The economics of direct-to-consumer advertising of prescription-only drugs: prescribed to improve consumer welfare?
According to economic theory, one might expect that the informational content of direct-to-consumer advertising of prescription-only drugs would improve consumers' welfare. However, contrasting the models of consumer and market behaviour underlying this theory with the realities of the prescription-only drug market reveals that this market is distinct in ways that render it unlikely that advertising will serve an unbiased and strictly informative function. A review of qualitative evidence regarding the informational content of drug advertising supports this conclusion. Direct-to-consumer prescription drug advertising concentrates on particular products, and features of those products, to the exclusion of others, and the information provided has frequently been found to be biased or misleading in regulatory and academic evaluations. Governments that have so far resisted direct-to-consumer advertising should invest in independent sources of evidence that could help consumers and professionals to better understand the risks and benefits of treating disease with alternative drug and non-drug therapies, rather than permitting direct-to-consumer prescription drug advertising.


Localization of substance P-like and enkephalin-like immunoreactivity within preganglionic terminals of the avian ciliary ganglion: light and electron microscopy.
The avian ciliary ganglion receives its only recognized input from the nucleus of Edinger-Westphal. This is known to be a cholinergic input. In the present study, using fluorescein isothiocyanate and peroxidase-antiperoxidase immunohistochemical methods, substance P-like and enkephalin-like immunoreactivity has been found within preganglionic terminals of the avian ciliary ganglion. The ciliary ganglion is known to consist of two distinct cell populations: small choroid cells that project to the smooth muscle coat of the choroid and large ciliary neurons that send axons to both the iris and the ciliary body. Preganglionic terminals on choroid cells consist of small boutonal endings, whereas ciliary neurons receive a calyx-like cap ending around the hilus of the cell. Substance P-like and enkephalin-like immunoreactivity was localized to preganglionic axons and to both boutonal and calyx-like terminations upon cells of the ciliary ganglion. Electron microscopic studies of both substance P-like and enkephalin-like immunoreactive terminals revealed small clear core vesicles (approximately 58 nm in diameter) and two sizes of dense core vesicles (approximately 85 and approximately 119 nm in diameter). Immunoreactive staining was observed only in the smaller dense core vesicles. The unlabeled clear core vesicles were clustered at synaptic release sites, while the immunoreactive and larger unlabeled dense core vesicles usually were not near these synaptic specializations. These observations strongly imply that neuropeptides co-occur with acetylcholine in preganglionic axons of the ciliary ganglion.


A new bacterial sphingophospholipid containing 3-aminopropane-1,2-diol.
1. A new sphingophospholipid has been isolated from the bacterial fraction of sheep rumen contents. 2. This new lipid has been characterized as a ceramide phosphate moiety esterified to 3-aminopropane-1,2-diol through the primary alcohol group. 3. Mass spectrometry has shown the intact lipid to contain a vicinal hydroxyl amino grouping, and oxidation with periodate converts it quantitatively into a new phospholipid which is probably ceramide phosphorylglycolaldehyde. 4. The sphingophospholipid contains a mixture of saturated long-chain bases mainly with branched-chain alkyl groups, which are typical of a microbial origin. 5. A Gram-negative bacterium isolated from rumen contents contains about 30% of the new lipid in its phospholipids when grown in pure culture.


Effect of tobacco smoking and alcohol consumption on the prevalence of nickel sensitization and contact sensitization.
There is evidence that stimulants such as alcohol and tobacco have an effect on the immune system, but little is known about how these lifestyle factors affect the prevalence of contact sensitization. This study investigated whether smoking and alcohol consumption were associated with contact sensitization and nickel sensitization. A random sample of adults (n=3460) from the general population of Copenhagen was invited to participate in a general health examination including patch-testing. Alcohol consumption was not associated with nickel sensitization, whereas a significant trend (p<0.05) was identified between smoking status and nickel sensitization in an adjusted model; i.e. nickel sensitization was higher among both previous smokers (odds ratio (OR) = 1.19; confidence interval (CI) = 0.81-1.76), current light smokers (OR=1.50; CI=0.94-2.37) and current heavy smokers (OR=1.56; CI = 0.87-2.80) compared with never smokers. This study confirmed that smoking is associated with nickel sensitization, but rejected an association with alcohol consumption.


The Arabidopsis COG1 gene encodes a Dof domain transcription factor and negatively regulates phytochrome signaling.
Light is a critical environmental factor that influences almost all developmental aspects of plants, including seed germination, seedling morphogenesis, and transition to reproductive growth. Plants have therefore developed an intricate network of mechanisms to perceive and process environmental light information. To further characterize the molecular basis of light-signaling processes in plants, we screened an activation tagging pool of Arabidopsis for altered photoresponses. A dominant mutation, cog1-D, attenuated various red (R) and far-red (FR) light-dependent photoresponses. The mutation was caused by overexpression of a gene encoding a member of the Dof family of transcription factors. The photoresponses in Arabidopsis were inversely correlated with the expression levels of COG1 mRNA. When the COG1 gene was overexpressed in transgenic plants, the plants exhibited hyposensitive responses to R and FR light in a manner inversely dependent on COG1 mRNA levels. On the other hand, transgenic lines expressing antisense COG1 were hypersensitive to R and FR light. Expression of the COG1 gene is light inducible and requires phytochrome A (phyA) for FR light-induced expression and phytochrome B (phyB) for R light-induced expression. Thus, the COG1 gene functions as a negative regulator in both the phyA- and phyB-signaling pathways. We suggest that these phytochromes positively regulate the expression of COG1, a negative regulator, as a mechanism for fine tuning the light-signaling pathway.


What matters for people with brain cancer? Selecting clinical quality indicators for an Australian Brain Cancer Registry.
The goal of a clinical quality registry is to deliver immediate gains in survival and quality of life by delivering timely feedback to practitioners, thereby ensuring every patient receives the best existing treatment. We are developing an Australian Brain Cancer Registry (ABCR) to identify, describe, and measure the impact of the variation and gaps in brain cancer care from the time of diagnosis to the end of life. To determine a set of clinical quality indicators (CQIs) for the ABCR, a database and internet search were used to identify relevant guidelines, which were then assessed for quality using the AGREE II Global Rating Scale. Potential indicators were extracted from 21 clinical guidelines, ranked using a modified Delphi process completed in 2 rounds by a panel of experts and other stakeholders, and refined by a multidisciplinary Working Group. Nineteen key quality reporting domains were chosen, specified by 57 CQIs detailing the specific inclusion and outcome characteristics to be reported. The selected CQIs will form the basis for the ABCR, provide a framework for achievable data collection, and specify best practices for patients and health care providers, with a view to improving care for brain cancer patients. To our knowledge, the systematic and comprehensive approach we have taken is a world first in selecting the reporting specifications for a brain cancer clinical registry.


Is the low-grade squamous intraepithelial lesion/atypical squamous cells cannot exclude high-grade squamous intraepithelial lesion category associated with cervical intraepithelial neoplasia 2?
A number of cervical smears may exhibit unequivocal low-grade squamous intraepithelial lesions (LSIL) in association with atypical cells cytomorphologically suspicious, but not sufficient to be interpreted as high-grade squamous intraepithelial lesions (HSIL). These lesions are presently called LSIL, atypical squamous cells cannot exclude HSIL (LSIL/ASC-H). Previous studies have shown that LSIL/ASC-H and ASC-H are both equivocal for HSIL and have a high risk of underlying HSIL. However, in researching the literature only two studies were found which rendered the results as cervical intraepithelial neoplasia (CIN) 2 and CIN3 separately. The purpose of this study was to compare the distribution of biopsy results for CIN2 and CIN3 in patients with ASC-H, HSIL, and LSIL/ASC-H. Between January 2005 and December 2011, cervicovaginal smears (98,594) with a diagnosis of ASC-H, LSIL, LSIL/ASC-H, or HSIL were re-evaluated to determine the prevalence of future lesion development. A total of 252 patients who had histologic follow-up within a year were selected. Among these, LSIL/ASC-H (31.7%) had the highest prevalence of CIN2 between LSIL (9.3%), ASC-H (10%), and HSIL (16%). All differences were statistically significant. Because of the high predictive value of CIN2, LSIL/ASC-H may have further importance, especially in women of different age groups.


The D-diastereomer of ShK toxin selectively blocks voltage-gated K+ channels and inhibits T lymphocyte proliferation.
The polypeptide toxin ShK is a potent blocker of Kv1.3 potassium channels, which are crucial in the activation of human effector memory T cells (T(EM)); selective blockers constitute valuable therapeutic leads for the treatment of autoimmune diseases mediated by T(EM) cells, such as multiple sclerosis, rheumatoid arthritis, and type-1 diabetes. The critical motif on the toxin for potassium channel blockade consists of neighboring lysine and tyrosine residues. Because this motif is sufficient for activity, an ShK analogue was designed based on D-amino acids. D-allo-ShK has a structure essentially identical with that of ShK and is resistant to proteolysis. It blocked Kv1.3 with K(d) 36 nm (2,800-fold lower affinity than ShK), was 2-fold selective for Kv1.3 over Kv1.1, and was inactive against other K(+) channels tested. D-allo-ShK inhibited human T(EM) cell proliferation at 100-fold higher concentration than ShK. Its circulating half-life was only slightly longer than that of ShK, implying that renal clearance is the major determinant of its plasma levels. D-allo-ShK did not bind to the closed state of the channel, unlike ShK. Models of D-allo-ShK bound to Kv1.3 show that it can block the pore as effectively as ShK but makes different interactions with the vestibule, some of which are less favorable than for native ShK. The finding that an all-D analogue of a polypeptide toxin retains biological activity and selectivity is highly unusual. Being resistant to proteolysis and nonantigenic, this analogue should be useful in K(+) channel studies; all-d analogues with improved Kv1.3 potency and specificity may have therapeutic advantages.


Introducing a Regulatory Sandbox Into the Indonesian Health System Using e-Malaria as a Use Case: Participatory Action Study.
Regulatory sandboxes offer an alternative solution to address regulatory challenges in adopting disruptive technologies. Although regulatory sandboxes have been widely implemented in the financial sector across more than 50 countries, their application to the health sector remains limited. This study aims to explore stakeholders' perspectives on introducing a regulatory sandbox into the Indonesian health system using e-malaria as a use case. Using a participatory action research approach, this study conducted qualitative research, including desk reviews, focus group discussions, and in-depth interviews with stakeholders. This study sought to understand stakeholders' concerns and interests regarding the regulatory sandbox and to collaboratively develop a regulatory sandbox model to support the malaria program. The study revealed that most stakeholders had limited awareness of the regulatory sandbox concept. Concerns have been raised regarding the time required to establish regulations, knowledge gaps among stakeholders, data protection issues, and limited digital infrastructure in malaria endemic areas. Existing regulations have been found to be inadequate to accommodate disruptive healthtech for malaria. Nevertheless, through a collaborative process, stakeholders successfully developed a regulatory sandbox model specifically for e-malaria, with the crucial support of the Ministry of Health. The regulatory sandbox holds the potential for adoption in the Indonesian health system to address the limited legal framework and to facilitate the rapid and safe adoption of disruptive healthtech in support of the malaria elimination program. Through stakeholder involvement, guidelines for implementing the regulatory sandbox were developed and innovators were successfully invited to participate in the first-ever trial of a health regulatory sandbox for e-malaria in Indonesia. Future studies should provide further insights into the challenges encountered during the e-malaria regulatory sandbox pilot study, offering a detailed account of the implementation process.


Genome-wide identification and characterization of WOX genes in Cucumis sativus.
WUSCHEL-related homeobox (WOX) proteins are plant-specific transcription factors that are profoundly involved in regulation of plant development and stress responses. In this study, we totally identified 11 WOX transcription factor family members in cucumber (Cucumis sativus, CsWOX) genome and classified them into three clades with nine subclades based on phylogenetic analysis results. Alignment of amino acid sequences revealed that all WOX members in cucumber contained the typical homeodomain, which consists of 60-66 amino acids and is folded into a helix-turn-helix structure. Gene duplication event analysis indicated that CsWOX1a and CsWOX1b were a segment duplication pair, which might affect the number of WOX members in cucumber genome. The expression profiles of CsWOX genes in different tissues demonstrated that the members sorted into the ancient clade (CsWOX13a and CsWOX13b) were constitutively expressed at higher levels in comparison to the others. Cis-element analysis in promoter regions suggested that the expression of CsWOX genes was associated with phytohormone pathways and stress responses, which was further supported by RNA-seq data. Taken together, our results provide new insights into the evolution of cucumber WOX genes and improve our understanding about the biological functions of the CsWOX gene family.


Assessing the biosynthetic capabilities of secretory glands in Citrus peel.
Epithelial cells (ECs) lining the secretory cavities of Citrus peel have been hypothesized to be responsible for the synthesis of essential oil, but direct evidence for such a role is currently sparse. We used laser-capture microdissection and pressure catapulting to isolate ECs and parenchyma cells (as controls not synthesizing oil) from the peel of young grapefruit (Citrus × paradisi 'Duncan'), isolated RNA, and evaluated transcript patterns based on oligonucleotide microarrays. A Gene Ontology analysis of these data sets indicated an enrichment of genes involved in the biosynthesis of volatile terpenoids and nonvolatile phenylpropanoids in ECs (when compared with parenchyma cells), thus indicating a significant metabolic specialization in this cell type. The gene expression patterns in ECs were consistent with the accumulation of the major essential oil constituents (monoterpenes, prenylated coumarins, and polymethoxylated flavonoids). Morphometric analyses demonstrated that secretory cavities are formed early during fruit development, whereas the expansion of cavities, and thus oil accumulation, correlates with later stages of fruit expansion. Our studies have laid the methodological and experimental groundwork for a vastly improved knowledge of the as yet poorly understood processes controlling essential oil biosynthesis in Citrus peel.


Hyperproliferative embryotoxon simulating double cornea.
Posterior embryotoxon, an anteriorly displaced Schwalbe's line, is the most common feature of Axenfeld Rieger syndrome. We report a case of Axenfeld anomaly with unusual corneal manifestation, that is, a fairly symmetric, hyperproliferated posterior embryotoxon mimicking double cornea as well as a double pupil.


Soluble Epoxide Hydrolase Pharmacological Inhibition Decreases Alveolar Bone Loss by Modulating Host Inflammatory Response, RANK-Related Signaling, Endoplasmic Reticulum Stress, and Apoptosis.
Epoxyeicosatrienoic acids (EETs), metabolites of arachidonic acid derived from the cytochrome P450 enzymes, are mainly metabolized by soluble epoxide hydrolase (sEH) to their corresponding diols. EETs but not their diols, have anti-inflammatory properties, and inhibition of sEH might provide protective effects against inflammatory bone loss. Thus, in the present study, we tested the selective sEH inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), in a mouse model of periodontitis induced by infection with Aggregatibacter actinomycetemcomitans Oral treatment of wild-type mice with TPPU and sEH knockout (KO) animals showed reduced bone loss induced by A. actinomycetemcomitans This was associated with decreased expression of key osteoclastogenic molecules, receptor activator of nuclear factor-κB/RANK ligand/osteoprotegerin, and the chemokine monocyte chemotactic protein 1 in the gingival tissue without affecting bacterial counts. In addition, downstream kinases p38 and c-Jun N-terminal kinase known to be activated in response to inflammatory signals were abrogated after TPPU treatment or in sEH KO mice. Moreover, endoplasmic reticulum stress was elevated in periodontal disease but was abrogated after TPPU treatment and in sEH knockout mice. Together, these results demonstrated that sEH pharmacological inhibition may be of therapeutic value in periodontitis.


Precision patterning with luminescent nanocrystal-functionalized beads.
A reliable strategy is presented to combine the preparation of functional building blocks based on polymer beads decorated with luminescent nanocrystals (NCs) and their precise positioning onto suitable patterns by capillary assembly technique. In particular, a layer-by-layer (LbL) polyelectrolyte (PE) deposition procedure has been implemented to provide uniform NC coverage on PS beads, thus conveying the optical properties of luminescent nanocrystals to highly processable PS beads. The latter have then been integrated into patterned stamps by means of template-driven capillary assembly. Their selective positioning has been directed by means of pattern geometry. The use of luminescent (CdSe)ZnS NCs offers a direct optical probe to evaluate the efficiency of the positioning procedure on the substrate, enabling the extension of the method to a wide range of materials, i.e., NCs with different compositions and specific geometry-dependent properties. Moreover, the precise control over the pattern geometry and the micrometer accuracy in positioning achieved by capillary assembly make such functional patterned structures excellent candidates for integration into devices exploiting specific size-dependent NC properties.


Randomized controlled trial of unflued gas heater replacement on respiratory health of asthmatic schoolchildren.
Previous studies do not provide a clear picture of the relationship between nitrogen dioxide (NO(2)) exposure and asthma. Eighteen schools using unflued gas heating in winter were randomly allocated to either retain their heaters (10 control schools) or to have replacement flued gas or electric heaters installed at the beginning of winter (8 intervention schools). Fortnightly telephone interviews were used to record daily individual asthma symptoms that occurred over 12 weeks (including winter). Lung function and histamine challenge tests were performed at baseline and the end of the study. NO(2) was measured in each school classroom on 9 days and in each household on 3 days spread over the study period. From 199 primary school children that met the eligibility criteria, 45 intervention and 73 control children agreed to participate. Baseline characteristics were similar between groups. Difficulty breathing during the day (Relative Risk [RR] = 0.41; 95% CI: 0.07, 0.98) and night (RR = 0.32; 95% CI: 0.14, 0.69), chest tightness during the day (RR = 0.45; 95% CI: 0.25, 0.81), and daytime asthma attacks (RR = 0.39; 95% CI: 0.17, 0.93) were significantly reduced in the intervention group. Percentage predicted forced expiratory volume in one second (FEV(1)), the concentration of histamine inducing a 20% fall in FEV(1) (PD(20)), and the dose-response slope (DRS) were similar between groups at follow-up. Mean (standard deviation) NO(2) levels were 15.5 (6.6) parts per billion (ppb) and 47.0 (26.8) ppb in the intervention and control schools respectively (P < 0.001). Asthma symptoms were reduced following a replacement intervention that removed high exposure to NO(2). Such replacement should be considered a public health priority for schools using unflued gas heating during winter.


Carbon monoxide: a novel neural messenger or putative neurotransmitter?
The novel data indicating the role of carbon monoxide as an eventual putative neurotransmitter are discussed. The perspectives of further studies are delineated. Actually following scarce points suggest that carbon monoxide (CO) my be eventually neurotransmitter: an uneven distribution in the nervous system of heme oxygenase, which produces CO; the generation of long term potentiation in hippocampus; possible mediation of release of hypothalamic factors; eventual signalling role of CO in immune system.


Antibacterial Filtration Membranes Based on PVDF-co-HFP Nanofibers with the Addition of Medium-Chain 1-Monoacylglycerols.
The efficiency of filtration membranes is substantially lowered by bacterial attachments and potential fouling processes, which reduce their durability and lifecycle. The antibacterial and antifouling properties exhibited by the added materials play a substantial role in their application. We tested a material poly(vinylidene fluoride)-co-hexafluoropropylene (PDVF-co-HFP) based on an electrospun copolymer, where an agent was incorporated with a small amount of ester of glycerol consecutively with caprylic, capric, and lauric acids. Each of these three materials differing in the esters (1-monoacylglycerol, 1-MAG) used was prepared with three weighted concentrations of 1-MAG (1, 2, and 3 wt %). The presence of 1-MAG with an amphiphilic structure resulted in the hydrophilic character of the prepared materials that contributed to the filtration performance. The tested materials (membranes) were characterized with rheological, optical (scanning electron microscopy, SEM), Fourier transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD), and other methods to evaluate antibacterial and antifouling activities. The pure water flux was 6 times higher than that of the neat PVDF-co-HFP membrane when the added 1-MAG attained only 1 wt %. It was experimentally shown that the PVDF-co-HFP/1-MAG membrane with high wettability improved antibacterial activity and antifouling ability. This membrane is highly promising for water treatment due to the safety of antibacterial 1-MAG additives.


Dynamic tradeoffs in the raft-mediated entry of human immunodeficiency virus type 1 into cells.
To initiate an infection human immunodeficiency virus type 1 (HIV-1) particles must first bind to receptors on the surface of their host cells, a process that eventually leads to fusion of viral and cellular membranes and release of the viral genome into the cytoplasm. Understanding the molecular mechanisms of these processes may enable the development of new anti-HIV strategies. Disagreement currently prevails on the role in virus entry of microdomains within the cellular plasma membrane known as lipid rafts. Experiments have suggested that lipid rafts, in their interactions with cellular receptors and viral particles, either promote or have minimal effect on viral entry. Here we develop a dynamic model for HIV-1 entry that enables us to identify and quantitatively assess tradeoffs that can arise from the clustering of receptors in rafts. Specifically, receptor clustering can be detrimental to the initiation of viral infection by reducing the probability that a virus particle finds its primary receptor, CD4. However, receptor clustering can also enable a virus particle, once bound, to rapidly form multivalent interactions with receptors and co-receptors that are required for virus-cell membrane fusion. We show how the resolution of such tradeoffs hinges on the level and spatial distribution of receptors and co-receptors on the cell surface, and we discuss implications of these effects for the design of therapeutics that inhibit HIV-1 entry.


Vitamin D and tibiofemoral joint orientation angles in children.
Vitamin D is an important component in musculoskeletal development and function in children. The aim of our study was to investigate serum vitamin D levels and tibiofemoral joint orientation angles in children. We performed a retrospective review on a consecutive series of children presenting with lower limb complaints. The children underwent an assessment of serum vitamin D level and full-length standing lower limb anteroposterior radiographs, and were divided into normal and deficient vitamin D groups. Tibiofemoral angles (TFAs) [lateral distal femoral angle (LDFA); medial proximal tibial angle (MPTA)] were measured by three independent observers and compared between the groups. Correlation tests between serum vitamin D level and TFAs were also performed. Sixty (39 boys, 21 girls) children were reviewed. The mean serum vitamin D level for the entire group was 26.8 ng/ml and 75% of the children were deficient. The mean serum vitamin D levels in the normal (11 boys, four girls) and deficient (28 boys, 17 girls) groups were 46.7 ng/ml (range: 32-100) and 20.2 ng/ml (range: 4-29), respectively. The mean right and left LDFAs were significantly higher in the normal compared to the deficient vitamin D group (right LDFA: 98.7° vs. 92.2°, P=0.031; left LDFA: 99.1° vs. 92.6°, P=0.018). We also found a correlation between serum vitamin D level and LDFAs (right ρ=0.29, P=0.03; left ρ=0.30, P=0.02). We found no difference in the right and left MPTAs in the normal and deficient vitamin D groups. In addition, we could not find a correlation between serum vitamin D level and MPTAs. The majority of children were vitamin D deficient. Serum vitamin D level was associated with a change and correlation to the LDFAs compared to MPTAs. Further work is required to investigate the effect of vitamin D supplementation on TFAs in children.


MUC4 mucin-induced epithelial to mesenchymal transition: a novel mechanism for metastasis of human ovarian cancer cells.
The acquisition of invasiveness in ovarian cancer (OC) is accompanied by the process of epithelial-to-mesenchymal transition (EMT). The MUC4 mucin is overexpressed in ovarian tumors and has a role in the invasiveness of OC cells. The present study was aimed at evaluating the potential involvement of MUC4 in the metastasis of OC cells by inducing EMT. Ectopic overexpression of MUC4 in OC cells (SKOV3-MUC4) resulted in morphological alterations along with a decreased expression of epithelial markers (E-cadherin and cytokeratin (CK)-18) and an increased expression of mesenchymal markers (N-cadherin and vimentin) compared with the control cells (SKOV3-vector). Also, pro-EMT transcription factors TWIST1, TWIST2 and SNAIL showed an upregulation in SKOV3-MUC4 cells. We further investigated the pathways upstream of N-cadherin, such as focal adhesion kinase (FAK), MKK7, JNK1/2 and c-Jun, which were also activated in the SKOV3-MUC4 cells compared with SKOV3-vector cells. Inhibition of phospho-FAK (pFAK) and pJNK1/2 decreased N-cadherin expression in the MUC4-overexpressing cells, which further led to a significant decrease in cellular motility. Knockdown of N-cadherin decreased the activation of extracellular signal-regulated kinase-1/2 (ERK1/2), AKT and matrix metalloproteinase 9 (MMP9), and inhibited the motility in the SKOV3-MUC4 cells. Upon in vivo tumorigenesis and metastasis analysis, the SKOV3-MUC4 cells produced significantly larger tumors and demonstrated a higher incidence of metastasis to distance organs (peritoneal wall, colon, intestine, stomach, lymph nodes, liver and diaphragm). Taken together, our study reveals a novel role for MUC4 in inducing EMT through the upregulation of N-cadherin and promoting metastasis of OC cells.


Family caregiving of persons following neurotrauma: issues in research, service and policy.
Family caregivers of persons following neurotrauma function as de facto extensions of our health care system. Their challenges may result in negative consequences for their physical and mental health, which directly impacts the well-being of their care-recipient. In this paper, we survey current practices in providing caregiver support, outline considerations for developing collaborative interventions, and make recommendations for assessing intervention effectiveness consistent with the nature of the adjustment processes among caregivers and care recipients.


Altered neurocircuitry in the dopamine transporter knockout mouse brain.
The plasma membrane transporters for the monoamine neurotransmitters dopamine, serotonin, and norepinephrine modulate the dynamics of these monoamine neurotransmitters. Thus, activity of these transporters has significant consequences for monoamine activity throughout the brain and for a number of neurological and psychiatric disorders. Gene knockout (KO) mice that reduce or eliminate expression of each of these monoamine transporters have provided a wealth of new information about the function of these proteins at molecular, physiological and behavioral levels. In the present work we use the unique properties of magnetic resonance imaging (MRI) to probe the effects of altered dopaminergic dynamics on meso-scale neuronal circuitry and overall brain morphology, since changes at these levels of organization might help to account for some of the extensive pharmacological and behavioral differences observed in dopamine transporter (DAT) KO mice. Despite the smaller size of these animals, voxel-wise statistical comparison of high resolution structural MR images indicated little morphological change as a consequence of DAT KO. Likewise, proton magnetic resonance spectra recorded in the striatum indicated no significant changes in detectable metabolite concentrations between DAT KO and wild-type (WT) mice. In contrast, alterations in the circuitry from the prefrontal cortex to the mesocortical limbic system, an important brain component intimately tied to function of mesolimbic/mesocortical dopamine reward pathways, were revealed by manganese-enhanced MRI (MEMRI). Analysis of co-registered MEMRI images taken over the 26 hours after introduction of Mn(2+) into the prefrontal cortex indicated that DAT KO mice have a truncated Mn(2+) distribution within this circuitry with little accumulation beyond the thalamus or contralateral to the injection site. By contrast, WT littermates exhibit Mn(2+) transport into more posterior midbrain nuclei and contralateral mesolimbic structures at 26 hr post-injection. Thus, DAT KO mice appear, at this level of anatomic resolution, to have preserved cortico-striatal-thalamic connectivity but diminished robustness of reward-modulating circuitry distal to the thalamus. This is in contradistinction to the state of this circuitry in serotonin transporter KO mice where we observed more robust connectivity in more posterior brain regions using methods identical to those employed here.


Steady-state pharmacokinetic and safety profiles of voriconazole and ritonavir in healthy male subjects.
Since there is a likelihood of coadministration of voriconazole and ritonavir, two studies were conducted to evaluate the potential of drug interaction. Study A was a randomized, placebo-controlled, two-period, parallel-group trial (n = 34). Study B had the same design without the placebo group (n = 17). In period 1, subjects received 200 mg voriconazole or placebo twice daily (BID) for 3 days (400 mg BID on day 1). In period 2, following a 7-day washout, subjects received ritonavir alone at 400 mg BID (study A) or 100 mg BID (study B) for 10 days (days 11 to 20), and then ritonavir was coadministered with 200 mg BID voriconazole or placebo for the next 10 days (days 21 to 30). Serial plasma samples were collected on days 3, 20, and 30, and safety data were collected throughout the study. High-dose (400 mg BID) ritonavir substantially reduced the steady-state mean voriconazole exposure (area under the concentration-time curve from 0 to 12 h [AUC(0-12)], -82%; maximum concentration [C(max)], -66%). However, the effect of low-dose (100 mg BID) ritonavir was less pronounced (AUC(0-12), -39%; C(max), -24%). The decrease in voriconazole exposure was probably due to the induction of CYP2C19 and CYP2C9 by ritonavir. It is interesting that one subject in each study exhibited the opposite effect of ritonavir on voriconazole exposure (a 2.5- to 3-fold increase), probably due to lack of CYP2C19. Voriconazole had no apparent effect on the exposure of high-dose ritonavir but slightly decreased the exposure of low-dose ritonavir (AUC(0-12), -14%; C(max), -24%). The safety profile of combination therapy was not notably different from that of voriconazole or ritonavir alone. Due to the significant effect of ritonavir on voriconazole exposure, coadministration of voriconazole with 400 mg BID ritonavir is contraindicated; coadministration with 100 mg BID ritonavir should be avoided, unless an assessment of the benefit/risk to the patient justifies the use.


Periostin potently promotes metastatic growth of colon cancer by augmenting cell survival via the Akt/PKB pathway.
Molecular mechanisms associated with tumor metastasis remain poorly understood. Here we report that acquired expression of periostin by colon cancer cells greatly promoted metastatic development of colon tumors. Periostin is overexpressed in more than 80% of human colon cancers examined with highest expression in metastatic tumors. Periostin expression dramatically enhanced metastatic growth of colon cancer by both preventing stress-induced apoptosis in the cancer cells and augmenting endothelial cell survival to promote angiogenesis. At the molecular level, periostin activated the Akt/PKB signaling pathway through the alpha(v)beta(3) integrins to increase cellular survival. These data demonstrated that the survival-promoting function is crucial for periostin to promote tumor metastasis of colon cancer.


Temporal profile of endogenous anatomical repair and functional recovery following spinal cord injury in adult zebrafish.
Regenerated cerebrospinal axons are considered to be involved in the spontaneous recovery of swimming ability following a spinal cord injury in adult zebrafish. We employed behavioral analysis, neuronal tracing, and immunocytochemistry to determine the exact temporal relationship between swimming ability and regenerated cerebrospinal axon number in adult zebrafish with a complete spinal cord transection. Between two and eight weeks post-lesion, swimming gradually improved to 44% of sham-injured zebrafish. Neurons within the reticular formation, magnocellular octaval nucleus, and nucleus of the medial longitudinal fascicle grew their axon across and at least four millimeters beyond the lesion. The largest increases in swimming ability and number of regenerated cerebrospinal axons were observed between two and four weeks post-lesion. Regression analyses revealed a significant correlation between swimming ability and the number of regenerated axons. Our results indicate the involvement of cerebrospinal axons in swimming recovery after spinal cord injury in adult zebrafish.


Two host-inducible genes of Rhizobium fredii and characterization of the inducing compound.
Random transcription fusions with Mu d1(Kan lac) generated three mutants in Rhizobium fredii (strain USDA 201) which showed induction of beta-galactosidase when grown in root exudate of the host plants Glycine max, Phaseolus vulgaris, and Vigna ungliculata. Two genes were isolated from a library of total plasmid DNA of one of the mutants, 3F1. These genes, present in tandem on a 4.2-kilobase HindIII fragment, appear in one copy each on the symbiotic plasmid and do not hybridize to the Rhizobium meliloti common nodulation region. They comprise two separate transcriptional units coding for about 450 and 950 nucleotides, both of which are transcribed in the same direction. The two open reading frames are separated by 586 base pairs, and the 5H regions of the two genes show a common sequence. No similarity was found with the promoter areas of Rhizobium trifolii, R. meliloti, or Bradyrhizobium japonicum nif genes and with any known nodulation genes. Regions homologous to both sequences were detected in EcoRI digests of genomic DNAs from B. japonicum USDA 110, USDA 122, and 61A76, but not in genomic DNA from R. trifolii, Rhizobium leguminosarum, or Rhizobium phaseoli. Mass spectrometry and nuclear magnetic resonance analysis indicated that the inducing compound has properties of 4',7-dihydroxyisoflavone, daidzein. These results suggest that, in addition to common nodulation genes, several other genes appear to be specifically induced by compounds in the root exudate of the host plants.


[Carcinoid tumors, adenoid-cystic carcinomas and muco-epidermoid carcinomas of the tracheo-bronchial tree (author's transl)].
A retrospective study of 25 cases with a so-called bronchial adenoma was made. Classification by this old-fashioned nomenclature included 76% carcinoid tumors, 20% adenoid-cystic carcinomas and 4% muco-epidermoid carcinomas of the trachea and bronchial tree. With regard to their malignant potential, the correlation between histological differentiation, invasiveness, metastatic spread and clinical evolution is discussed. An outline of the extent of therapy for each of the 3 types is given.


Nanotools for the delivery of antimicrobial peptides.
Antimicrobial peptide drugs are increasingly attractive therapeutic agents as their roles in physiopathological processes are being unraveled and because the development of recombinant DNA technology has made them economically affordable in large amounts and high purity. However, due to lack of specificity regarding the target cells, difficulty in attaining them, or reduced half-lives, most current administration methods require high doses. On the other hand, reduced specificity of toxic drugs demands low concentrations to minimize undesirable side-effects, thus incurring the risk of having sublethal amounts which favour the appearance of resistant microbial strains. In this scenario, targeted delivery can fulfill the objective of achieving the intake of total quantities sufficiently low to be innocuous for the patient but that locally are high enough to be lethal for the infectious agent. One of the major advances in recent years has been the size reduction of drug carriers that have dimensions in the nanometer scale and thus are much smaller than -and capable of being internalized by- many types of cells. Among the different types of potential antimicrobial peptide-encapsulating structures reviewed here are liposomes, dendritic polymers, solid core nanoparticles, carbon nanotubes, and DNA cages. These nanoparticulate systems can be functionalized with a plethora of biomolecules providing specificity of binding to particular cell types or locations; as examples of these targeting elements we will present antibodies, DNA aptamers, cell-penetrating peptides, and carbohydrates. Multifunctional Trojan horse-like nanovessels can be engineered by choosing the adequate peptide content, encapsulating structure, and targeting moiety for each particular application.


A perspective on judgment and choice: mapping bounded rationality.
Early studies of intuitive judgment and decision making conducted with the late Amos Tversky are reviewed in the context of two related concepts: an analysis of accessibility, the ease with which thoughts come to mind; a distinction between effortless intuition and deliberate reasoning. Intuitive thoughts, like percepts, are highly accessible. Determinants and consequences of accessibility help explain the central results of prospect theory, framing effects, the heuristic process of attribute substitution, and the characteristic biases that result from the substitution of nonextensional for extensional attributes. Variations in the accessibility of rules explain the occasional corrections of intuitive judgments. The study of biases is compatible with a view of intuitive thinking and decision making as generally skilled and successful.


Three-dimensional micro-optical components embedded in photosensitive glass by a femtosecond laser.
We show that three-dimensional micro-optical components can be embedded in a photosensitive glass by a femtosecond (fs) laser. After exposure to the tightly focused fs laser beam, latent images are written inside the sample. Modified regions are developed by a postbaking process and then preferentially etched away in a 10%-dilute solution of hydrofluoric acid. After this process, hollow internal structures are formed that act as a mirror and a beam splitter. Furthermore, we find that postannealing smoothes the surfaces of the fabricated hollow structures, resulting in great improvement of their optical properties.


Psychometric properties of the attachment style questionnaire in Swedish pregnant women: short and full versions.
(i) To evaluate the reliability and factor structure of the Attachment Style Questionnaire - Short Form (ASQ-SF) for use in pregnant women and (ii) to compare the reliability and factor structure of the short- and full version-ASQ among pregnant women. Adult attachment insecurity is currently included as a major risk factor in studies of perinatal health. None of the self-report measures with a Swedish translation have been psychometrically evaluated in a pregnant cohort. A population-based cohort of 1631 pregnant women answered the ASQ in late pregnancy. Internal consistency (item-subscale correlations, Cronbach's α, and α if item deleted) was evaluated for the seven available subscales. Confirmatory factor analysis (CFA) was run to examine the factor structure of the short form compared with the full-version. Test-retest correlations were assessed in a subgroup (n = 48). All mean item-subscale correlations for the ASQ-SF were > 0.30. Cronbach's α's for ASQ-SF dimensions were as follows: Avoidance (0.87); Anxiety (0.89); Discomfort with Closeness (0.85); Relationships as Secondary (0.54); Confidence (0.83); Need for Approval (0.76); and Preoccupation with Relationships (0.77). No item removal substantively increased subscale α's. The CFA demonstrated better model fit for the ASQ-SF than for the full-version ASQ, while other reliability measures were similar. Test-retest correlations ranged from 0.65 to 0.84. The ASQ-SF showed similar psychometric properties in pregnant women as in the general population and had good reliability, but the optimal factor structure needs to be studied further. Results support the usage of the ASQ-SF in pregnant cohorts.


Pain management in mice using the aqueous and ethanol extracts of four medicinal plants.
There are many traditionally used analgesic plants in Ethiopia. They, however, have not been subject to scientific investigation for their efficacy and safety. To evaluate both prophylactic and relieving effects of aqueous and ethanol extracts of four traditionally used medicinal plants in Ethiopia. An experimental design in which five group of albino mice weighing 30-35 grams representing positive and negative control, and extract treated groups respectively. The extracts, standard drugs and normal saline were administered into GIT by gavage to evaluate the analgesic effect. Department of Drug Research at Ethiopian Health and Nutrition Research Institute and Department of Pharmacology at Faculty of Medicine, Addis Ababa university. Analgesic effects of water and ethanol extracts of four plants were evaluated against distilled water and standard analgesics (morphine and acetylsalicylic acid) with acetic acid induced writhing tests in mice. The four plants used for this screening were Ocimum sauve, Ocimum lamiifolium, Lippia adoensis and Ajuga remota. All extracts of the four plant materials were observed to possess both inhibiting and treatment activities against acetic acid induced pain. Dose related analgesic effect was also observed with all extracts of all plants with different potencies. Ethanol extracts of all the four plant materials were more potent than their water extracts at all dose levels except O. sauve, and L. adoensis whose water extracts seem to be a bit more potent at low dose. The analgesic potencies of both extracts of all the four plants were shown to be less than those of the standard analgesics. Of all the extracts, the ethanol extract of O. lamiifolium was found to be the most potent, while its water extract was the least. Acetic acid induced writhing was relieved with medium dose of both extracts in most cases and with low dose in few. Hundred percent relief was achieved with both standard analgesics at a very low dose. The present study show that all the extracts of all the plant materials have got both inhibiting and relieving effects of pain.


Rapid diagnosis of acute hemorrhagic conjunctivitis due to coxsackievirus A24 variant by real-time one-step RT-PCR.
Coxsackievirus A24 variant is, together with enterovirus 70 and adenoviruses, the major etiological agent involved in acute hemorrhagic conjunctivitis outbreaks worldwide. However, the standard virus isolation method followed by serotyping or VP1 region sequencing is time-consuming. A rapid method for the detection of coxsackievirus A24 variant from conjunctival swab specimens would be useful in the context of explosive and extensive outbreaks. A one-step real-time RT-PCR assay based on TaqMan technology was thus developed and assessed on 36 conjunctival swabs from outbreaks of conjunctivitis in Morocco in 2004 due to a coxsackievirus A24 variant and in Corsica in 2006 due to adenovirus type 3, and 83 virus strains including 41 coxsackievirus A24 variant collected in French Guiana and Guadeloupe in 2003, in the Democratic Republic of the Congo in 2003, in Morocco in 2004 and 42 other virus species genetically close or known to be responsible for conjunctivitis. All the conjunctival swabs from coxsackievirus A24 variant related outbreak and the 41 coxsackievirus A24 variant strains were tested positive by the RT-PCR assay within 4h. This novel single-tube real-time RT-PCR assay is sensitive and specific, and consists in a reliable and faster alternative to the viral culture for recent and future acute hemorrhagic conjunctivitis outbreaks caused by coxsackievirus A24 variant.


Isolation and mapping of 62 new RFLP markers on human chromosome 11.
To obtain new RFLP markers on human chromosome 11 for a high-resolution map, we constructed a cosmid library from a Chinese hamster x human somatic hybrid cell line that retains only human chromosome 11 in a Chinese hamster genomic background. A total of 3,500 cosmids were isolated by colony hybridization with labeled human genomic DNA. DNA was prepared from 130 of these cosmid clones and examined for RFLP. In 62 of them, polymorphism was detected with one or more enzymes; four RFLPs were VNTR systems. All polymorphic clones were assigned to one of 22 intervals obtained by mapping on a deletion panel of 15 somatic hybrid cell lines containing parts of chromosome 11; 11 clones were finely mapped by in situ hybridization. Although RFLP markers were scattered on the whole chromosome, they were found predominantly in the regions of R-banding. These DNA markers will contribute to fine mapping of genes causing inherited disorders and tumor-suppressor genes that reside on chromosome 11. Furthermore, as one-third of the cosmid clones revealed a band or bands in Chinese hamster DNA, indicating sequence conservation, this subset of clones may be useful for isolating biologically important genes on chromosome 11.


Increases in a marker of immune system reconstitution are predated by decreases in 24-h urinary cortisol output and depressed mood during a 10-week stress management intervention in symptomatic HIV-infected men.
Stress management interventions reduce distress symptoms and hypothalamic-pituitary-adrenal (HPA) axis hormones such as cortisol, which has been related to a down-regulation of immune system components relevant to the human immunodeficiency virus (HIV) infection. We previously showed that HIV+ men assigned to a 10-week cognitive behavioral stress management (CBSM) intervention showed more CD4+CD45RA+CD29+ lymphocytes, an indicator of immune system reconstitution, at a 6- to 12-month follow-up compared with controls. Here, we tested whether reductions in urinary cortisol output and depressed mood during the 10-week CBSM intervention period mediated its effects on this immune system reconstitution marker at follow-up. Twenty-five HIV-infected men randomized to either a 10-week CBSM intervention or a wait-list control provided 24-h urine samples and psychological responses pre- to postintervention, which were related to changes in immune status over a 6- to 12-month follow-up period. Greater reductions in cortisol output and depressed mood during CBSM appeared to mediate the effects of this intervention on this indicator of immune system reconstitution over the 6- to 12-month follow-up period. Changes in mood were maintained over the follow-up period, although these did not add explanatory information beyond the cortisol and mood changes that were observed during the 10-week intervention period. These findings were not explained by the changes in medications or health behaviors during follow-up. A time-limited CBSM intervention may affect the rate of immune system reconstitution in HIV-infected men by modifying the stress of symptomatic disease. This intervention may work by decreasing depressed mood and normalizing HPA axis functioning.


The Reliability and Validity of the Loadsol® under Various Walking and Running Conditions.
The assessment of loading during walking and running has historically been limited to data collection in laboratory settings or with devices that require a computer connection. This study aims to determine if the loadsol®-a single sensor wireless insole-is a valid and reliable method of assessing force. Thirty (17 male and 13 female) recreationally active individuals were recruited for a two visit study where they walked (1.3 m/s) and ran (3.0 and 3.5 m/s) at a 0%, 10% incline, and 10% decline, with the visits approximately one week apart. Ground reaction force data was collected on an instrumented treadmill (1440 Hz) and with the loadsol® (100 Hz). Ten individuals completed the day 1 protocol with a newer 200 Hz loadsol®. Intraclass correlation coefficients (ICC3,k) were used to assess validity and reliability and Bland⁻Altman plots were generated to better understand loadsol® validity. Across conditions, the peak force ICCs ranged from 0.78 to 0.97, which increased to 0.84⁻0.99 with the 200 Hz insoles. Similarly, the loading rate ICCs improved from 0.61 to 0.97 to 0.80⁻0.96 and impulse improved from 0.61 to 0.97 to 0.90⁻0.97. The 200 Hz insoles may be needed for loading rate and impulse in running. For both walking and running, the loadsol® has excellent between-day reliability (>0.76).


Beyond the scope of Free-Wilson analysis: building interpretable QSAR models with machine learning algorithms.
A novel methodology was developed to build Free-Wilson like local QSAR models by combining R-group signatures and the SVM algorithm. Unlike Free-Wilson analysis this method is able to make predictions for compounds with R-groups not present in a training set. Eleven public data sets were chosen as test cases for comparing the performance of our new method with several other traditional modeling strategies, including Free-Wilson analysis. Our results show that the R-group signature SVM models achieve better prediction accuracy compared with Free-Wilson analysis in general. Moreover, the predictions of R-group signature models are also comparable to the models using ECFP6 fingerprints and signatures for the whole compound. Most importantly, R-group contributions to the SVM model can be obtained by calculating the gradient for R-group signatures. For most of the studied data sets, a significant correlation with that of a corresponding Free-Wilson analysis is shown. These results suggest that the R-group contribution can be used to interpret bioactivity data and highlight that the R-group signature based SVM modeling method is as interpretable as Free-Wilson analysis. Hence the signature SVM model can be a useful modeling tool for any drug discovery project.


Granulocyte/macrophage-colony stimulating factor produced by recombinant avian poxviruses enriches the regional lymph nodes with antigen-presenting cells and acts as an immunoadjuvant.
Recombinant avian poxviruses [fowlpox and canarypox (ALVAC)], restricted for replication in nonavian cell substrates and expressing granulocyte/macrophage-colony stimulating factor (avipox-GM-CSF), were evaluated for their ability to enrich an immunization site with antigen-presenting cells (APCs) and, in turn, function as biological vaccine adjuvants. Avipox-GM-CSF administered as a single s.c. injection significantly enhanced the percentage and absolute number of APCs in the regional lymph nodes that drain the injection site. Both the magnitude and duration of the cellular and phenotypic increases within the lymph nodes induced by the avipox-GM-CSF viruses were significantly (P < 0.05) greater than those measured in mice treated with four daily injections of recombinant GM-CSF protein. Temporal studies revealed that the APC enrichment of regional lymph nodes was sustained for 21-28 days after injection of the recombinant avipox virus expressing GM-CSF and, moreover, three injections of the recombinant virus could be given without any appreciable loss of in vivo bioactivity. Mice expressing human carcinoembryonic antigen (CEA) as a transgene (CEA.Tg) developed CEA-specific humoral and cell-mediated immunity after being immunized with avipox-CEA. The coadministration of recombinant avipox viruses expressing CEA and GM-CSF significantly enhanced CEA-specific host immunity with an accompanying immunotherapeutic response in tumor-bearing CEA.Tg mice. The optimal use of avipox-GM-CSF, in terms of dose and dose schedule, especially when used with different immunogens, remains to be determined. Nonetheless, the present findings demonstrate: (a) the effective delivery of GM-CSF to an immunization site using a recombinant avian poxvirus; (b) the compatibility of delivering an antigen and GM-CSF in replication-defective viruses to enhance antigen-specific immunity; and (c) the combined use of recombinant avipox viruses expressing CEA and GM-CSF to generate antitumor immunity directed at a self tumor antigen.


Intratesticular androgen levels, androgen receptor localization, and androgen receptor expression in adult rat Sertoli cells.
In the rat, quantitatively normal spermatogenesis is maintained only when intratesticular testosterone (ITT) levels greatly exceed the peripheral T concentration. When ITT concentrations fall below a threshold, germ cells are lost at specific stages of the seminiferous cycle. Germ cells can be restored by high doses of T that binds to androgen receptors (AR) in Sertoli cells. However, the relationships between germ cell dynamics, AR-mediated molecular events, and ITT concentrations are not established. ITT levels may regulate germ cell life and death through an effect on AR localization and AR mRNA or protein levels within Sertoli cells at specific stages of the cycle. We determined AR localization and mRNA and protein expression in adult rat Sertoli cells in relation to reduced and then restored ITT concentrations in vivo. ITT levels were reduced by implanting rats with T- and estradiol (E)-filled capsules for 7-28 days and subsequently restored with large T-filled capsules. AR is normally localized within Sertoli cell nuclei at stages VII-VIII of the seminiferous epithelium. After T/E treatment, AR immunostaining in Sertoli cell nuclei became nondetectable by 14-28 days but was restored 6 h following T restoration. The loss of Sertoli cell nuclear AR localization correlated with increasing numbers of apoptotic germ cells. AR mRNA levels in isolated Sertoli cells did not change through 14 days of T/E treatment, increased significantly by Day 28, and remained elevated 24 h after T restoration. AR mRNA levels in microdissected tubules at stages II-IV, VI-VIII, and IX-XII did not decrease through 14 days of T/E treatment. In contrast, AR protein levels were reduced in seminiferous tubules by Day 14 and in testes at Day 28 post-T/E treatment but were restored within 24 h by T repletion. Therefore, the reduction of ITT concentration results in a time-dependent redistribution of AR and reduced AR protein but not AR mRNA levels in Sertoli cells. Repletion of T restored AR protein and it relocated to Sertoli cell nuclei. By an unknown mechanism, T regulates AR localization within Sertoli cells to determine germ cell life or death.


Covalent Functionalization of Single-Walled Carbon Nanotubes by the Bingel Reaction for Building Charge-Transfer Complexes.
Functionalization of nanotubes with donor and acceptor partners by the Bingel reaction leads to the formation of charge-transfer dyads, which can operate in organic photovoltaic devices. In this work, we theoretically examine the mechanism of the Bingel reaction for the (6,5)-chiral, (5,5)-armchair, and (9,0)-zigzag single-walled carbon nanotubes (SWCNTs), and demonstrate that the reaction is regioselective and takes place at the perpendicular position of (6,5)- and (5,5)-SWCNTs, and the oblique position of (9,0)-SWCNT. Further, we design computationally the donor-acceptor complexes based on (6,5)-SWCNT coupled with partners of different electronic nature. Analysis of their excited states reveals that efficient photoinduced charge transfer can be achieved in the complexes with π-extended analogue of tetrathiafulvalene (exTTF), zinc tetraphenylporphyrin (ZnTPP), and tetracyanoanthraquinodimethane (TCAQ). The solvent can significantly affect the population of the charge-separated states. Our calculations show that electron transfer (ET) occurs in the normal Marcus regime on a sub-nanosecond time scale in the complexes with exTTF and ZnTPP, and in the inverted Marcus regime on a picosecond time scale in the case of the TCAQ derivative. The ET rate is found to be not very sensitive to the degree of functionalization of the nanotube.


Pharmacokinetic evaluation of pemetrexed.
Pemetrexed is a multi-targeted antifolate cytotoxic agent that has demonstrated activity in a number of very common cancer types including NSCLC in both first- and second-line settings and in the treatment of malignant mesothelioma. This article focuses on all of the currently published pharmacokinetic data of pemetrexed reviewing a number of different scenarios and patient populations. All the articles reviewed in this manuscript are from peer-reviewed English-spoken literature without any limitations to the time of publication. Pemetrexed's clearance correlates with renal function and it may be safely used with vitamin supplementation in patients with creatinine clearance ≥ 45 ml/min. The pharmacokinetics of pemetrexed is also largely unchanged in third-space fluids and can be feasibly and safely administered in combination with several other cytotoxic or targeted agents. It is the author's opinion that pemetrexed is already a valuable cytotoxic agent which has proved useful in several malignancies. However, future trials might expand on the combined use of pemetrexed with other targeted agents that could be beneficial to other selected patients harboring relevant mutations or other biological features.


Stimulation of lysine decarboxylase production in Escherichia coli by amino acids and peptides.
A commercial hydrolysate of casein stimulated production of lysine decarboxylase (EC 188.8.131.52) by Escherichia coli B. Cellulose and gel chromatography of this hydrolysate yielded peptides which were variably effective in this stimulation. Replacement of individual, stimulatory peptides by equivalent amino acids duplicated the enzyme levels attained with those peptides. There was no indication of specific stimulation by any peptide. The peptides were probably taken up by the oligopeptide transport system of E. coli and hydrolyzed intracellularly by peptidases to their constituent amino acids for use in enzyme synthesis. Single omission of amino acids from mixtures was used to screen them for their relative lysine decarboxylase stimulating abilities. Over 100 different mixtures were evaluated in establishing the total amino acid requirements for maximal synthesis of lysine decarboxylase by E. coli B. A mixture containing all of the common amino acids except glutamic acid, aspartic acid, and alanine increased lysine decarboxylase threefold over an equivalent weight of casein hydrolysate. The nine most stimulatory amino acids were methionine, arginine, cystine, leucine, isoleucine, glutamine, threonine, tyrosine, and asparagine. Methionine and arginine quantitatively were the most important. A mixture of these nine was 87% as effective as the complete mixture. Several amino acids were inhibitory at moderate concentrations, and alanine (2.53 mM) was the most effective. Added pyridoxine increased lysine decarboxylase activity 30%, whereas other B vitamins and cyclic adenosine 5'-monophosphate had no effect.


Hand injury in the accident and emergency service.
The management of hand injuries forms an important part of the hospital accident and emergency service, and early recognition and informed management are essential for a favourable outcome (Frazier et al., 1978). In Edinburgh a routine system of hand management is well established and includes the training of casualty officers. In order to evaluate the effectiveness of the hand service in the Accident and Emergency Department, Royal Infirmary of Edinburgh, a prospective study was undertaken to compare the outcome of treatment of hand injury by a routine system with treatment over a similar period by more experienced registrars in hand surgery training posts (Hand Fellows).


Ionizing radiation and nitric oxide donor sensitize Fas-induced apoptosis via up-regulation of Fas in human cervical cancer cells.
Fas/CD95/Apo1 is a transmembrane receptor known to trigger apoptotic cell death in several cell types. In the present study, we showed that ionizing radiation (IR) and NO donor, S-nitroso-N-acetyl-penicillamine (SNAP), sensitized Fas-induced apoptotic cell death of HeLa human cervical cancers. Suboptimal dose of IR and SNAP up-regulated the cell-surface Fas antigen, detected by FACScan using FITC-anti-Fas antibody. When combined with IR or SNAP, agonistic anti-Fas antibody CH-11 resulted in marked enhancement of apoptosis. This sensitization was completely abrogated by anti-Fas neutralizing antibody ZB4. During the IR and SNAP sensitized Fas-induced apoptosis, mitochondria permeabilization, cytochrome c release, and DNA fragmentation were detected. Furthermore, combined treatment of IR and SNAP additively up-regulated the surface Fas protein expression and sensitized Fas-induced apoptosis. Our findings demonstrate that sensitization of HeLa cervical cells to Fas-mediated apoptosis by IR and NO donor is most likely due to the up-regulation of Fas expression and also provides a means with which to sensitize tumors to the killing effects of cancer therapy via the Fas receptor.


Evaluation of macrocytosis in routine hemograms.
Macrocytosis, a condition in which erythrocytes are larger than normal manifests as an increase in mean corpuscular volume (MCV) more than 100 fl. The aim of this study was to identify the underlying causes of macrocytosis, detected in routine hemograms and to evaluate the hematological features in different etiologies. This study included 178 adult patients whose detailed medical history was recorded, and Vitamin B12 assay, folate assay, thyroid function tests, liver function tests, complete blood counts and peripheral smear evaluation was performed. Alcoholism was identified as the etiological factor in 65 cases (36.5%), Vitamin B12 deficiency in 43 cases (24.1%) and drug related in 23 cases (12.9%). These three conditions accounted for 73.6% of macrocytosis. Other causes identified were folate deficiency, liver disease, Myelodysplastic syndrome, chronic renal failure and Aplastic anemia. In 41 cases, the cause of macrocytosis could not be explained. Anemia was observed in 95 cases (53.3%) being most common in Vitamin B12 deficiency. 9 cases (20.9%) of Vitamin B12 deficiency presented with isolated macrocytosis without anemia. It was observed that mean hemoglobin was lower and red cell distribution width (RDW) higher in megaloblastic conditions. Peripheral smear revealed hypersegmented neutrophils in 86% and macro-ovalocytes in 72% of the megaloblastic cases. Complete medical history, red cell parameters and peripheral blood smear are simple, inexpensive tools which assist in identifying the underlying cause of macrocytosis, particularly in resource limited settings. Macrocytosis needs to be evaluated even in the absence of anemia, as it may be the first clue to an underlying pathology.


Low Toxocara Seroprevalence in People in Rural Durango, Mexico.
The epidemiology of Toxocara infection in rural Mexico is largely unknown. Therefore, we sought to determine the seroprevalence of Toxocara infection in rural people in a northern Mexican state. We performed a cross-sectional seroprevalence study of 641 people living in rural Durango State including 282 subjects of the general population, 214 subjects of Huichol ethnicity, and 145 subjects of Mennonite ethnicity. Sera of participants were analyzed for the presence of anti-Toxocara immunoglobulin G (IgG) antibodies using a commercially available enzyme immunoassay. Three (0.5%) of the 641 subjects tested were positive for anti-Toxocara IgG antibodies. Of the 3 Toxocara seropositive subjects, two were females, aged 19 and 39 years, and one was male, aged 59 years. They had contacted with dogs, cleaned cat excrement, consumed unwashed raw fruits, contacted soil, or lived in a house with soil floors. Seroprevalence of Toxocara infection was similar among the 3 groups of population studied: 0.4% for the general population, 0.9% for Huicholes, and 0.0% for Mennonites (P = 0.41). In conclusion, the Toxocara seroprevalence found in subjects in rural Durango is low as compared with those reported in people from rural areas in other countries.


Time based prospective memory deficits associated with binge drinking: evidence from the Cambridge Prospective Memory Test (CAMPROMPT).
To examine whether 'binge drinking' (BD) in young adults adversely affects prospective memory (PM). BD was defined as males drinking 8/more units and females 6/more units on at least one session per-week. BDs and non-binge drinkers (NBDs) were compared on self-reported and objective PM. An existing-groups design compared BDs with NBDs as the independent factor. Scores on the PM and retrospective memory (RM) subscales of the Prospective and Retrospective Memory Questionnaire (PRMQ) and scores on the Cambridge Prospective Memory Task (CAMPROMPT) were the dependent factors. Age, total years spent drinking, time since last drink consumed (hours), mood, strategy-use and pre-morbid IQ were measured as covariates. Each participant was tested in a laboratory setting. An opportunity sample of 28 BDs and 28 NBDs were compared. Self-reported PM and RM lapses were measured using the PRMQ and the CAMPROMPT measured objective PM. Drug use was assessed using a Recreational Drug Use Questionnaire. The Hospital Anxiety and Depression Scale measured mood. The strategy-scale from the Prospective Memory Questionnaire measured strategy use. The National Adult Reading Test measured pre-morbid IQ. BDs and NBDs did not differ in terms of gender makeup and a series of ANCOVAs (controlling for the covariates) revealed no significant between-groups differences on self-reported PM/RM lapses; but BDs exhibited reduced function on time-based PM, but not event-based PM, when compared with NBDs. BDs exhibit selective impairments on time-based PM; this deficit is a new finding in terms of the neuropsychological sequelae associated with BD.


Developing and integrating a practice model for health finance reform into wound healing programs: an examination of the triple aim approach.
Throughout the United States, government and private payers are exploring new payment models such as accountable care organizations and shared savings agreements. These models are widely based on the construct of the Triple Aim, a set of three principles for health services reform: improving population-based outcomes, improving patient care experiences, and reducing costs through better delivery systems. Wound programs may adapt to the new health financing environment by incorporating initiatives known to promote the Triple Aim, such as diabetes amputation reduction and pressure ulcer prevention programs, and by rethinking how health services can best be delivered to meet these new criteria. The existing literature supports that programmatic approaches can improve care, quality, and cost, especially in the field of diabetic foot ulcers. Wound healing programs have opportunities to develop new business plan models that provide quality, cost-efficient care to their patient population and to be leaders in the development of new types of partnerships with payers and health delivery organizations.


Epidemiology and clinical features of Mediterranean spotted fever in Italy.
Mediterranean Spotted Fever is caused by Rickettsia conorii and is transmitted to humans by Rhipicephalus sanguineus, the common dog tick. It is characterized by the symptomatologic triad: fever, exanthema and "tache noire", the typical eschar at the site of the tick bite. In Italy the most affected region is Sicily. The seasonal peak of the disease (from June through September) occurs during maximal activity of immature stage ticks. Severe forms of the disease have been reported in 6% of patients, especially adults with one of the following conditions: diabetes, cardiac disease, chronic alcoholism, glucose-6-phosphate dehydrogenase deficiency, end stage kidney disease. The mortality rate may reach 2.5%. Oral or parenteral administration of tetracyclines or chloramphenicol represent the standard treatment. Recent studies indicate that oral clarithromycin and azithromycin could constitute an acceptable alternative for the treatment of the disease in children; furthermore, they could be recommended during pregnancy.


Adherence to WCRF/AICR cancer prevention recommendations and risk of postmenopausal breast cancer.
In 2007, the World Cancer Research Fund (WCRF) and the American Institute for Cancer Research (AICR) released eight recommendations related to body fatness, physical activity, and diet aimed at preventing the most common cancers worldwide. However, limited information exists on the association between meeting these recommendations and risks of specific cancers, including breast cancer. We operationalized six recommendations (related to body fatness, physical activity, foods that promote weight gain, plant foods, red and processed meats, and alcohol) and examined their association with invasive breast cancer incidence over 6.7 years of follow-up in the Vitamins and Lifestyle (VITAL) study cohort. Participants included 30,797 postmenopausal women, ages 50-76 years at baseline in 2000-2002 with no history of breast cancer. Breast cancers (n = 899) were tracked through the Western Washington Surveillance, Epidemiology, and End Results database. Breast cancer risk was reduced by 60% in women who met at least five recommendations compared with those who met none [HR: 0.40; 95% confidence interval (CI): 0.25-0.65; Ptrend < 0.001]. Further analyses that sequentially removed individual recommendations least associated with reduced risk suggested that this reduction is due to meeting recommendations related to body fatness, plant foods, and alcohol (HR for meeting vs. not meeting these three recommendations: 0.38; 95% CI: 0.25-0.58; Ptrend < 0.001). Meeting the WCRF/AICR cancer prevention recommendations, specifically those related to alcohol, body fatness, and plant foods, is associated with reduced postmenopausal breast cancer incidence. Increased adherence to the WCRF/AICR cancer prevention recommendations could substantially reduce postmenopausal breast cancer risk in U.S. women.


Making allyship visible: evaluation of a faculty development DEI curriculum.
Undergraduate medical learners from historically marginalized groups face significant barriers, which was made concrete at our institution when a student presented her research indicating that Black students felt unsure about which faculty members to approach. To better support our students, we used Kern's model for curriculum development and a critical pedagogy approach to create a Faculty Allyship Curriculum (FAC). A total of 790 individuals attended 90 workshops across 16 months and 20 individuals have completed the FAC. A majority of participants reported they felt at least moderately confident in their ability to teach learners who are underrepresented in medicine, mentor learners who are different than they are, and teach allyship topics. An informal content analysis of open-ended responses indicated changes in awareness, attitude, insight, and use of language and being more likely to display advocacy. For others considering creating a similar program, partnering with an existing program allows for rapid implementation and reach to a wide audience. We also recommend: beginning with a coalition of willing learners to quickly build community and culture change; ensuring that the curriculum supports ongoing personal commitment and change for the learners; and supporting facilitators in modeling imperfection and upstanding, 'calling in' rather than 'calling out' learners.


Monotherapy with the novel human anti-CD154 monoclonal antibody ABI793 in rhesus monkey renal transplantation model.
This study assesses the safety and efficacy of the novel human anti-human CD154 monoclonal antibody ABI793 in rhesus monkeys. Outbred rhesus monkeys were used for renal transplantation from major histocompatibility complex-mismatched donors. Seven recipients were treated with ABI793, and six untreated recipients were used as controls. Graft function was monitored by urine output, serum creatinine, and renal biopsy. Phenotypic analysis of peripheral blood lymphocytes and mixed lymphocyte reaction were performed before transplantation and periodically after transplantation. Anti-donor major histocompatibility complex class I antibody levels were measured at the time of sacrifice. Monkeys in the treated group demonstrated prolonged graft survival compared with controls. One monkey was sacrificed because of a urine leak on postoperative day 13. Three monkeys were sacrificed because of acute rejection (days 44, 149, and 158). Two monkeys were sacrificed because of chronic active rejection (days 154 and 221). One monkey was sacrificed on day 139 without rejection to observe the effects of ABI793 in the absence of rejection. There were no obvious clinical side effects of ABI793, but microscopic thromboembolic changes were observed in two monkeys. Lymphocyte subsets remained unaltered in all monkeys. Mixed lymphocyte reaction showed nonspecific suppression 6 weeks after transplantation. The monkeys with chronic active rejection showed relatively strong alloantibody responses. ABI793 induces prolonged renal allograft survival in rhesus monkeys. Nevertheless, thromboembolic complications may occur and chronic allograft nephropathy may develop after anti-CD154 treatment is discontinued.


Support vector-based Takagi-Sugeno fuzzy system for the prediction of binding affinity of peptides.
High dimensional, complex and non-linear nature of the post-genome data often adversely affects the performance of predictive models. There are two methods that have been widely used to model such non-linear systems, namely Fuzzy System (FS) and Support Vector Machine (SVM). FS is good at modelling uncertainty and yielding a set of interpretable IF-THEN rules, but suffers from the curse of dimensionality whereas SVM is a method that has been shown to effectively deal with large number of dimensions leading to better generalization ability. In this paper, a hybrid system is therefore proposed to improve FS with the aid of SVM-based regression method and successfully applied to the prediction of binding affinity of peptides, which is regarded as one of the most complex modelling problems in the post-genome era due to the diversity of peptides discovered. The proposed hybrid method yields comparatively better results than what has been presented in the recently published papers, therefore can also be considered for other bioinformatics applications.


The structure of the BfrB-Bfd complex reveals protein-protein interactions enabling iron release from bacterioferritin.
Ferritin-like molecules are unique to cellular iron homeostasis because they can store iron at concentrations much higher than those dictated by the solubility of Fe(3+). Very little is known about the protein interactions that deliver iron for storage or promote the mobilization of stored iron from ferritin-like molecules. Here, we report the X-ray crystal structure of Pseudomonas aeruginosa bacterioferritin (Pa-BfrB) in complex with bacterioferritin-associated ferredoxin (Pa-Bfd) at 2.0 Å resolution. As the first example of a ferritin-like molecule in complex with a cognate partner, the structure provides unprecedented insight into the complementary interface that enables the [2Fe-2S] cluster of Pa-Bfd to promote heme-mediated electron transfer through the BfrB protein dielectric (~18 Å), a process that is necessary to reduce the core ferric mineral and facilitate mobilization of Fe(2+). The Pa-BfrB-Bfd complex also revealed the first structure of a Bfd, thus providing a first view to what appears to be a versatile metal binding domain ubiquitous to the large Fer2_BFD family of proteins and enzymes with diverse functions. Residues at the Pa-BfrB-Bfd interface are highly conserved in Bfr and Bfd sequences from a number of pathogenic bacteria, suggesting that the specific recognition between Pa-BfrB and Pa-Bfd is of widespread significance to the understanding of bacterial iron homeostasis.


Regional cortical white matter reductions in velocardiofacial syndrome: a volumetric MRI analysis.
Velocardiofacial syndrome, caused by a microdeletion on chromosome 22q.11, is associated with craniofacial anomalies, cardiac defects, learning disabilities, and psychiatric disorders. To understand how the 22q.11 deletion affects brain development, this study examined gray and white matter volumes in major lobar brain regions of children with velocardiofacial syndrome relative to control subjects. Subjects were ten children with velocardiofacial syndrome and ten age- and gender-matched unaffected children. Coronal images were acquired with a 3-D spoiled gradient echo series and partitioned into 124, 1.5-mm contiguous slices. A stereotaxic grid was used to subdivide brain tissue into cerebral lobes, which were segmented into gray, white, and CSF compartments using an algorithm based on intensity values and tissue boundaries. Nonparametric statistics were used to compare lobar volumes of gray and white matter. Analyses indicated that children with velocardiofacial syndrome had significantly smaller volumes in nonfrontal, but not frontal, lobar brain regions. Volume reductions affected nonfrontal white matter to a greater extent than nonfrontal gray matter. The presence of white matter reductions may be related to disturbances in myelination or axonal integrity in velocardiofacial syndrome. Further work is required to delineate the nature and extent of white matter anomalies, and to link them to variation in the neurocognitive and neuropsychiatric phenotype of velocardiofacial syndrome.


The economic value of an investment in physiotherapy education: a net present value analysis.
What is the economic value for an individual to invest in physiotherapy undergraduate education in Australia? How is this affected by increased education costs or decreased wages? A cost-benefit analysis using a net present value (NPV) approach was conducted and reported in Australian dollars. In relation to physiotherapy education, the NPV represents future earnings as a physiotherapist minus the direct and indirect costs in obtaining the degree. Sensitivity analyses were conducted to consider varying levels of experience, public versus private sector, and domestic versus international student fees. Comparable calculations were made for educational investments in medicine and nursing/midwifery. Assuming an expected discount rate of 9.675%, investment in education by domestic students with approximately 34 years of average work experience yields a NPV estimated at $784,000 for public sector physiotherapists and $815,000 for private sector therapists. In relation to international students, the NPV results for an investment and career as a physiotherapist is estimated at $705,000 in the public sector and $736,000 in the private sector. With an approximate payback period of 4 years, coupled with strong and positive NPV values, physiotherapy education in Australia is a financially attractive prospect and a viable value proposition for those considering a career in this field.


Internal dynamics of tRNA(Phe) studied by depolarized dynamic light scattering.
The collective internal dynamics of transfer RNA(Phe) from brewer's yeast in solution was studied by depolarized dynamic light scattering (DDLS). Within the melting region of tRNA the depolarized spectra consist of two Lorentzian, where the narrow (slow) component describes the overall rotation of the macromolecule. The broad component is attributed to the collective reorientation of the bases within the biopolymer. At high temperature only this relaxation process is observed in the spectrum. The viscosity dependence of the collective internal relaxation process is described by the Stokes-Einstein-Debye equation for rotational diffusion. Estimates of the internal orientational pair correlation factor from the integral depolarized intensities of tRNA(Phe) solutions indicates that the observed dynamics correspond to the collective reorientation of approximately 5 bases. A comparison of the results presented with DDLS studies on the aggregation of the mononucleotide guanosine-5'-monophosphate confirms this result. For a further characterization of the relaxation process we studied the effect of hydrostatic pressure (1-1000 bar) on the depolarized spectra of tRNA. While other spectroscopic methods like nmr, fluorescence polarization anisotropy decay, or ESR give information about the very local motion of a single base within the DNA or RNA, this study shows that by DDLS one can characterize collective internal motions of macromolecules.


The cyclic nucleotide-gated ion channel CNGA3 contributes to coolness-induced responses of Grueneberg ganglion neurons.
Localized to the vestibule of the nasal cavity, neurons of the Grueneberg ganglion (GG) respond to cool ambient temperatures. The molecular mechanisms underlying this thermal response are still elusive. Recently, it has been suggested that cool temperatures may activate a cyclic guanosine monophosphate (cGMP) pathway in the GG, which would be reminiscent of thermosensory neurons in Caenorhabditis elegans. In search for other elements of such a cascade, we have found that the cyclic nucleotide-gated ion channel CNGA3 was strongly expressed in the GG and that expression of CNGA3 was confined to those cells that are responsive to coolness. Further experiments revealed that the response of GG neurons to cool temperatures was significantly reduced in CNGA3-deficient mice compared to wild-type conspecifics. The observation that a cGMP-activated non-selective cation channel significantly contributes to the coolness-evoked response in GG neurons strongly suggests that a cGMP cascade is part of the transduction process.


Adherence to guideline-recommended HbA1c testing frequency and better outcomes in patients with type 2 diabetes: a 5-year retrospective cohort study in Australian general practice.
Clinical practice guidelines emphasise the role of regular monitoring of glycated haemoglobin A1c (HbA1c) for patients with type 2 diabetes, with most recommending 6-monthly testing. Nonetheless, there are few in-depth studies evaluating the clinical impact of the recommended testing frequency for patients to underpin the significance of guideline adherence. This study aimed to examine associations between patient outcomes and adherence to HbA1c testing frequencies recommended by Australian guidelines (6-monthly for patients with adequate glycaemic control and 3-monthly for patients with inadequate glycaemic control). The primary and secondary outcomes of interest were longitudinal changes in HbA1c values and development of ischaemic heart disease (IHD) and chronic kidney disease (CKD). This 5-year retrospective cohort study (July 2013-June 2018) evaluated HbA1c testing frequency in a subset of patients with type 2 diabetes identified within data collected from approximately 250 Australian general practices. The study included patients who were aged ≥18 in 2013 and had a record of HbA1c testing in study practices during the study period. Each patient's adherence rate was defined by the proportion of HbA1c tests performed within the testing intervals recommended by Australian guidelines. Based on the adherence rate, adherence level was categorised into low (≤33%), moderate (34%-66%) and high (>66%). Generalised additive mixed models were used to examine associations between adherence to the recommended HbA1c testing frequency and patient outcomes. In the 6424 patients with diabetes, the overall median HbA1c testing frequency was 1.6 tests per year with an adherence rate of 50%. The estimated HbA1c levels among patients with low adherence gradually increased or remained inadequately controlled, while HbA1c values in patients with high adherence remained controlled or improved over time. The risk of developing CKD for patients with high adherence was significantly lower than for patients with low adherence (OR: 0.42, 95% CI 0.18 to 0.99). No association between IHD and adherence to the recommended HbA1c frequency was observed. Better adherence to guideline-recommended HbA1c testing frequency was associated with better glycaemic control and lower risk of CKD. These findings may provide valuable evidence to support the use of clinical guidelines for better patient outcomes in patients with type 2 diabetes.


Molecular genetic characterization reveals new subsets of mantle cell lymphoma.
Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy, which is believed to originate from naive B-cells in the mantle zone of lymph nodes. Recently, a more diverse cellular origin has been implicated in MCL, since the disease was shown to consist of two subsets based on immunoglobulin heavy-chain variable (IGHV) gene analysis; a major subset with unmutated IGHV genes and a smaller subset (approximately 20 to 30%) displaying mutated IGHV genes. Presence of somatic hypermutation in the 'mutated' subset suggests either exposure to a germinal centre (GC) environment or that somatic hypermutation has been acquired in a non-GC context. Furthermore, a preferential IGHV gene utilization has been revealed in MCL, where IGHV3-21 and IGHV4-34 are the most predominant. MCLs with an IGHV3-21 usage almost exclusively share the same light chain (IGLV3-19) use and this subset is also related to a better prognosis. MCL cases utilising the IGHV3-21 gene display less chromosomal alterations than MCLs using other IGHV genes and in addition, gains in 15q and losses in 9p were not observed in any of these cases. These latter findings are in favour of the hypothesis that IGHV3-21(+) tumours may represent a distinct MCL subentity and that there is a possible role for antigens in MCL development. In this review, we will summarise these recent studies of IG gene rearrangements in MCL as well as molecular cytogenetic characteristics of this malignancy.


Altering the Ad5 packaging domain affects the maturation of the Ad particles.
We have previously described a new family of mutant adenoviruses carrying different combinations of attB/attP sequences from bacteriophage PhiC31 flanking the Ad5 packaging domain. These novel helper viruses have a significantly delayed viral life cycle and a severe packaging impairment, regardless of the presence of PhiC31 recombinase. Their infectious viral titers are significantly lower (100-1000 fold) than those of control adenovirus at 36 hours post-infection, but allow for efficient packaging of helper-dependent adenovirus. In the present work, we have analyzed which steps of the adenovirus life cycle are altered in attB-helper adenoviruses and investigated whether these viruses can provide the necessary viral proteins in trans. The entry of attB-adenoviral genomes into the cell nucleus early at early timepoints post-infection was not impaired and viral protein expression levels were found to be similar to those of control adenovirus. However, electron microscopy and capsid protein composition analyses revealed that attB-adenoviruses remain at an intermediate state of maturation 36 hours post-infection in comparison to control adenovirus which were fully mature and infective at this time point. Therefore, an additional 20-24 hours were found to be required for the appearance of mature attB-adenovirus. Interestingly, attB-adenovirus assembly and infectivity was restored by inserting a second packaging signal close to the right-end ITR, thus discarding the possibility that the attB-adenovirus genome was retained in a nuclear compartment deleterious for virus assembly. The present study may have substantive implications for helper-dependent adenovirus technology since helper attB-adenovirus allows for preferential packaging of helper-dependent adenovirus genomes.


[Distribution features of gunshot residue from hunting Steyr Mannlicher AUG-Z3 carbine on targets].
To study the morphology of distribution of shot factors on white targets made of coarse calico at different distances. The study was conducted on 57 experimental damages of targets made of cotton fabric, caused by shots from hunting self-loading Steyr Mannlicher AUG-Z3 carbine of.223 Rem caliber. The number of experimental firings equal 19 was done by 3 shots at the distance from close range to 250 cm. The examination of shot targets was carried out using the visual, metric, stereoscopic (Leica 125M microscope) methods, in ultraviolet rays (LUMATEC SUPERLITE M Series light). The nature and morphology of distribution of gunshot residue on targets' surfaces made it possible to establish close range firing zones. The nature in which soot is deposited during shot under the conditions of point-blank range and in the first zone of close range (up to 8 cm) allows to establish the position of weapon's transverse plane relative to the target basing on a specific blowout of a gas-powder jet from special design of flame arrestor. The performed experimental shooting from hunting self-loading Steyr Mannlicher AUG-Z3 carbine made it possible to determine the metric and morphological characteristics of the close range firing zones: 1 zone is equal a distance up to 8 cm; 2 zone - up to 30 cm; 3 zone - up to 100 cm from muzzle of weapon. The design features of Steyr Mannlicher AUG-Z3 carbine's flame arrestor allow to identify the type of weapon according to the morphological pattern of target's damage. The complex of obtained data makes it possible to determine the firing distance with high accuracy.


Multifaceted Integration: Memory for Faces Is Subserved by Widespread Connections between Visual, Memory, Auditory, and Social Networks.
Our ability to recognize others by their facial features is at the core of human social interaction, yet this ability varies widely within the general population, ranging from developmental prosopagnosia to "super-recognizers". Previous work has focused mainly on the contribution of neural activity within the well described face network to this variance. However, given the nature of face memory in everyday life, and the social context in which it takes place, we were interested in exploring how the collaboration between different networks outside the face network in humans (measured through resting state connectivity) affects face memory performance. Fifty participants (men and women) were scanned with fMRI. Our data revealed that although the nodes of the face-processing network were tightly coupled at rest, the strength of these connections did not predict face memory performance. Instead, face recognition memory was dependent on multiple connections between these face patches and regions of the medial temporal lobe memory system (including the hippocampus), and the social processing system. Moreover, this network was selective for memory for faces, and did not predict memory for other visual objects (cars). These findings suggest that in the general population, variability in face memory is dependent on how well the face processing system interacts with other processing networks, with interaction among the face patches themselves accounting for little of the variance in memory ability.SIGNIFICANCE STATEMENT Our ability to recognize and remember faces is one of the pillars of human social interaction. Face recognition however is a very complex skill, requiring specialized neural resources in visual cortex, as well as memory, identity, and social processing, all of which are inherent in our real-world experience of faces. Yet in the general population, people vary greatly in their face memory abilities. Here we show that in the neural domain this variability is underpinned by the integration of visual, memory and social circuits, with the strength of the connections between these circuits directly linked to face recognition ability.


Sperm-induced local [Ca2+]i rise separated from the Ca2+ wave in sea urchin eggs in the presence of a gamete fusion inhibitor, jaspisin .
An increase in intracellular Ca2+ concentration ([Ca2+]i) at a focal plane was recorded simultaneously with sperm-egg binding and membrane current upon insemination of sea urchin Hemicentrotus pulcherrimus eggs. No change in current and [Ca2+]i occurred in the presence of jaspisin, a novel substance that inhibits metallo-endoproteinase and sperm-egg membrane fusion (S. Ikegami, H. Kobayashi, Y. Myotoishi, S. Ohta and K. H. Kato (1994) J. Biol. Chem. 269, 23262-23267). With low doses of jaspisin, a spermatozoon first produced a step inward current (I(on)) as an indication of gamete membrane fusion and then induced a local [Ca2+]i rise at the site of sperm attachment 6-10 seconds after I(on). The sperm, however, soon detached from the egg. Increasing inward current was abruptly cut off (I(off)) within 9-15 seconds and the local [Ca2+]i rise began to decline 1-3 seconds after I(off). In most cases, no further responses or an elevation of fertilization envelope (FE) occurred. In some cases, [Ca2+]i at the sperm attachment site increased again even after the sperm detached and triggered a Ca2+ wave which caused an activation current and FE formation. This recording of a gamete membrane-fusion-induced local [Ca2+]i rise, separated from the Ca2+ wave, is a key phenomenon for elucidating the initial sperm stimulation of the egg at fertilization.


[Pathogenesis of Parkinson's Disease Viewing from Modern Chinese Medicine].
Modern pathological studies of Parkinson's disease. (PD) reveal that 70% -80% sub- stantia nigra striatum nerve endings degenerate before -motor symptoms occur. But till now, Chinese medicine (CM) infers its pathogeneses still at the theoretical level. Braak H, et al. raised six pathological stages of PD. They also beleived that symptoms of PD occurred one by one acocrding to staging sequence. All these indicated important evidence for the developing process of PD's pathogenesis. Authors expounded modern CM pathogenesis of PD.