Design of an artificial three-dimensional composite metamaterial with magnetic resonances in the visible range of the electromagnetic spectrum.
We propose an artificial three-dimensional material that exhibits a strong resonance in the effective permeability in the visible spectral domain. This material may be implemented in a two-step procedure. First, a metamaterial made of densely packed metallic nanoparticles is fabricated that shows a Lorentz-type resonance in the permittivity at the collective plasmon frequency. Second, spheres are formed out of this material and arranged in a cubic lattice. This meta-metamaterial exhibits a strong resonance in the permeability which is caused by a Mie resonance associated with the magnetic mode of a single metamaterial sphere. Realization of this material based on self-organization in liquid crystals and the limitations of the approach are discussed.


A Fine-Tune Role of Mir-125a-5p on Foxn1 During Age-Associated Changes in the Thymus.
Decline of transcription factor FoxN1, which predominantly regulates thymic epithelial cell (TEC) differentiation and homeostasis lifelong, is demonstrated to be casually related to age-related thymic involution. Whereas, a global role of microRNAs (miRNAs) has also been demonstrated to control and maintain TEC-constituting thymic microenvironment and to be changed in expression profile in the aged thymus. Therefore, it is urgently necessary to build knowledge regarding whether and which miRNAs regulate FoxN1 gene in the aged thymus. We primarily compared changes in miRNA expression profile between young and aged murine TECs with Mus musculus miRBase-V20 arrays (containing 1892 unique probes), and clearly identified and validated that at least one miRNA, miR-125a-5p, was increased in aged thymus. Applying miR-125a-5p mimics was able to inhibit FoxN1 3'UTR luciferase activity in a 293T cell line and to suppress FoxN1 expression in murine TEC Z210 cells. Since a single miRNA can play a fine-tuning role to regulate expression of multiple genes and a single gene can be regulated by multiple miRNAs, our result adds a single miRNA, miR-125a-5p, into the panel of FoxN1-regulating miRNAs associated with thymic aging.


Avoiding tolerance against prostatic antigens with subdominant peptide epitopes.
A potential novel therapy for prostate cancer is the induction of immune responses to normal prostate-associated antigens (PAA). One approach is to use synthetic peptides from PAA to educate T cells as a means of developing a defined and specific immunotherapy for prostate cancer. A likely major hurdle when using normal PAA for this type of therapy is the tolerance that the immune system may already have for PAA. To evaluate mechanisms for overcoming tolerance, the authors assessed the level of tolerance to SV40T antigen in a transgenic mouse. The SV40T antigen is selectively expressed in the prostates of mice from the transgenic adenocarcinoma mouse prostate (TRAMP) model. The authors have shown that TRAMP mice are tolerant to a dominant cytotoxic T-lymphocyte (CTL) epitope from the SV40T antigen compared with nontransgenic littermates. The tolerance was exhibited as early as 4 weeks and as late as 24 weeks. The use of multiple injections of an oligonucleotide that contains an unmethylated CpG induced high levels of hematopoiesis but did not overcome the tolerance. Injection of an antibody to activate CD40 increased the CTL response in normal mice but also did not overcome tolerance. However, tolerance in the TRAMP mice was avoided when an epitope that had previously been characterized as a subdominant epitope was administered. The authors are investigating the potential of subdominant epitopes to induce prostatitis and antitumor responses. The results of this work should facilitate the development of immune-based therapies for prostate cancer.


Endogenous expression of ASLV viral proteins in specific pathogen free chicken embryos: relevance for the developmental biology research field.
The use of Specific Pathogen Free (SPF) eggs in combination with RCAS retrovirus, a member of the Avian Sarcoma-Leukosis Virus (ASLV) family, is of standard practice to study gene function and development. SPF eggs are certified free of infection by specific pathogen viruses of either exogenous or endogenous origin, including those belonging to the ASLV family. Based on this, SPF embryos are considered to be free of ASLV viral protein expression, and consequently in developmental research studies RCAS infected cells are routinely identified by immunohistochemistry against the ASLV viral proteins p19 and p27. Contrary to this generally accepted notion, observations in our laboratory suggested that certified SPF chicken embryos may endogenously express ASLV viral proteins p19 and p27. Since these observations may have significant implications for the developmental research field we further investigated this possibility. We demonstrate that certified SPF chicken embryos have transcriptionally active endogenous ASLV loci (ev loci) capable of expressing ASLV viral proteins, such as p19 and p27, even when those loci are not capable of producing viral particles. We also show that the extent of viral protein expression in embryonic tissues varies not only among flocks but also between embryos of the same flock. In addition, our genetic screening revealed significant heterogeneity in ev loci composition even among embryos of the same flock. These observations have critical implications for the developmental biology research field, since they strongly suggest that the current standard methodology used in experimental studies using the chick embryo and RCAS vectors may lead to inaccurate interpretation of results. Retrospectively, our observations suggest that studies in which infected cells have been identified simply by pan-ASLV viral protein expression may need to be considered with caution. For future studies, they point to a need for careful selection and screening of the chick SPF lines to be used in combination with RCAS constructs, as well as the methodology utilized for qualitative analysis of experimental results. A series of practical guidelines to ensure research quality animals and accuracy of the interpretation of results is recommended and discussed.


Discovery of a potent and selective inhibitor for human carbonyl reductase 1 from propionate scanning applied to the macrolide zearalenone.
In order to extend the chemical diversity available for organic polyketide synthesis, the concept of propionate scanning was developed. We observed that naturally occurring polyketides frequently comprise not only acetate, but also some propionate as building blocks. Therefore our approach consists of a systematic replacement of some of the acetate building blocks during synthesis by propionate moieties, resulting in additional methyl groups that may give rise to different properties of the polyketides. Here we present the results of a first 'proof of concept' study where a novel zearalenone analogue 5 was prepared that comprises an additional methyl group at C5'. Key steps in the synthesis of 5 include a Marshall-Tamaru reaction, a Suzuki cross-coupling reaction, and a Mitsunobu lactonization. Compared to the parent zearalenone (1), analogue 5 showed reduced binding to a panel of human protein kinases and no binding to human Hsp90. On the other hand, however, 5 turned out to be a potent (IC(50)=210 nM) inhibitor of human carbonyl reductase 1 (CBR1).


Time-dependent biodistribution of tetra(m-hydroxyphenyl)chlorin and benzoporphyrin derivative monoacid ring A in the hamster model: comparative fluorescence microscopy study.
The pharmacokinetics of the photosensitizer used play a key role in the understanding of the mechanism of photodynamic therapy-induced damage. Fluorescence microscopy was used to compare time-dependent biodistribution of tetra(m-hydroxyphenyl)chlorin (mTHPC) and benzoporphyrin derivative monoacid ring A (BPD-MA) in different hamster tissues, including an early, chemically induced, squamous cell carcinoma. Following injection of 0.5 mg/kg body weight of mTHPC and 2.0 mg/kg BPD-MA, groups of three animals were sacrificed at different time points and a series of fluorescence micrographs from different excised organs were analyzed. The highest fluorescence intensities of mTHPC were observed at 96 h for squamous epithelia and skin and at 48 h for smooth muscle. There is no real peak of BPD-MA fluorescence between 30 min and 3 h in the basal epithelial layers, fibroconnective tissue, muscles or blood vessels. At 4 h after injection, the fluorescence level of BPD-MA decreased and at 24 h it had returned to background level in all observed tissues. The significantly faster clearance of BPD-MA is the principal advantage as compared to mTHPC. However, similar localization patterns in different tissues with essentially vascular affinity represent a possible disadvantage for treating early malignancies with BPD-MA as compared to mTHPC, which is mainly localized in various epithelia. For both photosensitizers no significant selectivity between early squamous cell carcinoma and healthy mucosae is seen. Pharmacokinetic studies of different photosensitizers in an appropriate animal model are essential for selecting new-generation photosensitizers with the most favorable localization for photodynamic therapy of early malignancies in hollow organs.


Site specificity of yeast histone acetyltransferase B complex in vivo.
Saccharomyces cerevisiae Hat1, together with Hat2 and Hif1, forms the histone acetyltransferase B (HAT-B) complex. Previous studies performed with synthetic N-terminal histone H4 peptides found that whereas the HAT-B complex acetylates only Lys12, recombinant Hat1 is able to modify Lys12 and Lys5. Here we demonstrate that both Lys12 and Lys5 of soluble, non-chromatin-bound histone H4 are in vivo targets of acetylation for the yeast HAT-B enzyme. Moreover, coimmunoprecipitation assays revealed that Lys12/Lys5-acetylated histone H4 is bound to the HAT-B complex in the soluble cell fraction. Both Hat1 and Hat2, but not Hif1, are required for the Lys12/Lys5-specific acetylation and for histone H4 binding. HAT-B-dependent acetylation of histone H4 was detected in the soluble fraction of cells at distinct cell cycle stages, and increased when cells accumulated excess histones. Strikingly, histone H3 was not found in any of the immunoprecipitates obtained with the different components of the HAT-B enzyme, indicating the possibility that histone H3 is not together with histone H4 in this complex. Finally, the exchange of Lys for Arg at position 12 of histone H4 did not interfere with histone H4 association with the complex, but prevented acetylation on Lys5 by the HAT-B enzyme, in vivo as well as in vitro.


Race and sex differences in thrombogenicity: risk of ischemic events following coronary stenting.
Race and sex affect thrombogenicity. We have demonstrated that platelet-fibrin clot characteristics can be used to stratify patients for risk of ischemic events following percutaneous coronary intervention. We investigated race and sex differences in thrombogenicty and the relation to ischemic risk in 252 consecutive African-American and Caucasian men and women undergoing elective percutaneous coronary intervention. Platelet-fibrin clot characteristics were measured using the Thrombelastograph Hemostasis System. The incidence of adverse ischemic events was assessed over a 6-month follow-up period. Overall, 40 ischemic events (15.9%) occurred. Adverse events were higher in African-Americans than Caucasians (P = 0.14), and in women than men (P = 0.004). The incidence was highest in African-American women (37.5%) and lowest in African-American men (6.5%). Measured Thrombelastograph parameters were significantly different between ischemic and nonischemic patients (P < 0.05). African-American women in the ischemic group exhibited higher thrombogenicity than the other race and sex groups (P < 0.05). Multivariate logistic regression identified platelet-fibrin mediated clot strength (relative risk 2.52, P = 0.017) and sex (relative risk 2.56, P = 0.009) as significant independent predictors of ischemic events 6 months postpercutaneous coronary intervention. Thrombogenicity is a novel measurable cardiovascular risk factor that varies by race and sex, is highest in African-American women, and independently predicts the frequency of ischemic events following percutaneous coronary intervention. Point-of-service measurements of platelet-fibrin clot characteristics may lead to more intensified antithrombotic therapy and reduced mortality in selected patients.


The tradeoff between plasmonic enhancement and optical loss in silicon nanowire solar cells integrated in a metal back reflector.
We perform a systematic numerical study to characterize the tradeoff between the plasmonic enhancement and optical loss in periodically aligned, silicon nanowire (SiNW) arrays integrated with a silver back reflector (Ag BR). Optimizing the embedded depth of the wire bottoms into a silver reflector achieved a highly efficient SiNW solar cell. Compared to the SiNW solar cell employing a flat back reflector, the embedded depth of ~20 nm resulted in the relative increase of ~5% in ultimate solar cell efficiency.


Grasping primate origins.
The evolutionary history that led to Eocene-and-later primates of modern aspect (Euprimates) has been uncertain. We describe a skeleton of Paleocene plesiadapiform Carpolestes simpsoni that includes most of the skull and many postcranial bones. Phylogenetic analyses indicate that Carpolestidae are closely related to Euprimates. C. simpsoni had long fingers and an opposable hallux with a nail. It lacked orbital convergence and an ankle specialized for leaping. We infer that the ancestor of Euprimates was primitively an arboreal grasper adapted for terminal branch feeding rather than a specialized leaper or visually directed predator.


DNA barcoding a taxonomically complex hemiparasitic genus reveals deep divergence between ploidy levels but lack of species-level resolution.
DNA barcoding is emerging as a useful tool not only for species identification but also for studying evolutionary and ecological processes. Although plant DNA barcodes do not always provide species-level resolution, the generation of large DNA barcode data sets can provide insights into the mechanisms underlying the generation of species diversity. Here, we study evolutionary processes in taxonomically complex British Euphrasia (Orobanchaceae), a group with multiple ploidy levels, frequent self-fertilization, young species divergence and widespread hybridization. We use a phylogenetic approach to investigate the colonization history of British Euphrasia, followed by a DNA barcoding survey and population genetic analyses to reveal the causes of shared sequence variation. Phylogenetic analysis shows Euphrasia have colonized Britain from mainland Europe on multiple occasions. DNA barcoding reveals that no British Euphrasia species has a consistent diagnostic sequence profile, and instead, plastid haplotypes are either widespread across species, or are population specific. The partitioning of nuclear genetic variation suggests differences in ploidy act as a barrier to gene exchange, while the divergence between diploid and tetraploid ITS sequences supports the polyploids being allotetraploid in origin. Overall, these results show that even when lacking species-level resolution, analyses of DNA barcoding data can reveal evolutionary patterns in taxonomically complex genera.


Cognitive control functions of anterior cingulate cortex in macaque monkeys performing a Wisconsin Card Sorting Test analog.
Monkeys were trained to select one of three targets by matching in color or matching in shape to a sample. Because the matching rule frequently changed and there were no cues for the currently relevant rule, monkeys had to maintain the relevant rule in working memory to select the correct target. We found that monkeys' error commission was not limited to the period after the rule change and occasionally occurred even after several consecutive correct trials, indicating that the task was cognitively demanding. In trials immediately after such error trials, monkeys' speed of selecting targets was slower. Additionally, in trials following consecutive correct trials, the monkeys' target selections for erroneous responses were slower than those for correct responses. We further found evidence for the involvement of the cortex in the anterior cingulate sulcus (ACCs) in these error-related behavioral modulations. First, ACCs cell activity differed between after-error and after-correct trials. In another group of ACCs cells, the activity differed depending on whether the monkeys were making a correct or erroneous decision in target selection. Second, bilateral ACCs lesions significantly abolished the response slowing both in after-error trials and in error trials. The error likelihood in after-error trials could be inferred by the error feedback in the previous trial, whereas the likelihood of erroneous responses after consecutive correct trials could be monitored only internally. These results suggest that ACCs represent both context-dependent and internally detected error likelihoods and promote modes of response selections in situations that involve these two types of error likelihood.


An open study of dehydroepiandrosterone in systemic lupus erythematosus.
To determine if dehydroepiandrosterone (DHEA) has clinical benefits in patients with systemic lupus erythematosus (SLE). Ten female patients with mild to moderate SLE and various disease manifestations were given DHEA (200 mg/day orally) for 3-6 months. The patients were given other medications as clinically indicated, and followed with respect to overall disease activity and specific outcome parameters. After 3-6 months of DHEA treatment, indices for overall SLE activity including the SLEDAI (SLE Disease Activity Index) score and physician's overall assessment were improved, and corticosteroid requirements were decreased. Of 3 patients with significant proteinuria, 2 showed marked and 1 modest reductions in protein excretion. DHEA was well tolerated, the only frequently noted side effect being mild acneiform dermatitis. DHEA shows promise as a new therapeutic agent for the treatment of mild to moderate SLE. Further studies of DHEA in the treatment of SLE are warranted.


Direct to consumer advertising via the Internet, a study of hip resurfacing.
With increased use of the internet for health information and direct to consumer advertising from medical companies, there is concern about the quality of information available to patients. The aim of this study was to examine the quality of health information on the internet for hip resurfacing. An assessment tool was designed to measure quality of information. Websites were measured on credibility of source; usability; currentness of the information; content relevance; content accuracy/completeness and disclosure/bias. Each website assessed was given a total score, based on number of scores achieved from the above categories websites were further analysed on author, geographical origin and possession of an independent credibility check. There was positive correlation between the overall score for the website and the score of each website in each assessment category. Websites by implant companies, doctors and hospitals scored poorly. Websites with an independent credibility check such as Health on the Net (HoN) scored twice the total scores of websites without. Like other internet health websites, the quality of information on hip resurfacing websites is variable. This study highlights methods by which to assess the quality of health information on the internet and advocates that patients should look for a statement of an "independent credibility check" when searching for information on hip resurfacing.


Conspiracy Theories: Evolved Functions and Psychological Mechanisms.
Belief in conspiracy theories-such as that the 9/11 terrorist attacks were an inside job or that the pharmaceutical industry deliberately spreads diseases-is a widespread and culturally universal phenomenon. Why do so many people around the globe believe conspiracy theories, and why are they so influential? Previous research focused on the proximate mechanisms underlying conspiracy beliefs but ignored the distal, evolutionary origins and functions. We review evidence pertaining to two competing evolutionary hypotheses: (a) conspiracy beliefs are a by-product of a suite of psychological mechanisms (e.g., pattern recognition, agency detection, threat management, alliance detection) that evolved for different reasons, or (b) conspiracy beliefs are part of an evolved psychological mechanism specifically aimed at detecting dangerous coalitions. This latter perspective assumes that conspiracy theories are activated after specific coalition cues, which produce functional counterstrategies to cope with suspected conspiracies. Insights from social, cultural and evolutionary psychology provide tentative support for six propositions that follow from the adaptation hypothesis. We propose that people possess a functionally integrated mental system to detect conspiracies that in all likelihood has been shaped in an ancestral human environment in which hostile coalitions-that is, conspiracies that truly existed-were a frequent cause of misery, death, and reproductive loss.


Comparison of EGF with VEGF non-viral gene therapy for cutaneous wound healing of streptozotocin diabetic mice.
To accelerate the healing of diabetic wounds, various kinds of growth factors have been employed. It is the short half-life of administered growth factors in hostile wound beds that have limited wide-spread clinical usage. To overcome this limitation, growth factor gene therapy could be an attractive alternative rather than direct application of factors onto the wound beds. We administered two growth factor DNAs, epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) into a cutaneous wound on diabetic mice. We compared the different characteristics of the healing wounds. Streptozotocin was injected intraperitoneally to induce diabetes into C57BL/6J mice. The ultrasound micro-bubble destruction method with SonoVue as a bubbling agent was used for non-viral gene delivery of EGF(828) and VEGF(165) DNAs. Each gene was modified for increasing efficacy as FRM-EGF(828) or minicircle VEGF(165). The degree of neoangiogenesis was assessed using qualitative laser Doppler flowmetry. We compared wound size and histological findings of the skin wounds in each group. In both groups, accelerated wound closure was observed in the mice receiving gene therapy compared with non treated diabetic control mice. Blood flow detected by laser doppler flowmetry was better in the VEGF group than in the EGF group. Wound healing rates and histological findings were more accelerated in the EGF gene therapy group than the VEGF group, but were not statistically significant. Both non-viral EGF and VEGF gene therapy administrations could improve the speed and quality of skin wound healing. However, the detailed histological characteristics of the healing wounds were different.


Partial reconstitution of DNA large loop repair with purified proteins from Saccharomyces cerevisiae.
Small looped mispairs are corrected by DNA mismatch repair. In addition, a distinct process called large loop repair (LLR) corrects heteroduplexes up to several hundred nucleotides in bacteria, yeast and human cells, and in cell-free extracts. Only some LLR protein components are known, however. Previous studies with neutralizing antibodies suggested a role for yeast DNA polymerase delta (Pol delta), RFC and PCNA in LLR repair synthesis. In the current study, biochemical fractionation studies identified FEN1 (Rad27) as another required LLR component. In the presence of purified FEN1, Pol delta, RFC and PCNA, repair occurred on heteroduplexes with loops ranging from 8 to 216 nt. Repair utilized a 5' nick, with correction directed to the nicked strand, irrespective of which strand contained the loop. In contrast, repair of a G/T mismatch occurred at low levels, suggesting specificity of the reconstituted system for looped mispairs. The presence of RPA enhanced reactivity on some looped substrates, but RPA was not required for activity. Although additional LLR factors remain to be identified, the excision and resynthesis steps of LLR from a 5' nick can be reconstituted in a purified system with FEN1 and Pol delta, together with PCNA and its loader RFC.


The nocebo effect: a clinicians guide.
This paper aims to provide an overview on the nocebo effect, focusing on recognition - its phenomenology, at-risk demographic profiles, clinical situations and personality factors, as well as discriminating somatic symptoms in the general population from treatment-related adverse effects. Lastly, the paper addresses available evidence-based strategies for management and minimisation of the nocebo effect. Data for this paper were identified by searching PubMed using the search terms "nocebo" and "nocebo effect", augmented by a manual search of the references of the key papers and the related literature. The nocebo effect refers to non-pharmacodynamic, harmful or undesirable effects occurring after inactive treatment, a phenomenon that also occurs in the context of active therapy. Known drivers include classical conditioning and negative expectations concerning treatment. Recent meta-analyses have reported a considerable prevalence, ranging from 18% in the symptomatic treatment of migraine, to more than 74% in multiple sclerosis. Recognition of the nocebo-driven adverse effects presents a challenge, especially because of its non-specific nature and the similarity to the active medication's expected profile. Traits such as neuroticism, pessimism and type A personalities may predispose individuals to this phenomenon. Clinical management of the nocebo effect includes awareness and recognition, changing the manner of disclosure of potential drug-related adverse effects, shaping patients' expectations and enhancing the treatment alliance. The nocebo effect is a common, clinically significant, yet covert driver of clinical outcomes. Increased awareness of its features, as well as knowledge of strategies on how to manage it, are fundamental so that clinicians can mitigate its impact on clinical practice.


High sensitivity gas spectroscopy of porous, highly scattering solids.
We present minimalistic and cost-efficient instrumentation employing tunable diode laser gas spectroscopy for the characterization of porous and highly scattering solids. The sensitivity reaches 3 x 10(-6) (absorption fraction), and the improvement with respect to previous work in this field is a factor of 10. We also provide the first characterization of the interference phenomenon encountered in high-resolution spectroscopy of turbid samples. Revealing that severe optical interference originates from the samples, we discuss important implications for system design. In addition, we introduce tracking coils and sample rotation as new and efficient tools for interference suppression. The great value of the approach is illustrated in an application addressing structural properties of pharmaceutical materials.


Cancer-associated changes in the expression of TMPRSS2-ERG, PCA3, and SPINK1 in histologically benign tissue from cancerous vs noncancerous prostatectomy specimens.
To investigate whether messenger ribonucleic acid (mRNA) expression of TMPRSS2-ERG fusion gene, a suggested prostate cancer (PCa) biomarker, was specific to cancerous lesions alone and to study the expression of SPINK1 and PCA3 mRNAs in the same cohort to also explore the proposed mutual exclusivity of TMPRSS2-ERG and SPINK1 expression. Levels of 2 TMPRSS2-ERG transcripts, PCA3, and SPINK1 mRNAs were measured with highly standardized reverse transcription quantitative polymerase chain reaction assays in cystoprostatectomy specimens from 19 patients with invasive bladder cancer and 174 radical prostatectomy (RP) samples (88 histologically benign prostate [HBP] tissues and 86 from cancerous lesions) from 87 patients with clinically localized PCa. Expression of TMPRSS2-ERG transcripts was detected in 45 of 88 (51%) HBP tissues from RP specimens and more frequently (57 of 86, 66%) found in cancerous lesions. In contrast, TMPRSS2-ERG expression was detected in only 2 of 19 (11%) cystoprostatectomy specimens, both with incidental PCa foci elsewhere in the gland. Similar trends of changes in the expression of PCA3 and SPINK1 were present in HBP tissue from RP compared with cystoprostatectomy specimens. Although the expression of TMPRSS2-ERG, SPINK1, and PCA3 mRNA is higher or more frequently found in cancerous lesions, HBP tissues from patients with clinically localized PCa manifest molecular, mRNA level changes that are absent in cystoprostatectomy specimens lacking incidental PCa foci or infrequent in cystoprostatectomy specimens containing incidental PCa. If this finding is replicated, these molecular assays could be used to inform men with negative biopsy results about the likelihood of cancerous lesions in unsampled regions and hence the need for repeat biopsy.


Multispikes and synchronization in a large neural network with temporal delays.
Coherent rhythms in the gamma frequency range are ubiquitous in the nervous system and thought to be important in a variety of cognitive activities. Such rhythms are known to be able to synchronize with millisecond precision across distances with significant conduction delay; it is mysterious how this can operate in a setting in which cells receive many inputs over a range of time. Here we analyze a version of mechanism, previously proposed, that the synchronization in the CA1 region of the hippocampus depends on the firing of "doublets" by the interneurons. Using a network of local circuits that are arranged in a possibly disordered lattice, we determine the conditions on parameters for existence and stability of synchronous solutions in which the inhibitory interneurons fire single spikes, doublets, or triplets per cycle. We show that the synchronous solution is only marginally stable if the interneurons fire singlets. If they fire doublets, the synchronous state is asymptotically stable in a larger subset of parameter space than if they fire triplets. An unexpected finding is that a small amount of disorder in the lattice structure enlarges the parameter regime in which the doublet solution is stable. Synaptic noise reduces the regime in which the doublet configuration is stable, but only weakly.


Chelation-assisted de-aryloxylative amination of 2-aryloxy quinolines: a new synthetic route to a key fragment of a bioactive PRMT5 inhibitor.
A highly regioselective de-aryloxylative amination of O- or N-chelating group-functionalized 2-aryloxy quinolines has been accomplished by means of a copper catalyst. The chelating functional groups of the substrate play a crucial role in directing the C-2-selective amination process, which proceeds through a novel aromatic nucleophilic substitution of the aryloxy group. The methodology provides expedient access to an important class of functionalized 2-aminoquinolines (up to 88% isolated yield) and was successfully applied for the synthesis of a key fragment of an important bioactive PRMT5 inhibitor.


Importance of human papillomavirus endemicity in the incidence of cervical cancer: an extension of the hypothesis on sexual behavior.
The risk of cervical cancer for a woman depends largely on the probability of being infected with some specific types of Human Papillomavirus (HPV). In the control groups of four case-control studies in Colombia and Spain we have shown a strong correlation between the number of sexual partners of males and females and HPV DNA prevalence in the genital tract. Our results suggest that the lifetime number of sexual partners in both sexes are surrogates of the probability of HPV infection and, as such, insufficiently explain the geographical variation in the incidence of cervical cancer. It is proposed that the high rates of cervical cancer in Latin America are linked to the largely unknown characteristics of the HPV endemicity in the population and to the absence of widespread screening for cervical neoplasia. Reliable surveys on the HPV prevalences in selected social groups (i.e., young males and prostitutes) as well as in populations in countries at different risk of cervical cancer are required.


Flow Visualization with Quantified Spatial and Temporal Errors Using Edge Maps.
Robust analysis of vector fields has been established as an important tool for deriving insights from the complex systems these fields model. Traditional analysis and visualization techniques rely primarily on computing streamlines through numerical integration. The inherent numerical errors of such approaches are usually ignored, leading to inconsistencies that cause unreliable visualizations and can ultimately prevent in-depth analysis. We propose a new representation for vector fields on surfaces that replaces numerical integration through triangles with maps from the triangle boundaries to themselves. This representation, called edge maps, permits a concise description of flow behaviors and is equivalent to computing all possible streamlines at a user defined error threshold. Independent of this error streamlines computed using edge maps are guaranteed to be consistent up to floating point precision, enabling the stable extraction of features such as the topological skeleton. Furthermore, our representation explicitly stores spatial and temporal errors which we use to produce more informative visualizations. This work describes the construction of edge maps, the error quantification, and a refinement procedure to adhere to a user defined error bound. Finally, we introduce new visualizations using the additional information provided by edge maps to indicate the uncertainty involved in computing streamlines and topological structures.


Antibiotic failure mediated by a resistant subpopulation in Enterobacter cloacae.
Antibiotic resistance is a major public health threat, further complicated by unexplained treatment failures caused by bacteria that appear antibiotic susceptible. We describe an Enterobacter cloacae isolate harbouring a minor subpopulation that is highly resistant to the last-line antibiotic colistin. This subpopulation was distinct from persisters, became predominant in colistin, returned to baseline after colistin removal and was dependent on the histidine kinase PhoQ. During murine infection, but in the absence of colistin, innate immune defences led to an increased frequency of the resistant subpopulation, leading to inefficacy of subsequent colistin therapy. An isolate with a lower-frequency colistin-resistant subpopulation similarly caused treatment failure but was misclassified as susceptible by current diagnostics once cultured outside the host. These data demonstrate the ability of low-frequency bacterial subpopulations to contribute to clinically relevant antibiotic resistance, elucidating an enigmatic cause of antibiotic treatment failure and highlighting the critical need for more sensitive diagnostics.


Hip and trunk muscles activity during nordic hamstring exercise.
The nordic hamstring exercise (NHE) is a dynamic lengthening hamstring exercise that requires trunk and hip muscles activation. Thigh muscles activation, specifically hamstring/quadriceps contractions has been previously examined during NHE. Trunk and hip muscles activity have not been enough studied. The aim of this study was to analyze of hip and trunk muscles activity during NHE. Surface electromyography (EMG) and kinematic data were collected during NHE. Ten healthy men with the age range of 21-36 years performed two sets of two repetitions with downward and upward motions each of NHE. EMG activity of fifteen trunk and hip muscles and knee kinematic data were collected. Muscle activity levels were calculated through repeated measure analysis of variance in downward and upward motions, through Paired t-test between downward and upward motions and gluteus maximus to erector spine activity ratio (Gmax/ES ratio) using Pearson correlation analyses were evaluated. Semitendinosus and biceps femoris muscles activity levels were the greatest in both motions and back extensors and internal oblique muscles activity were greater than other muscles (P<0.05). The decreased Gmax/ES ratio was significantly related to peak knee extension angle in downward (r=0.687) and upward motions (r=0.753) (P<0.05). These findings indicate the importance of synergistic muscles and trunk muscles coactivation in eccentric and concentric hamstrings contractions. It could be important for early assessment of subjects with hamstring injury risk.


Oral melatonin reduces blood coagulation activity: a placebo-controlled study in healthy young men.
Melatonin has previously been suggested to affect hemostatic function but studies on the issue are scant. We hypothesized that, in humans, oral administration of melatonin is associated with decreased plasma levels of procoagulant hemostatic measures compared with placebo medication and that plasma melatonin concentration shows an inverse association with procoagulant measures. Forty-six healthy men (mean age 25 +/- 4 yr) were randomized, single-blinded, to either 3 mg of oral melatonin (n = 25) or placebo medication (n = 21). One hour thereafter, levels of melatonin, fibrinogen, and D-dimer as well as activities of coagulation factor VII (FVII:C) and VIII (FVIII:C) were measured in plasma. Multivariate analysis of covariance and regression analysis controlled for age, body mass index, mean arterial blood pressure, heart rate, and norepinephrine plasma level. Subjects on melatonin had significantly lower mean levels of FVIII:C (81%, 95% CI 71-92 versus 103%, 95% CI 90-119; P = 0.018) and of fibrinogen (1.92 g/L, 95% CI 1.76-2.08 versus 2.26 g/L, 95% CI 2.09-2.43; P = 0.007) than those on placebo explaining 14 and 17% of the respective variance. In all subjects, increased plasma melatonin concentration independently predicted lower levels of FVIII:C (P = 0.037) and fibrinogen (P = 0.022) explaining 9 and 11% of the respective variance. Melatonin medication and plasma concentration were not significantly associated with FVII:C and D-dimer levels. A single dose of oral melatonin was associated with lower plasma levels of procoagulant factors 60 min later. There might be a dose-response relationship between the plasma concentration of melatonin and coagulation activity.


CD4 T cells selected by antigen under Th2 polarizing conditions favor an elongated TCR alpha chain complementarity-determining region 3.
The affinity of the MHC/peptide/TCR interaction is thought to be one factor determining the differentiation of CD4+ T cells into Th1 or Th2 phenotypes. To study whether CD4+ cells generated under conditions favoring Th1 or Th2 responses select structurally different TCRs, Th1 and Th2 clones and lines were generated from nonobese diabetic and nonobese diabetic H2-E transgenic mice against the peptides proteolipoprotein 56-70, glutamic acid decarboxylase(65) 524-543, and heat shock protein-60 peptides 168-186 and 248-264. Th1/Th2 polarization allowed the generation of clones and lines with fixed peptide specificity and class II restriction but differing in Th1/Th2 phenotype in which the impact on TCR selection and structure could be studied. The Th2 clones tended to use longer TCR complementarity-determining region (CDR)3alpha loops than their Th1 counterparts. This trend was confirmed by analyzing TCRalpha transcripts from Th1 and Th2 polarized, bulk populations. Molecular modeling of Th1- and Th2-derived TCRs demonstrated that Th2 CDR3alpha comprised larger side chain residues than Th1 TCRs. The elongated, bulky Th2 CDR3alpha loops may be accommodated at the expense of less optimal interactions between the MHC class II/peptide and other CDR loops of the TCR. We propose that CD4+ T cells selected from the available repertoire under Th2 polarizing conditions tend to have elongated TCR CDR3alpha loops predicted to alter TCR binding, reducing contact at other interfaces and potentially leading to impeded TCR triggering.


Trends in cranial capacity and cranial index in Subsaharan Africa during the Holocene.
Craniometric data have been collected from published and unpublished reports of numerous authors on 961 male and 439 female crania from various sites in Subsaharan Africa spanning the last 100 ka. All data available in the literature, irrespective of their "racial" affinities, were used to cover the prehistoric and early historic times (up to 400 a BP). Samples covering the last 400 years do not include European colonists and consist of skeletons exavated at archeological sites, collected by early European travelers and derived from anatomical collections. Cranial capacity, depending on the mode of its calculation, has decreased by 95-165 cm3 among males and by 74-106 cm3 among females between the Late Stone Age (30-2 ka BP) and modern times (last 200 years). Values of the cranial index did not show any trend over time and their averages remained in the dolichocephalic category. The decrease in cranial capacity in Subsaharan Africa is similar to that previously found in Europe, West Asia, and North Africa, but, unlike the latter, it is not accompanied by brachycephalization. © 1993 Wiley-Liss, Inc.


Noncovalent functionalization of mesoporous silica nanoparticles with amphiphilic peptides.
The surface of mesoporous silica nanoparticles (MSNs) has been modified for enhancing their cellular uptake, cell targeting, bioimaging, and controlled drug release. For this purpose, covalent anchorage on the silica surface was predominantly exploited with a wide range of bioactive molecules. Here, we describe a facile self-assembly method to prepare a hybrid peptide silica system composed of octyl-modified mesoporous silica nanoparticles (MSNs) and peptide amphiphiles (PAs). The hydrophobic organosilane surface of mesoporous silica was coated with amphiphilic peptide molecules. The peptide functionalized particles exhibited good cyto-compatibility with vascular smooth muscle and vascular endothelial cells. The peptide coating also improved the cellular uptake of particles up to 6.3 fold, which is promising for the development of highly efficient MSN based theranostic agents.


Uniparental disomy determined by whole-exome sequencing in a spectrum of rare motoneuron diseases and ataxias.
The genetic causes of many rare inherited motoneuron diseases and ataxias (MND and ATX) remain largely unresolved, especially for sporadic patients, despite tremendous advances in gene discovery. Whole exome data is often available for patients, but it is rarely evaluated for unusual inheritance patterns, such as uniparental disomy (UPD). UPD is the inheritance of two copies of a chromosomal region from one parent, which may generate homozygosity for a deleterious recessive variant from only one carrier-parent. Detection of UPD-caused homozygous disease-causing variants is detrimental to accurate genetic counseling. Whole-exome sequencing can allow for the detection of such events. We systematically studied the exomes of a phenotypically heterogeneous cohort of unresolved cases (n = 96 families) to reveal UPD events hindering a diagnosis and to evaluate the prevalence of UPD in recessive MND and ATX. One hereditary spastic paraplegia case harbored homozygous regions spanning 80% of chromosome 16. A homozygous disease-causing mutation in the SPG35 disease gene was then identified within this region. This study demonstrates the ability to detect UPD in exome data of index patients. Our results suggest that UPD is a rare mechanism for recessive MND and ATX.


A cracking-assisted micro-/nanofluidic fabrication platform for silver nanobelt arrays and nanosensors.
Nanowires (NWs) with a high surface-to-volume ratio are advantageous for bio- or chemical sensor applications with high sensitivity, high selectivity, rapid response, and low power consumption. However, NWs are typically fabricated by combining several nanofabrication and even microfabrication processes, resulting in drawbacks such as high fabrication cost, extensive labor, and long processing time. Here, we show a novel NW fabrication platform based on "crack-photolithography" to produce a micro-/nanofluidic channel network. Solutions were loaded along the microchannel, while chemical synthesis was performed in the nanoslit-like nanochannels for fabricating silver nanobelts (AgNBs). In addition, the NW/NB fabrication platform not only made it possible to produce AgNBs in a repeatable, high-throughput, and low-cost manner but also allowed the simultaneous synthesis and alignment of AgNBs on a chip, eliminating the need for special micro- and/or nanofabrication equipment and dramatically reducing the processing time, labor, and cost. Finally, we demonstrated that the AgNBs can be used as chemical sensors, either as prepared or when integrated in a flexible substrate, to detect target analytes such as hydrogen peroxide.


Birth and evolution of an optical vortex.
When a phase singularity is suddenly imprinted on the axis of an ordinary Gaussian beam, an optical vortex appears and starts to grow radially, by effect of diffraction. This radial growth and the subsequent evolution of the optical vortex under focusing or imaging can be well described in general within the recently introduced theory of circular beams, which generalize the hypergeometric-Gaussian beams and which obey novel kinds of ABCD rules. Here, we investigate experimentally these vortex propagation phenomena and test the validity of circular-beam theory. Moreover, we analyze the difference in radial structure between the newly generated optical vortex and the vortex obtained in the image plane, where perfect imaging would lead to complete closure of the vortex core.


Anticancer ruthenium(III) complex KP1019 interferes with ATP-dependent Ca2+ translocation by sarco-endoplasmic reticulum Ca2+-ATPase (SERCA).
Sarco-endoplasmic reticulum Ca2+-ATPase (SERCA), a P-type ATPase that sustains Ca2+ transport and plays a major role in intracellular Ca2+ homeostasis, represents a therapeutic target for cancer therapy. Here, we investigated whether ruthenium-based anticancer drugs, namely KP1019 (indazolium [trans-tetrachlorobis(1H-indazole)ruthenate(III)]), NAMI-A (imidazolium [trans-tetrachloro(1H-imidazole)(S-dimethylsulfoxide)ruthenate(III)]) and RAPTA-C ([Ru(η6-p-cymene)dichloro(1,3,5-triaza-7-phosphaadamantane)]), and cisplatin (cis-diammineplatinum(II) dichloride) might act as inhibitors of SERCA. Charge displacement by SERCA adsorbed on a solid-supported membrane was measured after ATP or Ca2+ concentration jumps. Our results show that KP1019, in contrast to the other metal compounds, is able to interfere with ATP-dependent translocation of Ca2+ ions. An IC50 value of 1 μM was determined for inhibition of calcium translocation by KP1019. Conversely, it appears that KP1019 does not significantly affect Ca2+ binding to the ATPase from the cytoplasmic side. Inhibition of SERCA at pharmacologically relevant concentrations may represent a crucial aspect in the overall pharmacological and toxicological profile of KP1019.


Rhinoplasty outcome measurement.
The literature includes few publications dealing with the measurement of rhinoplasty outcomes. We also lack reliable instruments for such measurements. In a population of 228 patients who underwent rhinoplasty performed by the same surgeon, we evaluated patient satisfaction using Alsarraf's questionnaire and an evaluation of cosmetic improvement using standardised pre- and post-operative photographs (Photograph Score from 1- great to 7- monstrous). We correlated these data with the severity of the pre-operative nasal deformities, (Predictable Difficulty Score) with the complexity of the surgical procedure, (Surgical Complexity Score) and with four specific surgical procedures (Spreader Grafting, Domal Interruption, Grafting of the Dorsum, Tip Grafting). Both Alsarraf's questionnaire and the photograph score identified a significant difference between the pre-operative and post-operative data and appear to be reliable instruments for measuring patient satisfaction. The questionnaire takes into account the functional outcome that the PS did not. In our hands, the mean improvement evaluated by the questionnaire was 50.2%, and 2.8 according to the PS, regardless of primary or revision surgery, traumatic or non-traumatic nose, mixed cosmetic/functional or purely cosmetic goals. The relative size of the difference between the pre- and post-operative scores was linked more to the satisfaction of the patient than to the absolute post-operative level. These two instruments (the questionnaire and the photograph score), although they are in agreement, did not allow for the establishment of any correlation between the satisfaction of the patient and the predicted difficulty score (PDS), the surgical complexity score (SCS), or three of the four specific procedures that were considered (SG, DI, GD and TG). Domal interruption was the only procedure in which we found that patient satisfaction was higher than with the other procedures (65.6% for the questionnaire and 3.8 for the photograph score).


A 21-base pair insertion/duplication at codon 69 of the HIV type 1 reverse transcriptase in a patient undergoing multiple nucleoside therapy.
We describe the selection of a previously unreported 21-base pair insertion following codon 69 of the HIV-1 reverse transcriptase (RT) from a patient undergoing multiple nucleoside analogue therapy. This insertion was a direct duplication of the preceding 21 bases of HIV-RT, and was selected in a background of NRTI-resistance mutations including substitutions at RT codons 41, 67, 184, 210, and 215. Longitudinal genotypic and phenotypic resistance tests performed before and after selection of the insertion suggested that the insertion conferred an additional decrease in susceptibility to some nucleoside analogues, most notably didanosine, stavudine, abacavir, and tenofovir. However, phenotypic analysis of an insertion-containing site-directed mutant constructed in an HIV-1 HXB2 background revealed no direct association between the 21-base pair insertion and decreased susceptibility to NRTIs, suggesting that the insert requires the context of the patients' virus in order to confer resistance. These observations may offer new insight into the relative contribution of HIV-RT codon 69 insertion mutations to antiretroviral resistance.


Demographic collapse and low genetic diversity of the Irrawaddy dolphin population inhabiting the Mekong River.
In threatened wildlife populations, it is important to determine whether observed low genetic diversity may be due to recent anthropogenic pressure or the consequence of historic events. Historical size of the Irrawaddy dolphin (Orcaella brevirostris) population inhabiting the Mekong River is unknown and there is significant concern for long-term survival of the remaining population as a result of low abundance, slow reproduction rate, high neonatal mortality, and continuing anthropogenic threats. We investigated population structure and reconstructed the demographic history based on 60 Irrawaddy dolphins samples collected between 2001 and 2009. The phylogenetic analysis indicated reciprocal monophyly of Mekong River Orcaella haplotypes with respect to haplotypes from other populations, suggesting long-standing isolation of the Mekong dolphin population from other Orcaella populations. We found that at least 85% of all individuals in the two main study areas: Kratie and Stung Treng, bore the same mitochondrial haplotype. Out of the 21 microsatellite loci tested, only ten were polymorphic and exhibited very low levels of genetic diversity. Both individual and frequency-based approaches suggest very low and non-significant genetic differentiation of the Mekong dolphin population. Evidence for recent bottlenecks was equivocal. Some results suggested a recent exponential decline in the Mekong dolphin population, with the current size being only 5.2% of the ancestral population. In order for the Mekong dolphin population to have any potential for long-term survival, it is imperative that management priorities focus on preventing any further population fragmentation or genetic loss, reducing or eliminating anthropogenic threats, and promoting connectivity between all subpopulations.


Fully Threaded Versus Partially Threaded Screws: Determining Shear in Cancellous Bone Fixation.
Many researchers have studied and compared various forms of intraosseous fixation. No studies have examined the effects of shear through stiffness and failure strength of a fully threaded versus a partially threaded screw. Our hypothesis was that the fully threaded lag screw technique would provide greater shear strength and resistance. Thirty-six synthetic sawbone blocks were used to test screw fixation. In group 1 (n = 9), 2 blocks were fixed together using a fully threaded 4.0-mm stainless steel cancellous bone screw and the lag technique. In group 2 (n = 8), 2 blocks were fixed together using the standard manufacturer-recommended method for inserting 4.0-mm partially threaded stainless steel cancellous bone screws. The constructs were then mechanically tested. Shear was applied by compressing each construct at an axial displacement rate of 0.5 mm/s until failure. The fully threaded screw had a significantly greater (p = .026) initial stiffness (106.4 ± 15.8 N/mm) than the partially threaded screw (80.1 ± 27.5 N/mm). The yield load and displacement for the fully threaded group (429.4 ± 11.7 N and 7.2 ± 0.35 mm) were 64% and 67% greater than those for the partially threaded screw group (261.4 ± 26.1 N and 4.3 ± 1.03 mm), respectively. The results of the present study have demonstrated the importance of a full-thread construct to prevent shear and to decrease strain at the fracture. The confirmation of our hypothesis questions the future need and use of partially threaded screws for cancellous bone fixation.


Preferential induction of fos-like immunoreactivity in granule cells of the cochlear nucleus by acoustic stimulation in behaving rats.
Neuronal activity in the cochlear nucleus was mapped in relation to acoustic stimuli that signalled a sensory-motor response, using Fos-like immunoreactivity. Rats were trained to associate an acoustic stimulus with a reward and then to discriminate between two sounds ('learning' rats; n = 18). The same stimuli carrying no behavioural significance were pseudo-randomly presented to 'control' rats (n = 4) to differentiate stimulus related- from learning related-activity. To establish a baseline, Fos-like immunoreactivity was determined in rats (n = 2) unexposed to acoustic stimulation. The number of Fos-positive cells was significantly increased in the rats exposed to sounds ('learning' and 'control') as compared to the non-stimulated animals. This stimulus related increase of Fos-like activity in the cochlear nucleus was most prominent in a subpopulation of small neurons, whose spatial distribution corresponds to that of the granule cells. There was also an increase in the number of Fos-positive neurons of larger size, but less prominent than for the small cells. Brief exposure to sounds (30 s) was sufficient to induce Fos-like activity.


KSR1 and EPHB4 Regulate Myc and PGC1β To Promote Survival of Human Colon Tumors.
Identification and characterization of survival pathways active in tumor cells but absent in normal tissues provide opportunities to develop effective anticancer therapies with reduced toxicity to the patient. We show here that, like kinase suppressor of Ras 1 (KSR1), EPH (erythropoietin-producing hepatocellular carcinoma) receptor B4 (EPHB4) is aberrantly overexpressed in human colon tumor cell lines and selectively required for their survival. KSR1 and EPHB4 support tumor cell survival by promoting the expression of downstream targets, Myc and the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1β (PGC1β). While KSR1 promotes the aberrant expression of Myc and the PGC1β protein via a posttranscriptional mechanism, EPHB4 has a greater effect on Myc and PGC1β expression via its ability to elevate mRNA levels. Subsequent analysis of the posttranscriptional regulation demonstrated that KSR1 promotes the translation of Myc protein. These findings reveal novel KSR1- and EPHB4-dependent signaling pathways supporting the survival of colorectal cancer cells through regulation of Myc and PGC1β, suggesting that inhibition of KSR1 or EPHB4 effectors may lead to selective toxicity in colorectal tumors.


Interconversions between haloperidol and reduced haloperidol in schizophrenic patients and guinea pigs: a steady-state study.
Plasma concentrations of haloperidol (HAL) and reduced haloperidol (RHAL) were measured in 8 schizophrenic patients, neuroleptic-free for at least 4 weeks, after repeated oral administrations of 10 mg HAL and RHAL. Each agent was given for 10 days with a 2-week washout period between the two compounds. HAL and RHAL were interconverted in all subjects. Plasma RHAL/HAL ratios at steady state during HAL treatment were significantly greater than the HAL/RHAL ratios after repeated reduced HAL administration (0.51 +/- 0.12 vs. 0.16 +/- 0.04 SD, p less than 0.0005). This result suggests that the interconversions between HAL and RHAL are apparently not equivalent in humans. A negative correlation was found between RHAL/HAL ratios after HAL administrations and HAL/RHAL ratios after RHAL administrations (r = -0.82, p less than 0.05). Repeated injections of HAL or RHAL at low (0.1 mg/kg) or high (1.0 mg/kg) doses were conducted in guinea pigs. Drug concentrations in striatum and plasma were measured. Both RHAL/HAL ratios after HAL injections and HAL/RHAL ratios after RHAL injections were dose- and time-dependent. High doses and repeated injections produced greater RHAL/HAL ratios after HAL and smaller HAL/RHAL ratios after RHAL than those observed with low doses and single injections, respectively. Compared with the results obtained from schizophrenic patients, the conversion from HAL to RHAL in guinea pigs was greater than that in humans, but the back conversions appeared to be similar between the guinea pigs and humans. Based upon the dose-dependent increase in RHAL/HAL ratios, a hypothesis of the therapeutic window effect for HAL treatment is proposed.


Toxocara eggs in public places worldwide - A systematic review and meta-analysis.
Toxocariasis is a neglected tropical disease of humans. Although many studies have indicated or shown that environmental contamination with Toxocara species eggs is a major risk factor for toxocariasis in humans, there has been no comprehensive analysis of published data or information. Here, we conducted the first systematic review and meta-analysis of current literature to assess the global prevalence of Toxocara eggs in public places (including beaches, parks and playgrounds). We conducted searches of the PubMed, Embase, Scopus and Science Direct databases for relevant studies published until 20 April 2018, and assessed the prevalence rates of Toxocara eggs in public places. We used the random effects model to calculate pooled prevalence estimates, with 95% confidence intervals (CIs), and analysed data in relation to WHO geographical regions. Subgroup analysis and meta-regressions regarding the geographical and environmental variables were also performed. Of 2384 publications identified, 109 studies that tested 42,797 soil samples in 40 countries were included in the meta-analysis. The pooled global prevalence of Toxocara eggs in public places was 21% (95% CI, 16-27%; 13,895/42,797). The estimated prevalence rates in the different WHO regions ranged from 13% to 35%: Western Pacific (35%; 95% CI, 15-58%), Africa (27%; 95% CI, 11-47%), South America (25%; 95% CI, 13-33%), South-East Asia (21%; 95% CI, 3-49%), Middle East and North Africa (18%; 95% CI, 11-24%), Europe (18%; 95% CI, 14-22%), and North and Central Americas (13%; 95% CI, 8-23%). A high prevalence was significantly associated with high geographical longitude (P = 0.04), low latitude (P = 0.02) and high relative environmental humidity (P = 0.04). This meta-analysis of data from published records indicates that public places are often heavily contaminated with eggs of Toxocara. This finding calls for measures to reduce the potential risk of infection and disease in humans.


Thrombectomy for acute ischemic stroke in the elderly: a 'real world' experience.
Completed randomized trials on endovascular thrombectomy (ET) did not independently assess the efficacy of ET in the elderly (≥80 years old) who were often excluded or under-represented in trials. There were also inconsistent criteria for patient selection in this population across the different trials. This work evaluates outcomes after ET for acute ischemic stroke (AIS) in the elderly at a high volume stroke center. We reviewed all cases of AIS that underwent a direct aspiration first pass technique (ADAPT) thrombectomy for large vessel occlusions between March 2013 and October 2017 while comparing outcomes in the elderly with younger counterparts. We also reviewed AIS cases in elderly patients undergoing medical management who were matched to the ET counterparts by demographics, comorbidities, baseline deficits, and stroke severity. Of 560 patients undergoing ET for AIS, 108 patients were in the elderly group (≥80 years of age), and had a significantly lower likelihood of functional independence (defined as a modified Rankin Scale score of 0-2) at 90 days compared with younger patients (20.5% vs 44.4%, P<0.001), and higher mortality rates (34.3% vs 20%, P<0.001). When compared with patients undergoing medical management, elderly patients did not have a significant improvement in rates of good outcomes (20.5% vs 19.5%, P>0.05), and had significantly higher rates of hemorrhage (40.7% vs 9.3%, P<0.001). We also identified baseline stroke severity and the incidence of hemorrhage as two independent predictors of outcome in the elderly patients. ET in the elderly did not show a similar benefit to younger patients when compared with medical management. These findings emphasize the need for more optimal selection criteria for the elderly population to improve the risk to benefit ratio of ET.


Back hand approach to radial access: The snuff box approach.
Transradial access is becoming the default strategy for routine coronary procedures, but there is still room for improvement. For instance, left radial access is known to offer some advantages for graft cases, less tortuosity, amongst other potential benefits. The downside has been the applicability of this access point on patients with a larger body mass index both from the viewpoint of the patient and the operator. The patient must lay with their arm in a supine position and the operator as a result must stand in a flexed position for an unknown period of time. Additionally, patients with various orthopedic injuries, including frozen shoulders, on may be unable to supinate their wrist for optimal access. One solution to this dilemma is to approach the radial artery from the dorsal aspect of the hand so the wrist can pronate naturally if body habitus requires the arm to be shifted towards the operator. This report outlines the steps and background behind this approach and an educational opportunity for those interested in expanding their access skills.


Pathway of glycine betaine biosynthesis in Aspergillus fumigatus.
The choline oxidase (CHOA) and betaine aldehyde dehydrogenase (BADH) genes identified in Aspergillus fumigatus are present as a cluster specific for fungal genomes. Biochemical and molecular analyses of this cluster showed that it has very specific biochemical and functional features that make it unique and different from its plant and bacterial homologs. A. fumigatus ChoAp catalyzed the oxidation of choline to glycine betaine with betaine aldehyde as an intermediate and reduced molecular oxygen to hydrogen peroxide using FAD as a cofactor. A. fumigatus Badhp oxidized betaine aldehyde to glycine betaine with reduction of NAD(+) to NADH. Analysis of the AfchoAΔ::HPH and AfbadAΔ::HPH single mutants and the AfchoAΔAfbadAΔ::HPH double mutant showed that AfChoAp is essential for the use of choline as the sole nitrogen, carbon, or carbon and nitrogen source during the germination process. AfChoAp and AfBadAp were localized in the cytosol of germinating conidia and mycelia but were absent from resting conidia. Characterization of the mutant phenotypes showed that glycine betaine in A. fumigatus functions exclusively as a metabolic intermediate in the catabolism of choline and not as a stress protectant. This study in A. fumigatus is the first molecular, cellular, and biochemical characterization of the glycine betaine biosynthetic pathway in the fungal kingdom.


Ion dynamics during seizures.
Changes in membrane voltage brought about by ion fluxes through voltage and transmitter-gated channels represent the basis of neural activity. As such, electrochemical gradients across the membrane determine the direction and driving force for the flow of ions and are therefore crucial in setting the properties of synaptic transmission and signal propagation. Ion concentration gradients are established by a variety of mechanisms, including specialized transporter proteins. However, transmembrane gradients can be affected by ionic fluxes through channels during periods of elevated neural activity, which in turn are predicted to influence the properties of on-going synaptic transmission. Such activity-induced changes to ion concentration gradients are a feature of both physiological and pathological neural processes. An epileptic seizure is an example of severely perturbed neural activity, which is accompanied by pronounced changes in intracellular and extracellular ion concentrations. Appreciating the factors that contribute to these ion dynamics is critical if we are to understand how a seizure event evolves and is sustained and terminated by neural tissue. Indeed, this issue is of significant clinical importance as status epilepticus-a type of seizure that does not stop of its own accord-is a life-threatening medical emergency. In this review we explore how the transmembrane concentration gradient of the six major ions (K(+), Na(+), Cl(-), Ca(2+), H(+)and [Formula: see text]) is altered during an epileptic seizure. We will first examine each ion individually, before describing how multiple interacting mechanisms between ions might contribute to concentration changes and whether these act to prolong or terminate epileptic activity. In doing so, we will consider how the availability of experimental techniques has both advanced and restricted our ability to study these phenomena.


The Effect of Coffee and Caffeine Consumption on Patients with Multiple Sclerosis-Related Fatigue.
Background: Coffee and caffeine are considered to have beneficial effects in patients with multiple sclerosis (MS), an autoimmune disease of the central nervous system (CNS) that can lead to disability and chronic fatigue. Methods: In the present study the preference in terms of coffee and caffeine consumption in patients with MS was assessed. In total the opinions of 124 MS patients were explored with a questionnaire, which was developed to investigate the consumption behavior and associated beneficial and harmful effects of coffee and caffeine concerning symptoms of fatigue. Results: Our study showed that 37.1% of the included patients experience severe symptoms of fatigue. In our cohort, fatigue was not related to age, type of diagnosis or duration of the disease. The effects of coffee did not differ between MS patients with and without fatigue. Very few side effects linked to coffee consumption were reported, and we could demonstrate that coffee consumption had no negative impact on quality of sleep. A positive effect on everyday life was observed particularly among patients with a mid-level expanded disability status scale (EDSS). The strongest effects of coffee consumption were observed regarding a better ability to concentrate while fulfilling tasks, an expanded attention span and a better structured daily routine. Conclusions: Since coffee showed no severe side effects and in the absence of an effective fatigue therapy, coffee consumption might be a therapeutic approach for selected patients with MS-related fatigue.


Clinical Score Predicting Long-Term Survival after Repeat Resection for Recurrent Adrenocortical Carcinoma.
Adrenocortical carcinoma (ACC) is an aggressive malignancy typically resistant to chemotherapy and radiation. Surgery, even in the setting of locally recurrent or metastatic disease, remains the only potentially curative option. However, the subset of patients who will benefit from repeat resection in this setting remains ill defined. The objective of this study was to propose a prognostic clinical score that facilitates selection of patients for repeat resection of recurrent ACC. Patients who underwent curative-intent repeat resection for recurrent ACC at 1 of 13 academic medical centers participating in the US ACC Study Group were identified. End points included morbidity, mortality, and overall survival. Fifty-six patients underwent repeat curative-intent resection for recurrent ACC (representing 21% of 265 patients who underwent resection for primary ACC) from 1997 to 2014. Median age was 52 years. Sites of resected recurrence included locoregional only (54%), lung only (14%), liver only (12%), combined locoregional and lung (4%), combined liver and lung (4%), and other distant sites (12%). Thirty-day morbidity and mortality rates were 40% and 5.4%, respectively. Cox regression analysis revealed that the presence of multifocal recurrence, disease-free interval <12 months, and extrapulmonary distant metastases were independent predictors of poor survival. A clinical score consisting of 1-point each for the 3 variables demonstrated good discrimination in predicting survival after repeat resection (5-year: 72% for 0 points, 32% for 1 point, 0% for 2 or 3 points; p = 0.0006, area under the curve = 0.78). Long-term survival after repeat resection for recurrent ACC is feasible when 2 of the following factors are present: solitary tumor, disease-free interval >12 months, and locoregional or pulmonary recurrence.


Stem and progenitor cells in human umbilical cord blood.
Both stem cells and progenitor cells are present in umbilical cord blood (UCB) at a high frequency, making these cells a major target population for experimental and clinical studies. As the use of autologous or allogeneic hematopoietic stem cell transplantation in the treatment of various diseases has grown rapidly in recent years, the concept of UCB banking for future use has drawn increasing interest. Stem and progenitor cells derived from UCB offer multiple advantages over adult stem cells, such as their immaturity (which may play a significant role in reducing rejection after transplantation into a mismatched host) and ability to produce large quantities of homogeneous tissue or cells. These cells can also differentiate across tissue lineage boundaries into neural, cardiac, epithelial, hepatic, and dermal tissues. Human UCB provides an alternative cell source that is ethically acceptable and widely supported by the public. This paper summarizes the characteristics of human UCB-derived stem and progenitor cells and their potential therapeutic use for tissue and cell regeneration.


Antidiabetic and hypolipidemic effect of salacia oblonga in streptozotocin induced diabetic rats.
The present study was conducted to evaluate the effect of a standardized hydroalcoholic root extract of Sala¬cia oblonga (SOE) on the Random Blood Glucose (RBG) levels, serum insulin, glycated haemoglobin (HbA1c) and the serum lipid profile in long standing, experimentally induced Diabetes Mellitus (DM) with glibenclamide (Glb) as the standard. Streptozotocin (STZ) induced, dia-betic, Wistar rats of either sex were treated with two oral doses of SOE, 100 and 50mg/kg body wt /day, for a period of 16 weeks. The RBG was estimated at day-1 and at the end of the 16 weeks by using a glucometer. The fasting serum insulin was determined by an ELISA technique. The plasma HbA1c was evaluated by a Turbidimetric Inhibition Immunoassay (TINIA) and the lipid profile was estimated enzymatically. A 45% decrease in the RBG was seen after the treatment with the higher dose of SOE, whereas a 44% decrease was observed with the lower dose as com¬pared to the diabetic control. Serum insulin was significantly increased (P<0.05) in all the treated groups as compared to the diabetic control. Plasma HbA1c was significantly decreased (P<0.05). The serum Triacyl Glycerol (TG) levels were signifi¬cantly decreased (P<0.05) in the treated rats as compared to the diabetic control. A significant increase in HDL-cholesterol (P<0.05) in the diabetic rats as a result of the 100mg/kg SOE treatment was a remarkable finding. SOE improves the glycaemic parameters in diabetic rats after a prolonged treatment. The serum TG levels were normalized on treatment. A higher dose of the extract could not alter the parameters significantly, except for HDL-C.


Familiarity impairments after anterior temporal-lobe resection with hippocampal sparing: Lessons learned from case NB.
We review evidence from an extensive single case study in an individual (NB) who underwent a rare left-sided anterior temporal-lobe resection with sparing of the hippocampus. Our study aimed to determine whether memory functions of perirhinal cortex, which was largely removed in the resection, can be impaired against a background of preserved hippocampus-dependent memory processing. This research was guided by the proposal that item-based familiarity assessment relies on contributions of perirhinal cortex, and that the hippocampus plays a unique role in the relational binding of items to episodic contexts, which is critical for recollection. Seven sets of findings have emerged from our research on NB (synthesized from five primary research articles), and from follow-up work in other patients: (i) Familiarity impairments can be selective and be revealed with multiple methods; (ii) selective familiarity and selective recollection impairments can be double dissociated; (iii) selective familiarity impairments show material specificity; (iv) selective familiarity impairments extend to assessment of cumulative lifetime experience; (v) selective familiarity impairments are sensitive to degree of feature overlap between object concepts; (vi) selective familiarity impairments are associated with preserved task-related fMRI signals in the hippocampus; (vii) selective familiarity impairments can be observed in other lesion cases. Despite our main focus on the dual-process framework, we also discuss implications for the functional organization of the medial temporal lobes in broader terms. We argue that our findings shed light on this organization even if the functional specialization of different medial temporal structures is ultimately not fully captured with reference to the cognitive distinction between familiarity and recollection.


A comparison of two headless compression screws for operative treatment of scaphoid fractures.
The purpose of this study was to compare the interfragmentary compression force across a simulated scaphoid fracture by two commonly used compression screw systems; the Acutrak 2 Standard and the 3.0 mm Synthes headless compression screw. Sixteen (8 pairs; 6 female, 2 male) cadaver scaphoids were randomly assigned to receive either the Acutrak 2 or Synthes screw with the contralateral scaphoid designated to receive the opposite. Guide wires were inserted under fluoroscopic control. Following transverse osteotomy, the distal and proximal fragments were placed on either side of a custom load cell, to measure interfragmentary compression. Screws were placed under fluoroscopic control using the manufacturer's recommended surgical technique. Compressive forces were measured during screw insertion. Recording continued for an additional 60s in order to measure any loss of compression after installation was complete. The peak and final interfragmentary compression were recorded and paired t-tests performed. The mean peak compression generated by the Acutrak 2 Standard was greater than that produced by the Synthes compression screw (103.9 ± 33.2 N vs. 88.7 ± 38.6 N respectively, p = 0.13). The mean final interfragmentary compression generated by the Acutrak 2 screw (68.6 ± 36.4 N) was significantly greater (p = 0.04) than the Synthes screw (37.2 ± 26.8 N). Specimens typically reached a steady state of compression by 120-150s after final tightening. Peak interfragmentary compression observed during screw installation was similar for both screw systems. However, the mean interfragmentary compression generated by the Acutrak 2 Standard was significantly greater. Our study demonstrates that the Synthes headless compression screw experienced a greater loss of interfragmentary compressive force from the time of installation to the final steady state compression level. The higher post-installation compression of the Acutrak 2 Standard may be attributable to the greater number of threads throughout the entire length of the screw. The clinical significance of these results, are, at this point uncertain. We do demonstrate that a fully threaded design offers a more reliable compression that may translate to more predictable bony union.


Effects of Coenzyme Q10 Supplementation on Inflammatory Cytokines (TNF-α, IL-6) and Oxidative Stress in Rheumatoid Arthritis Patients: A Randomized Controlled Trial.
Overproduction of proinflammatory cytokines is a main trait of rheumatoid arthritis. Coenzyme Q10 (CoQ10), an endogenous antioxidant, has shown anti-inflammatory effects in some diseases. In this study we aimed to assess the effects of CoQ10 supplementation on cytokines generation and oxidative stress in rheumatoid arthritis. In this double-blind, randomized controlled clinical trial, 44 patients with rheumatoid arthritis were recruited. Twenty two patients received 100 mg/day capsules of CoQ10 and 22 patients took placebo for 2 months. At the beginning and the end of the intervention, 7 mL of fasting blood was taken from patients to measure malondialdehyde (MDA), total antioxidant capacity (TAC), interleukin (IL)-6 and tumor necrosis factor alpha (TNF-α). At the end of the study, serum MDA significantly decreased in supplemented group (mean difference = -1.47 nmol/mL; 95% confidence interval (CI), -2.52 to -0.43; p = 0.008). CoQ10 also suppressed overexpression of TNF-α (difference in median was +1.1 in placebo vs. +0.03 in CoQ10 group; p = 0.033). There was no significant difference in TAC and IL-6 levels between groups. This study showed beneficial effects of CoQ10 supplementation on inflammatory cytokines and oxidative stress in rheumatoid arthritis patients.


Expression of and response to growth regulatory peptides by two human pancreatic carcinoma cell lines.
Two human pancreatic adenocarcinoma cell lines (PANC 1 and MIA PACA 2) were examined for expression of growth factors that could potentially play a role either in growth regulation of the tumor cells, or in cells that comprise the stromal elements of tumors. Both cell lines expressed transforming growth factor-alpha (TGF alpha), basic fibroblast growth factor (bFGF), c-sis (PDGF B chain), TGF beta 1, and TGF beta 3 mRNA by Northern blot analysis. Only the PANC 1 cells, however, expressed the TGF beta 2 transcript. TGF beta-like competing activity was found in medium conditioned by either cell line, but TGF alpha-like [epidermal growth factor (EGF)-competing] activity was not detected in the medium from either cell line by radioreceptor assay. TGF alpha and EGF caused concentration-dependent stimulation of soft agar colony growth of the MIA PACA 2 cells, while only TGF alpha caused a significant but less dramatic stimulation of soft agar growth of the PANC 1 cells. Insulin stimulated the anchorage-independent growth of MIA PACA 2 but not PANC 1 cells. Likewise, bFGF also caused a concentration-dependent stimulation of MIA PACA 2 but not PANC 1 growth in soft agar, and PDGF had no effect on the growth of either cell line. TGF beta had no inhibitory or stimulatory effect on soft agar colony growth of either the PANC 1 or the MIA PACA 2 cells, although both cell lines exhibited high affinity, saturable TGF beta binding sites, and TGF beta 1 was capable of autoinduction of TGF beta 1 mRNA expression in PANC 1 cells. The ability to continue to respond to positive growth regulatory factors coupled with the loss of responsiveness to negative growth factors may be important in the pathogenicity of these aggressive tumors.


Arterial Resistance in Late First Trimester as a Predictor of Subsequent Pregnancy-Related Hypertension.
This study aimed to examine the association between indicators of arterial resistance occurring late in the first trimester and the subsequent development of pregnancy-related hypertension. This study took place between May 2014 and August 2015 and included 329 consecutive women with singleton pregnancies attending the antenatal clinics of a medical college in Karnataka, India, during this period. Pulse pressure (PP) and uterine artery Doppler parameters were recorded between 11-14 gestational weeks. Consequently, women were followed-up until after delivery for subsequent hypertension. Hypertension occurred more frequently if PP was high (17.6% versus 14.4% of pregnancies without high PP; P = 0.713), if a diastolic notch (DN) was present (15.1% versus 12.8% of pregnancies with an absent DN; P = 0.612) and if the resistive index (RI) was raised (22.2% versus 14.3% of pregnancies without raised RI; P = 0.366). A raised pulsatility index (PI) was significantly associated with hypertension (P = 0.013). The risk of hypertension was approximately seven-fold higher if two or more arterial resistance indicators were used, except with a present DN plus a raised RI or a present DN plus high PP. All arterial resistance indicators showed negative predictability (>85.6%) and good specificity (≥95.0%), except for the presence of a DN. A population-specific cut-off PI value of 1.72 had high negative predictability (92.8%) and good sensitivity (70.8%) and specificity (65.1%). Raised PI in the late first trimester was a significant predictor of hypertension later in pregnancy. A combination of arterial resistance indicators may enhance prediction of subsequent hypertension.


Weight uniformity of scored tablet halves manufactured by palestinian pharmaceutical companies.
The purpose of this study was to evaluate the weight uniformity of some commonly divided tablets produced by Palestinian Pharmaceutical companies. Volunteers were asked to divide scored tablets. The split units were individually weighed and the relative standard deviation for each product was calculated. Five scored tablet products failed the United States Pharmacopeia test of mass uniformity; this indicates that the splitting of these tablet products is not reliable for the provision of accurate doses. The practice of dividing tablets to achieve therapeutic and economic benefits for the patient may cause significant problems, especially in drugs with low therapeutic indices. Pharmacists may resolve this inconvenience by reformulating the tablet into a new dosage form, such as capsules, which should contain the exact amount of the medication.


Considerations for Integration of Perioperative Electronic Health Records Across Institutions for Research and Quality Improvement: The Approach Taken by the Multicenter Perioperative Outcomes Group.
Use of the electronic health record (EHR) has become a routine part of perioperative care in the United States. Secondary use of EHR data includes research, quality, and educational initiatives. Fundamental to secondary use is a framework to ensure fidelity, transparency, and completeness of the source data. In developing this framework, competing priorities must be considered as to which data sources are used and how data are organized and incorporated into a useable format. In assembling perioperative data from diverse institutions across the United States and Europe, the Multicenter Perioperative Outcomes Group (MPOG) has developed methods to support such a framework. This special article outlines how MPOG has approached considerations of data structure, validation, and accessibility to support multicenter integration of perioperative EHRs. In this multicenter practice registry, MPOG has developed processes to extract data from the perioperative EHR; transform data into a standardized format; and validate, deidentify, and transfer data to a secure central Coordinating Center database. Participating institutions may obtain access to this central database, governed by quality and research committees, to inform clinical practice and contribute to the scientific and clinical communities. Through a rigorous and standardized approach to ensure data integrity, MPOG enables data to be usable for quality improvement and advancing scientific knowledge. As of March 2019, our collaboration of 46 hospitals has accrued 10.7 million anesthesia records with associated perioperative EHR data across heterogeneous vendors. Facilitated by MPOG, each site retains access to a local repository containing all site-specific perioperative data, distinct from source EHRs and readily available for local research, quality, and educational initiatives. Through committee approval processes, investigators at participating sites may additionally access multicenter data for similar initiatives. Emerging from this work are 4 considerations that our group has prioritized to improve data quality: (1) data should be available at the local level before Coordinating Center transfer; (2) data should be rigorously validated against standardized metrics before use; (3) data should be curated into computable phenotypes that are easily accessible; and (4) data should be collected for both research and quality improvement purposes because these complementary goals bolster the strength of each endeavor.


Eleven worthy aims for clinical leadership of health system reform.
Clinicians ought to be playing a central role in making the changes in the health care system that will allow the system to offer better outcomes, greater ease of use, lower cost, and more social justice in health status. Instead, most of the proposed changes that are today called "health care reform" are actually changes in the surroundings of care rather than changes in the care itself. Clinicians have an opportunity to exercise leadership for the improvement of care, but they must first agree to address the aims of reform and to adopt an agenda of specific changes in their own work that are likely to meet the social needs driving the reform movement. Health services research offers a sound scientific basis for identifying promising improvement aims for clinician-led reform. Eleven plausible aims are these: (1) reducing inappropriate surgery, hospital admissions, and diagnostic tests; (2) reducing key underlying root causes of illness (especially smoking, handgun violence, preventable childhood injuries, and alcohol and cocaine abuse); (3) reducing cesarean section rates to pre-1980 levels; (4) reducing the use of unwanted medical procedures at the end of life; (5) simplifying pharmaceutical use, especially for antibiotics and medication of the elderly; (6) increasing active patient participation in therapeutic decision making; (7) decreasing waiting times in health care settings; (8) reducing inventory levels in health care organizations; (9) recording only useful information only once; (10) consolidating and reducing the total supply of high-technology medical and surgical care; and (11) reducing the racial gap in infant mortality and low birth weight. Health care professions and their professional organizations in concert should embrace these 11 aims, establish measurements of progress toward them, and commit to continuous and fundamental changes in their pursuit.


Monitoring of Epstein-Barr virus load after hematopoietic stem cell transplantation for early intervention in post-transplant lymphoproliferative disease.
Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disease is a life-threatening complication following hematopoietic stem cell transplantation. A quantitative polymerase chain reaction to evaluate EBV-genome copy numbers based on a nested polymerase chain reaction and an end-point dilution was used. Applying this assay EBV load was prospectively screened weekly in 123 patients after transplantation. The results demonstrate that EBV reactivations with more than 1,000 EBV-genome copies measured in 10(5) peripheral blood mononuclear cells were observed in 31 patients (25.2%). Three patients developed lymphoproliferative disease with extremely high EBV-genome copies in peripheral blood mononuclear cells (>100,000 copies/10(5) cells) and plasma. After combined antiviral and immune therapy two of three patients showed a dramatic decrease of EBV load and survived, while the third patient died of lymphoma. A subclinical EBV reactivation was observed in 24 cases (19.5%) with EBV-genome copies in 10(5) peripheral blood mononuclear cells ranging between 2,500 and mostly 10,000. After reduction of immunosuppression the EBV levels normalized. In four patients, the high copy number of > or =80,000 copies/10(5) peripheral blood mononuclear cells and plasma positivity prompted us to start pre-emptive therapy with rituximab and cidofovir for prevention of lymphoproliferative disease. After drug administration the high EBV load was reduced remarkably. Ninety-two patients (74.8%) who had < or =1,000 copies/10(5) peripheral blood mononuclear cells did not develop EBV-associated lymphoproliferative disease. In conclusion, monitoring of EBV load is a sensitive and useful parameter in the surveillance of EBV reactivation for early intervention in EBV-associated lymphoproliferative disease as well as for follow-up of the efficacy of therapy.


Effects of Internet popular opinion leaders (iPOL) among Internet-using men who have sex with men.
The Internet has become a popular venue for facilitating sex networking for men who have sex with men (MSM). The study aimed to evaluate the effectiveness of Internet popular opinion leaders (iPOL) in disseminating information about the human immunodeficiency virus (HIV), increasing the frequency of HIV testing, and reducing risky behaviors among MSM in Taiwan. A quasi-experimental study with a nonequivalent control website for comparison was used to estimate the effectiveness of iPOL. A community-level intervention, iPOL, was conducted at the Facebook social networking website and at top1069 as a control. The iPOLs actively disseminated HIV-related information via the platform of Internet opinion leaders and AIDS information center, and discussed and responded to questions or replied to Internet-using MSM. A total of 369 iPOLs posted 432 articles and 503 replies to others, influencing 959,088 persons on Facebook. A total of 1037 MSM, 552 (53.23%) from an intervention website and 485 (46.76%) from a control website, participated in the follow-up study survey (response rate 96%). At the 6-month follow-up after the intervention was conducted, MSM who visited the intervention website were more likely to receive HIV-related information (25.49% versus 10.47%, P<.001), discuss HIV issues with others (41.88% versus 23.79%, P<.001), review articles about HIV (90.58% versus 79.73%, P<.001), and be asked about or discuss HIV-related questions (51.11% versus 31.78%, P<.001) than those on the control website. In addition, MSM were more likely to have HIV tests within 6 months (43.89% versus 22.31%, P<.001) and consistently use condoms during anal sex with online sex partners than those using the control website (34.15% versus 26.19%, P=.004). The study showed the feasibility and effectiveness of the iPOL intervention as an online HIV prevention program. These findings underscore the importance of disseminating HIV information online, as well as the challenges inherent in the efforts of iPOL to reduce HIV-related risky behaviors among Internet-using MSM.


Purified interleukin-3 and erythropoietin support the terminal differentiation of hemopoietic progenitors in serum-free culture.
We studied the effect of purified interleukin-3 (IL-3) and erythropoietin on colony formation by hemopoietic progenitors in serum-free cultures of spleen cells from 5-fluorouracil (5-FU)-treated mice. In the presence of IL-3 alone, most of the multilineage (three or more lineages) colonies did not contain erythroid cells. However, in the presence of IL-3 and erythropoietin, most of the multilineage colonies contained various numbers of erythroid cells. Replating experiments suggest that IL-3 maintains the growth of the progenitor cells, which could differentiate into erythroid cells. Erythropoietin facilitated the terminal differentiation and amplification of erythroid cells, although it did not sustain the growth of multipotential stem cells. Single-cell transfer experiments demonstrate that IL-3 supported the late stages of differentiation of neutrophils, macrophages, eosinophils, and megakaryocytes in the absence of lineage-specific factors. Therefore, IL-3 supports the differentiation of multilineage hemopoietic progenitors, and the terminal differentiation of most hemopoietic lineages, with the exception of the erythroid lineage.


Selection of microsatellite markers for bladder cancer diagnosis without the need for corresponding blood.
Microsatellite markers are used for loss-of-heterozygosity, allelic imbalance and clonality analyses in cancers. Usually, tumor DNA is compared to corresponding normal DNA. However, normal DNA is not always available and can display aberrant allele ratios due to copy number variations in the genome. Moreover, stutter peaks may complicate the analysis. To use microsatellite markers for diagnosis of recurrent bladder cancer, we aimed to select markers without stutter peaks and a constant ratio between alleles, thereby avoiding the need for a control DNA sample. We investigated 49 microsatellite markers with tri- and tetranucleotide repeats in regions commonly lost in bladder cancer. Based on analysis of 50 blood DNAs the 12 best performing markers were selected with few stutter peaks and a constant ratio between peaks heights. Per marker upper and lower cut off values for allele ratios were determined. LOH of the markers was observed in 59/104 tumor DNAs. We then determined the sensitivity of the marker panel for detection of recurrent bladder cancer by assaying 102 urine samples of these patients. Sensitivity was 63% when patients were stratified for LOH in their primary tumors. We demonstrate that up-front selection of microsatellite markers obliterates the need for a corresponding blood sample. For diagnosis of bladder cancer recurrences in urine this significantly reduces costs. Moreover, this approach facilitates retrospective analysis of archival tumor samples for allelic imbalance.


Paracetamol and cyclooxygenase inhibition: is there a cause for concern?
Paracetamol is recommended as first-line therapy for pain associated with osteoarthrosis and is one of the most widely used over-the-counter analgesic drugs worldwide. Despite its extensive use, its mode of action is still unclear. Although it is commonly stated that paracetamol acts centrally, recent data imply an inhibitory effect on the activity of peripheral prostaglandin-synthesising cyclooxygenase enzymes. In this context paracetamol has been suggested to inhibit both isoforms in tissues with low levels of peroxide by reducing the higher oxidation state of cyclooxygenase enzymes. Two recent studies have also demonstrated a preferential cyclooxygenase 2 (COX-2) inhibition by paracetamol under different clinically relevant conditions. This review attempts to relate data on paracetamol's inhibitory action on peripheral cyclooxygenase enzymes to the published literature on its anti-inflammatory action and its hitherto underestimated side-effects elicited by cyclooxygenase inhibition. As a result, a pronounced COX-2 inhibition by paracetamol is expected to occur in the endothelium, possibly explaining its cardiovascular risk in epidemiological studies. A careful analysis of paracetamol's cardiovascular side-effects in randomised studies is therefore strongly advised. On the basis of epidemiological data showing an increased gastrointestinal risk of paracetamol at high doses or when co-administered with classic cyclooxygenase inhibitors, paracetamol's long-term gastrointestinal impact should be investigated in randomised trials. Finally, paracetamol's fast elimination and consequently short-lived COX-2 inhibition, which requires repetitive dosing, should be definitely considered to avoid overdosage leading to hepatotoxicity.


Pulsed dye laser for the treatment of hypergranulation tissue with chronic ulcer in postsurgical defects.
Hypergranulation tissue may complicate postoperative wounds, causing them to become chronic nonhealing ulcers. There is no reliably effective treatment. We report the use of the 595-nm pulsed-dye laser (PDL) for the treatment of wounds healing by second intention and complicated by hypergranulation tissue after Mohs micrographic surgery. In a retrospective case review, 9 patients with slow-healing or nonhealing postoperative wounds with hypergranulation tissue were treated with the 595-nm PDL. The majority of the wounds were located on the scalp, forehead, and temple. All of the patients demonstrated dramatic improvement after one treatment. Most patients achieved complete or near complete re-epithelialization of the ulcers after 1 to 2 treatments. The PDL treatment required no local anesthesia, and there were no postlaser treatment complications reported. The 595-nm PDL is an effective, safe, and reliable treatment to promote second intention healing in postsurgical wounds complicated by the formation of hypergranulation tissue.