Ovarian volume and menopausal status.
The purposes of this study were to (1) examine whether ovarian volume differs by age and menopausal status in healthy women; (2) evaluate whether ovarian volume could be a sensitive and specific predictor of menopausal status; and (3) assess whether ovarian volume is affected by cigarette smoke, oral contraceptives (OCs), and hormone replacement therapy (HRT). Each participant (527 women) completed an extensive in-home interview that assessed age, menopausal status, smoking history, OC use, and HRT use. Each participant also received a transvaginal ultrasound that measured ovarian volume. Geometric means for ovarian volume were compared between premenopausal and postmenopausal women using t tests. Tests for trends were conducted using linear regression analyses. Ovarian volume declined with age (p < or = 0.0001) and also differed by menopausal status; postmenopausal women had smaller ovarian volumes than premenopausal women of the same age (p < or = 0.0001). Ovarian volume was not associated with smoking history or HRT use. However, it was significantly smaller in current users of OCs compared with past users of or those who never used OCs (p < or = 0.0001). Ovarian volume was a sensitive and specific predictor of postmenopausal status. The data suggest that age, menopausal status, and OC use may be determinants of ovarian volume. They also suggest that ovarian volume may be useful for predicting menopausal status in women.


Insulin Regimens to Treat Hyperglycemia in Hospitalized Patients on Nutritional Support: Systematic Review and Meta-Analyses.
The best insulin regimen to treat hyperglycemia in hospitalized patients on nutritional support (NS) is unclear. We searched electronic databases to identify cohort studies or randomized clinical trials in order to evaluate the efficacy of different insulin regimens used to treat hyperglycemia in hospitalized patients on NS on diverse outcomes: mean blood glucose (MBG), hypoglycemia, length of stay in hospital, and mortality. Seventeen studies from a total of 5,030 were included. Enteral Group included 8 studies; 1,203 patients using rapid, glargine, NPH, or Premix insulin; MBG 108-225 mg/dL; hypoglycemia 0-13%. In indirect meta-analyses, NPH insulin ranked best for glucose control (MD 95% CI -2.50 mg/dL [2.65 to -2.35]). Parenteral Group included 4 studies; 228 patients using regular and glargine or NPH insulin; MBG 137-202 mg/dL; hypoglycemia 0-40%. In meta-analyses comparing regular insulin added to parenteral nutrition bag with glargine, MBG (MD 95% CI -3.78 mg/dL [-11.93 to 4.37]; I2 = 0%) or hypoglycemia frequency (RR 95% CI 1.37 [0.43-4.32]; I2 = 70.7%) did not differ. The description related to hospital length of stay and mortality was inconsistent between groups. The best insulin regimen to treat hyperglycemia in hospitalized patients on NS has not been established; best results using insulin regimens with NPH in enteral nutrition do not seem to be clinically relevant.


Geno- and phenotypic characteristics of a transfected Babesia bovis 6-Cys-E knockout clonal line.
Babesia bovis is an intra-erythrocytic tick-transmitted apicomplexan protozoan parasite. It has a complex lifestyle including asexual replication in the mammalian host and sexual replication occurring in the midgut of host tick vector, typically, Rhipicephalus microplus. Previous evidence showed that certain B. bovis genes, including members of 6-Cys gene family, are differentially expressed during tick and mammalian stages of the parasite's life cycle. Moreover, the 6-Cys E gene is differentially expressed in the T3Bo strain of B. bovis tick stages, and anti 6-Cys E antibodies were shown to be able to inhibit in vitro growth of the phenotypically distinct B. bovis Mo7clonal line. In this study, the 6-Cys E gene of B. bovis T3Bo strain was disrupted by transfection using a plasmid containing 6-Cys gene E 5' and 3' regions to guide homologous recombination, and the egfp-bsd fusion gene under control of a ef-1α promoter, yielding a B. bovis clonal line designated 6-Cys EKO-cln. Full genome sequencing of 6-Cys EKO-cln parasites was performed and in vitro inhibition assays using anti 6-Cys E antibodies. Full genome sequencing of 6-Cys EKO-cln B. bovis demonstrated single insertion of egfp-bsd gene that disrupts the integrity of 6-Cys gene E. Undistinguishable growth rate of 6-Cys EKO-cln line compared to wild-type 6-Cys E intact T3Bo B. bovis strain in in vitro cultures indicates that expression of gene 6-Cys E is not essential for blood stage replication in this strain. In vitro inhibition assays confirmed the ability of anti-6 Cys E antibodies to inhibit the growth of the wild-type Mo7 and T3Bo B. bovis parasites, but no significant inhibition was found for 6-Cys EKO-cln line parasites. Overall, the data suggest that the anti-6 Cys E antibody neutralising effect on the wild type strains is likely due to mechanical hindrance, or cross-reactivity, rather than due to functional requirements of 6-Cys gene E product for survival and development of the erythrocyte stages. Further investigation is underway to determine if the 6-Cys E protein is required for replication and sexual stage development of B. bovis during tick stages.


Characterization of two kinds of subgenomic RNAs produced by citrus leaf blotch virus.
Citrus leaf blotch virus (CLBV) has a single-stranded, positive-sense, genomic RNA (gRNA) organized in three ORFs, which encode a polyprotein involved in replication (RP), a potential movement protein (MP), and coat protein (CP). Northern blot hybridization of total, virion, or double-stranded RNA with probes of different gRNA regions revealed that CLBV produces two 3'-coterminal and two 5'-coterminal subgenomic RNAs (sgRNAs). The 3'-coterminal sgRNAs contain the MP (3'MP sgRNA) and CP (3'CP sgRNA) genes and untranslated regions (UTRs) of 123 and 284 nt, respectively, at their 5' end. These sgRNAs start with a hexanucleotide which is also present at the 5' terminus of the gRNA. The 5'-coterminal sgRNAs have 6795 and 5798 nt, colinear with the gRNA, and contain ORF1 and most MP gene (5'RPMP sgRNA) and most ORF1 (5'RP sgRNA), respectively. Their 3' termini map 35 and 40 nt upstream of the transcription initiation of the 3'CP and 3'MP sgRNAs, respectively, next to a potential promoter element. Our results suggest that, as in alphaviruses, CLBV internal genes are expressed via 3'-coterminal sgRNAs transcribed from the minus gRNA strand. The 5'-coterminal sgRNAs may result from early termination of the gRNA during the plus-strand synthesis.


Natal conditions alter age-specific reproduction but not survival or senescence in a long-lived bird of prey.
1. Natal conditions and senescence are two major factors shaping life-history traits of wild animals. However, such factors have rarely been investigated together, and it remains largely unknown whether they interact to affect age-specific performance. 2. We used 27 years of longitudinal data collected on tawny owls with estimates of prey density (field voles) from Kielder Forest (UK) to investigate how prey density at birth affects ageing patterns in reproduction and survival. 3. Natal conditions experienced by tawny owls, measured in terms of vole density, dramatically varied among cohorts and explained 87% of the deviance in first-year apparent survival (annual estimates ranging from 0·07 to 0·33). 4. We found evidence for senescence in survival for females as well as for males. Model-averaged estimates showed that adult survival probability declined linearly with age for females from age 1. In contrast, male survival probability, lower on average than for female, declined after a plateau at age 1-3. 5. We also found evidence for reproductive senescence (number of offspring). For females, reproductive performance increased until age 9 then declined. Males showed an earlier decline in reproductive performance with an onset of senescence at age 3. 6. Long-lasting effects of natal environmental conditions were sex specific. Female reproductive performance was substantially related to natal conditions (difference of 0·24 fledgling per breeding event between females born in the first or third quartile of vole density), whereas male performance was not. We found no evidence for tawny owls born in years with low prey density having accelerated rates of senescence. 7. Our results, combined with previous findings, suggest the way natal environmental conditions affect senescence varies not only across species but also within species according to gender and the demographic trait considered.


Bisphosphonate-related osteonecrosis of the jaw is associated with polymorphisms of the cytochrome P450 CYP2C8 in multiple myeloma: a genome-wide single nucleotide polymorphism analysis.
We have explored the potential role of genetics in the development of osteonecrosis of the jaw (ONJ) in multiple myeloma (MM) patients under bisphosphonate therapy. A genome-wide association study was performed using 500 568 single nucleotide polymorphisms (SNPs) in 2 series of homogeneously treated MM patients, one with ONJ (22 MM cases) and another without ONJ (65 matched MM controls). Four SNPs (rs1934951, rs1934980, rs1341162, and rs17110453) mapped within the cytochrome P450-2C gene (CYP2C8) showed a different distribution between cases and controls with statistically significant differences (P = 1.07 x 10(-6), P = 4.231 x 10(-6), P = 6.22 x 10(-6), and P = 2.15 x 10(-6), respectively). SNP rs1934951 was significantly associated with a higher risk of ONJ development even after Bonferroni correction (P corrected value = .02). Genotyping results displayed an overrepresentation of the T allele in cases compared with controls (48% vs 12%). Thus, individuals homozygous for the T allele had an increased likelihood of developing ONJ (odds ratio 12.75, 95% confidence interval 3.7-43.5).


Illumination of the melanopsin signaling pathway.
In mammals, a small population of intrinsically photosensitive retinal ganglion cells (ipRGCs) plays a key role in the regulation of nonvisual photic responses, such as behavioral responses to light, pineal melatonin synthesis, pupillary light reflex, and sleep latency. These ipRGCs also express melanopsin (Opn4), a putative opsin-family photopigment that has been shown to play a role in mediating these nonvisual photic responses. Melanopsin is required for the function of this inner retinal pathway, but its precise role in generating photic responses has not yet been determined. We found that expression of melanopsin in Xenopus oocytes results in light-dependent activation of membrane currents through the Galpha(q)/Galpha(11) G protein pathway, with an action spectrum closely matching that of melanopsin-expressing ipRGCs and of behavioral responses to light in mice lacking rods and cones. When coexpressed with arrestins, melanopsin could use all-trans-retinaldehyde as a chromophore, which suggests that it may function as a bireactive opsin. We also found that melanopsin could activate the cation channel TRPC3, a mammalian homolog of the Drosophila phototransduction channels TRP and TRPL. Melanopsin therefore signals more like an invertebrate opsin than like a classical vertebrate rod-and-cone opsin.


Pediatric Markers of Adult Cardiovascular Disease.
Cardiovascular diseases are the leading cause of death worldwide. While cardiovascular disease typically does not occur until adulthood, the pathogenesis of atherosclerotic cardiovascular disease starts in early childhood. The purpose of this review is to describe the evidence that the process of atherosclerosis begins in childhood, as well as identify the risk factors present in childhood that are associated with the presence of atherosclerotic cardiovascular disease in childhood as well as future cardiovascular events in adulthood. There is much accumulating evidence linking modifiable risk factors that are already present in childhood and that strongly predict future cardiovascular disease. The selective targeting of modifiable risk factors in childhood, including body mass index, holds promise in reducing the burden of adult cardiovascular disease. Future research studies should focus on elucidating the mechanisms which drive the pathogenesis of atherosclerosis in childhood and young adulthood, as well as identifying which interventions are most effective at limiting the progression of atherosclerosis and thus reducing future cardiovascular disease.


Evaluation of antismoking advertising campaigns.
Active and passive smoking are the first and third leading preventable causes of death. Many states are running or initiating antitobacco media campaigns. To review research on the effectiveness of different antismoking messages and published evidence of the effectiveness of paid antismoking advertising. Focus group studies conducted by professional advertising agencies that contract with California, Massachusetts, and Michigan to run their antismoking advertising campaigns, the Centers for Disease Control and Prevention's Media Campaign Resource Book, and copies of the advertisements. In total, we reviewed the results of 186 focus groups involving more than 1500 children and adults dealing with 118 advertisements that had actually been aired and additional concept advertisements that were not produced. Published literature was located using MEDLINE and standard bibliographic sources on the effectiveness of large, paid antitobacco media campaigns. We also reviewed reports and studies conducted by, or for, the California and Massachusetts health departments on program effectiveness, and conducted our own comparison of California vs Massachusetts using cigarette consumption data from the Tobacco Institute. All available studies. Eight advertising strategies to prevent people from starting to smoke and persuading them to stop were reviewed: industry manipulation, secondhand smoke, addiction, cessation, youth access, short-term effects, long-term health effects, and romantic rejection. These focus groups identified strategies that would be expected to be effective and ineffective. Regression analysis was used to compare the cost-effectiveness of the California and Massachusetts programs. Focus group participants indicated that industry manipulation and secondhand smoke are the most effective strategies for denormalizing smoking and reducing cigarette consumption. Addiction and cessation can be effective when used in conjunction with the industry manipulation and secondhand smoke strategies. Youth access, short-term effects, long-term health effects, and romantic rejection are not effective strategies. More aggressive advertising strategies appear to be more effective at reducing tobacco consumption.


Selective CXCR4+ Cancer Cell Targeting and Potent Antineoplastic Effect by a Nanostructured Version of Recombinant Ricin.
Under the unmet need of efficient tumor-targeting drugs for oncology, a recombinant version of the plant toxin ricin (the modular protein T22-mRTA-H6) is engineered to self-assemble as protein-only, CXCR4-targeted nanoparticles. The soluble version of the construct self-organizes as regular 11 nm planar entities that are highly cytotoxic in cultured CXCR4+ cancer cells upon short time exposure, with a determined IC50 in the nanomolar order of magnitude. The chemical inhibition of CXCR4 binding sites in exposed cells results in a dramatic reduction of the cytotoxic potency, proving the receptor-dependent mechanism of cytotoxicity. The insoluble version of T22-mRTA-H6 is, contrarily, moderately active, indicating that free, nanostructured protein is the optimal drug form. In animal models of acute myeloid leukemia, T22-mRTA-H6 nanoparticles show an impressive and highly selective therapeutic effect, dramatically reducing the leukemia cells affectation of clinically relevant organs. Functionalized T22-mRTA-H6 nanoparticles are then promising prototypes of chemically homogeneous, highly potent antitumor nanostructured toxins for precise oncotherapies based on self-mediated intracellular drug delivery.


Evaluating the Completeness of the SEER-Medicare Linked Database for Oral and Pharyngeal Cancer.
Oral and pharyngeal cancer is a persistent oral health problem. Baseline and trend data to measure progress are lacking. Our long-term goal is to create an algorithm using Medicare claims to identify oral and pharyngeal cancer cases among those ages 65 and older. The goal of this project was to assess the completeness of the SEER-Medicare linked database for identifying incident oral and pharyngeal cancer cases. We compared incidence rates from the "gold-standard" SEER limited-use database to those from the SEER-Medicare linked database using a quasi-likelihood extension of Poisson regression, allowing for over-dispersion. Adjustment for age, sex, race and ethnicity, and interaction terms between these explanatory variables with data source were used to assess the completeness of the SEER-Medicare linked database among these subgroups. Approximately 6.4% of the cases were missing from the SEER-Medicare linked database. The completeness varied by race and ethnicity (p=0.066). Future development of an algorithm to identify oral and pharyngeal cancer cases using Medicare claims alone can potentially identify over 93% of the cases; however, Hispanic, non-Hispanic black, and non-Hispanic other race and ethnicity subgroups will be less likely than non-Hispanic whites to be identified in such future algorithms.


Preparation and characterization of novel coenzyme Q10 nanoparticles engineered from microemulsion precursors.
The purpose of these studies was to prepare and characterize nanoparticles into which Coenzyme Q10 (CoQ10) had been incorporated (CoQ10-NPs) using a simple and potentially scalable method. CoQ10-NPs were prepared by cooling warm microemulsion precursors composed of emulsifying wax, CoQ10, Brij 78, and/or Tween 20. The nanoparticles were lyophilized, and the stability of CoQ10-NPs in both lyophilized form and aqueous suspension was monitored over 7 days. The release of CoQ10 from the nanoparticles was investigated at 37 degrees C. Finally, an in vitro study of the uptake of CoQ10-NPs by mouse macrophage, J774A.1, was completed. The incorporation efficiency of CoQ10 was approximately 74% +/- 5%. Differential Scanning Calorimetry (DSC) showed that the nanoparticle was not a physical mixture of its individual components. The size of the nanoparticles increased over time if stored in aqueous suspension. However, enhanced stability was observed when the nanoparticles were stored at 4 degrees C. Storage in lyophilized form demonstrated the highest stability. The in vitro release profile of CoQ10 from the nanoparticles showed an initial period of rapid release in the first 9 hours followed by a period of slower and extended release. The uptake of CoQ10-NPs by the J774A.1 cells was over 4-fold higher than that of the CoQ10-free nanoparticles (P < .05). In conclusion, CoQ10-NPs with potential application for oral CoQ10 delivery were engineered readily from microemulsion precursors.


Bayesian procedures for phase I/II clinical trials investigating the safety and efficacy of drug combinations.
Many formal statistical procedures for phase I dose-finding studies have been proposed. Most concern a single novel agent available at a number of doses and administered to subjects participating in a single treatment period and returning a single binary indicator of toxicity. Such a structure is common when evaluating cytotoxic drugs for cancer. This paper concerns studies of combinations of two agents, both available at several doses. Subjects participate in one treatment period and provide two binary responses: one an indicator of benefit and the other of harm. The word 'benefit' is used loosely here: the response might be an early indicator of physiological change which, if induced in patients, is of potential therapeutic value. The context need not be oncology, but might be any study intended to meet both the phase I aim of establishing which doses are safe and the phase II goal of exploring potential therapeutic activity. A Bayesian approach is used based on an assumption of monotonicity in the relationship between the strength of the dose-combination and the distribution of the bivariate outcome. Special cases are described, and the procedure is evaluated using simulation. The parameters that define the model have immediate and simple interpretation. Graphical representations of the posterior opinions about model parameters are shown, and these can be used to inform the discussions of the trial safety committee.


Bayesian decoding using unsorted spikes in the rat hippocampus.
A fundamental task in neuroscience is to understand how neural ensembles represent information. Population decoding is a useful tool to extract information from neuronal populations based on the ensemble spiking activity. We propose a novel Bayesian decoding paradigm to decode unsorted spikes in the rat hippocampus. Our approach uses a direct mapping between spike waveform features and covariates of interest and avoids accumulation of spike sorting errors. Our decoding paradigm is nonparametric, encoding model-free for representing stimuli, and extracts information from all available spikes and their waveform features. We apply the proposed Bayesian decoding algorithm to a position reconstruction task for freely behaving rats based on tetrode recordings of rat hippocampal neuronal activity. Our detailed decoding analyses demonstrate that our approach is efficient and better utilizes the available information in the nonsortable hash than the standard sorting-based decoding algorithm. Our approach can be adapted to an online encoding/decoding framework for applications that require real-time decoding, such as brain-machine interfaces.


Management of difficult germ-cell tumors.
Although testicular cancer is a rare disease accounting for only 1% of all male neoplasms, it represents a paradigm for cancer curability. Overall, more than 95% of patients can expect to be cured of their disease with minimal long-term toxicity. Given these expectations, it is critical that cancer care providers are familiar with the diagnostic and therapeutic challenges encountered in these rare patients. In particular, clinicians managing these patients should be aware of some of the pitfalls encountered when determining relapse. In a series of case presentations, we review the evaluation and management of patients with persistent elevation of serum tumor markers and postchemotherapy residual radiographic abnormalities.


In-vivo and in-vitro determination of components of rabbit early pregnancy factors.
Two types of rabbit early pregnancy factor (EPF) components, prepared from the in-vitro perfused ovary and oviduct and from serum ammonium sulphate fractions, were investigated to elucidate the source of EPF production. The state of the animals, i.e. pregnant, pseudopregnant, unstimulated or platelet activating factor (PAF)-treated, and order of addition of the components to the assay lymphocytes were varied to characterize conditions of production and expression of EPF activity. Although each component alone had no EPF activity, combination of two components, i.e. ovary and oviduct components, or serum precipitate and supernatant components, expressed EPF activity. The oviduct and serum supernatant components were produced in pregnancy and pseudopregnancy but the ovary and serum precipitate components were produced only in pregnancy. The similarity of the production pattern and ability of the perfusate and serum components to yield EPF activity when combined suggests that they are similar or the same. The sources of stimulation of EPF production did not appear to affect component production because the activity produced by the perfused ovary and oviduct in pregnancy or in response to PAF stimulation appeared similar. Oviduct and supernatant components apparently bound directly to lymphocytes. These results suggest that EPF components are produced in the ovary and oviduct individually and that the combination of the two components expresses EPF activity in the rabbit.


Genetic polymorphisms related to vitamin D and the therapeutic potential of vitamin D in multiple sclerosis.
Vitamin D receptors (VDRs), which are responsible for most vitamin D functions, are expressed on various immune cells. Vitamin D is considered to be a potent immunomodulator. A variety of cells in the central nervous system (CNS) also express VDRs; thus, vitamin D may play a role in the regulation of neurodegeneration and repair processes within the CNS. Considered together with epidemiological studies, low vitamin D status is reckoned to be one of the risk factors for multiple sclerosis (MS). Further, vitamin D is considered to be a possible treatment for MS. However, previous clinical trials with small cohorts have not demonstrated significant effects of vitamin D in MS. Current ongoing clinical trials with large cohorts could provide answers with respect to the clinical effects of vitamin D in MS. However, genetic studies have suggested that genes associated with vitamin D, including VDRs, are susceptible genes for MS. Vitamin D needs to be considered from the perspective of the interaction between vitamin-D-related genetic factors and environmental factors affecting vitamin D levels.


Effects of neutralization pattern and stereochemistry on DNA bending by methylphosphonate substitutions.
Asymmetric phosphate neutralization has been hypothesized to play a role in DNA bending by proteins. Neutralization is thought to involve salt bridges between the negatively charged phosphate backbone of duplex DNA and the cationic amino acids of an approaching protein. According to this model, the resulting unbalanced charge distribution along the duplex DNA induces the double helix to collapse toward the neutralized surface. Previous work has confirmed that DNA bending is induced by the asymmetric incorporation of racemic methylphosphonate linkages creating a neutral region on one face of duplex DNA. Neutralization was accomplished by substitution of three consecutive phosphodiesters on each strand, arranged across one minor groove of the DNA (a total of six neutralized phosphates). We now measure DNA bending induced by a more diffuse patch of neutralization (alternating neutralized and anionic phosphates) and explore the effect of methylphosphonate stereochemistry. DNA duplexes with patches of alternating methylphosphonate and phosphodiester linkages are less bent than DNAs wherein consecutive phosphates are neutralized. Furthermore, duplexes neutralized by incorporation of pure (RP)-methylphosphonate isomers are bent approximately 30% less than duplexes neutralized by racemic methylphosphonates.


Genetic ablation of NMDA receptor subunit NR3B in mouse reveals motoneuronal and nonmotoneuronal phenotypes.
NR3B is a modulatory subunit of the NMDA receptor, abundantly expressed in both cranial and spinal somatic motoneurons and at lower levels in other regions of the brain as well. Recently, we found the human NR3B gene (GRIN3B) to be highly genetically heterogeneous, and that approximately 10% of the normal European-American population lacks NR3B due to homozygous occurrence of a null allele in the gene. Therefore, it is especially important to understand the phenotypic consequences of the genetic loss of NR3B in both humans and animal models. We here provide results of behavioral analysis of mice genetically lacking NR3B, which is an ideal animal model due to homogeneity in genetic and environmental background. The NR3B(-/-) mice are viable and fertile. Consistent with the expression of NR3B in somatic motoneurons, the NR3B(-/-) mice showed a moderate but significant impairment in motor learning or coordination, and decreased activity in their home cages. Remarkably, the NR3B(-/-) mice showed a highly increased social interaction with their familiar cage mates in their home cage but moderately increased anxiety-like behaviour and decreased social interaction in a novel environment, consistent with the inhibitory role of NR3B on the functions of NMDA receptors. This work is the first reporting of the functional significance of NR3B in vivo and may give insight into the contribution of genetic variability of NR3B in the phenotypic heterogeneity among human population.


Hydrogen storage behavior of nanocrystalline and amorphous Mg-Ni-Cu-La alloys.
Alloying and structural modification are two effective ways to enhance the hydrogen storage kinetics and decrease the thermal stability of Mg and Mg-based alloys. In order to enhance the characteristics of Mg2Ni-type alloys, Cu and La were added to an Mg2Ni-type alloy, and the sample alloys (Mg24Ni10Cu2)100-x La x (x = 0, 5, 10, 15, 20) were prepared by melt spinning. The influences of La content and spinning rate on the gaseous and electrochemical hydrogen storage properties of the sample alloys were explored in detail. The structural identification carried out by XRD and TEM indicates that the main phase of the alloys is Mg2Ni and the addition of La results in the formation of the secondary phases LaMg3 and La2Mg17. The as-spun alloys have amorphous and nanocrystalline structures, and the addition of La promotes glass formation. The electrochemical properties examined by an automatic galvanostatic system show that the samples possess a good activation capability and achieve their maximal discharge capacities within three cycles. The discharge potential characteristics were vastly ameliorated by melt spinning and La addition. The discharge capacities of the samples achieve their maximal values as the La content changes, and the discharge capacities always increase with increasing spinning rate. The addition of La leads to a decline in hydrogen absorption capacity, but it can effectively enhance the rate of hydrogen absorption. The addition of La and melt spinning significantly increase the hydrogen desorption rate due to the reduced activation energy.


Direct reconstruction of an object from dual exposure Fourier intensity measurements.
The reconstruction of an object with a method using a dual exposure single inverse Fourier transform is investigated. The method calculates phase information in the Fourier plane to perform the inverse Fourier transform. The phase information in the Fourier plane is calculated from the intensity distributions formed by an object with and without a reference electric field. The method successfully reconstructs an object in a simple and fast manner. For the practical use of the method, the effects of the intensity digitization and the noise in the intensity distributions are examined in reconstructing an object.


Rapid 96-well plates DNA extraction and sequencing procedures to identify genome-wide transposon insertion sites in a difficult to lyse bacterium: Lactobacillus casei.
Random transposon mutagenesis followed by adequate screening methods is an unavoidable procedure to characterize genetics of bacterial adaptation to environmental changes. We have recently constructed a mutant library of Lactobacillus casei and we aimed to fully annotate it. However, we have observed that, for L. casei which is a difficult to lyse bacterium, methods used to identify the transposon insertion site in a few mutants (transposon rescue by restriction and recircularization or PCR-based methods) were not transposable for a larger number because they are too time-consuming and sometimes not reliable. Here, we describe a method for large-scale and reliable identification of transposon insertion sites in a L. casei mutant library of 9250 mutants. DNA extraction procedure based on silica membranes in 96-column format was optimized to obtain genomic DNA from a large number of mutants. Then reliable direct genomic sequencing was improved to fit the obtained genomic DNA extracts. Using this procedure, readable and identifiable sequences were obtained for 87% of the L. casei mutants. This method extends the applications of a library of this type, reduces the number of insertions needed to be screened, and allows selection of specific mutants from an arrayed and stored mutant library. This method is applicable to any already existing mutant library (obtained by transposon or insertional mutagenesis) and could be useful for other bacterial species, especially for highly lysis-resistant bacteria species such as lactic acid bacteria.


Low Power Systolic Array Based Digital Filter for DSP Applications.
Main concepts in DSP include filtering, averaging, modulating, and correlating the signals in digital form to estimate characteristic parameter of a signal into a desirable form. This paper presents a brief concept of low power datapath impact for Digital Signal Processing (DSP) based biomedical application. Systolic array based digital filter used in signal processing of electrocardiogram analysis is presented with datapath architectural innovations in low power consumption perspective. Implementation was done with ASIC design methodology using TSMC 65 nm technological library node. The proposed systolic array filter has reduced leakage power up to 8.5% than the existing filter architectures.


The structure of human 5-lipoxygenase.
The synthesis of both proinflammatory leukotrienes and anti-inflammatory lipoxins requires the enzyme 5-lipoxygenase (5-LOX). 5-LOX activity is short-lived, apparently in part because of an intrinsic instability of the enzyme. We identified a 5-LOX-specific destabilizing sequence that is involved in orienting the carboxyl terminus, which binds the catalytic iron. Here, we report the crystal structure at 2.4 angstrom resolution of human 5-LOX stabilized by replacement of this sequence.


Evaluation of pharmacokinetics of single-dose chloroquine in malnourished children with malaria- a comparative study with normally nourished children.
Studies on antimalarial kinetics in children or adults who are undernourished or malnourished are both limited and have yielded conflicting results. The present study was carried out with the objectives of evaluating the pharmacokinetics of single dose chloroquine and its metabolite desethylchloroquine in children who were undernourished and compare them with children who were normally nourished. Children of either gender between the ages of 5 and 12 years, smear positive for P. vivax malaria and classified either as well nourished or undernourished were included. Undernourishment was adjudged based on the Indian Academy of Pediatrics (IAP) classification of protein energy malnutrition [PEM] which in turn was based on Khadilkar's growth charts. All participants received 10 mg/kg on the first day followed by 10 mg/kg on Day 2 and 5 mg/kg on Day 3 along with supportive treatment. Blood samples for the levels of chloroquine [CQ] and desethylchloroquine [DECQ] were collected at 0, 0.5, 1, 2 4, 8, 12, 24, 48, 72 hours and 14 days after the first dose and levels assessed by High Performance Liquid Chromatography. A total of 12 children who were normally nourished and 13 who were undernourished were studied. Wide inter-individual variability was seen in the levels of both drug and metabolite in both groups of patients. However, the differences in Cmax, AUC 0-inf, Clearance, half life and Vd between the two groups were not significantly different. Our results indicate that dosage requirement is unlikely to be needed for chloroquine in undernourished children with uncomplicated P. vivax malaria.


Structure, variation, and assembly of the root-associated microbiomes of rice.
Plants depend upon beneficial interactions between roots and microbes for nutrient availability, growth promotion, and disease suppression. High-throughput sequencing approaches have provided recent insights into root microbiomes, but our current understanding is still limited relative to animal microbiomes. Here we present a detailed characterization of the root-associated microbiomes of the crop plant rice by deep sequencing, using plants grown under controlled conditions as well as field cultivation at multiple sites. The spatial resolution of the study distinguished three root-associated compartments, the endosphere (root interior), rhizoplane (root surface), and rhizosphere (soil close to the root surface), each of which was found to harbor a distinct microbiome. Under controlled greenhouse conditions, microbiome composition varied with soil source and genotype. In field conditions, geographical location and cultivation practice, namely organic vs. conventional, were factors contributing to microbiome variation. Rice cultivation is a major source of global methane emissions, and methanogenic archaea could be detected in all spatial compartments of field-grown rice. The depth and scale of this study were used to build coabundance networks that revealed potential microbial consortia, some of which were involved in methane cycling. Dynamic changes observed during microbiome acquisition, as well as steady-state compositions of spatial compartments, support a multistep model for root microbiome assembly from soil wherein the rhizoplane plays a selective gating role. Similarities in the distribution of phyla in the root microbiomes of rice and other plants suggest that conclusions derived from this study might be generally applicable to land plants.


A Computational Perspective of the Role of the Thalamus in Cognition.
The thalamus has traditionally been considered as only a relay source of cortical inputs, with hierarchically organized cortical circuits serially transforming thalamic signals to cognitively relevant representations. Given the absence of local excitatory connections within the thalamus, the notion of thalamic relay seemed like a reasonable description over the past several decades. Recent advances in experimental approaches and theory provide a broader perspective on the role of the thalamus in cognitively relevant cortical computations and suggest that only a subset of thalamic circuit motifs fits the relay description. Here, we discuss this perspective and highlight the potential role for the thalamus, and specifically the mediodorsal (MD) nucleus, in the dynamic selection of cortical representations through a combination of intrinsic thalamic computations and output signals that change cortical network functional parameters. We suggest that through the contextual modulation of cortical computation, the thalamus and cortex jointly optimize the information and cost trade-off in an emergent fashion. We emphasize that coordinated experimental and theoretical efforts will provide a path to understanding the role of the thalamus in cognition, along with an understanding to augment cognitive capacity in health and disease.


Latent Cytomegalovirus-Driven Recruitment of Activated CD4+ T Cells Promotes Virus Reactivation.
Human cytomegalovirus (HCMV) infection is not cleared by the initial immune response but persists for the lifetime of the host, in part due to its ability to establish a latent infection in cells of the myeloid lineage. HCMV has been shown to manipulate the secretion of cellular proteins during both lytic and latent infection; with changes caused by latent infection mainly investigated in CD34+ progenitor cells. Whilst CD34+ cells are generally bone marrow resident, their derivative CD14+ monocytes migrate to the periphery where they briefly circulate until extravasation into tissue sites. We have analyzed the effect of HCMV latent infection on the secretome of CD14+ monocytes, identifying an upregulation of both CCL8 and CXCL10 chemokines in the CD14+ latency-associated secretome. Unlike CD34+ cells, the CD14+ latency-associated secretome did not induce migration of resting immune cell subsets but did induce migration of activated NK and T cells expressing CXCR3 in a CXCL10 dependent manner. As reported in CD34+ latent infection, the CD14+ latency-associated secretome also suppressed the anti-viral activity of stimulated CD4+ T cells. Surprisingly, however, co-culture of activated autologous CD4+ T cells with latently infected monocytes resulted in reactivation of HCMV at levels comparable to those observed using M-CSF and IL-1β cytokines. We propose that these events represent a potential strategy to enable HCMV reactivation and local dissemination of the virus at peripheral tissue sites.


Admission lactate concentration has predictive value for death or severe complications within 30 days after admission in cattle with long-bone fractures.
To determine the prognostic value of lactate concentration measurements at admission in cattle with long-bone fractures. 43 cattle with long-bone fractures between July 2016 and Dec 2018. In this prospective cohort study, lactate concentration was measured in systemic venous blood and locally in capillary blood sampled from the fractured and contralateral limbs of cattle and assessed for outcome prediction. The cutoff value was determined by maximizing the Youden index from receiver-operating characteristic curves. Multivariable logistic regression was employed to verify whether higher lactate concentrations compared with the cutoff value were an independent risk factor for poor outcomes at 30 days or 3 years after admission. Poor outcome was associated with higher capillary lactate concentration in the fractured limb (P < .001) and greater difference with systemic blood (P = .005). A cutoff value of lactate difference ≥ 2.4 mmol/L (sensitivity = 0.80; specificity = 0.965) between capillary lactate in the fractured limb and systemic blood was the best predictor of death ≤ 30 days after admission (P < .001). Multivariable analysis revealed that this cutoff value was an independent risk factor for 30-day and 3-year outcomes (P < .001). Admission blood lactate concentration difference ≥ 2.4 mmol/L between the fractured limb and systemic blood was a robust and independent predictor of outcome for cattle of the present report. Lactate metabolism is locally impaired in fractured limbs of nonsurviving or at higher complication risk cattle, which may help identify patients at high risk for poor outcomes.


Comparative Study of Different Acidic Surface Structures in Solid Catalysts Applied for the Isobutene Dimerization Reaction.
Dimerization of isobutene (IBE) to C8s olefins was evaluated over a range of solid acid catalysts of diverse nature, in a fixed bed reactor working in a continuous mode. All catalytic materials were studied in the title reaction performed between 50-250 °C, being the reaction feed a mixture of IBE/helium (4:1 molar ratio). In all materials, both conversion and selectivity increased with increasing reaction temperature and at 180 °C the best performance was recorded. Herein, we used thermogravimetry analysis (TGA) and temperature programmed desorption of adsorbed ammonia (NH3-TPD) for catalysts characterization. We place emphasis on the nature of acid sites that affect the catalytic performance. High selectivity to C8s was achieved with all catalysts. Nicely, the catalyst with higher loading of Brønsted sites displayed brilliant catalytic performance in the course of the reaction (high IBE conversion). However, optimum selectivity towards C8 compounds led to low catalyst stability, this being attributed to the combined effect between the nature of acidic sites and structural characteristics of the catalytic materials used. Therefore, this study would foment more research in the optimization of the activity and the selectivity for IBE dimerization reactions.


From anti-p200 pemphigoid to anti-laminin gamma1 pemphigoid.
Anti-laminin gamma1 pemphigoid is an autoimmune subepidermal bullous disease first described in 1996, and has been distinct from previously known subepidermal blistering diseases, such as bullous pemphigoid and epidermolysis bullosa acquisita. Circulating autoantibodies of the patients do not react to any known autoantigen of the skin, but react to a 200-kDa molecule (p200) from dermal extracts. The identity of p200 was unmasked as laminin gamma1, an extracellular matrix glycoprotein composing several forms of laminin heterotrimers. We renamed this disease from the previously used anti-p200 pemphigoid to anti-laminin gamma1 pemphigoid, a new entity of an autoimmune bullous disease. In this decade, we have experienced over 70 cases of this disease. Although the number of the cases of anti-laminin gamma1 pemphigoid is half as many as the number of definitely diagnosed cases of epidermolysis bullosa acquisita in the same duration, a considerable number of the cases could be clinically misdiagnosed as epidermolysis bullosa acquisita. Unveiling the pathogenicity and development of a useful diagnostic method is necessary for appropriate management of this new disease.


Soliton multistability as a result of double-resonance wave mixing in chi((2)) media.
We investigate analytically and numerically the existence and stability properties of three-wave solitons resulting from double-resonance (type I plus type II) parametric interaction in a purely quadratic nonlinear medium. The existence of a family of stable solitons for the double-resonance model is demonstrated in a broad parameter range. Moreover, these solitons are shown to exhibit multistability, a feature that is potentially useful for optical switching applications. Finally, we find and present a novel family of quasi solitons.


Family satisfaction with family conferences about end-of-life care in the intensive care unit: increased proportion of family speech is associated with increased satisfaction.
Family members of critically ill patients report dissatisfaction with family-clinician communication about withdrawing life support, yet limited data exist to guide clinicians in this communication. The hypothesis of this analysis was that increased proportion of family speech during ICU family conferences would be associated with increased family satisfaction. Cross-sectional study. We identified family conferences in intensive care units of four Seattle hospitals during which discussions about withdrawing life support were likely to occur. Participants were 214 family members from 51 different families. There were 36 different physicians leading the conferences, as some physicians led more than one conference. Fifty-one conferences were audiotaped. We measured the duration of time that families and clinicians spoke during the conference. All participants were given a survey assessing satisfaction with communication. The mean conference time was 32.0 mins with an sd of 14.8 mins and a range from 7 to 74 mins. On average, family members spoke 29% and clinicians spoke 71% of the time. Increased proportion of family speech was significantly associated with increased family satisfaction with physician communication. Increased proportion of family speech was also associated with decreased family ratings of conflict with the physician. There was no association between the duration of the conference and family satisfaction. This study suggests that allowing family members more opportunity to speak during conferences may improve family satisfaction. Future studies should assess the effect of interventions to increase listening by critical care clinicians on the quality of communication and the family experience.


Anti-Cancer Effect of Quercetin in Xenograft Models with EBV-Associated Human Gastric Carcinoma.
Licorice extracts have been widely used in herbal and folk medications. Glycyrrhiza contains diverse range of biological compounds including triterpenes (glycyrrhizin, glycyrrhizic acid) and flavonoids (quercetin, liquiritin, liquiritigenin, glabridin, licoricidin, isoliquiritigenin). The flavonoids in licorice are known to have strong anti-cancer activities. Quercetin, the most abundant flavonoid, has been shown to have anti-ulcer, anti-cancer, antioxidant, and anti-inflammatory properties. Latent Epstein-Barr virus (EBV) infection can lead to serious malignancies, such as, Burkitt's lymphoma, Hodgkin's disease and gastric carcinoma(GC), and (Epstein-Barr virus associated gastric carcinoma) EBVaGC is one of the most common EBV-associated cancers. In this study, the authors first examined the anti-cancer effects of quercetin and isoliquiritigenin in vivo xenograft animal models implanted with EBV(+) human gastric carcinoma (SNU719) or EBV(-) human gastric carcinoma (MKN74), and then explored the molecular mechanisms responsible for their anti-cancer activities. The results obtained showed that anti-cancer effect of quercetin was greater than isoliquiritigenin in mice injected with EBV(+) human gastric carcinoma (SNU719) cells. On the other hand, quercetin and isoliquiritigenin had similar anti-cancer effects in mice injected with EBV(-) human gastric carcinoma (MKN74) cells. Interestingly, quercetin inhibited EBV viral protein expressions, including EBNA-1 and LMP-2 proteins in tumor tissues from mice injected with EBV(+) human gastric carcinoma. Quercetin more effectively induced p53-dependent apoptosis than isoliquiritigenin in EBV(+) human gastric carcinoma, and this induction was correlated with increased expressions of the cleaved forms of caspase-3, -9, and Parp. In EBV(-)human gastric carcinoma (MKN74), both quercetin and isoliquiritigenin induced the expressions of p53, Bax, and Puma and the cleaved forms of caspase-3 and -9 and Parp at similar levels.


The impact of symptomatic hoarding in OCD and its treatment.
The value of defining subtypes in obsessive compulsive disorder (OCD) has become an important issue for recent debate. Probably the most robust example of subtyping is the identification of hoarding as being different both in terms of psychopathology and response to treatment. To identify differences in psychopathology and treatment response in OCD patients with and without additional hoarding symptoms. Patients who had undertaken CBT for OCD were selected as falling into either a high or a low hoarding group. The high hoarding group (n = 18) was selected on the basis of a high score on the hoarding subscale of a self-report measure of OCD symptoms in addition to reaching clinician judged "threshold" on the hoarding item of the Obsessive Compulsive Personality Disorder (OCPD) SCID-II module. The low hoarding group (n = 20) was selected on the basis of a low score on the hoarding subscale and a clinician judgement that the hoarding item of the OCPD SCID-II module was "absent". On some measures of pre-treatment psychopathology, patients with OCD with hoarding symptoms were more severely affected than those without hoarding symptoms. It was found that there was no difference in eventual treatment outcome between the two groups, although there was some evidence that the hoarding group showed greater symptom decreases. The presence of hoarding symptoms does not negatively impact on the treatment of OCD.


Microarray analysis of high-glucose diet-induced changes in mRNA expression in jejunums of C57BL/6J mice reveals impairment in digestion, absorption.
Long term intake of high-glucose diet (HGD) may induce many diseases such as dyslipidemia, fatty liver and diabetes disease. Most of the research for molecular mechanisms of the association between HGD and the above diseases focus on the metabolism of glucose and lipid. However, there are few studies on molecular mechanism of the effect of HGD on digestion and absorption. We used HGD (containing 20% glucose) to feed C57BL/6J mice for 4 weeks, detected the expressions of 13,098 genes in jejunums of C57BL/6J mice with DNA microarray. Microarray analysis showed the expression of genes related to digestive enzyme, gastrointestinal peptide and nutrient transporters were significantly changed, which indicated that HGD induced the suppression of digestive enzyme gene expression, attenuation of alimentary tract movement and nutrient transportation. In one word, the microarray analysis suggested that HGD impaired the function of digestion and absorption in jejunum of C57BL/6J mice. We validated our microarray findings by conducting real-time RT-PCR assays on selected genes and detecting the activities of disaccharidases such as lactase, maltase and sucrase in jejunum of C57BL/6J mice.


Transmission of Schistosoma japonicum in marshland and hilly regions of China: parasite population genetic and sibship structure.
The transmission dynamics of Schistosoma japonicum remain poorly understood, as over forty species of mammals are suspected of serving as reservoir hosts. However, knowledge of the population genetic structure and of the full-sibship structuring of parasites at two larval stages will be useful in defining and tracking the transmission pattern between intermediate and definitive hosts. S. japonicum larvae were therefore collected in three marshland and three hilly villages in Anhui Province of China across three time points: April and September-October 2006, and April 2007, and then genotyped with six microsatellite markers. Results from the population genetic and sibling relationship analyses of the parasites across two larval stages demonstrated that, within the marshland, parasites from cattle showed higher genetic diversity than from other species; whereas within the hilly region, parasites from dogs and humans displayed higher genetic diversity than those from rodents. Both the extent of gene flow and the estimated proportion of full-sib relationships of parasites between two larval stages indicated that the cercariae identified within intermediate hosts in the marshlands mostly came from cattle, whereas in the hilly areas, they were varied between villages, coming primarily from rodents, dogs or humans. Such results suggest a different transmission process within the hilly region from within the marshlands. Moreover, this is the first time that the sibling relationship analysis was applied to the transmission dynamics for S. japonicum.


PET/MR in cancers of the head and neck.
One early application of PET/MRI in clinical practice may be the imaging of head and neck cancers. This is because the morphologic imaging modalities, CT and MR, are recognized as similarly effective tools in cross-sectional oncological imaging of the head and neck. The addition of PET with FDG is believed to enhance the accuracy of both modalities to a similar degree. However, there are a few specific scenarios in head and neck cancer imaging where MR is thought to provide an edge over CT, including perineural spread of tumors and the infiltration of important anatomical landmarks, such as the prevertebral fascia and great vessel walls. Here, hybrid PET/MR might provide higher diagnostic certainty than PET/CT or a separate acquisition of PET/CT and MR. Another advantage of MR is the availability of several functional techniques. Although some of them might enhance the imaging of head and neck cancer with PET/MR, other functional techniques actually might prove dispensable in the presence of PET. In this overview, we discuss current trends and potential clinical applications of PET/MR in the imaging of head and neck cancers, including clinical protocols. We also discuss potential benefits of implementing functional MR techniques into hybrid PET/MRI of head and neck cancers.


Loop-mediated isothermal amplification (LAMP) for point-of-care detection of asymptomatic low-density malaria parasite carriers in Zanzibar.
Asymptomatic, low parasite density malaria infections are difficult to detect with currently available point-of-care diagnostics. This study piloted a loop-mediated isothermal amplification (LAMP) kit for field-friendly, high-throughput detection of asymptomatic malaria infections during mass screening and treatment (MSAT) in Zanzibar, a malaria pre-elimination setting. Screening took place in three known hotspot areas prior to the short rains in November. Finger-prick blood was taken for screening by rapid diagnostic test (RDT) and LAMP and collected on filter paper for subsequent polymerase chain reaction (PCR) analyses. LAMP results were compared to RDT and to PCR using McNemar's test. Approximately 1,000 people were screened. RDT detected ten infections (1.0% (95% CI 0.3-1.6)) whilst both LAMP and PCR detected 18 (1.8% (95% CI 0.9-2.6)) infections. However, PCR identified three infections that LAMP did not detect and vice versa. LAMP testing was easy to scale-up in field conditions requiring minimal training and equipment, with results ready one to three hours after screening. Despite lower than expected prevalence, LAMP detected a higher number of infections than the currently used diagnostic, RDT. LAMP is a field-friendly, sensitive diagnostic test that could be useful for MSAT malaria campaigns which require quick results to enable prompt treatment.


Comparison of IgM capture ELISA with a commercial rapid immunochromatographic card test & IgM microwell ELISA for the detection of antibodies to dengue viruses.
There is a need for a reliable test for the early diagnosis of dengue fever (DF), which is now active in many parts of India especially in the post monsoon months. This study evaluated two commercial tests with an assay available from a national laboratory in India to obtain information and to make a comparison among the three tests as to which will be the most suited for the detection of IgM antibodies to dengue virus. An IgM capture ELISA (National Institute of Virology, Pune, India) was compared with two commercial tests, the PanBio Rapid Immunochromatographic Card Test (Brisbane, Australia) and the PanBio Microwell IgM ELISA for the detection of IgM antibodies to dengue virus. We tested 154 samples from individuals with febrile illnesses having DF--like symptoms. The NIV IgM capture ELISA (MAC-ELISA) showed a high positivity rate (38.9%) as compared to the PanBio Rapid (22.7%) and the PanBio IgM ELISA (20.7%). The true prevalence of disease, sensitivity and specificity of the three tests were estimated using 2LC latent class models using expectation-maximization (EM) algorithm. The NIV MAC-ELISA showed a high sensitivity (96%) as compared to PanBio Rapid (73%) and PanBio IgM ELISA (72%). A subset of 68 samples (of the 154 tested) were analyzed by the NIV MAC-ELISA for IgM antibodies additionally to Japanese encephalitis (JE) and West Nile (WN) of which 31 samples showed positivity to either one, two or all three flaviviruses. Out of the 8 samples which were positive for dengue IgM alone by the NIV MAC-ELISA, only 2 (25%) each were picked up by the other 2 tests. While out of 7 samples positive for IgM to all three flaviviruses IgM by the NIV MAC-ELISA, 5 (71%) were picked up by the other 2 tests. Of the 5 that were picked up by the PanBio tests, 3 had the highest absorbance values to WN by the NIV MAC-ELISA, indicating cross reactivity by PanBio tests. The MAC-ELISA though a 3 day procedure, would be a valuable screening test for the detection of IgM to dengue in routine diagnostic laboratories because of its high sensitivity and specificity rates. The test uses specific viral antigens to detect IgM antibodies not only to dengue but also to JE and West Nile as a result of which IgM antibodies to all the 3 commonly encountered flaviviruses can be detected in a single run. It also has the advantage in that depending on the strength of the antibody units obtained to a specific flaviviral antigen, presumptive diagnosis as to which particular arboviral infection has occurred can be made in conjunction with clinical presentation.


Triggering the intentional stance.
While humans possess a ready capacity to view a target (biological or otherwise) as an intentional agent (i.e. the 'intentional stance'), the conditions necessary for spontaneously eliciting these mentalizing processes are less well understood. Although research examining people's tendency to construe the motion of geometric shapes as intentional has done much to illuminate this issue, due to methodological limitations (a reliance on subjective self-report) this work has not fully addressed the potentially automatic and obligatory nature of mentalizing. Acknowledging this problem, recent research using prelinguistic infants, neuroimaging technology and methods that avoid explicit self-report all provide unique paths to circumvent this shortcoming. While work of this kind has generally corroborated the results of previous investigations, it has also raised a number of new issues. One such issue is whether spontaneous mentalizing processes for abstract non-biological stimuli are instantiated in the same neural architecture as those for realistic representations of intentional biological agents. This question is considered in the current chapter.


Fano resonances in metasurfaces made of linear trimers of plasmonic nanoparticles.
We investigate Fano resonances in planar two-dimensional periodic arrays of linear trimers of plasmonic nanoparticles that appear under plane wave incidence. The observed Fano resonances are associated to resonances belonging to the trimer (metamolecule) itself, where some are found to be strongly affected by the array periodicity. We observe that array-dependent resonances appearing for oblique incidence are resistant to losses, whereas narrow dipolar-like Fano resonances associated mainly to the metamolecule, which appear also under normal incidence, disappear when losses are too high. In particular, we prove the latter by theoretical (dipolar approximation) and full-wave simulations, in good agreement. We propose that the use of very low-loss plasmonic materials or the use of gain materials to mitigate plasmonic losses may lead to (high-quality factor) dipolar-like Fano resonances under normal incidence, exhibiting a certain degree of fabrication defect tolerance, which might be employed to improve sensors, lasing, switching, and nonlinear devices, for example.


PET in LRRK2 mutations: comparison to sporadic Parkinson's disease and evidence for presymptomatic compensation.
Parkinson's disease may arise from multiple aetiologies, including genetic mutations that are for the most part uncommon. We describe here the positron emission tomography (PET) findings in clinically affected and asymptomatic, high-risk members of two autosomal dominantly inherited Parkinson's disease kindreds with recently described mutations at the PARK8 locus, in a novel gene encoding a leucine-rich repeat kinase (LRRK2). Affected family members have L-dopa-responsive parkinsonism with loss of dopaminergic nigral neurons and pleomorphic subcellular pathology. Fifteen family members underwent PET using: 18F-6-fluoro-L-dopa (18F-dopa) to assess dopamine (DA) synthesis and storage, 11C-(+/-)-dihydrotetrabenazine (11C-DTBZ) for the vesicular monoamine transporter, and 11C-d-threo-methylphenidate (11C-MP) for the membrane dopamine transporter (DAT). Measurements were compared with normal (n = 33) and sporadic Parkinson's disease (sPD) (n = 67) control groups. Four clinically affected members had findings similar to sPD, with impaired presynaptic DA function affecting the putamen more than the caudate. In two affected members, D2 dopamine receptor binding was intact. Two asymptomatic mutation carriers had abnormal DAT binding with another two developing such abnormalities over 4 years of follow-up. In these individuals, 18F-dopa uptake remained normal, although two of them also displayed abnormal 11C-DTBZ binding. Our study demonstrates that the in vivo neurochemical phenotype of LRRK2 mutations is indistinguishable from that of sPD, despite the pathological heterogeneity of the condition. Furthermore, we suggest that compensatory changes including downregulation of the DAT and upregulation of decarboxylase activity may delay the onset of parkinsonian symptoms.


Bull's-Eye and Nontarget Skin Lesions of Lyme Disease: An Internet Survey of Identification of Erythema Migrans.
Introduction. Lyme disease is an emerging worldwide infectious disease with major foci of endemicity in North America and regions of temperate Eurasia. The erythema migrans rash associated with early infection is found in approximately 80% of patients and can have a range of appearances including the classic target bull's-eye lesion and nontarget appearing lesions. Methods. A survey was designed to assess the ability of the general public to distinguish various appearances of erythema migrans from non-Lyme rashes. Participants were solicited from individuals who visited an educational website about Lyme disease. Results. Of 3,104 people who accessed a rash identification survey, 72.7% of participants correctly identified the classic target erythema migrans commonly associated with Lyme disease. A mean of 20.5% of participants was able to correctly identify the four nonclassic erythema migrans. 24.2% of participants incorrectly identified a tick bite reaction in the skin as erythema migrans. Conclusions. Participants were most familiar with the classic target erythema migrans of Lyme disease but were unlikely to correctly identify the nonclassic erythema migrans. These results identify an opportunity for educational intervention to improve early recognition of Lyme disease and to increase the patient's appropriate use of medical services for early Lyme disease diagnosis.


Antioxidant Potential of the Extracts, Fractions and Oils Derived from Oilseeds.
The polyphenolic extracts and oils were obtained from ajwain, mustard, fenugreek and poppy seeds. The extracts were partitioned into acidic and neutral polyphenolic fractions and following estimation of total phenolics in the crude extract, acidic and neutral fractions and oil, all were analyzed for their DPPH (2,2-diphenyl-1-picrylhydrazyl) scavenging potential, ferric reducing ability and chelating power. The highest amount of polyphenols was found in ajwain (8330 ± 107), then in mustard seeds (2844 ± 56.00) and in fenugreek (1130 ± 29.00), and least in poppy seeds (937 ± 18.52). The higher amounts of polyphenols were estimated in neutral fraction compared to acidic (p < 0.05). % Inhibition of DPPH by the crude extract and fractions of all oilseeds was quite significant, being higher for acidic than neutral. The highest % DPPH inhibition was shown by ajwain extract than mustard > fenugreek and least by poppy seed extracts (p < 0.05). The reducing power and the chelating effect of the oilseeds followed the same order as DPPH, but higher % chelation was shown by neutral than acidic fraction (p < 0.05). Though low in polyphenols, the oil fractions were as strong antioxidants as the acidic one. Though oilseeds are used in very small quantity in food, they are potential sources of natural antioxidants and may replace synthetic ones.


The Rab5-Rab11 Endosomal Pathway is Required for BDNF-Induced CREB Transcriptional Regulation in Hippocampal Neurons.
Brain-derived neurotrophic factor (BDNF) is a key regulator of the morphology and connectivity of central neurons. We have previously shown that BDNF/TrkB signaling regulates the activity and mobility of the GTPases Rab5 and Rab11, which in turn determine the postendocytic sorting of signaling TrkB receptors. Moreover, decreased Rab5 or Rab11 activity inhibits BDNF-induced dendritic branching. Whether Rab5 or Rab11 activity is important for local events only or for regulating nuclear signaling and gene expression is unknown. Here, we investigated, in rat hippocampal neuronal cultures derived from embryos of unknown sex, whether BDNF-induced signaling cascades are altered when early and recycling endosomes are disrupted by the expression of dominant-negative mutants of Rab5 and Rab11. The activity of both Rab5 and Rab11 was required for sustained activity of Erk1/2 and nuclear CREB phosphorylation, and increased transcription of a BDNF-dependent program of gene expression containing CRE binding sites, which includes activity-regulated genes such as Arc, Dusp1, c-fos, Egr1, and Egr2, and growth and survival genes such as Atf3 and Gem Based on our results, we propose that early and recycling endosomes provide a platform for the integration of neurotrophic signaling from the plasma membrane to the nucleus in neurons, and that this mechanism is likely to regulate neuronal plasticity and survival.SIGNIFICANCE STATEMENT BDNF is a neurotrophic factor that regulates plastic changes in the brain, including dendritic growth. The cellular and molecular mechanisms underlying this process are not completely understood. Our results uncover the cellular requirements that central neurons possess to integrate the plasma membrane into nuclear signaling in neurons. Our results indicate that the endosomal pathway is required for the signaling cascade initiated by BDNF and its receptors at the plasma membrane to modulate BDNF-dependent gene expression and neuronal dendritic growth mediated by the CREB transcription factor. CREB is a key transcription factor regulating circuit development and learning and memory.


Amino acid signatures of salinity on an environmental scale with a focus on the Dead Sea.
The increase of the acidic nature of proteins as an adaptation to hypersalinity has been well documented within halophile isolates. Here we explore the effect of salinity on amino acid preference on an environmental scale. Via pyrosequencing, we have obtained two distinct metagenomic data sets from the Dead Sea, one from a 1992 archaeal bloom and one from the modern Dead Sea. Our data, along with metagenomes from environments representing a range of salinities, show a strong linear correlation (R(2) = 0.97) between the salinity of an environment and the ratio of acidic to basic amino acids encoded by its inhabitants. Using the amino acid composition of putative protein-encoding reads and the results of 16S rRNA amplicon sequencing, we differentiate recovered sequences representing microorganisms indigenous to the Dead Sea from lateral gene transfer events and foreign DNA. Our methods demonstrate lateral gene transfer events between a halophilic archaeon and relatives of the thermophilic bacterial genus Thermotoga and suggest the presence of indigenous Dead Sea representatives from 10 traditionally non-hyperhalophilic bacterial lineages. The work suggests the possibility that amino acid bias of hypersaline environments might be preservable in fossil DNA or fossil amino acids, serving as a proxy for the salinity of an ancient environment. Finally, both the amino acid profile of the 2007 Dead Sea metagenome and the V9 amplicon library support the conclusion that the dominant microorganism inhabiting the Dead Sea is most closely related to a thus far uncultured relative of an alkaliphilic haloarchaeon.


Genomic variation and strain-specific functional adaptation in the human gut microbiome during early life.
The human gut microbiome matures towards the adult composition during the first years of life and is implicated in early immune development. Here, we investigate the effects of microbial genomic diversity on gut microbiome development using integrated early childhood data sets collected in the DIABIMMUNE study in Finland, Estonia and Russian Karelia. We show that gut microbial diversity is associated with household location and linear growth of children. Single nucleotide polymorphism- and metagenomic assembly-based strain tracking revealed large and highly dynamic microbial pangenomes, especially in the genus Bacteroides, in which we identified evidence of variability deriving from Bacteroides-targeting bacteriophages. Our analyses revealed functional consequences of strain diversity; only 10% of Finnish infants harboured Bifidobacterium longum subsp. infantis, a subspecies specialized in human milk metabolism, whereas Russian infants commonly maintained a probiotic Bifidobacterium bifidum strain in infancy. Groups of bacteria contributing to diverse, characterized metabolic pathways converged to highly subject-specific configurations over the first two years of life. This longitudinal study extends the current view of early gut microbial community assembly based on strain-level genomic variation.


The interaction of the gammaherpesvirus 68 orf73 protein with cellular BET proteins affects the activation of cell cycle promoters.
Infection of mice with murine gammaherpesvirus 68 (MHV-68) provides a valuable animal model for gamma-2 herpesvirus (rhadinovirus) infection and pathogenesis. The MHV-68 orf73 protein has been shown to be required for the establishment of viral latency in vivo. This study describes a novel transcriptional activation function of the MHV-68 orf73 protein and identifies the cellular bromodomain containing BET proteins Brd2/RING3, Brd3/ORFX, and BRD4 as interaction partners for the MHV-68 orf73 protein. BET protein members are known to interact with acetylated histones, and Brd2 and Brd4 have been implicated in fundamental cellular processes, including cell cycle regulation and transcriptional regulation. Using MHV-68 orf73 peptide array assays, we identified Brd2 and Brd4 interaction sites in the orf73 protein. Mutation of one binding site led to a loss of the interaction with Brd2/4 but not the retinoblastoma protein Rb, to impaired chromatin association, and to a decreased ability to activate the BET-responsive cyclin D1, D2, and E promoters. The results therefore pinpoint the binding site for Brd2/4 in a rhadinoviral orf73 protein and suggest that the recruitment of a member of the BET protein family allows the MHV-68 orf73 protein to activate the promoters of G(1)/S cyclins. These findings point to parallels between the transcriptional activator functions of rhadinoviral orf73 proteins and papillomavirus E2 proteins.


Facilitating Discourse Analysis with Interactive Visualization.
A discourse parser is a natural language processing system which can represent the organization of a document based on a rhetorical structure tree-one of the key data structures enabling applications such as text summarization, question answering and dialogue generation. Computational linguistics researchers currently rely on manually exploring and comparing the discourse structures to get intuitions for improving parsing algorithms. In this paper, we present DAViewer, an interactive visualization system for assisting computational linguistics researchers to explore, compare, evaluate and annotate the results of discourse parsers. An iterative user-centered design process with domain experts was conducted in the development of DAViewer. We report the results of an informal formative study of the system to better understand how the proposed visualization and interaction techniques are used in the real research environment.


Dissecting the N-terminal myosin binding site of human cardiac myosin-binding protein C. Structure and myosin binding of domain C2.
Myosin-binding protein C (MyBP-C) binds to myosin with two binding sites, one close to the N terminus and the other at the C terminus. Here we present the solution structure of one part of the N-terminal binding site, the third immunoglobulin domain of the cardiac isoform of human MyBP-C (cC2) together with a model of its interaction with myosin. Domain cC2 has the beta-sandwich structure expected from a member of the immunoglobulin fold. The C-terminal part of the structure of cC2 is very closely related to telokin, the myosin binding fragment of myosin light chain kinase. Domain cC2 also contains two cysteines on neighboring strands F and G, which would be able to form a disulfide bridge in a similar position as in telokin. Using NMR spectroscopy and isothermal titration calorimetry we demonstrate that cC2 alone binds to a fragment of myosin, S2Delta, with low affinity (kD = 1.1 mM) but exhibits a highly specific binding site. This consists of the C-terminal surface of the C'CFGA' beta-sheet, which includes Glu(301), a residue mutated to Gln in the disease familial hypertrophic cardiomyopathy. The binding site on S2 was identified by a combination of NMR binding experiments of cC2 with S2Delta containing the cardiomyopathy-linked mutation R870H and molecular modeling. This mutation lowers the binding affinity and changes the arrangement of side chains at the interface. Our model of the cC2-S2Delta complex gives a first glimpse of details of the MyBP-C-myosin interaction. Using this model we suggest that most key interactions are between polar amino acids, explaining why the mutations E301Q in cC2 and R870H in S2Delta could be involved in cardiomyopathy. We expect that this model will stimulate future research to further refine the details of this interaction and their importance for cardiomyopathy.


Antibody Responses to Plasmodium falciparum and Plasmodium vivax and Prospective Risk of Plasmodium spp. Infection Postpartum.
AbstractPostpartum women may have an altered susceptibility to Plasmodium falciparum and Plasmodium vivax. The relationship between naturally acquired malarial immunity and susceptibility to malaria postpartum is yet to be determined. IgG levels were measured against P. falciparum and P. vivax antigens from delivery in 201 postpartum and 201 nonpregnant controls over 12 weeks. Associations between time-varying antibody levels and time to first microscopically confirmed species-specific infection were determined by Cox regression. Associations between antibody levels and prospective risk of Plasmodium infection were similar in postpartum and control women. A 2-fold increase in P. falciparum antibody levels was associated with increased prospective risk of P. falciparum infection (hazard ratio [HR] range = 1.37-1.94). Antibody levels against most P. vivax antigens displayed no association with prospective risk of P. vivax infection (HR range = 1.02-1.05) with the exception of PvMSP119 antibodies that were weakly associated with prospective risk of P. vivax infection (HR = 1.14 (95% confidence interval = 1.02, 1.28) per 2-fold increase in levels). Associations between antibody levels and prospective risk of infection attenuated when adjusted for documented retrospective exposure. Serology may be a useful tool to predict and monitor women at increased risk of P. falciparum infection postpartum, particularly in the absence of a detailed history of retrospective infections.


Latent deformation models for multivariate functional data and time-warping separability.
Multivariate functional data present theoretical and practical complications that are not found in univariate functional data. One of these is a situation where the component functions of multivariate functional data are positive and are subject to mutual time warping. That is, the component processes exhibit a common shape but are subject to systematic phase variation across their domains in addition to subject-specific time warping, where each subject has its own internal clock. This motivates a novel model for multivariate functional data that connect such mutual time warping to a latent-deformation-based framework by exploiting a novel time-warping separability assumption. This separability assumption allows for meaningful interpretation and dimension reduction. The resulting latent deformation model is shown to be well suited to represent commonly encountered functional vector data. The proposed approach combines a random amplitude factor for each component with population-based registration across the components of a multivariate functional data vector and includes a latent population function, which corresponds to a common underlying trajectory. We propose estimators for all components of the model, enabling implementation of the proposed data-based representation for multivariate functional data and downstream analyses such as Fréchet regression. Rates of convergence are established when curves are fully observed or observed with measurement error. The usefulness of the model, interpretations, and practical aspects are illustrated in simulations and with application to multivariate human growth curves and multivariate environmental pollution data.


Myeloid-Derived Suppressor Cells as an Immune Parameter in Patients with Concurrent Sunitinib and Stereotactic Body Radiotherapy.
The clinical effects of sunitinib on human myeloid-derived suppressor cell (MDSC) subsets and correlation of the T-cell-mediated immune responses and clinical outcomes in patients with oligometastases treated by stereotactic body radiotherapy (SBRT) have been evaluated. The numbers of granulocytic and monocytic MDSC subsets, effector T cells, and regulatory T cells in the peripheral blood were evaluated pre- and post-sunitinib treatment and concurrent with SBRT. Correlations between MDSC, Treg, and T-cell responses and clinical outcomes were analyzed. Patients with oligometastases of various cancer types had elevated granulocytic MDSC and certain subsets of monocytic MDSC population. Sunitinib treatment resulted in a significant reduction in monocytic MDSC, phosphorylated STAT3, and arginase levels in monocytic MDSC (CD33(+)CD14(+)CD16(+)), and an increase in T-cell proliferative activity in cancer patients. Interestingly, the effects of sunitinib on reducing the accumulation and immune-suppressive function of MDSC were significantly correlated with Treg reduction, in responders but not in nonresponding patients. SBRT synergized the therapeutic effects of sunitinib, especially as related to decreased numbers of monocytic MDSC, Treg, and B cells, and augmented Tbet expression in primary CD4 and CD8 T cells. These effects were not observed in patients receiving radiation therapy alone. Most interestingly, the responders, defined by sunitinib-mediated reduction in CD33(+)CD11b(+) myeloid cell populations, tend to exhibit improved progression-free survival and cause-specific survival. Sunitinib treatment increased the efficacy of SBRT in patients with oligometastases by reversing MDSC and Treg-mediated immune suppression and may enhance cancer immune therapy to prevent tumor recurrence post-SBRT.


Integrative and systemic approaches for evaluating PPARβ/δ (PPARD) function.
The peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptors that function as transcription factors regulating the expression of genes involved in cellular differentiation, development, metabolism and also tumorigenesis. Three PPAR isotypes (α, β/δ and γ) have been identified, among which PPARβ/δ is the most difficult to functionally examine due to its tissue-specific diversity in cell fate determination, energy metabolism and housekeeping activities. PPARβ/δ acts both in a ligand-dependent and -independent manner. The specific type of regulation, activation or repression, is determined by many factors, among which the type of ligand, the presence/absence of PPARβ/δ-interacting corepressor or coactivator complexes and PPARβ/δ protein post-translational modifications play major roles. Recently, new global approaches to the study of nuclear receptors have made it possible to evaluate their molecular activity in a more systemic fashion, rather than deeply digging into a single pathway/function. This systemic approach is ideally suited for studying PPARβ/δ, due to its ubiquitous expression in various organs and its overlapping and tissue-specific transcriptomic signatures. The aim of the present review is to present in detail the diversity of PPARβ/δ function, focusing on the different information gained at the systemic level, and describing the global and unbiased approaches that combine a systems view with molecular understanding.


Establishment of population-based stroke registry in Ludhiana city, northwest India: feasibility and methodology.
The Indian Council of Medical Research (ICMR) initiated the Task Force Project to evaluate the feasibility of conducting a population-based stroke registry in Ludhiana city, Punjab, Northwest India. All first-ever, stroke patients over 18 years from the city of Ludhiana were included in the study from March 26th 2010 to March 25th 2011. Stroke information was collected based on the WHO STEPS approach from the participating hospitals, scan centres and doctors. Modified Rankin Scale (mRS) was administered by telephonic interview at 28 days after stroke. The information on stroke deaths was obtained from the Municipal Corporation (MC) office. A total of 905 first-ever stroke patients were documented. After excluding duplicate cases and patients from outside the city, 493 patients were included. The practical issues identified in data collection from these centres were reluctance to take informed consent, lack of willingness to share the data, difficulty to identify key persons from each centre, retrieving medical records from public hospitals and poor documentation of deaths in MC office. Population-based stroke registry was feasible in an urban population with the above methodology. The issues related to feasibility were identified and necessary changes were made for the main phase of the registry.


Fatty acids and expression of adipokines.
Adipose tissue has been recognised as the quantitatively most important energy store of the human body for many years, in addition to its functions as mechanical and thermic insulator. In mammals, the adipose organ is localised in several depots including white as well as brown adipose tissues. The largest depots are found subcutaneously and in the abdominal region. Several secretory proteins are synthesised in adipose tissue including leptin, resistin, adiponectin, tumor necrosis factor (TNFalpha), angiotensinogen, adipsin, acylation-stimulating protein, retinol-binding protein (RBP), interleukin (IL)-1b, IL-6, IL-8, IL-10, plasminogen activator inhibitor-1 (PAI-1), fasting-induced adipose factor, fibrinogen-angiopoietin-related protein, metallothionein, tissue factor (TF), complement C3, fibronectin, haptoglobin, entactin/nidogen, collagen VI alpha 3, pigment epithelium-derived factor (PEDF), hippocampal cholinergic neurostimulating peptide (HCNP), neutrophil gelatinase-associated lipocalin (NGAL) and adiponutrin. Fatty acids may influence the expression of adipokines like leptin, resistin or adiponectin directly by interaction with transcription factors, or indirectly via unknown mechanisms possibly linked to fatty acid oxidation, synthesis or storage. Because fatty acids are the main components of adipose tissue, it is of essential interest to clarify the biological effects of different types of fatty acids on the expression of relevant adipokines.


Complete primary structure and functional characterization of the sixth component of the human complement system. Identification of the C5b-binding domain in complement C6.
Complement C6 is one of five plasma proteins that are incorporated into the lytic terminal complement complex on lipid membranes (C5b-9m) upon activation of the complement cascade. Oligonucleotide probes derived from partial amino acid sequences of purified C6 were used to isolate cDNA clones from a human liver cDNA library. The complete polypeptide structure of mature C6 deduced from the cDNA sequence consists of 913 amino acid residues preceded by a typical 21-residue signal peptide. C6 is most similar in structure to complement C7, sharing 33.5% identical residues with C7 including all 56 cysteine residues. The low density lipoprotein receptor class A and B modules, the thrombospondin type I module at the carboxyl terminus, and the two short consensus repeat modules are arranged in the same way as in C7. In contrast to C7 and other terminal complement proteins, the thrombospondin type I module at the amino terminus occurs as a tandem repeat in C6. The last tandem repeat at the carboxyl terminus of C6 and C7 has been identified as a new distinct module (factor I module), which is closely related to a segment in the heavy chain of complement control factor I. Binding studies with filter-bound C6 fragments generated by proteolysis showed that the C5b-binding domain of C6 was located in the 34-kDa carboxyl terminal fragment consisting of two short consensus repeats and two factor I modules.


A phase II study of [90Y] yttrium-capromab pendetide in the treatment of men with prostate cancer recurrence following radical prostatectomy.
There is currently no curative therapy for men who have disseminated prostate cancer following failed radical prostatectomy. The purpose of this trial was to investigate systemic radioimmunotherapy in these men. Eight patients with occult metastatic prostate cancer following radical prostatectomy as evidenced solely by a rising serum PSA and evidence of soft tissue lesions outside the prostatic fossa detected by an [111I]indiumcapromab pendetide scan received an infusion of 10 mg of capromab pendetide labeled with 9 mCi/m2 of [90Y]yttrium. Serum PSA was used to measure response rate. There were no complete or partial responses by PSA criteria. Significant unexpected bone marrow toxicity developed in the first 6 of 8 patients treated. The last two patients received co-infusion of edetate calcium disodium in an effort to decrease marrow suppression. In these two patients less marrow toxicity was seen. Repeat 111In-capromab pendetide scans were uninterpretable due to grossly altered whole-body biodistribution of the radioimmunoconjugate. Retrospective analysis of serial PSA values after closure of the study showed a decrease in the log slope PSA for seven of eight patients following radioimmunotherapy, with a statistically significant change in the mean log slope (p = 0.01). The clinical significance of this small but measurable change is uncertain. We conclude that radioimmunotherapy for occult metastatic prostate cancer using 90Y-capromab-pendetide at the dose described does not lower serum PSA, is associated with significant hematologic toxicity, and leads to complexation of the immunoconjugate following subsequent capromab pendetide infusion.


The emergence of AIDS in Guatemala: inpatient experience at the Hospital General San Juan de Dios.
Little is known about the effect of human immunodeficiency virus (HIV) infection on the Central American healthcare system. We describe HIV-related admissions in a Guatemalan medical service. The study was conducted at Guatemala City's largest public hospital. Data were derived from standardized data collection sheets maintained by the HIV testing service and by HIV clinic physicians. Data were collected for 295 medicine admissions of 257 HIV-infected adults during an 18-month period in 1999 and 2000; 30% of the patients were women. Average age was 33 years. Only 12.5% of the patients had been diagnosed with HIV infection prior to 1999 and nearly all had symptomatic AIDS. 60.3% of the patients were diagnosed with HIV infection during their hospitalization. The most common discharge diagnoses were tuberculosis (13.9%), toxoplasmosis, diarrhoea, candida and other fungal infections, and meningitis. Mean length of stay for HIV-positive patients was 17 days. 23.7% of the patients died during their hospitalization; this was double the mortality of non-HIV patients. HIV-infected patients represented 5.8% of the total admissions of the general medical wards. In a country where HIV prevalence is thought to be less than 1%, AIDS is now responsible for over 5% of admissions to a large medical service at a cost of $500,000 per year. These findings underline the importance of HIV infection in Central America and demonstrate the utility of tracking hospital admission data as a method of surveillance.


Local structure and dynamics of lithium garnet ionic conductors: tetragonal and cubic Li7La3Zr2O7.
To better understand the ionic conduction in lithium garnet oxides, we employed molecular dynamics simulation to investigate the local structure and dynamics of a model material Li7La3Zr2O12 and origin of its tetragonal to cubic phase transition. Our simulations were able to produce lattice parameter, neutron scattering, and conductivity data close to those gathered using experimental techniques, which allows us to study atomic-scale details of this complex material. First, it was found that lithium atoms primarily perform oscillation and "structured diffusion" dynamics in the tetragonal and cubic phase, respectively. Second, we believe that the tetragonal to cubic phase transition is an entropy-driven one that involves redistribution of lithium atoms among all tetrahedral sites. The transition is likely to initiate on the tetrahedral 8a site but needs the cooperation of neighboring octahedral 32g Li as relay atoms. Finally, it was found that a few types of lithium clusters dominate in both phases of Li7La3Zr2O12, which leads to highly correlated motion of lithium atoms. The local symmetry of these clusters dictates a "center-pass" mechanism as lithium goes through the bottleneck.


The mutational spectrum of hunter syndrome reveals correlation between biochemical and clinical profiles in Tunisian patients.
Mucopolysaccharidosis type II (MPS II) or Hunter syndrome is an X-linked recessive lysosomal storage disorder resulting from deficient activity of iduronate 2-sulfatase (IDS) and the progressive lysosomal accumulation of sulfated glycosaminoglycans (GAGs). A diagnosis of MPS II or Hunter syndrome was performed based on the following approach after a clinical and paraclinical suspicion. Two biochemical and molecular tests were carried out separately and according to the availability of the biological material. All patients in this cohort presented the most common MPS II clinical features. Electrophoresis of GAGs on a cellulose acetate plate in the presence of a high concentration of heparane sulfate showed an abnormal dermatan sulfate band in the patients compared with that in a control case. Furthermore, leukocyte IDS activity ranged from 0.00 to 0.75 nmol/h/mg of leukocyte protein in patients. Five previously reported mutations were identified in this study patients: one splice site mutation, c.240 + 1G > A; two missense mutations, p.R88P and p.G94D; a large deletion of exon 1 to exon 7; and one nonsense mutation, p.Q396*. In addition, two novel alterations were identified in the MPS II patients: one frame shift mutation, p.D450Nfs*95 and one nonsense mutation, p.Q204*. Additionally, five known IDS polymorphisms were identified in the patients: c.419-16 delT, c.641C > T (p.T214M), c.438 C > T (p.T146T), c.709-87G > A, and c.1006 + 38 T > C. The high level of urine GAGs and the deficiency of iduronate 2-sulfatase activity was associated with the phenotype expression of Hunter syndrome. Molecular testing was useful for the patients' phenotypic classification and the detection of carriers.


Segmentation-based registration of ultrasound volumes for glioma resection in image-guided neurosurgery.
In image-guided surgery for glioma removal, neurosurgeons usually plan the resection on images acquired before surgery and use them for guidance during the subsequent intervention. However, after the surgical procedure has begun, the preplanning images become unreliable due to the brain shift phenomenon, caused by modifications of anatomical structures and imprecisions in the neuronavigation system. To obtain an updated view of the resection cavity, a solution is to collect intraoperative data, which can be additionally acquired at different stages of the procedure in order to provide a better understanding of the resection. A spatial mapping between structures identified in subsequent acquisitions would be beneficial. We propose here a fully automated segmentation-based registration method to register ultrasound (US) volumes acquired at multiple stages of neurosurgery. We chose to segment sulci and falx cerebri in US volumes, which remain visible during resection. To automatically segment these elements, first we trained a convolutional neural network on manually annotated structures in volumes acquired before the opening of the dura mater and then we applied it to segment corresponding structures in different surgical phases. Finally, the obtained masks are used to register US volumes acquired at multiple resection stages. Our method reduces the mean target registration error (mTRE) between volumes acquired before the opening of the dura mater and during resection from 3.49 mm (± 1.55 mm) to 1.36 mm (± 0.61 mm). Moreover, the mTRE between volumes acquired before opening the dura mater and at the end of the resection is reduced from 3.54 mm (± 1.75 mm) to 2.05 mm (± 1.12 mm). The segmented structures demonstrated to be good candidates to register US volumes acquired at different neurosurgical phases. Therefore, our solution can compensate brain shift in neurosurgical procedures involving intraoperative US data.


c-Jun/c-Fos heterodimers regulate cellular genes via a newly identified class of methylated DNA sequence motifs.
CpG methylation in mammalian DNA is known to interfere with gene expression by inhibiting the binding of transactivators to their cognate sequence motifs or recruiting proteins involved in gene repression. An Epstein-Barr virus-encoded transcription factor, Zta, was the first example of a sequence-specific transcription factor that preferentially recognizes and selectively binds DNA sequence motifs with methylated CpG residues, reverses epigenetic silencing and activates gene transcription. The DNA binding domain of Zta is homologous to c-Fos, a member of the cellular AP-1 (activator protein 1) transcription factor family, which regulates cell proliferation and survival, apoptosis, transformation and oncogenesis. We have identified a novel AP-1 binding site termed meAP-1, which contains a CpG dinucleotide. If methylated, meAP-1 sites are preferentially bound by the AP-1 heterodimer c-Jun/c-Fos in vitro and in cellular chromatin in vivo. In activated human primary B cells, c-Jun/c-Fos locates to these methylated elements in promoter regions of transcriptionally activated genes. Reminiscent of the viral Zta protein, c-Jun/c-Fos is the first identified cellular member of the AP-1 family of transactivators that can induce expression of genes with methylated, hence repressed promoters, reversing epigenetic silencing.