectra. Computed UV-visible spectra were compared to deconvoluted spectra. Interpretation of the prominent bands of H(2)O-Fe(III)PPIX largely conforms to previous literature. Owing to the weak paramagnetism of μ-[Fe(III)PPIX](2)O at room temperature and the larger number of underlying excitations, interpretation of its experimental UV-visible spectrum was necessarily tentative. Nonetheless, comparison with the calculated spectra of antiferromagnetically coupled and paramagnetic forms of the μ-oxo dimer of Fe(III)porphine suggested that the composition of the Soret band involves a mixture of π→π* and π→d(π) charge transfer transitions. The Q-band and charge transfer bands appear to amalgamate into a mixed low energy envelope consisting of excitations with heavily admixed π→π* and charge transfer transitions.


UPLC-MS/MS assay of riluzole in human plasma and cerebrospinal fluid (CSF): Application in samples from spinal cord injured patients.
In the present study, a sensitive and robust LC-MS/MS method has been developed and validated for the quantification of riluzole in human plasma and cerebrospinal fluid (CSF) in clinical samples from patients with spinal cord injury (SCI). Riluzole and its labeled internal standard (IS) were isolated from plasma and CSF by liquid-liquid extraction using ethyl acetate. Riluzole (m/z 235→166) and IS (m/z 238→169) were detected by electrospray ionization (ESI) using multiple reaction monitoring (MRM) in a positive mode. The assay was linear in the concentration range of 0.5 (LLOQ, signal/noise ratio>10)-800ng/ml in plasma, and 1.0 (LLOQ)-800ng/ml in CSF samples. The intra- and inter-day accuracy in plasma were 94.2-110.0% and 97.8-102.0%, respectively, and those in CSF were 87.6-105.1% and 91.9-98.8%, respectively. The intra- and inter-day precision were 2.2-7.2% and 4.0-9.1%, respectively, in plasma, and 1.4-14.1% and 2.6-11.5%, respectively in CSF. Matrix effect was negligible from both matrices with signal percentages of 97.6-100.6% in plasma and 99.4-106.4% in CSF. The recoveries were >75% in plasma, >84% in CSF with low protein (53.9mg/dl), and >68% in CSF with high protein (348.2mg/dl). This method was successfully applied to quantify riluzole concentrations in plasma and CSF from patients with SCI.


CdSe quantum dot sensitized solar cells. Shuttling electrons through stacked carbon nanocups.
The charge separation between excited CdSe semiconductor quantum dots and stacked-cup carbon nanotubes (SCCNTs) has been successfully tapped to generate photocurrent in a quantum dot sensitized solar cell (QDSC). By employing an electrophoretic deposition technique we have cast SCCNT-CdSe composite films on optically transparent electrodes (OTEs). The quenching of CdSe emission, as well as transient absorption measurements, confirms ultrafast electron transfer to SCCNTs. The rate constant for electron transfer increases from 9.51 x 10(9) s(-1) to 7.04 x 10(10) s(-1) as we decrease the size of CdSe nanoparticles from 4.5 to 3 nm. The ability of SCCNTs to collect and transport electrons from excited CdSe has been established from photocurrent measurements. The morphological and excited state properties of SCCNT-CdSe composites demonstrate their usefulness in energy conversion devices.


Statistical learning of target selection and distractor suppression shape attentional priority according to different timeframes.
Recent findings suggest that attentional and oculomotor control is heavily affected by past experience, giving rise to selection and suppression history effects, so that target selection is facilitated if they appear at frequently attended locations, and distractor filtering is facilitated at frequently ignored locations. While selection history effects once instantiated seem to be long-lasting, whether suppression history is similarly durable is still debated. We assessed the permanence of these effects in a unique experimental setting investigating eye-movements, where the locations associated with statistical unbalances were exclusively linked with either target selection or distractor suppression. Experiment 1 and 2 explored the survival of suppression history in the long and in the short term, respectively, revealing that its lingering traces are relatively short lived. Experiment 3 showed that in the very same experimental context, selection history effects were long lasting. These results seem to suggest that different mechanisms support the learning-induced plasticity triggered by selection and suppression history. Specifically, while selection history may depend on lasting changes within stored representations of the visual space, suppression history effects hinge instead on a functional plasticity which is transient in nature, and involves spatial representations which are constantly updated and adaptively sustain ongoing oculomotor control.


Enhancement of Optical Telecommunication Bands: Pr3+-Doped Halide Phosphate Glasses Display Broadband NIR Photoluminescence Emission.
In the optical energy gap, visible and near-IR emission of halide phosphate glasses with a composition of 40P2O5-30ZnO-20LiCl-10BaF2 in mol% doped with 3.5 × 104 ppm Pr2O3, referred to as PZLBPr, were synthesized. The UV-VIS-NIR and spectroscopic properties of these glasses were also predicted. The current glasses had broadband emission photoluminescence covering a wavelength range of 1250 to 1700 nm when excited at 455 nm. These bands for near-infrared emission luminescence relate to the transitions 1G4 → 3H5, 1D2 → 1G4, and 3H4 → 3F3, 3F4 in the optical telecommunication window. The significant PL emission wideband was caused by the radiative transition from Pr3+: 1D2 to 1G4. At 445 nm excitation, these glasses exhibited emission bands that corresponded to blue/reddish orange spectral ranges in visible ranges. The prepared glass has a high lasing quality factor (Ω4/Ω6 = 0.9), high optical energy (4.72 eV), and quantum efficiency = 87.3% with FWHM = 156 nm of transition emission from the 1D2 → 1G4 level. As a result, broadband near infrared optical amplifiers can be fabricated from the prepared glasses.


Diagnosis of blunt cerebrovascular injuries.
Blunt cerebrovascular injuries (BCVI) are being increasingly recognized. The optimal criteria for screening, and the best diagnostic test, remain a matter of controversy. This review analyzes the available literature to propose management guidelines for the diagnosis of BCVI. A number of centers are screening asymptomatic patients for BCVI. The criteria vary from center to center. The incidence of injuries diagnosed is proportional to the breadth of screening criteria. Noninvasive diagnostic modalities such as duplex ultrasonography, computed tomographic angiography, and magnetic resonance angiography have been proposed as screening tools. Although they are all capable of identifying many injuries, prospective comparisons reveal inaccuracies. Screening for BCVI is appropriate. Institutions should adopt formal criteria, recognizing that more restrictive criteria are likely to miss injuries. Noninvasive modalities must be used with caution, because they have been found to be inferior to arteriography.


Freshwater snails and Schistosomiasis mansoni in the state of Rio de Janeiro, Brazil: III--Baixadas Mesoregion.
In this paper, the third of a series dealing with the survey of freshwater gastropods of the state of Rio de Janeiro, the results of collections carried out in the Mesoregion Baixadas from 2000 to 2002 are presented. Twenty-two species, belonging to seven families, were found. As to the snail intermediate hosts of Schistosoma mansoni, the most frequent species was Biomphalaria tenagophila besides some new findings of Biomphalaria straminea. No specimens were found harboring larval forms of S. mansoni although different kinds of cercariae had been observed.


Sequential molecule-triggered-release system based on acetylated amylose helix aggregates.
We developed a novel sequential molecule-triggered-release system based on acetylated amylose helix aggregates with a proper degree of substitution, in which a loaded molecule can be trigger-released by trigger molecules in sequence. The system is sensitive and capable of time-controllable triggered release. The mechanism involves the sequential pushing of wrapped molecules with low binding free energy out of the helix cavity by a triggered molecule with a high binding free energy.


On the nature and significance of bony proliferation in "rheumatoid variant" disorders.
Radiographic and pathologic abnormalities of the peripheral joints in a cadaver with ankylosing spondylitis are described. Bony proliferation about involved articulations is is characteristic of all "rheumatoid variant" disorders and results from subchondral bony hyperplasia and periosteal new bone formation. Such proliferation may be related to the presence of the histocompatibility antigen B27 in these diseases.


Impact of squamous and/or glandular differentiation on recurrence and progression following transurethral resection for non-muscle invasive urothelial carcinoma of bladder.
The aim of the present study was to investigate the impact of squamous and/or glandular differentiation on the recurrence and progression in patients with nonmuscle invasive urothelial carcinoma of bladder (NMIUCB) following transurethral resection (TURBT). A total of 869 patients with NMIUCB who had been treated with TURBT at The Second Hospital of Tianjin Medical University (Tianjin, China) between January 2006 and January 2011 were retrospectively selected for the present analysis. Associations among squamous and/or glandular differentiation with other clinical and pathological features were assessed by the χ2 test. Recurrence-free survival (RFS) and progression-free survival (PFS) curves were estimated using the Kaplan-Meier method. Univariate and multivariate analyses were performed through a Cox's proportional hazards regression model. Among the 869 patients, 232 (26.7%) patients had squamous and/or glandular differentiation. High grade tumors were more common in patients with squamous and/or glandular differentiation compared with those with pure urothelial carcinoma of bladder (P<0.001). Associations between age (P=0.115), sex (P=0.184), tumor size (P=0.223), tumor multiplicity (P=0.108), pathological tumor stage (P=0.909) and squamous and/or glandular differentiation were not observed to be statistically significant. There was a significant tendency towards higher recurrence rate and shorter RFS time in patients with squamous and/or glandular differentiation. However, no statistically significant differences were observed in progression rate and PFS between the two groups. The multivariate Cox regression analysis, identified squamous and/or glandular differentiation as an independent prognostic predictor of recurrence (hazard ratio =1.46, 95% confidence interval=1.10-1.92, P=0.008). In the present study, the presence of squamous and/or glandular differentiation was associated with a higher recurrence rate and shorter RFS time in patients with NMIUCB. Squamous and/or glandular differentiation is therefore an independent prognostic predictor of recurrence.


Inhibition of mitochondrial respiration by nitric oxide: its role in glucose metabolism and neuroprotection.
There is an increasing body of evidence demonstrating that inhibition of cytochrome c oxidase by nitric oxide (NO) may be one more step in a signaling cascade involved in the physiologic regulation of cell functions. For example, in both astrocytes and neurons the inhibition of mitochondrial respiration by endogenously produced NO induces transient and modest decreases in cellular ATP concentrations. This mitochondrial impairment may serve as a cellular sensor of energy charges, hence modulating metabolic pathways, such as glycolysis, through AMP-activated protein kinase (AMPK) in astrocytes. In neurons, the NO derivative peroxynitrite anion triggers signaling pathways leading to glucose oxidation through the pentose-phosphate pathway to form reducing equivalents in the form of NADPH. The modulation of these metabolic pathways by nitric oxide or its derivatives may be important for understanding the mechanisms by which this free radical affects neuronal death or survival.


Intracellular Molecular Targets and Signaling Pathways Involved in Antioxidative and Neuroprotective Effects of Cannabinoids in Neurodegenerative Conditions.
In the last few decades, endocannabinoids, plant-derived cannabinoids and synthetic cannabinoids have received growing interest as treatment options in neurodegenerative conditions. In various experimental settings, they have displayed antioxidative, anti-inflammatory, antiapoptotic, immunomodulatory, and neuroprotective effects. However, due to numerous targets and downstream effectors of their action, the cellular and molecular mechanisms underlying these effects are rather complex and still under discussion. Cannabinoids are able to neutralize free radicals and modulate the production of reactive oxygen species and the activity of antioxidative systems acting on CB1 and CB2 cannabinoid receptors. The activation of CB1 receptors stimulates signaling pathways involved in antioxidative defense and survival (such as the phosphoinositide 3-kinase (PI3K)/Akt, mitogen-activated protein kinase (MAPK), and Nrf2 pathways) and regulates glutamatergic signaling, the activation of N-methyl-D-aspartate (NMDA) receptors, calcium influx, and the induction of Ca2+-regulated signaling cascades, whereas the neuroprotective effects mediated by CB2 receptors are due to the suppression of microglial activation and the release of prooxidative and proinflammatory mediators. This review summarizes the main molecular mechanisms and new advances in understanding the antioxidative and neuroprotective effects of cannabinoids. Because of the plethora of possible pharmacological interventions related to oxidative stress and cannabinoid-mediated neuroprotection, future research should be directed towards a better understanding of the interplay between activated signal transduction pathways and molecular targets with the aim to improve treatment options and efficacy by targeting the endocannabinoid system.


Intraocular melanoma spread to regional lymph nodes: report of two cases.
To report two cases of regional lymphatic spread of primary uveal melanoma. The clinical records of two patients who underwent enucleation for uveal melanoma and later developed regional lymph node metastases were reviewed. One of the two eyes was initially treated with proton beam irradiation. Histologic sections of the enucleated eyes and excised lymph nodes were examined. The melanomas arose in the choroid and ciliary body of the two patients and spread to regional lymph nodes 2 years after enucleation. The choroidal melanoma recurred after irradiation, diffusely infiltrated the uveal tract, and extended into the conjunctiva via an emissary canal. The ciliary body melanoma spread through the trabecular meshwork to the conjunctiva. Choroidal and ciliary body melanoma may rarely exhibit regional lymph node metastasis. This mode of metastasis may occur after extraocular spread and invasion of conjunctival lymphatics.