Systematic review of economic evaluations of preparedness strategies and interventions against influenza pandemics.
Although public health guidelines have implications for resource allocation, these issues were not explicitly considered in previous WHO pandemic preparedness and response guidance. In order to ensure a thorough and informed revision of this guidance following the H1N1 2009 pandemic, a systematic review of published and unpublished economic evaluations of preparedness strategies and interventions against influenza pandemics was conducted. The search was performed in September 2011 using 10 electronic databases, 2 internet search engines, reference list screening, cited reference searching, and direct communication with relevant authors. Full and partial economic evaluations considering both costs and outcomes were included. Conversely, reviews, editorials, and studies on economic impact or complications were excluded. Studies were selected by 2 independent reviewers. 44 studies were included. Although most complied with the cost effectiveness guidelines, the quality of evidence was limited. However, the data sources used were of higher quality in economic evaluations conducted after the 2009 H1N1 pandemic. Vaccination and drug regimens were varied. Pharmaceutical plus non-pharmaceutical interventions are relatively cost effective in comparison to vaccines and/or antivirals alone. Pharmaceutical interventions vary from cost saving to high cost effectiveness ratios. According to ceiling thresholds (Gross National Income per capita), the reduction of non-essential contacts and the use of pharmaceutical prophylaxis plus the closure of schools are amongst the cost effective strategies for all countries. However, quarantine for household contacts is not cost effective even for low and middle income countries. The available evidence is generally inconclusive regarding the cost effectiveness of preparedness strategies and interventions against influenza pandemics. Studies on their effectiveness and cost effectiveness should be readily implemented in forthcoming events that also involve the developing world. Guidelines for assessing the impact of disease and interventions should be drawn up to facilitate these studies.


Bacterial expression, correct membrane targeting and functional folding of the HIV-1 membrane protein Vpu using a periplasmic signal peptide.
Viral protein U (Vpu) is a type-III integral membrane protein encoded by Human Immunodeficiency Virus-1 (HIV- 1). It is expressed in infected host cells and plays several roles in viral progeny escape from infected cells, including down-regulation of CD4 receptors. But key structure/function questions remain regarding the mechanisms by which the Vpu protein contributes to HIV-1 pathogenesis. Here we describe expression of Vpu in bacteria, its purification and characterization. We report the successful expression of PelB-Vpu in Escherichia coli using the leader peptide pectate lyase B (PelB) from Erwinia carotovora. The protein was detergent extractable and could be isolated in a very pure form. We demonstrate that the PelB signal peptide successfully targets Vpu to the cell membranes and inserts it as a type I membrane protein. PelB-Vpu was biophysically characterized by circular dichroism and dynamic light scattering experiments and was shown to be an excellent candidate for elucidating structural models.


Through neural stimulation to behavior manipulation: a novel method for analyzing dynamical cognitive models.
The dynamical systems' approach to cognition (Dynamicism) promises computational models that effectively embed cognitive processing within its more natural behavioral context. Dynamical cognitive models also pose difficult, analytical challenges, which motivate the development of new analytical methodology. We start by illustrating the challenge by applying two conventional analytical methods to a well-known Dynamicist model of categorical perception. We then introduce our own analysis, which works by analogy with neural stimulation methods, and which yields some novel insights into the way the model works. We then extend and apply the method to a second Dynamicist model, which captures the key psychophysical trends that emerge when humans and animals compare two numbers. The results of the analysis-which reveals units with tuning functions that are monotonically related to the magnitudes of the numbers that the agents must compare-offer a clear contribution to the contentious debate concerning the way number information is encoded in the brain.


Modification of the surface of superparamagnetic iron oxide nanoparticles to enable their safe application in humans.
Combined individually tailored methods for diagnosis and therapy (theragnostics) could be beneficial in destructive diseases, such as rheumatoid arthritis. Nanoparticles are promising candidates for theragnostics due to their excellent biocompatibility. Nanoparticle modifications, such as improved surface coating, are in development to meet various requirements, although safety concerns mean that modified nanoparticles require further review before their use in medical applications is permitted. We have previously demonstrated that iron oxide nanoparticles with amino-polyvinyl alcohol (a-PVA) adsorbed on their surfaces have the unwanted effect of increasing human immune cell cytokine secretion. We hypothesized that this immune response was caused by free-floating PVA. The aim of the present study was to prevent unwanted immune reactions by further surface modification of the a-PVA nanoparticles. After cross-linking of PVA to nanoparticles to produce PVA-grafted nanoparticles, and reduction of their zeta potential, the effects on cell viability and cytokine secretion were analyzed. PVA-grafted nanoparticles still stimulated elevated cytokine secretion from human immune cells; however, this was inhibited after reduction of the zeta potential. In conclusion, covalent cross-linking of PVA to nanoparticles and adjustment of the surface charge rendered them nontoxic to immune cells, nonimmunogenic, and potentially suitable for use as theragnostic agents.


Test of cure for genital Chlamydia trachomatis infection in women.
Convenient, reliable tests of cure for genital chlamydial infections have not been evaluated. Cervical appearance, endocervical Gram stain, enzyme immunoassay, and culture for Chlamydia trachomatis were evaluated during a pretreatment visit and at two subsequent randomized test-of-cure visits for 64 nongravid women with endocervical C trachomatis of 3544 patients screened. There were no useful correlations between C trachomatis resolution and cervical appearance. Endocervical Gram stain was determined to be unreliable for test-of-cure use. Both C trachomatis culture and enzyme-linked immunosorbent assay (ELISA) were shown to be effective for test-of-cure evaluation. The ELISA test became reliably negative 10 days after initiation of treatment and 1 to 5 days after the clearance of viable organisms detected by culture (P = .03). Convenience and cost considerations favor antigen detection methods. This study suggests that antigen detection methods can be used for situations in which test of cure is indicated, such as therapy noncompliance, circumstances supporting reinfection, pregnancy, complicated infections, requests for psychological reassurance, and evidence of persistent cervicitis.


A systematic survey of the integration of animal behavior into conservation.
The role of behavioral ecology in improving wildlife conservation and management has been the subject of much recent debate. We sought to answer 2 foundational questions about the current use of behavioral knowledge in conservation: To what extent is behavioral knowledge used in wildlife conservation and management, and how does the use of animal behavior differ among conservation fields in both frequency and types of use? We searched the literature for intersections between key fields of animal behavior and conservation and created a systematic heat map (i.e., graphical representation of data where values are represented as colors) to visualize relative efforts. Some behaviors, such as dispersal and foraging, were commonly considered (mean [SE] of 1147.38 [353.11] and 439.44 [108.85] papers per cell, respectively). In contrast, other behaviors, such as learning, social, and antipredatory behaviors were rarely considered (mean [SE] of 33.88 [7.62], 44.81 [10.65], and 22.69 [6.37] papers per cell, respectively). In many cases, awareness of the importance of behavior did not translate into applicable management tools. Our results challenge previous suggestions that there is little association between the fields of behavioral ecology and conservation and reveals tremendous variation in the use of different behaviors in conservation. We recommend that researchers focus on examining underutilized intersections of behavior and conservation themes for which preliminary work shows a potential for improving conservation and management, translating behavioral theory into applicable and testable predictions, and creating systematic reviews to summarize the behavioral evidence within the behavior-conservation intersections for which many studies exist.


Effects of long-acting methylphenidate in adults with attention deficit hyperactivity disorder: a study with paired-pulse transcranial magnetic stimulation.
Methylphenidate improves attention deficits, hyperactivity and impulsivity in attention deficit hyperactivity disorder (ADHD). Recent investigations into motor cortex excitability with paired-pulse transcranial magnetic stimulation (ppTMS) technique have shown inhibition deficits in ADHD which correlate with clinical symptomatology. Therefore, we investigated the neurophysiological effects of long-acting methylphenidate (LA-Mph) with the ppTMS technique in adult patients with ADHD. Thirteen right-handed adult ADHD patients who were first diagnosed with ADHD were included in this ppTMS study. Measurements took place before and during treatment with LA-Mph (30-54 mg/day). Statistical analyses were performed to investigate treatment effects and correlations with clinical symptomatology. LA-Mph significantly decreased the relative short intracortical motor inhibition (SICI) magnetically evoked potential (MEP) amplitude at 3-ms interstimulus interval (conditioned/unconditioned MEP amplitude: 0.83 ± 0.76 drug-free vs. 0.29 ± 0.19 with LA-Mph; p=0.020). The relative intracortical facilitation MEP amplitude at 11 ms interstimulus interval (conditioned/unconditioned MEP amplitude: 1.51 ± 0.92 drug-free vs. 1.79 ± 0.95 with LA-Mph) was not significantly increased. The reduced relative SICI MEP amplitude with LA-Mph correlated significantly with the improvement of the psychopathological ADHD self-rating total scores (p=0.046). These results show that in adult patients with ADHD, LA-Mph significantly improves motor disinhibition and might have differential stabilizing effects on motor hyperexcitability.


Ligand-induced conformational changes in the crystal structures of Pneumocystis carinii dihydrofolate reductase complexes with folate and NADP+.
Structural data from two independent crystal forms (P212121 and P21) of the folate (FA) binary complex and from the ternary complex with the oxidized coenzyme, NADP+, and recombinant Pneumocystis carinii dihydrofolate reductase (pcDHFR) refined to an average of 2.15 A resolution, show the first evidence of ligand-induced conformational changes in the structure of pcDHFR. These data are also compared with the crystal structure of the ternary complex of methotrexate (MTX) with NADPH and pcDHFR in the monoclinic lattice with data to 2.5 A resolution. Comparison of the data for the FA binary complex of pcDHFR with those for the ternary structures reveals significant differences, with a >7 A movement of the loop region near residue 23 that results in a new "flap-open" position for the binary complex, and a "closed" position in the ternary complexes, similar to that reported for Escherichia coli (ec) DHFR complexes. In the orthorhombic lattice for the binary FA pcDHFR complex, there is also an unwinding of a short helical region near residue 47 that places hydrophobic residues Phe-46 and Phe-49 toward the outer surface, a conformation that is stabilized by intermolecular packing contacts. The pyrophosphate moiety of NADP+ in the ternary folate pcDHFR complexes shows significant differences in conformation compared with that observed in the MTX-NADPH-pcDHFR ternary complex. Additionally, comparison of the conformations among these four pcDHFR structures reveals evidence for subdomain movement that correlates with cofactor binding states. The larger binding site access in the new "flap-open" loop 23 conformation of the binary FA complex is consistent with the rapid release of cofactor from the product complex during catalysis as well as the more rapid release of substrate product from the binary complex as a result of the weaker contacts of the closed loop 23 conformation, compared to ecDHFR.


The health of a nation predicts their mate preferences: cross-cultural variation in women's preferences for masculinized male faces.
Recent formulations of sexual selection theory emphasize how mate choice can be affected by environmental factors, such as predation risk and resource quality. Women vary greatly in the extent to which they prefer male masculinity and this variation is hypothesized to reflect differences in how women resolve the trade-off between the costs (e.g. low investment) and benefits (e.g. healthy offspring) associated with choosing a masculine partner. A strong prediction of this trade-off theory is that women's masculinity preferences will be stronger in cultures where poor health is particularly harmful to survival. We investigated the relationship between women's preferences for male facial masculinity and a health index derived from World Health Organization statistics for mortality rates, life expectancies and the impact of communicable disease. Across 30 countries, masculinity preference increased as health decreased. This relationship was independent of cross-cultural differences in wealth or women's mating strategies. These findings show non-arbitrary cross-cultural differences in facial attractiveness judgements and demonstrate the use of trade-off theory for investigating cross-cultural variation in women's mate preferences.


Measuring unmet need for contraception as a point prevalence.
This study proposes a framework to address conceptual concerns with the standard indicator of unmet need for contraception. We define new point prevalence measures of current status (CS) unmet need and CS unmet demand, by linking contraceptive behaviours to pregnancy exposure and to women's future contraceptive intentions. We explore the difference between standard and CS unmet need and estimate the proportion of women with CS unmet demand, who may be more likely to adopt contraception. We use Demographic and Health Survey data from 46 low-income and middle-income countries released between 2010 and 2018. We assess differences in women's classification between standard and CS unmet need indicators and estimate the percentage of women with CS unmet demand for contraception, defined as the percentage of women with CS unmet need who intend to use contraception in the future. We find substantial country-level differences between standard and CS estimates of unmet need, ranging from -8.3% points in Niger to +11.1% points in Nepal. The average predictive value of the standard measure across the 46 countries for identifying prevalent cases of unmet need is 53%. Regardless of indicator (standard or CS), only half of women with unmet need intend to use contraception. The results of this study suggest that the standard measure of unmet need has low predictive value in identifying women with current unmet need. Thus, the standard indicator does not reflect a prevalence estimate of unmet need.


Hidden word learning capacity through orthography in aphasia.
The ability to learn to use new words is thought to depend on the integrity of the left dorsal temporo-frontal speech processing pathway. We tested this assumption in a chronic aphasic individual (AA) with an extensive left temporal lesion using a new-word learning paradigm. She exhibited severe phonological problems and Magnetic Resonance Imaging (MRI) suggested a complete disconnection of this left-sided white-matter pathway comprising the arcuate fasciculus (AF). Diffusion imaging tractography confirmed the disconnection of the direct segment and the posterior indirect segment of her left AF, essential components of the left dorsal speech processing pathway. Despite her left-hemispheric damage and moderate aphasia, AA learned to name and maintain the novel words in her active vocabulary on par with healthy controls up to 6 months after learning. This exceeds previous demonstrations of word learning ability in aphasia. Interestingly, AA's preserved word learning ability was modality-specific as it was observed exclusively for written words. Functional magnetic resonance imaging (fMRI) revealed that in contrast to normals, AA showed a significantly right-lateralized activation pattern in the temporal and parietal regions when engaged in reading. Moreover, learning of visually presented novel word-picture pairs also activated the right temporal lobe in AA. Both AA and the controls showed increased activation during learning of novel versus familiar word-picture pairs in the hippocampus, an area critical for associative learning. AA's structural and functional imaging results suggest that in a literate person, a right-hemispheric network can provide an effective alternative route for learning of novel active vocabulary. Importantly, AA's previously undetected word learning ability translated directly into therapy, as she could use written input also to successfully re-learn and maintain familiar words that she had lost due to her left hemisphere lesion.


Nonlinear nonstationary Wiener model of infant EEG seizures.
This paper presents the estimation of a nonstationary nonlinear model of seizures in infants based on parallel Wiener structures. The model comprises two parts and is partly derived from the Roessgen et al. seizure model. The first part consists of a nonlinear Wiener model of the pure background activity, and the second part in a nonlinear Wiener model of the pure seizure activity with a time-varying deterministic input signal. The two parts are then combined in a parallel structure. The Wiener model consists of an autoregressive moving average filter followed by a nonlinear shaping function to take into account the non-Gaussian statistical behavior of the data. Model estimation was performed on 64 infants of whom four showed signs of clinical and electrical seizures. Model validation is performed using time-frequency-based entropy distance and shows an averaged improvement of 50% in modeling performance compared with the Roessgen model.


Diffraction pattern of self-supporting transmission gratings.
Self-supporting transmission gratings suitable for the soft x-ray and extreme ultraviolet must be reinforced by support structures which, if regularly placed, tend to produce undesirable artifacts in the diffraction plane. Because these artifacts appear in the neighborhood of the principal maxima and can be substantial in magnitude, they may confuse the spectrum. Methods are described whereby these unwanted diffraction effects are much reduced or eliminated. In one method, the members of the support structure parallel to the grating slits are placed in a random pattern so that on the average the coherence of the support structure is drastically reduced everywhere. In a second method, these support structure members are distributed pseudorandomly in such a manner that the diffraction pattern of the support structure is completely removed from the diffraction plane. A third method is investigated in which the pseudorandom placement of supports is organized into a repeated pattern, which may be easier to manufacture than the configurations of the first two methods.


Neural mechanisms of atrial arrhythmias.
The past 5 years have seen great advances in the knowledge of neural mechanisms of atrial arrhythmogenesis. Direct autonomic nerve recordings demonstrate that simultaneous sympathovagal discharges and intrinsic cardiac nerve activities are common triggers of paroxysmal atrial tachycardia and atrial fibrillation. While activity of the autonomous nervous system (ANS) is crucial in triggering paroxysmal atrial fibrillation, a high incidence of sympathovagal co-activation at baseline is associated with a high vulnerability to pacing-induced sustained atrial fibrillation, suggesting that ANS has a role in the development of persistent atrial fibrillation. Modulation of ANS activity may constitute an important therapeutic strategy for the management of atrial tachyarrhythmias. Specifically, continuous, low-level stimulation of the left cervical vagus nerve effectively suppresses atrial tachyarrhythmias by reducing the nerve activity of the stellate ganglion. Clinically, compared with pulmonary vein isolation alone, the addition of ablation of intrinsic cardiac ganglia may confer better outcomes for patients with paroxysmal atrial fibrillation. These findings suggest that further investigation of the neural mechanisms of atrial arrhythmias might lead to better management of patients with atrial arrhythmias. In this article, we review the role of the ANS in the induction and maintenance of atrial arrhythmias and the role of neural modulation as a treatment strategy for atrial arrhythmias.


Identification and evaluation of suitable reference genes for gene expression studies in the whitefly Bemisia tabaci (Asia I) by reverse transcription quantitative realtime PCR.
This study presents a reliable method for performing reverse transcription quantitative realtime PCR (RT-qPCR) to measure gene expression in the whitefly Bemisia tabaci (Asia I) (Gennadius) (Hemiptera: Aleyrodidae), utilising suitable reference genes for data normalisation. We identified orthologs of commonly used reference genes (actin (ACT), cyclophilin 1 (CYP1), elongation factor 1α (EF1A), glyceraldehyde 3-phosphate dehydrogenase (GAPDH), ribosomal protein L13a (RPL13A), and α-tubulin (TUB1A)), measured the levels of their transcripts by RT-qPCR during development and in response to thermal stress, and evaluated their suitability as endogenous controls using geNorm, BestKeeper, and NormFinder programs. Overall, TUB1A, RPL13A, and CYP1 were the most stable reference genes during B. tabaci development, and TUB1A, GAPDH, and RPL13A were the most stable reference genes in the context of thermal stress. An analysis of the effects of reference gene choice on the transcript profile of a developmentally-regulated gene encoding vitellogenin demonstrated the importance of selecting the correct endogenous controls for RT-qPCR studies. We propose the use of TUB1A, RPL13A, and CYP1 as endogenous controls for transcript profiling studies of B. tabaci development, whereas the combination of TUB1A, GAPDH, and RPL13A should be employed for studies into thermal stress. The data pre- sented here will assist future transcript profiling studies in whiteflies.


Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia.
The initial cases of novel coronavirus (2019-nCoV)-infected pneumonia (NCIP) occurred in Wuhan, Hubei Province, China, in December 2019 and January 2020. We analyzed data on the first 425 confirmed cases in Wuhan to determine the epidemiologic characteristics of NCIP. We collected information on demographic characteristics, exposure history, and illness timelines of laboratory-confirmed cases of NCIP that had been reported by January 22, 2020. We described characteristics of the cases and estimated the key epidemiologic time-delay distributions. In the early period of exponential growth, we estimated the epidemic doubling time and the basic reproductive number. Among the first 425 patients with confirmed NCIP, the median age was 59 years and 56% were male. The majority of cases (55%) with onset before January 1, 2020, were linked to the Huanan Seafood Wholesale Market, as compared with 8.6% of the subsequent cases. The mean incubation period was 5.2 days (95% confidence interval [CI], 4.1 to 7.0), with the 95th percentile of the distribution at 12.5 days. In its early stages, the epidemic doubled in size every 7.4 days. With a mean serial interval of 7.5 days (95% CI, 5.3 to 19), the basic reproductive number was estimated to be 2.2 (95% CI, 1.4 to 3.9). On the basis of this information, there is evidence that human-to-human transmission has occurred among close contacts since the middle of December 2019. Considerable efforts to reduce transmission will be required to control outbreaks if similar dynamics apply elsewhere. Measures to prevent or reduce transmission should be implemented in populations at risk. (Funded by the Ministry of Science and Technology of China and others.).


Coccidioidomycosis and other endemic mycoses in Mexico.
The endemic mycoses traditionally include coccidioidomycosis, histoplasmosis, blastomycosis and paracoccidioidomycosis. Although sporotrichosis and chromomycosis are technically not included among the endemic mycoses, they are frequently diagnosed in Mexico. Most systemic endemic mycoses are a consequence of inhaling the fungi, while subcutaneous mycoses are acquired through the inoculation of vegetable matter or soil containing the organism. Coccidioidomycosis is caused by Coccidioides spp., a dimorphic pathogenic fungus. Approximately 60% of exposures result in asymptomatic infection; in the rest there are protean manifestations that range from a benign syndrome also known as "Valley Fever" to progressive pulmonary or extrapulmonary disease. Histoplasmosis, caused by the dimorphic fungus Histoplasma capsulatum, is endemic to the Americas. Pulmonary histoplasmosis manifestations are protean, ranging from a brief period of malaise to a severe, prolonged illness. The spectrum of illness in disseminated histoplasmosis ranges from a chronic, intermittent course to an acute and rapidly fatal infection. Paracoccidioidomycosis is a chronic, granulomatous systemic disease caused by Paracoccidioides brasiliensis that characteristically produces a primary pulmonary infection, often asymptomatic, and then disseminates to form ulcerative granulomata of the oral, nasal and occasionally the gastrointestinal mucosa. Sporotrichosis, caused by Sporothrix schenckii, has diverse clinical manifestations; the most frequent is the lymphocutaneous form. Generally, infection results from inoculation of the fungus through thorns, splinters, scratches and small traumas. Chromomycosis (Chromoblastomycosis) is a slowly progressive cutaneous and subcutaneous mycosis attributed to various saprophyte Hypomycetes fungi. The primary lesion is also thought to develop as a result of percutaneous traumatic inoculation.


Angiotensin blockade and the progression of renal damage in the spontaneously hypertensive rat.
The pathophysiological role of angiotensin II in the development of renal sclerosis was investigated in 5/6-nephrectomized, 12-week-old male spontaneously hypertensive rats. After 1 week of a control period, nephrectomized rats received one of the following treatments for 4 weeks: the selective nonpeptide angiotensin II type 1 receptor antagonist TCV-116 (1 mg/kg per day), the angiotensin converting enzyme inhibitor delapril (30 mg/kg per day), hydralazine (15 mg/kg per day), or vehicle. Urinary protein and albumin excretions and systolic blood pressure were determined every week. Rats with reduced renal mass treated with vehicle had a poor survival rate (30%). Although TCV-116, delapril, and hydralazine treatment significantly improved the survival rate for 4 weeks, hydralazine failed to improve proteinuria and albuminuria as well as the decline in renal function compared with delapril or TCV-116. Histological examination revealed that both TCV-116 and delapril protected glomeruli from sclerosis, whereas hydralazine did not improve histological findings (5%, 7%, and 30% of glomeruli were affected, respectively). These results indicate that angiotensin II plays a dominant role through its type 1 receptor in the pathogenesis of renal deterioration by hypertension.


Portal vein thrombosis: insight into physiopathology, diagnosis, and treatment.
Portal vein thrombosis (PVT) is a relatively common complication in patients with liver cirrhosis, but might also occur in absence of an overt liver disease. Several causes, either local or systemic, might play an important role in PVT pathogenesis. Frequently, more than one risk factor could be identified; however, occasionally no single factor is discernable. Clinical examination, laboratory investigations, and imaging are helpful to provide a quick diagnosis, as prompt treatment might greatly affect a patient's outcome. In this review, we analyze the physiopathological mechanisms of PVT development, together with the hemodynamic and functional alterations related to this condition. Moreover, we describe the principal factors most frequently involved in PVT development and the recent knowledge concerning diagnostic and therapeutic procedures. Finally, we analyze the implications of PVT in the setting of liver transplantation and its possible influence on patients' future prognoses.


Rapamycin and less immunosuppressive analogs are toxic to Candida albicans and Cryptococcus neoformans via FKBP12-dependent inhibition of TOR.
Candida albicans and Cryptococcus neoformans cause both superficial and disseminated infections in humans. Current antifungal therapies for deep-seated infections are limited to amphotericin B, flucytosine, and azoles. A limitation is that commonly used azoles are fungistatic in vitro and in vivo. Our studies address the mechanisms of antifungal activity of the immunosuppressive drug rapamycin (sirolimus) and its analogs with decreased immunosuppressive activity. C. albicans rbp1/rbp1 mutant strains lacking a homolog of the FK506-rapamycin target protein FKBP12 were found to be viable and resistant to rapamycin and its analogs. Rapamycin and analogs promoted FKBP12 binding to the wild-type Tor1 kinase but not to a rapamycin-resistant Tor1 mutant kinase (S1972R). FKBP12 and TOR mutations conferred resistance to rapamycin and its analogs in C. albicans, C. neoformans, and Saccharomyces cerevisiae. Our findings demonstrate the antifungal activity of rapamycin and rapamycin analogs is mediated via conserved complexes with FKBP12 and Tor kinase homologs in divergent yeasts. Taken together with our observations that rapamycin and its analogs are fungicidal and that spontaneous drug resistance occurs at a low rate, these mechanistic findings support continued investigation of rapamycin analogs as novel antifungal agents.


Use of different but overlapping determinants in a retrovirus receptor accounts for non-reciprocal interference between xenotropic and polytropic murine leukemia viruses.
Retrovirus infection depends on binding of the retroviral envelope (Env) protein to specific cell-surface protein receptors. Interference, or superinfection resistance, is a frequent consequence of retroviral infection, and occurs when newly-synthesized Env binds to receptor proteins resulting in a block to entry by retroviruses that use the same receptors. Three groups of viruses demonstrate a non-reciprocal pattern of interference (NRI), which requires the existence of both a common receptor utilized by all viruses within the group, and a specific receptor that is used by a subset of viruses. In the case of amphotropic and 10A1 murine leukemia viruses (MLV), the common and specific receptors are the products of two related genes. In the case of avian sarcoma and leukosis virus types B, D, and E, the two receptors are distinct protein products of a single gene. NRI also occurs between xenotropic and polytropic MLV. The common receptor, Xpr1, has been identified, but a specific receptor has yet to be described. Using chimeric receptor proteins and interference studies, we have identified a region of Xpr1 that is uniquely utilized by xenotropic MLV and show that this receptor domain is required for non-reciprocal interference. We propose a novel pattern of receptor usage by xenotropic and polytropic MLV to explain the NRI observed between these viruses. We propose that the specific and common receptor determinants for xenotropic and polytropic viruses are simultaneously present in discreet domains of a single Xpr1 protein.


Oncologic treatment strategies and relative survival of patients with stage I-III rectal cancer - A EURECCA international comparison between the Netherlands, Belgium, Denmark, Sweden, England, Ireland, Spain, and Lithuania.
The aim of this EURECCA international comparison is to compare oncologic treatment strategies and relative survival of patients with stage I-III rectal cancer between European countries. Population-based national cohort data from the Netherlands (NL), Belgium (BE), Denmark (DK), Sweden (SE), England (ENG), Ireland (IE), Spain (ES), and single-centre data from Lithuania (LT) were obtained. All operated patients with (y)pTNM stage I-III rectal cancer diagnosed between 2004 and 2009 were included. Oncologic treatment strategies and relative survival were calculated and compared between neighbouring countries. We included 57,120 patients. Treatment strategies differed between NL and BE (p < 0.001), DK and SE (p < 0.001), and ENG and IE (p < 0.001). More preoperative radiotherapy as single treatment before surgery was administered in NL compared with BE (59.7% vs. 13.1%), in SE compared with DK (55.1% vs. 10.4%), and in ENG compared with IE (15.2% vs. 9.6%). Less postoperative chemotherapy was given in NL (9.6% vs. 39.1%), in SE (7.9% vs. 14.1%), and in IE (12.6% vs. 18.5%) compared with their neighbouring country. In ES, 55.1% of patients received preoperative chemoradiation and 62.3% postoperative chemotherapy. There were no significant differences in relative survival between neighbouring countries. Large differences in oncologic treatment strategies for patients with (y)pTNM I-III rectal cancer were observed across European countries. No clear relation between oncologic treatment strategies and relative survival was observed. Further research into selection criteria for specific treatments could eventually lead to individualised and optimal treatment for patients with non-metastasised rectal cancer.


Microsatellite and chromosome evolution of parthenogenetic sitobion aphids in Australia.
Single-locus microsatellite variation correlated perfectly with chromosome number in Sitobion miscanthi aphids. The microsatellites were highly heterozygous, with up to 10 alleles per locus in this species. Despite this considerable allelic variation, only seven different S. miscanthi genotypes were discovered in 555 individuals collected from a wide range of locations, hosts and sampling periods. Relatedness between genotypes suggests only two successful colonizations of Australia. There was no evidence for genetic recombination in 555 S. miscanthi so the occurrence of recent sexual reproduction must be near zero. Thus diversification is by mutation and chromosomal rearrangement alone. Since the aphids showed no sexual recombination, microsatellites can mutate without meiosis. Five of seven microsatellite differences were a single repeat unit, and one larger jump is likely. The minimum numbers of changes between karyotypes corresponded roughly one-to-one with microsatellite allele changes, which suggests very rapid chromosomal evolution. A chromosomal fission occurred in a cultured line, and a previously unknown chromosomal race was detected. All 121 diverse S. near fragariae were heterozygous but revealed only one genotype. This species too must have a low rate of sexual reproduction and few colonizations of Australia.


Silver(i)-organic frameworks constructed from silver(i) 3,6-pyrazyldiethynide and 3,8-1,10-phenanthrolyldiethynide complexes.
Two diynes bearing functional groups with different binding modes, 3,6-diethynylpyrazine (H2L1) and 3,8-diethynyl-1,10-phenanthroline (H2L2), were utilized as ligands to synthesize two new organometallic units, Ag2L1·3AgNO3 (1) and Ag2L2·6AgNO3 (2), in order to investigate the effect of the bridging and chelating modes of the ligands on the structures of networks constructed from silver-ethynide compounds. Structural studies show that in 1, silver-ethynide cluster units aggregate to form chair-like organometallic slides through Ag-N coordination bonds. These slides are linked through argentophilic interaction to generate novel 2D ladder-like layers, and are further bridged by nitrate anions to afford a 3D network in the solid state. It is observed that all the Ag ions in one layer interact to afford a 2D silver network. However, in 2, the silver-ethynide cluster units only interact to generate unique sine wave-like organometallic chains through argentophilic interaction, which are further connected by nitrate anions to form a 3D network. In the solid state, both 1 and 2 are luminescent at room temperature.


Clinical ultraviolet dosimetry with a CCD monochromator array spectroradiometer.
Single monochromator charge-coupled device (CCD) array spectroradiometers have the advantage of ease of use and speed compared with double grating instruments. Their inherently inferior stray-light rejection, however, can critically affect their accuracy in phototherapy and research-related dosimetry applications. This paper shows that without adequate correction the HR4000 (Ocean Optics Inc., Dunedin, USA) array device can overestimate the CIE erythema-weighted irradiance of common phototherapy sources and solar simulator beams by over 100%. A software stray-light correction (Ylianttila et al 2005 Photochem. Photobiol. 81 333-41), using the measured slit function of the HR4000, has been applied to spectra acquired from sources used in phototherapy and photobiology (PUVA, UV21, TL01 and solar simulator). The resulting corrected erythema-weighted irradiance measurements from the HR4000 are within 10% of those from a DM150 double grating spectroradiometer (Bentham Instruments Ltd, Reading, UK). A simple model is considered for combining estimates of measurement uncertainties. The importance of exposure bracketing to improve the dynamic range of the HR4000 is illustrated, along with the difficulty in making direct comparison of spectral values between two instruments due to wavelength scale uncertainties. Comparison with a double grating instrument in a solar simulator beam is examined here as a basis for validating CCD array device measurements. The study demonstrates that the HR4000 array spectroradiometer can provide an adequate level of accuracy for common phototherapy and photobiology applications only where a suitable stray-light correction is carefully applied and where the instrument's effective dynamic range is improved.


Methylprednisolone acetate injection plus casting versus casting alone for the treatment of de Quervain's tenosynovitis.
There is no consensus in the treatment of de Quervain's tenosynovitis, but wrist support with or without local corticosteroid injection has been considered as an effective treatment modality. Some patients have expressed reluctance for steroid injections because of the fear of probable adverse reactions. This study was performed to compare the outcome of methylprednisolone acetate injection plus thumb spica cast versus cast alone for the treatment of de Quervain's tenosynovitis. This randomized prospective study was conducted from January 2005 to July 2008 in the orthopedic clinics of our hospital and private offices. A total of 73 patients with de Quervain's tenosynovitis were managed with either of these methods: 1) injection of methylpredmisolone acetate in the first dorsal compartment of the wrist followed by wrist thumb spica cast. 2) casting alone. Wrist casting duration in both groups was one month and the patients were followed for 6 months. In the first group, a total of 37 patients were included (injection plus wrist immobilization by cast), and 36 patients in the second group (wrist casting alone). The mean age was 32.6 years (21 - 61 years) in all patients. There were 63 women and 10 men. Overall success rate was 86.5% in the first and 36.1% in the second groups, with a significant difference for both groups with respect to pain score and cure rate (P<0.05). Temporary pain was the most common adverse reaction at the site of injection and was noted in 40% of patients. Despite this adverse reaction which was related to methylprednisolone injection, a higher success rate was seen in the injection group in comparison to patients treated solely by casting. Support of the wrist with casting alone had less favorable outcome in de Quervain's tenosynovitis. Adding methylprednisolone acetate injection into the first dorsal compartment of the wrist is necessary for more optimal results.


Percutaneous stereotactic radiofrequency lesioning for trigeminal neuralgia: determination of minimum clinically important difference in pain improvement for patient-reported outcomes.
The Visual Analog Scale (VAS) and the Barrow Neurological Institute Pain Scale (BNI-PS) are 2 patient-reported outcome (PRO) tools frequently used to rate pain from trigeminal neuralgia (TN). Outcomes studies often use these patient-reported outcomes to assess treatment effectiveness, but it is unknown exactly what degree of change in the numerical scores constitutes the minimum clinically important difference (MCID). MCID remains uninvestigated for percutaneous stereotactic radiofrequency lesioning (RFL), a common surgical procedure for TN. To determine MCID values for the VAS and BNI-PS in patients undergoing RFL. Forty-three consecutive patients with TN who underwent RFL by a single surgeon were prospectively assessed with the VAS and BNI-PS preoperatively and 3 years postoperatively. Three anchors were used to assign each patient's outcome: satisfaction, willingness to have the surgery again, and Health Transition Index. We then used 3 well-established, anchor-based methods to calculate MCID: average change, minimum detectable change, and change difference. Patients experienced substantial improvement in both VAS (9.81 vs 3.35; P < .001) and BNI-PS (4.95 vs 2.44; P < .001) after RFL. The 3 MCID calculation methods generated a range of MCID values for each of the PROs (VAS, 4.13-8.20; BNI-PS, 1.03-3.30). The area under the receiver-operating characteristic curve was greater for BNI-PS compared with VAS for all 3 anchors, indicating that BNI-PS is probably better suited for calculating MCID. RFL-specific MCID is variable on the basis of the calculation technique. With the use of the minimum detectable change calculation method with the Health Transition Index anchor, the minimum clinically important difference is 4.49 for VAS and 1.16 for BNI-PS after RFL for TN. AUC, area under the receiver-operating characteristic curveBNI-PS, Barrow Neurological Institute Pain ScaleHTI, Health Transition IndexMCID, minimum clinically important differenceMDC, minimum detectable changePRO, patient-reported outcomeRFL, percutaneous stereotactic radiofrequency lesioningTN, trigeminal neuralgiaVAS, Visual Analog Scale.


Rapid Stabilization of Immiscible Fluids using Nanostructured Interfaces via Surfactant Association.
Surfactant molecules have been extensively used as emulsifying agents to stabilize immiscible fluids. Droplet stability has been shown to be increased when ordered nanoscale phases form at the interface of the two fluids due to surfactant association. Here, we report on using mixtures of a cationic surfactant and long chained alkenes with polar head groups [e.g., cetylpyridinium chloride (CPCl) and oleic acid] to create an ordered nanoscale lamellar morphology at aqueous-oil interfaces. The self-assembled nanostructure at the liquid-liquid interface was characterized using small-angle x-ray scattering, and the mechanical properties were measured using interfacial rheology. We hypothesize that the resulting lamellar morphology at the liquid-liquid interface is driven by the change in critical packing parameter when the CPCl molecules are diluted by the presence of the long chain alkenes with polar head groups, which leads to a spherical micelle-to-lamellar phase transition. The work presented here has larger implications for using nanostructured interfacial material to separate different fluids in flowing conditions for biosystems and in 3D printing technology.


Dopamine D1 receptor activation contributes to light-adapted changes in retinal inhibition to rod bipolar cells.
Dopamine modulation of retinal signaling has been shown to be an important part of retinal adaptation to increased background light levels, but the role of dopamine modulation of retinal inhibition is not clear. We previously showed that light adaptation causes a large reduction in inhibition to rod bipolar cells, potentially to match the decrease in excitation after rod saturation. In this study, we determined how dopamine D1 receptors in the inner retina contribute to this modulation. We found that D1 receptor activation significantly decreased the magnitude of inhibitory light responses from rod bipolar cells, whereas D1 receptor blockade during light adaptation partially prevented this decline. To determine what mechanisms were involved in the modulation of inhibitory light responses, we measured the effect of D1 receptor activation on spontaneous currents and currents evoked from electrically stimulating amacrine cell inputs to rod bipolar cells. D1 receptor activation decreased the frequency of spontaneous inhibition with no change in event amplitudes, suggesting a presynaptic change in amacrine cell activity in agreement with previous reports that rod bipolar cells lack D1 receptors. Additionally, we found that D1 receptor activation reduced the amplitude of electrically evoked responses, showing that D1 receptors can modulate amacrine cells directly. Our results suggest that D1 receptor activation can replicate a large portion but not all of the effects of light adaptation, likely by modulating release from amacrine cells onto rod bipolar cells. NEW & NOTEWORTHY We demonstrated a new aspect of dopaminergic signaling that is involved in mediating light adaptation of retinal inhibition. This D1 receptor-dependent mechanism likely acts through receptors located directly on amacrine cells, in addition to its potential role in modulating the strength of serial inhibition between amacrine cells. Our results also suggest that another D2/D4 receptor-dependent or dopamine-independent mechanism must also be involved in light adaptation of inhibition to rod bipolar cells.


HMGA1a Induces Alternative Splicing of the Estrogen Receptor-αlpha Gene by Trapping U1 snRNP to an Upstream Pseudo-5' Splice Site.
Objectives: The high-mobility group A protein 1a (HMGA1a) protein is known as a transcription factor that binds to DNA, but recent studies have shown it exerts novel functions through RNA-binding. We were prompted to decipher the mechanism of HMGA1a-induced alternative splicing of the estrogen receptor alpha (ERα) that we recently reported would alter tamoxifen sensitivity in MCF-7 TAMR1 cells. Methods: Endogenous expression of full length ERα66 and its isoform ERα46 were evaluated in MCF-7 breast cancer cells by transient expression of HMGA1a and an RNA decoy (2'-O-methylated RNA of the HMGA1a RNA-binding site) that binds to HMGA1a. RNA-binding of HMGA1a was checked by RNA-EMSA. In vitro splicing assay was performed to check the direct involvement of HMGA1a in splicing regulation. RNA-EMSA assay in the presence of purified U1 snRNP was performed with psoralen UV crosslinking to check complex formation of HMGA1a-U1 snRNP at the upstream pseudo-5' splice site of exon 1. Results: HMGA1a induced exon skipping of a shortened exon 1 of ERα in in vitro splicing assays that was blocked by the HMGA1a RNA decoy and sequence-specific RNA-binding was confirmed by RNA-EMSA. RNA-EMSA combined with psoralen UV crosslinking showed that HMGA1a trapped purified U1 snRNP at the upstream pseudo-5' splice site. Conclusions: Regulation of ERα alternative splicing by an HMGA1a-trapped U1 snRNP complex at the upstream 5' splice site of exon 1 offers novel insight on 5' splice site regulation by U1 snRNP as well as a promising target in breast cancer therapy where alternative splicing of ERα is involved.


Acupuncture as complementary therapy for back pain.
Back pain affects more than 9 million people in the United States and accounts for 25% of disability in all work-related injuries. It has a lifetime prevalence of 60%-90% and it costs more than $50 billion annually to manage back pain. The incidence of back pain in nurses is over 80% and accounts for more than 150 million working days per year being lost. Western treatment of back pain is controversial and often ineffective. Acupuncture as a therapeutic intervention is practiced widely in the United States. Research has demonstrated that acupuncture may benefit those who suffer from back pain when they have failed to respond to previous treatment by drugs, bed rest, epidural injection, physiotherapy, osteopathy, chiropractics, and surgery. Acupuncture is a powerful and complementary therapy for back pain.


Highly active antiretroviral therapy potently suppresses HIV infection in humanized Rag2-/-gammac-/- mice.
Humanized Rag2(-/-)gamma(c)(-/-) mice (Hu-DKO mice) become populated with functional human T cells, B cells, and dendritic cells following transplantation with human hematopoietic stem cells (HSC) and represent an improved model for studying HIV infection in vivo. In the current study we demonstrated that intrasplenic inoculation of hu-DKO mice with HIV-1 initiated a higher level of HIV infection than intravenous or intraperitoneal inoculation, associated with a reciprocal decrease in peripheral CD4(+) T cells and increase in peripheral CD8(+) T cells. HIV infection by intrasplenic injection increased serum levels of human IgG and IgM including human IgM and IgG specific for HIV-1 gp120. There was a significant inverse correlation between the level of HIV-1 infection and the extent of CD4(+) T cell depletion. Highly active antiretroviral therapy (HAART) initiated 1 week after HIV-1 inoculation markedly suppressed HIV-1 infection and prevented CD4(+) T cell depletion. Taken together, these findings demonstrate that intrasplenic injection of hu-DKO mice with HIV is a more efficient route of HIV infection than intravenous or intraperitoneal injection and generates increased infection associated with an increased anti-HIV humoral response. This animal model can serve as a valuable in vivo model to study the efficacy of anti-HIV therapies.


NK cells and pre-eclampsia.
The immunological interaction between the mother and fetus has classically been thought of as one between paternal antigen and maternal T cells. However, the MHC antigen expression on human trophoblast and the immune cell populations present in the decidua suggest that this interaction primarily involves decidual NK cells rather than T cells, and this is supported by new functional studies. It is becoming apparent also that the maternal systemic immune response in pregnancy (Th1/Th2 shift) primarily involves NK cells. Aberrant NK cell activation both locally in the decidua and systemically in the maternal blood may be the cause of pre-eclampsia.


Oesophagitis, signs of reflux, and gastric acid secretion in patients with symptoms of gastro-oesophageal reflux disease.
In a study comprising 100 patients referred to a surgical clinic with symptoms suggestive of gastro-oesophageal reflux disease the value of different diagnostic procedures was investigated. Positive acid perfusion and 24-h pH tests were the commonest findings. Forty-nine per cent showed a normal oesophageal mucosa or diffuse oesophagitis at endoscopy. The severity of heartburn and regurgitation did not differ between patients with normal oesophageal mucosa and oesophagitis of various severities. The severity of macroscopic oesophagitis was significantly correlated to the total reflux time, the presence of reflux or a hiatal hernia at radiology, an open cardia or reflux at endoscopy, pressure transmission or reflux and low lower oesophageal sphincter pressure at manometry. Gastric hypersecretion was found in 66% of the patients. Gastric acid secretion was not correlated to the severity of oesophagitis or to the findings at 24-h pH test. In patients with severe oesophagitis the sensitivity for radiologic, manometric, and endoscopic signs of incompetence of the gastro-oesophageal junction was 94%.


Blood parasite infection differentially relates to carotenoid-based plumage and bill color in the American goldfinch.
Male and female American goldfinches (Spinus tristis) express condition-dependent carotenoid-based plumage and bill coloration. Plumage color is relatively static, as pigments incorporated into feathers during the spring molt cannot be mobilized thereafter. In contrast, bill color is dynamic, reflecting changes in condition over short time periods. Previous studies have shown that male and female ornaments, though similar in expression, are differentially related to measures of immunocompetence, suggesting that the relationship between ornamentation and parasite infection may differ between the sexes. In this study, we evaluate the relationship between condition-dependent ornamentation (plumage and bill color) and blood parasite infection in male and female American goldfinches. We captured goldfinches after completion of the pre-alternate molt and prior to the onset of nesting and assessed prevalence of Trypanosoma parasites via blood smears. Plumage color strongly predicted trypanosome infection: Birds with more colorful plumage were less likely to present infections. In contrast, we detected no relationship between infection and bill color, which in other studies has been shown to dynamically reflect current condition. Sex did not affect the relationship between infection status and either ornament. Together, these results suggest that physiological pathways linking carotenoid ornamentation and infection may vary even within a single species.


Regulation of ER-phagy by a Ypt/Rab GTPase module.
Accumulation of misfolded proteins on intracellular membranes has been implicated in neurodegenerative diseases. One cellular pathway that clears such aggregates is endoplasmic reticulum autophagy (ER-phagy), a selective autophagy pathway that delivers excess ER to the lysosome for degradation. Not much is known about the regulation of ER-phagy. The conserved Ypt/Rab GTPases regulate all membrane trafficking events in eukaryotic cells. We recently showed that a Ypt module, consisting of Ypt1 and autophagy-specific upstream activator and downstream effector, regulates the onset of selective autophagy in yeast. Here we show that this module acts at the ER. Autophagy-specific mutations in its components cause accumulation of excess membrane proteins on aberrant ER structures and induction of ER stress. This accumulation is due to a block in transport of these membranes to the lysosome, where they are normally cleared. These findings establish a role for an autophagy-specific Ypt1 module in the regulation of ER-phagy. Moreover, because Ypt1 is a known key regulator of ER-to-Golgi transport, these findings establish a second role for Ypt1 at the ER. We therefore propose that individual Ypt/Rabs, in the context of distinct modules, can coordinate alternative trafficking steps from one cellular compartment to different destinations.


A macrocyclic calpain inhibitor slows the development of inherited cortical cataracts in a sheep model.
We used sheep with an autosomal dominant gene for cortical cataract as an animal model to evaluate novel macrocyclic calpain inhibitors with potential for the medical treatment of human cataract. The macrocyclic aldehyde, CAT811, identified previously as a calpain inhibitor that prevents calcium-induced opacification in cultured sheep lenses, was tested for its ability to protect cytoskeletal proteins from calpain proteolysis. CAT811 and its alcohol analogue, CAT505, were formulated separately into ointments, and each was applied twice daily to the right eye of sheep with early cataracts for five months. Progress of cataracts in the sheep was determined by ophthalmologic examination and comparison with a matched sample of sheep treated similarly with ointment that did not contain the active ingredient. The novel macrocyclic aldehyde, CAT811, was able to inhibit calpain proteolysis of lens cytoskeletal proteins at micromolar concentrations. When applied topically to the eyes of sheep, CAT811 was able to slow cataract development by 27% in the initial three months of treatment (P < 0.05). Its alcohol analogue, CAT505, was not able to slow cataractogenesis significantly. The inherited sheep cataract provides a reproducible model of cortical cataract over a time scale of several months. The data reported here, using this model, demonstrated the potential of the macrocyclic calpain inhibitor, CAT811, to act as a therapeutic for treatment of cortical cataract.


Novel utility of cryoablation for ventricular arrhythmias arising from the left aortic cusp near the left main coronary artery: a case series.
Ablation of ventricular tachycardia and premature ventricular contraction arising at the aortic root has been described. The use of radiofrequency ablation energy has been associated with life-threatening collateral damage. The use of cryoablation as a safer alternative energy source at the aortic root has not been previously described. To demonstrate that cautious cryoablation near the ostia of the left main coronary artery is technically feasible and is a safe, effective alternative energy source for ablation at the aortic root. Six patients (mean age 36 years; 4 women) with refractory frequent premature ventricular contractions or ventricular tachycardia underwent electrophysiological study and ablation. Two patients had associated nonischemic cardiomyopathy. Patients' ventricular arrhythmias were localized by using 3D mapping, with arrhythmia foci being mapped to the left aortic cusp near the left main coronary artery. The proximity to the ostium of the left main coronary artery was confirmed by using intracardiac ultrasound and coronary angiogram. Focal ablation, up to 240 seconds with freeze-thaw-freeze cycles, was performed by using an 8-mm cryoablation catheter via a retrograde aortic approach. Termination of ventricular arrhythmia during ablation was observed in all 6 patients. All patients were followed for greater than 6-month postablation. One patient had acute ST-segment elevation during ablation below the left main ostium that resolved within 30 seconds of termination of ablation. There were no postprocedure complications and no significant arrhythmia recurrences. Aortic root ventricular arrhythmia ablation carries an increased risk for collateral damages. This case series demonstrates that cautious cryoablation near the ostia of the left main coronary artery can be performed and is a safe, effective alternative energy source for ablation at the aortic root.


Understanding the mechanism of the chiral phosphoric acid-catalyzed aza-Cope rearrangement.
The first catalytic enantioselective aza-Cope rearrangement was reported in 2008 by Rueping et al. The reaction is catalyzed by a 1,1'-bi-2-naphthol-derived (BINOL-derived) phosphoric acid and achieved high yields and enantioselectivities (up to 97 : 3 er with 75% yield). This work utilizes Density Functional Theory to understand the mechanism of the reaction and explain the origins of the enantioselectivity. An extensive conformational search was carried out to explore the different activation modes by the catalyst and, the Transition State (TS) leading to the major product was found to be 1.3 kcal mol-1 lower in energy than the TS leading to the minor product. The origin of this stabilization was rationalized with NBO and NCI analysis: it was found that the major TS has a greater number of non-bonding interactions between the substrate and the catalyst, and shows stronger H-bond interactions between H atoms in the substrate and the O atoms in the phosphate group of the catalyst.


LISA: a web-based decision-support system for trial management of childhood acute lymphoblastic leukaemia.
Continuation chemotherapy is a key component of the treatment of childhood acute lymphoblastic leukaemia. During this treatment phase, weekly dose adjustments are carried out based on current and historical full blood counts (FBCs). The dose decision pathway is complex and suboptimal therapy may result if information on FBC results is not readily available and/or the prescriber is inexperienced. A web-based decision-support system (Leukaemia Intervention Scheduling and Advice, 'LISA') was designed to facilitate access to FBC information across geographical locations and to assist with dosage adjustments. A balanced-block crossover analysis was performed to evaluate the system. Thirty-six clinicians with varying degrees of experience were each asked to decide on appropriate oral chemotherapy dosages for eight simulated cases: four using LISA and four without. LISA significantly reduced the number of erroneous prescriptions (zero of 144 with LISA vs. 54 of 144 without; P < 0.0001) without affecting the number of times subjects deliberately overrode the protocol (seven of 144 times using LISA and six of 144 without). Using LISA reduced the time taken by novices to reach a decision for each case but increased the time taken by experts. Thirty-five of 36 subjects said they would be likely to use the system if it were available. A system like LISA is likely to be acceptable to clinicians, and has the potential to increase protocol compliance and decrease prescribing errors while allowing clinicians to override the protocol in specific cases where sound reasons exist for doing so.


Diffraction effects from giant segmented-mirror telescopes.
Ultrahigh contrast imaging with giant segmented-mirror telescopes will involve light levels of order 10(-6) times that of the central diffraction spike or less. At these levels it is important to quantify accurately various diffraction effects, including segmentation geometry, intersegment gaps, obscuration by the secondary mirror and its supports, and segment alignment and figure errors. We describe an accurate method for performing such calculations and present preliminary results in the context of the California Extremely Large Telescope.


Analysis of clinical information and reverse transcriptase-polymerase chain reaction for early diagnosis of enteroviral meningitis.
Meningitis is among the most common infections affecting the central nervous system. It can be difficult to determine the exact pathogen responsible for the infection and patients are often treated with empiric antibiotics. This study was conducted to identify the most common clinical characteristics of enteroviral meningitis in children and evaluate the diagnostic efficacy of reverse transcriptase-polymerase chain reaction (RT-PCR) for early detection of an enterovirus. We analyzed the medical records of children admitted to Korea University Medical Center and diagnosed with meningitis on the basis of cerebrospinal fluid (CSF) analysis and RT-PCR from CSF and other samples from January 2010 to August 2013. A total of 333 patients were enrolled and classified into four groups based on diagnosis: enteroviral meningitis (n=110), bacterial meningitis (n=23), other viral meningitis (n=36), and unknown etiology (n=164). Patients with bacterial meningitis were younger than those in the other groups (P<0.001). Pleocytosis in CSF was similar across all groups. Of patients in the enteroviral meningitis group, 92.7% were diagnosed based on RT-PCR findings. Mean length of hospital stay for patients with enteroviral meningitis was 6.08 days, which was significantly shorter than that for patients with meningitis of bacterial etiology (19.73 days, P<0.001). Diagnosis of enteroviral meningitis before viral culture results are available is possible using RT-PCR. Accurate diagnosis reduces the length of hospital stay and helps to avoid unnecessary empiric antibiotic treatment.


Red blood cell transfusions in acute paediatrics.
Red blood cell (RBC) transfusions should usually be given only to restore or maintain oxygen delivery to vital organs and tissues. Medical history has clearly documented the importance of blood transfusion in saving lives threatened by acute haemorrhage or severe anaemia. The availability of blood products has facilitated many surgical and medical advances, allowing the support of patients who could not have previously survived invasive therapies. Consequently, the use of blood products has increased steadily over the past half century. However, recent years have seen much greater emphasis on the consequences and costs of transfusion, leading to widespread attempts to restrict blood product use. Balancing the risks and benefits of transfusion has becoming increasingly complex; while restricting transfusion reduces unwanted effects and cost, the thresholds at which the risks of poor oxygen carriage outweigh these are not always clear. Children have different physiology and pathology than adults and many aspects of transfusion practice are poorly researched in the young. This article discusses the most recent evidence available from adult and paediatric research to guide clinical RBC transfusion practice in acute paediatrics. It also discusses the current provision of RBC components for children.


Genome-wide analysis of abnormal H3K9 acetylation in cloned mice.
Somatic nuclear transfer is a cloning technique that shows great promise in the application to regenerative medicine. Although cloned animals are genetically identical to their donor counterparts, abnormalities in phenotype and gene expression are frequently observed. One hypothesis is that the cause of these abnormalities is due to epigenetic aberration. In this report, we focused our analysis on the acetylation of histone H3 at lysine9 (H3K9Ac). Through the use of whole genome tiling arrays and quantitative PCR, we examined this epigenetic event and directly compared and assessed the differences between a cloned mouse (C1) and its parental nuclear donor (D1) counterpart. We identified 4720 regions of chromosomal DNA that showed notable differences in H3K9Ac and report here many genes identified in these hyper- and hypo-acetylated regions. Analysis of a second clone (C2) and its parental donor counterpart (D2) for H3K9Ac showed a high degree of similarity to the C1/D1 pair. This conservation of aberrant acetylation is suggestive of a reproducible epigenetic phenomenon that may lead to the frequent abnormalities observed in cloned mice, such as obesity. Furthermore, we demonstrated Crp which was identified as a hyper-acetylated gene in this study is related to the body mass, suggesting that Crp is a possible candidate of a cause for the abnormal obesity in cloned mice. In this, one of the first reports describing genome-wide epigenetic aberration between parental and nuclear transfer-cloned mammals, we propose that aberrant acetylation of histones (H3K9Ac) flanking promoter regions highly correlates with gene-expression and may itself be an epigenetic change that accounts for variable expression patterns observed in cloned animals.


Tissue inhibitor of metalloproteinse-1 is a marker of diastolic dysfunction using tissue doppler in patients with type 2 diabetes and hypertension.
Tissue inhibitor of metalloproteinase-1 (TIMP-1) is associated with increased fibrosis of the extracellular matrix (ECM). Myocardial stiffness is a feature of diastolic dysfunction. We assessed circulating TIMP-1 as a marker of diastolic dysfunction in patients with type 2 diabetes mellitus (DM) and hypertension, who were compared with healthy controls. We recruited 54 patients (43 males; mean age 68 +/- 5 years) with treated type 2 DM (i.e. controlled glycaemia, hypertension, hyperlipidaemia), 35 (30 males; 69 +/- 8 years) treated nondiabetic hypertensives, and 31 healthy controls (18 males; 66 +/- 5 years). Circulating TIMP-1 was measured by ELISA. Using transthoracic echocardiography, the early (E) diastolic mitral inflow velocity was measured with pulse wave Doppler, and the early mitral annular velocity (e'), a recognized index of diastolic relaxation, was measured with tissue Doppler. The E/A ratio was also calculated and isovolumic relaxation time measured. Mean e' levels differed significantly between controls, diabetics and hypertensives (P < 0.0001). Circulating TIMP-1 was significantly different between patients and controls (P = 0.006), but there was no statistically significant difference between the DM and hypertension group. In both groups, only e' was negatively correlated with TIMP-1 levels, with a stronger correlation among the hypertensive patients (Spearman r = -0.544, P = 0.001) when compared with the diabetic group (r = -0.341, P = 0.011). Diastolic relaxation is impaired in diabetes and hypertensive patients. The relationship between TIMP-1 and e' may reflect increased myocardial fibrosis and consequent diastolic dysfunction, which may be more prominent in hypertension.


Wide Dynamic Range Vegetation Index for remote quantification of biophysical characteristics of vegetation.
The Normalized Difference Vegetation Index (NDVI) is widely used for monitoring, analyzing, and mapping temporal and spatial distributions of physiological and biophysical characteristics of vegetation. It is well documented that the NDVI approaches saturation asymptotically under conditions of moderate-to-high aboveground biomass. While reflectance in the red region (rho(red)) exhibits a nearly flat response once the leaf area index (LAI) exceeds 2, the near infrared (NIR) reflectance (PNIR) continue to respond significantly to changes in moderate-to-high vegetation density (LAI from 2 to 6) in crops. However, this higher sensitivity of the rho(NIR) has little effect on NDVI values once the rho(NIR) exceeds 30%. In this paper a simple modification of the NDVI was proposed. The Wide Dynamic Range Vegetation Index, WDRVI = (a * rho(NIR-rho(red))/(a * rho(NIR) + rho(red)), where the weighting coefficient a has a value of 0.1-0.2, increases correlation with vegetation fraction by linearizing the relationship for typical wheat, soybean, and maize canopies. The sensitivity of the WDRVI to moderate-to-high LAI (between 2 and 6) was at least three times greater than that of the NDVI. By enhancing the dynamic range while using the same bands as the NDVI, the WDRVI enables a more robust characterization of crop physiological and phenological characteristics. Although this index needs further evaluation, the linear relationship with vegetation fraction and much higher sensitivity to change in LAI will be especially valuable for precision agriculture and monitoring vegetation status under conditions of moderate-to-high density. It is anticipated that the new index will complement the NDVI and other vegetation indices that are based on the red and NIR spectral bands.


A TNF receptor 2 selective agonist rescues human neurons from oxidative stress-induced cell death.
Tumor necrosis factor (TNF) plays a dual role in neurodegenerative diseases. Whereas TNF receptor (TNFR) 1 is predominantly associated with neurodegeneration, TNFR2 is involved in tissue regeneration and neuroprotection. Accordingly, the availability of TNFR2-selective agonists could allow the development of new therapeutic treatments of neurodegenerative diseases. We constructed a soluble, human TNFR2 agonist (TNC-scTNF(R2)) by genetic fusion of the trimerization domain of tenascin C to a TNFR2-selective single-chain TNF molecule, which is comprised of three TNF domains connected by short peptide linkers. TNC-scTNF(R2) specifically activated TNFR2 and possessed membrane-TNF mimetic activity, resulting in TNFR2 signaling complex formation and activation of downstream signaling pathways. Protection from neurodegeneration was assessed using the human dopaminergic neuronal cell line LUHMES. First we show that TNC-scTNF(R2) interfered with cell death pathways subsequent to H(2)O(2) exposure. Protection from cell death was dependent on TNFR2 activation of the PI3K-PKB/Akt pathway, evident from restoration of H(2)O(2) sensitivity in the presence of PI3K inhibitor LY294002. Second, in an in vitro model of Parkinson disease, TNC-scTNF(R2) rescues neurons after induction of cell death by 6-OHDA. Since TNFR2 is not only promoting anti-apoptotic responses but also plays an important role in tissue regeneration, activation of TNFR2 signaling by TNC-scTNF(R2) appears a promising strategy to ameliorate neurodegenerative processes.


Effects of bilateral orbital decompression by an endoscopic endonasal approach in dysthyroid orbitopathy.
The efficacy of endoscopic endonasal orbital decompression in dysthyroid orbitopathy was analysed. In 21 consecutive cases of bilateral operation short term (10 (SD 6) days after operation) and long term (156 (12) days after operation) results were recorded. Short term results showed that vision of the more affected eye improved from a mean of 0.35 to 0.59; vision improved in all but one eye which remained unchanged. In the fellow eyes mean visual acuity improved from 0.6 to 0.7; three of these eyes showed a decrease. Mean proptosis returned from 23.0 mm to 20.0 mm. As to motility the mean abductive capacity decreased from 5.5 mm to 4.0 mm of monocular excursion, whereas adduction increased from 7.5 mm to 8.5 mm. Upgaze and downgaze did not show any major change. The mean angle of horizontal squint shifted from 7.5 degrees of convergence to 15.5 degrees while no significant vertical or cyclorotational deviation was induced. These immediate postoperative results proved to be stable for the period of long term follow up with only slight changes. No significant bleeding or specific otorhinolaryngological complication without resolve occurred intraoperatively or perioperatively. This method is believed to be superior to non-endoscopic techniques because it avoids external scars and antral pain. With regard to the relief of intraorbital pressure, the technique gives good results for visual acuity improvement, but in proptosis reduction the method is not as efficient as external or combined procedures. There seems to be no difference when compared with other approaches in induction of horizontal squint. The method has a protective long term effect against the recurrence of compressive optic neuropathy.


Peering into the brain to predict behavior: Peer-reported, but not self-reported, conscientiousness links threat-related amygdala activity to future problem drinking.
Personality traits such as conscientiousness as self-reported by individuals can help predict a range of outcomes, from job performance to longevity. Asking others to rate the personality of their acquaintances often provides even better predictive power than using self-report. Here, we examine whether peer-reported personality can provide a better link between brain function, namely threat-related amygdala activity, and future health-related behavior, namely problem drinking, than self-reported personality. Using data from a sample of 377 young adult university students who were rated on five personality traits by peers, we find that higher threat-related amygdala activity to fearful facial expressions is associated with higher peer-reported, but not self-reported, conscientiousness. Moreover, higher peer-reported, but not self-reported, conscientiousness predicts lower future problem drinking more than one year later, an effect specific to men. Remarkably, relatively higher amygdala activity has an indirect effect on future drinking behavior in men, linked by peer-reported conscientiousness to lower future problem drinking. Our results provide initial evidence that the perceived conscientiousness of an individual by their peers uniquely reflects variability in a core neural mechanism supporting threat responsiveness. These novel patterns further suggest that incorporating peer-reported measures of personality into individual differences research can reveal novel predictive pathways of risk and protection for problem behaviors.


Steering pluripotency and differentiation with N6-methyladenosine RNA modification.
Chemical modifications of RNA provide a direct and rapid way to modulate the existing transcriptome, allowing the cells to adapt rapidly to the changing environment. Among these modifications, N6-methyladenosine (m6A) has recently emerged as a widely prevalent mark of messenger RNA in eukaryotes, linking external stimuli to an intricate network of transcriptional, post-transcriptional and translational processes. m6A modification modulates a broad spectrum of biochemical processes, including mRNA decay, translation and splicing. Both m6A modification and the enzymes that control m6A metabolism are essential for normal development. In this review, we summarized the most recent findings on the role of m6A modification in maintenance of the pluripotency of embryonic stem cells (ESCs), cell fate specification, the reprogramming of somatic cells into induced pluripotent stem cells (iPSCs), and differentiation of stem and progenitor cells. This article is part of a Special Issue entitled: mRNA modifications in gene expression control edited by Dr. Soller Matthias and Dr. Fray Rupert.


Hip and spine surgery is of questionable value in spina bifida: an evidence-based review.
Although many children with spina bifida and associated scoliosis or dislocated hips undergo spine or hip surgery, the benefits are uncertain. The purpose was to perform an evidence-based review on the benefits and risks of surgery for dislocated hips and scoliosis in spina bifida. I performed a Medline(®) and Embase(®) search from 1950 to 2009 for Level I to Level III studies investigating the benefits and risks of surgery for scoliosis and hip dislocation in patients with spina bifida. When available, I extracted types of surgery, complication rates, functional outcomes of seating, walking, and overall physical function. All treatment recommendations received a Grade of Recommendation: Grade A (consistent Level I studies); Grade B (consistent Level II and III studies); Grade C (consistent level IV and V studies); or Grade I (insufficient or contradictory studies). Combined anterior and posterior surgery had lower rates of nonunion for scoliosis. Although there may be some benefit in seating, overall physical function measured in a different and nonstandardized fashion was not much changed and major complication rates, including nonunion and infections for scoliosis surgery, exceed 50% in several studies. For dislocated hips, the impact on walking ability appears related to contracture (not dislocation). Surgery for hip dislocation did not improve walking ability. The literature provides no guidance on the best treatment for unilateral dislocation. The benefits of scoliosis surgery are uncertain (Grade I). Spine surgery, if performed, should be anterior and posterior (Grade B). An all-pedicle approach for scoliosis surgery may be effective (Level I). Hip reduction surgery did not improve walking (Grade B) but may be appropriate in low-level unilateral dislocation (Level I).


Big data - a 21st century science Maginot Line? No-boundary thinking: shifting from the big data paradigm.
Whether your interests lie in scientific arenas, the corporate world, or in government, you have certainly heard the praises of big data: Big data will give you new insights, allow you to become more efficient, and/or will solve your problems. While big data has had some outstanding successes, many are now beginning to see that it is not the Silver Bullet that it has been touted to be. Here our main concern is the overall impact of big data; the current manifestation of big data is constructing a Maginot Line in science in the 21st century. Big data is not "lots of data" as a phenomena anymore; The big data paradigm is putting the spirit of the Maginot Line into lots of data. Big data overall is disconnecting researchers and science challenges. We propose No-Boundary Thinking (NBT), applying no-boundary thinking in problem defining to address science challenges.


Review of cytomegalovirus coinfection in HIV-infected individuals in Africa.
Cytomegalovirus (CMV) infection among HIV-infected individuals may cause end-organ disease, which is an AIDS-defining condition. Evidence from high-income countries suggests that CMV may alter the outcome of HIV infection, other than causing end-organ diseases. We reviewed literature on HIV and CMV coinfection in Africa. Systematic review of published studies on HIV and CMV coinfection in Africa using the PubMed database. High CMV seroprevalence was found throughout Africa, exceeding 90% in most populations. Retinitis, pneumonia, and colitis were the most commonly reported CMV manifestations in HIV-infected individuals. Among patients with pulmonary symptoms, the prevalence of CMV pneumonitis varied from 20% to over 60%, whereas CMV was found in 0% to 14% of patients with gastrointestinal manifestations. Cytomegalovirus retinitis was found in 0% to 2.6% of examined HIV-infected individuals. The diagnostics of CMV end-organ diseases were found complex and difficult to interpret in African settings. Cytomegalovirus viremia was correlated with significantly lower CD4 cell count and increase in activated and apoptosis vulnerable T-lymphocytes. Also, CMV coinfection was found to be associated with increased transmission and progression of HIV infection. Moreover, detectable CMV DNA was an independent predictor of HIV transmission and mortality among HIV-infected individuals. Cytomegalovirus is highly prevalent in Africa and a common cause of disease manifestations in HIV-infected individuals among all age groups. Cytomegalovirus coinfection in HIV-infected individuals in Africa is associated with increased transmission and mortality of HIV, but it is a neglected area of research.


A two-step control of secondary splenic pedicles using ligasure during laparoscopic splenectomy.
We modified the LigaSure vessel sealing into a two-step technique without using Endo-GIA stapler for the secondary splenic pedicle control in laparoscopic splenectomy (LS). This study evaluated the efficacy and safety outcomes of this technique. Patients (n = 105) scheduled for elective LS were consecutively and prospectively enrolled, including 24 males and 81 females, with a mean age of 43.6 (range 11-75) years. Following the mobilization of the spleen, the splenic inflow was interrupted by applying a Hem-o-lock clip. LigaSure was used to seal and transect the secondary splenic pedicles adjacent to the pancreatic tail and subsequently in proximity to the spleen. Of 105 patients, 103 patients (98.1%) underwent successful LS, whereas two patients (1.9%) required the conversion to laparotomy. The mean operative time was 100 min, whilst the mean volume of blood loss was 500 mL. No clinically significant morbidities or mortality occurred following LS. An average of 8,000 RMB (range: 6900 to 9000; 1 USD = 6.5 RMB) was saved by using this two-step technique. Secondary splenic pedicles can be successfully controlled in LS by using a two-step technique with the LigaSure vessel sealing system in an economically favorable way.


Local professionals' perceptions of health assets in a low-SES Dutch neighbourhood: a qualitative study.
Asset-based approaches have become popular in public health. As yet it is not known to what extent health and welfare professionals are able to identify and mobilise individual and community health assets. Therefore, the aim of this study was to understand professional's perceptions of health and health assets. In a low-SES neighbourhood, 21 health and welfare professionals were interviewed about their definition of health and their perceptions of the residents' health status, assets available in the neighbourhood's environment, and the way residents use these assets. A Nominal Group Technique (NGT) session was conducted for member check. Verbatim transcripts of the semi-structured interviews were coded and analysed using Atlas.ti. The professionals used a broad health concept, emphasizing the social dimension of health as most important. They discussed the poor health of residents, mentioning multiple health problems and unmet health needs. They provided many examples of behaviour that they considered unhealthy, in particular unhealthy diet and lack of exercise. Professionals considered the green physical environment, as well as health and social services, including their own services, as important health enhancing factors, whereas social and economic factors were considered as major barriers for good health. Poor housing and litter in public space were considered as barriers as well. According to the professionals, residents underutilized neighbourhood health assets. They emphasised the impact of poverty on the residents and their health. Moreover, they felt that residents were lacking individual capabilities to lead a healthy life. Although committed to the wellbeing of the residents, some professionals seemed almost discouraged by the (perceived) situation. They looked for practical solutions by developing group-based approaches and supporting residents' self-organisation. Our study shows, firstly, that professionals in the priority district Slotermeer rated the health of the residents as poor and their health behaviour as inadequate. They considered poverty and lack of education as important causes of this situation. Secondly, the professionals tended to talk about barriers in the neighbourhood rather than about neighbourhood health assets. As such, it seems challenging to implement asset-based approaches. However, the professionals, based on their own experiences, did perceive the development of collective approaches as a promising direction for future community health development.


Ascorbic acid and alpha-tocopherol protect anticancer drug cisplatin induced nephrotoxicity in mice: a comparative study.
Oxidative stress, resulting from an imbalance between prooxidant and antioxidant systems in favor of the former, largely contributes to immune system deregulation and complications observed in end-stage renal disease (ESRD) and patients treated with hemodialysis. Reactive oxygen species and free radicals are involved in the nephrotoxicity induced by a synthetic anticancer drug cisplatin. A comparative study on the nephroprotective effects of antioxidant vitamins (250 and 500 mg/kg, p.o.), vitamin C (ascorbic acid) and vitamin E (alpha-tocopherol), was evaluated using cisplatin (10 mg/kg body wt, i.p.) induced oxidative renal damage in mice. Urea and creatinine in serum were estimated for the renal function. Antioxidant status was estimated in kidney homogenate. We found that both vitamins at 500 mg/kg significantly (P<0.01) protected the nephrotoxicity induced by cisplatin. The cisplatin induced increase of urea and creatinine concentrations were reduced in the vitamins plus cisplatin (250 and 500 mg/kg, p.o.)-treated groups. However the cisplatin induced decline of renal antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) activities were increased only in the 500 mg/kg vitamins treated groups. Both vitamins at 250 and 500 mg/kg could increase the concentration of reduced glutathione (GSH) and protected the increase of cisplatin induced lipid peroxidation. Higher doses of vitamins are effective to protect oxidative renal damage and vitamin C is the better nephroprotective agent than vitamin E. The protection is mediated partially by preventing the decline of renal antioxidant status.


A taxonomy of bacterial microcompartment loci constructed by a novel scoring method.
Bacterial microcompartments (BMCs) are proteinaceous organelles involved in both autotrophic and heterotrophic metabolism. All BMCs share homologous shell proteins but differ in their complement of enzymes; these are typically encoded adjacent to shell protein genes in genetic loci, or operons. To enable the identification and prediction of functional (sub)types of BMCs, we developed LoClass, an algorithm that finds putative BMC loci and inventories, weights, and compares their constituent pfam domains to construct a locus similarity network and predict locus (sub)types. In addition to using LoClass to analyze sequences in the Non-redundant Protein Database, we compared predicted BMC loci found in seven candidate bacterial phyla (six from single-cell genomic studies) to the LoClass taxonomy. Together, these analyses resulted in the identification of 23 different types of BMCs encoded in 30 distinct locus (sub)types found in 23 bacterial phyla. These include the two carboxysome types and a divergent set of metabolosomes, BMCs that share a common catalytic core and process distinct substrates via specific signature enzymes. Furthermore, many Candidate BMCs were found that lack one or more core metabolosome components, including one that is predicted to represent an entirely new paradigm for BMC-associated metabolism, joining the carboxysome and metabolosome. By placing these results in a phylogenetic context, we provide a framework for understanding the horizontal transfer of these loci, a starting point for studies aimed at understanding the evolution of BMCs. This comprehensive taxonomy of BMC loci, based on their constituent protein domains, foregrounds the functional diversity of BMCs and provides a reference for interpreting the role of BMC gene clusters encoded in isolate, single cell, and metagenomic data. Many loci encode ancillary functions such as transporters or genes for cofactor assembly; this expanded vocabulary of BMC-related functions should be useful for design of genetic modules for introducing BMCs in bioengineering applications.


A novel enhanced softmax loss function for brain tumour detection using deep learning.
In deep learning, the sigmoid function is unsuccessfully used for the multiclass classification of the brain tumour due to its limit of binary classification. This study aims to increase the classification accuracy by reducing the risk of overfitting problem and supports multi-class classification. The proposed system consists of a convolutional neural network with modified softmax loss function and regularization. Classification accuracy for the different types of tumours and the processing time were calculated based on the probability score of the labeled data and their execution time. Different accuracy values and processing time were obtained when testing the proposed system using different samples of MRI images. The result shows that the proposed solution is better compared to the other systems. Besides, the proposed solution has higher accuracy by almost 2 % and less processing time of 40∼50 ms compared to other current solutions. The proposed system focused on classification accuracy of the different types of tumours from the 3D MRI images. This paper solves the issues of binary classification, the processing time, and the issues of overfitting of the data.


Intrathymic clonal deletion of V beta 6+ T cells in cyclophosphamide-induced tolerance to H-2-compatible, Mls-disparate antigens.
When C3H (H-2k, Mls-1b) mice were primed intravenously with 10(8) viable spleen cells from AKR (H-2k, Mls-1a) and treated intraperitoneally with 200 mg/kg of cyclophosphamide (CP) 2 d later, not only a long-lasting skin allograft tolerance but also a tolerance in mixed lymphocyte reaction to Mls-1a-encoded antigens was established. The cellular mechanisms of CP-induced tolerance were examined by assessing the V beta 6-bearing T cells that are strongly correlated with reactivity to Mls-1a-encoded antigens bound to MHC class II molecules. At the relatively early stage (2 or 5 wk) after the CP treatment, CD4+-V beta 6+ T cells of C3H origin were preferentially eliminated in the lymph nodes of the tolerant mice, whereas CD8+-V beta 6+ T cells remained. On the other hand, neither CD4+CD8- nor CD4-CD8+ thymocytes bearing a high density of V beta 6 was detected in the chimeric thymus. Namely, in the thymus of the tolerant C3H mice, neither mixed chimerism nor the clonal deletion of the V beta 6-bearing T cells was observed on day 14, whereas both of them were observed on day 35. The clonal deletion and mixed chimerism in the thymus were lasting for greater than 10 wk after the CP treatment. Expression of V beta 6 on the peripheral T cells in the tolerant C3H mice gradually reduced in the process of time. These results strongly suggested that the clonal deletion in the thymus was one of the essential mechanisms in the CP-induced tolerance system.


A Transdisciplinary Approach to Public Health Law: The Emerging Practice of Legal Epidemiology.
Public health law has roots in both law and science. For more than a century, lawyers have helped develop and implement health laws; over the past 50 years, scientific evaluation of the health effects of laws and legal practices has achieved high levels of rigor and influence. We describe an emerging model of public health law that unites these two traditions. This transdisciplinary model adds scientific practices to the lawyerly functions of normative and doctrinal research, counseling, and representation. These practices include policy surveillance and empirical public health law research on the efficacy of legal interventions and the impact of laws and legal practices on health and health system operation. A transdisciplinary model of public health law, melding its legal and scientific facets, can help break down enduring cultural, disciplinary, and resource barriers that have prevented the full recognition and optimal role of law in public health.


A comparative study of the peak expiratory flow rate of Indian and Nepalese young adults in a teaching institute.
Peak expiratory flow rate (PEFR) measurement is the easiest and cheapest method to evaluate respiratory functions. So, the study was carried out to evaluate PEFR of healthy Nepalese adults and compare their values with healthy Indian counterparts to know whether Indian prediction equations for PEFR can be used for Nepalese adult population or not. One hundred twenty-three healthy, young, non smoker adult Indian (64: 28 Males, 36 Females) and Nepalese (59: 32 Males, 27 Females) medical students of 18 to 20 years of age participated in the study. The mean PEFR of Indian (male: 490.4 liter/min, female: 386.0 liter/min) and Nepalese (male: 485.9 liter/min, Female: 365.2 liter/min) young adults were found to have no significant differences. As there is no significant difference in the mean PEFR of Indian and Nepalese young adults, prediction equations made for Indian adults can be used to predict PEFR of Nepalese subjects. Therefore, an attempt has been made to formulate a regression equation from the combined Indian and Nepalese subjects. A stepwise, multiple, linear, regression analysis was performed for this purpose. The analysis showed that height is the best predictor for PEFR in the present study. The regression equation based on height for the combined Indian and Nepalese young adults is calculated as: PEFR = 5.687 x Height (cm) - 495.787. However, a stepwise, multiple, linear, regression equation with residual analysis for the best fit model was performed to formulate prediction equation for PEFR and this showed a change of the earlier regression equation to PEFR = 5.930 x Height (cm) - 536.131.


A meta-analysis of alcohol drinking and cancer risk.
To evaluate the strength of the evidence provided by the epidemiological literature on the association between alcohol consumption and the risk of 18 neoplasms, we performed a search of the epidemiological literature from 1966 to 2000 using several bibliographic databases. Meta-regression models were fitted considering linear and non-linear effects of alcohol intake. The effects of characteristics of the studies, of selected covariates (tobacco) and of the gender of individuals included in the studies, were also investigated as putative sources of heterogeneity of the estimates. A total of 235 studies including over 117 000 cases were considered. Strong trends in risk were observed for cancers of the oral cavity and pharynx, oesophagus and larynx. Less strong direct relations were observed for cancers of the stomach, colon and rectum, liver, breast and ovary. For all these diseases, significant increased risks were found also for ethanol intake of 25 g per day. No significant nor consistent relation was observed for cancers of the pancreas, lung, prostate or bladder. Allowance for tobacco appreciably modified the relations with laryngeal, lung and bladder cancers, but not those with oral, oesophageal or colorectal cancers. This meta-analysis showed no evidence of a threshold effect for most alcohol-related neoplasms. The inference is limited by absence of distinction between lifelong abstainers and former drinkers in several studies, and the possible selective inclusion of relevant sites only in cohort studies.


Short report: differences in dihydrofolate reductase but not dihydropteroate synthase alleles in Plasmodium falciparum isolates from geographically distinct areas in Malaysia.
Dihydropteroate synthase (dhps) and dihydrofolate reductase (dhfr) alleles were typed in 67 Malaysian Plasmodium falciparum isolates. The isolates were collected from two geographically distinct locations: 51 from Sabah, Malaysian Borneo, where sulfadoxine/pyrimethamine (SDX/PYR) is used to treat uncomplicated malaria and 16 from Peninsular Malaysia where in vivo resistance to SDX/PYR has been reported. A total of seven dhps alleles were identified with no significant difference in allele frequency between the 2 populations. Two of the dhps alleles described here have not been previously reported. Four dhfr alleles were detected in 67 P. falciparum isolates. Eighty-seven percent of the isolates from the Peninsula, where clinical SDX/PYR failure has been reported, had dhfr alleles with triple point mutations while all of the isolates from Sabah had dhfr alleles with 2 or less point mutations. The difference in dhfr allele frequency between the two populations was highly significant. There was no correlation between in vitro PYR response and accumulation of dhfr point mutations.