MOLECULAR SURVEY OF APICOMPLEXA IN PODARCIS WALL LIZARDS DETECTS HEPATOZOON, SARCOCYSTIS AND EIMERIA SPECIES

The Journal of Parasitology. Nov, 2011  |  Pubmed ID: 22128850

Abstract The occurrence of Apicomplexan parasites in Podarcis wall lizards from the Iberian Peninsula and Balearic islands was studied by amplification and sequencing of the 18S rRNA gene. Species from three genera, Hepatozoon, Sarcocystis and Eimeria were detected. The phylogenetic analysis of the 18S rRNA gene provides unexpected insights into the evolutionary history of these parasites. All Hepatozoon specimens were recovered as part of a clade already identified in lizards from North Africa. The Sarcocystis species, detected in Podarcis lilfordi from Cabrera island, in the Balearic Islands, appears related to Sarcocystis gallotiae, known only from endemic Gallotia lizards from the Canary Islands. Based on the lack of snake predators on this island, this parasite form presumably presents an atypical transmission cycle that uses the same host species as both intermediate and final host through cannibalism, like S. gallotiae. Eimeria is reported for the first time from Podarcis lizards. This study shows the power of detecting multiple different Apicomplexa parasites through screening of tail tissue samples and blood drops that are often collected in reptiles for other purposes.

Cardiovascular Magnetic Resonance Myocardial Feature Tracking for Quantitative Viability Assessment in Ischemic Cardiomyopathy

International Journal of Cardiology. Nov, 2011  |  Pubmed ID: 22130224

BACKGROUND: Low dose dobutamine stress magnetic resonance imaging is valuable to assess viability in patients with ischemic cardiomyopathy. Analysis is usually qualitative with considerable operator dependency. The aim of the current study was to investigate the feasibility of cine images derived quantitative cardiac magnetic resonance (CMR) myocardial feature tracking (FT) strain parameters to assess viability in patients with ischemic cardiomyopathy. METHODS: 15 consecutive patients with ischemic cardiomyopathy referred for viability assessment were studied at 3T at rest and during low dose dobutamine stress (5 and 10μg/kg/min of dobutamine). Subendocardial and subepicardial circumferential (Ecc(endo) and Ecc(epi)) and radial (Err) strains were assessed using steady state free precession (SSFP) cine images orientated in 3 short axis slices covering 16 myocardial segments. RESULTS: Dysfunctional segments without scar (n=75) improved in all three strain parameters: Ecc(endo) (Rest: -10.5±6.9; 5μg: -12.1±6.9; 10μg: -14.1±9.2; p<0.05), Ecc(epi) (Rest: -7±4.8; 5μg: -8.2±5.5; 10μg: -9.1±5.9; p<0.05) and Err (Rest: 11.7±8.3; 5μg: 16±10.9; 10μg: 16.5±12.8; p<0.05). There was no response to dobutamine in dysfunctional segments with scar transmurality above 75% (n=6): Ecc(endo) (Rest: -4.7±3.0; 5μg: -2.9±2.5; 10μg: -6.6±3.3; p=ns), Ecc(epi) (Rest: -2.9±2.9; 5μg: -5.4±3.9; 10μg: -4.5±4.2; p=ns) and Err (Rest:9.5±5; 5μg:5.4±6.2; 10μg:4.9±3.3; p=ns). Circumferential strain (Ecc(endo), Ecc(epi)) improved in all segments up to a transmurality of 75% (n=60; p<0.05). Err improved in segments <50% transmurality (n=45; p<0.05) and remained unchanged above 50% transmurality (n=21; p=ns). CONCLUSIONS: CMR-FT is a novel technique, which detects quantitative wall motion derived from SSFP cine imaging at rest and with low dose dobutamine stress. CMR-FT holds promise of quantitative assessment of viability in patients with ischemic cardiomyopathy.

Clinical Study on the Efficacy of Chandra Kalka with Mahadalu Anupanaya in the Management of Pakshaghata (Hemiplegia)

Ayu. Jan, 2011  |  Pubmed ID: 22131754

Hemiplegia is a highly prevalent disease and can be correlated with Pakshaghata, a disease described in Ayurveda. In Sri-Lankan traditional system of medicine, Chandra Kalka with Mahadalu Anupanaya are used successfully in the management of early stage of Pakshaghata and mentioned in Vatika Prakaranaya, a book on traditional medicine. So far, no scientific studies have been performed to evaluate the efficacy of Chandra Kalka with Mahadalu Anupanaya. This study was conducted at Kurunegala Ayurvedic Base Hospital, Sri-Lanka. Thirty patients were selected and randomly divided into two groups. The first group consisted of twenty five patients and treated with one pill of (250 mg) Chandra Kalka with 40 ml of Mahadalu Anupanaya three times a day for fourteen days as an internal therapy. Second group consisted of five patients who were treated with placebo in single blind method. The response to the treatment was recorded and therapeutic effect was evaluated through symptomatic relief of the patients. In the group of patients treated with the above drugs, statistically significant reduction was observed in symptoms such as slurring of speech, swallowing difficulties, fasciculation of tongue, and mouth deviation. In view of this observation and results obtained in this study, it is concluded that the above drug is a very effective traditional preparation that could be used in early stage of management of Pakshaghata, providing speedily and positive effects with a powerful action in controlling symptoms of Pakshaghata.

Pancreaticobiliary Complications After Composite Visceral Transplantation: Incidence, Risk, and Management Strategies

Gastrointestinal Endoscopy. Dec, 2011  |  Pubmed ID: 22136789

Acute Infective Conjunctivitis in Primary Care: Who Needs Antibiotics? An Individual Patient Data Meta-analysis

The British Journal of General Practice : the Journal of the Royal College of General Practitioners. Sep, 2011  |  Pubmed ID: 22152728

Acute infective conjunctivitis is a common problem in primary care, traditionally managed with topical antibiotics. A number of clinical trials have questioned the benefit of topical antibiotics for patients with acute infective conjunctivitis.

Impact of Bilateral Open and Closed-angle Glaucoma on Glaucoma-specific Functioning in Asians

Journal of Glaucoma. Dec, 2011  |  Pubmed ID: 22157514

PURPOSE:: To evaluate the impact of bilateral primary glaucoma on glaucoma-specific functioning in Asians. METHODS:: Patients with bilateral primary open-angle glaucoma (POAG) and primary angle-closure glaucoma (PACG) aged 40 years or above of Chinese ethnicity in Singapore were recruited. All underwent a comprehensive clinical assessment of glaucoma. Glaucoma was diagnosed with a standard criteria including optic disc abnormality and visual field defect. The Glaucoma Quality of Life-15, a glaucoma-specific questionnaire, was used to evaluate the impact of glaucoma, and Rasch analysis was used to validate the Glaucoma Quality of Life-15. RESULTS:: A total of 192 patients (mean±SD age, 65.73±17.6 y and 65.1% male) were recruited, of which 56.2% (n=108) and 43.8% (n=84) had POAG and PACG, respectively. Fifty-four (28.1%), 85 (44.3%), and 53 (27.6%) had bilateral mild glaucoma, mild glaucoma in 1 eye and moderate/severe glaucoma in the other, and bilateral moderate/severe glaucoma, respectively. In multivariate analyses, compared with patients with mild glaucoma in both eyes, those with (a) mild glaucoma in 1 eye and moderate/severe in other; and (b) moderate/severe glaucoma in both eyes, reported significantly poorer functioning (β-coefficient=-8.20; confidence interval, -14.36 to -2.04; P<0.05) and (β=-21.05; confidence interval, -28.06 to -14.04; P<0.05), respectively. A similar independent association was found for POAG and PACG. These associations were also considered to be clinically significant while comparing bilateral mild glaucoma with bilateral moderate/severe glaucoma. We however, found no significant difference for functioning and severity of glaucoma between PACG and POAG patients (P<0.05). CONCLUSIONS:: Bilateral glaucoma is worse than the mild form in any eye and is significantly associated with poor glaucoma-specific functioning in this Singaporean Chinese sample. These data emphasize the need for strategies to identify patients early and prevent deterioration beyond the mild form of the condition.

Number of Natural Teeth and Oral Impacts: a Study on Sri Lankan Adults

International Journal of Dentistry. 2011  |  Pubmed ID: 22145004

The aim of the study was to determine the association between the number of natural teeth and oral impacts in Sri Lankan adults. The sample consisted of 476, 40-59 and 452, ≥60 year olds. Oral impacts were assessed using a validated Sinhalese translation of the Oral Health Impact Profile-14 scale. A receiver-operating characteristic (ROC) curve was plotted to determine the number of natural teeth that would best discriminate those with oral impacts from those without. Oral impacts were reported by 26% of the 40-59 year olds and 34% of the older individuals. In both groups there was a significant negative correlation between the number of teeth present and oral impacts. The ROC curve for the 40-59 year olds gave an area under the curve (AUC) of 0.758 (95% CI = 0.702-0.814; P < 0.001) with an optimal cut-off of 24/25 teeth while for the ≥60 year olds, the AUC of the ROC curve was 0.737 (95% CI = 0.684-0.790; P < 0.001) with an optimal cut-off of 18/19 teeth. Based on the ROC curves the optimal cutoffs of the number of natural teeth that best discriminated between those with and without oral impacts for 40-59 and ≥60 year olds were 24-25 and 18-19, respectively.

Systemic Corticosteroids for Acute Sinusitis

Cochrane Database of Systematic Reviews (Online). 2011  |  Pubmed ID: 22161418

Acute sinusitis is a common reason for patients to seek primary care consultations. The related impairment of daily functioning and quality of life is attributable to symptoms such as facial pain and nasal congestion.

Ultra-sensitive High-precision Spectroscopy of a Fast Molecular Ion Beam

The Journal of Chemical Physics. Dec, 2011  |  Pubmed ID: 22168687

Direct spectroscopy of a fast molecular ion beam offers many advantages over competing techniques, including the generality of the approach to any molecular ion, the complete elimination of spectral confusion due to neutral molecules, and the mass identification of individual spectral lines. The major challenge is the intrinsic weakness of absorption or dispersion signals resulting from the relatively low number density of ions in the beam. Direct spectroscopy of an ion beam was pioneered by Saykally and co-workers in the late 1980s, but has not been attempted since that time. Here, we present the design and construction of an ion beam spectrometer with several improvements over the Saykally design. The ion beam and its characterization have been improved by adopting recent advances in electrostatic optics, along with a time-of-flight mass spectrometer that can be used simultaneously with optical spectroscopy. As a proof of concept, a noise-immune cavity-enhanced optical heterodyne molecular spectroscopy (NICE-OHMS) setup with a noise equivalent absorption of ~2 × 10(-11) cm(-1) Hz(-1/2) has been used to observe several transitions of the Meinel 1-0 band of N(2) (+) with linewidths of ~120 MHz. An optical frequency comb has been used for absolute frequency calibration of transition frequencies to within ~8 MHz. This work represents the first direct spectroscopy of an electronic transition in an ion beam, and also represents a major step toward the development of routine infrared spectroscopy of rotationally cooled molecular ions.

Novel Sylvatic Rabies Virus Variant in Endangered Golden Palm Civet, Sri Lanka

Emerging Infectious Diseases. Dec, 2011  |  Pubmed ID: 22172202

Information is scarce about sylvatic rabies virus in Asia and about rabies in palm civets. We report a novel sylvatic rabies virus variant detected in a golden palm civet in Sri Lanka. Evolutionary analysis suggests the virus diverged from canine rabies viruses in Sri Lanka in ≈1933 (range 1886-1963).

Genogroup I and II Picobirnaviruses in Respiratory Tracts of Pigs

Emerging Infectious Diseases. Dec, 2011  |  Pubmed ID: 22172405

Sequence-independent amplification and specific reverse transcription PCRs identified genogroup I and II picobirnaviruses in respiratory tracts of pigs. These data expand knowledge of picobirnavirus diversity and tropism. Genetic relationships between porcine respiratory and human enteric picobirnaviruses suggest cross-species transmission of picobirnaviruses between pigs and humans.

MOLECULAR SURVEY OF APICOMPLEXA IN PODARCIS WALL LIZARDS DETECTS HEPATOZOON, SARCOCYSTIS AND EIMERIA SPECIES

The Journal of Parasitology. Dec, 2011  |  Pubmed ID: 22176558

Abstract The occurrence of Apicomplexan parasites in Podarcis wall lizards from the Iberian Peninsula and Balearic islands was studied by amplification and sequencing of the 18S rRNA gene. Species from three genera, Hepatozoon, Sarcocystis and Eimeria were detected. The phylogenetic analysis of the 18S rRNA gene provides unexpected insights into the evolutionary history of these parasites. All Hepatozoon specimens were recovered as part of a clade already identified in lizards from North Africa. The Sarcocystis species, detected in Podarcis lilfordi from Cabrera island, in the Balearic Islands, appears related to Sarcocystis gallotiae, known only from endemic Gallotia lizards from the Canary Islands. Based on the lack of snake predators on this island, this parasite form presumably presents an atypical transmission cycle that uses the same host species as both intermediate and final host through cannibalism, like S. gallotiae. Eimeria is reported for the first time from Podarcis lizards. This study shows the power of detecting multiple different Apicomplexa parasites through screening of tail tissue samples and blood drops that are often collected in reptiles for other purposes.

Current Status and Recent Advances of Liver Transplantation from Donation After Cardiac Death

World Journal of Gastrointestinal Surgery. Nov, 2011  |  Pubmed ID: 22180833

The last decade saw increased organ donation activity from donors after cardiac death (DCD). This contributed to a significant proportion of transplant activity. Despite certain drawbacks, liver transplantation from DCD donors continues to supplement the donor pool on the backdrop of a severe organ shortage. Understanding the pathophysiology has provided the basis for modulation of DCD organs that has been proven to be effective outside liver transplantation but remains experimental in liver transplantation models. Research continues on how best to further increase the utility of DCD grafts. Most of the work has been carried out exploring the use of organ preservation using machine assisted perfusion. Both ex-situ and in-situ organ perfusion systems are tested in the liver transplantation setting with promising results. Additional techniques involved pharmacological manipulation of the donor, graft and the recipient. Ethical barriers and end-of-life care pathways are obstacles to widespread clinical application of some of the recent advances to practice. It is likely that some of the DCD offers are in fact probably "prematurely" offered without ideal donor management or even prior to brain death being established. The absolute benefits of DCD exist only if this form of donation supplements the existing deceased donor pool; hence, it is worthwhile revisiting organ donation process enabling us to identify counter remedial measures.

Search for B(s)(0) †� μ+ μ- and B(0) †� μ+ μ- Decays in Pp Collisions at Sqrt[s] = 7 TeV

Physical Review Letters. Nov, 2011  |  Pubmed ID: 22181597

A search for the rare decays B(s)(0) → μ+ μ- and B(0) → μ+ μ- is performed in pp collisions at sqrt[s] = 7 TeV, with a data sample corresponding to an integrated luminosity of 1.14 fb(-1), collected by the CMS experiment at the LHC. In both cases, the number of events observed after all selection requirements is consistent with expectations from background and standard-model signal predictions. The resulting upper limits on the branching fractions are B(B(s)(0) → μ+ μ-) < 1.9 × 10(-8) and B(B(0) → μ+ μ-)<4.6 × 10(-9), at 95% confidence level.

Search for New Physics with a Monojet and Missing Transverse Energy in Pp Collisions at Sqrt[s]=7  TeV

Physical Review Letters. Nov, 2011  |  Pubmed ID: 22181725

A study of events with missing transverse energy and an energetic jet is performed using pp collision data at a center-of-mass energy of 7 TeV. The data were collected by the CMS detector at the LHC, and correspond to an integrated luminosity of 36  pb^{-1}. An excess of these events over standard model contributions is a signature of new physics such as large extra dimensions and unparticles. The number of observed events is in good agreement with the prediction of the standard model, and significant extension of the current limits on parameters of new physics benchmark models is achieved.

Search for Supersymmetry at the LHC in Events with Jets and Missing Transverse Energy

Physical Review Letters. Nov, 2011  |  Pubmed ID: 22182023

A search for events with jets and missing transverse energy is performed in a data sample of pp collisions collected at sqrt[s]=7  TeV by the CMS experiment at the LHC. The analyzed data sample corresponds to an integrated luminosity of 1.14  fb^{-1}. In this search, a kinematic variable α_{T} is used as the main discriminator between events with genuine and misreconstructed missing transverse energy. No excess of events over the standard model expectation is found. Exclusion limits in the parameter space of the constrained minimal supersymmetric extension of the standard model are set. In this model, squark masses below 1.1 TeV are excluded at 95% C.L. Gluino masses below 1.1 TeV are also ruled out at 95% C.L. for values of the universal scalar mass parameter below 500 GeV.

Towards a More Accurate Reference Interaction Site Model Integral Equation Theory for Molecular Liquids

The Journal of Chemical Physics. Dec, 2011  |  Pubmed ID: 22191861

A systematic approach for increasing the accuracy of the reference interaction site model (RISM) theory is introduced that uses input from simulation results to produce very accurate site-site pair correlation functions for single component molecular liquids. The methodology allows the computation of the "RISM bridge function." Realistic molecular liquids such as water, alcohols, amides, and others are investigated, and the merits and limitations of the method for each of these liquids are examined in relation to the known deficiencies of the RISM theory.

The Multitasking Organ: Recent Insights into Skin Immune Function

Immunity. Dec, 2011  |  Pubmed ID: 22195743

The skin provides the first line defense of the human body against injury and infection. By integrating recent findings in cutaneous immunology with fundamental concepts of skin biology, we portray the skin as a multitasking organ ensuring body homeostasis. Crosstalk between the skin and its microbial environment is also highlighted as influencing the response to injury, infection, and autoimmunity. The importance of the skin immune network is emphasized by the identification of several skin-resident cell subsets, each with its unique functions. Lessons learned from targeted therapy in inflammatory skin conditions, such as psoriasis, provide further insights into skin immune function. Finally, we look at the skin as an interacting network of immune signaling pathways exemplified by the development of a disease interactome for psoriasis.

2,9,16,23-Tetra-kis(1-methyl-eth-yl)-5,6,11,12,13,14,19,20,25,26,27,28-dodecadehydro-tetra-benzo[a,e,k,o]cyclo-eicosene

Acta Crystallographica. Section E, Structure Reports Online. Dec, 2011  |  Pubmed ID: 22199965

The title compound, C(48)H(40), is a tetra-isopropyl-substituted polyannulenoenyne. The unsubstituted polyannulenoenyne, C(36)H(16) (CSD: RICVEE; CAS: 186494-87-1), has quasi-D(2) (222) symmetry, as determined by least-squares fit (excluding H atoms) to a model optimized in D(2) symmetry by mol-ecular mechanics (r.m.s. deviation = 0.239 Å). The least-squares fits of 36 common C atoms of the title compound (at 90 K) to the parent (at 295 K) and to the optimized model show r.m.s. deviations of 0.419 and 0.426 Å, respectively.

Search for a Vectorlike Quark with Charge 2/3 in T+Z Events from Pp Collisions at Sqrt[s]=7  TeV

Physical Review Letters. Dec, 2011  |  Pubmed ID: 22243304

A search for pair-produced heavy vectorlike charge-2/3 quarks, T, in pp collisions at a center-of-mass energy of 7 TeV, is performed with the CMS detector at the LHC. Events consistent with the flavor-changing-neutral-current decay of a T quark to a top quark and a Z boson are selected by requiring two leptons from the Z-boson decay, as well as an additional isolated charged lepton. In a data sample corresponding to an integrated luminosity of 1.14  fb^{-1}, the number of observed events is found to be consistent with the standard model background prediction. Assuming a branching fraction of 100% for the decay T→tZ, a T quark with a mass less than 475  GeV/c^{2} is excluded at the 95% confidence level.

MEET: Motif Elements Estimation Toolkit

Conference Proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference. 2011  |  Pubmed ID: 22255823

MEET is an R package that integrates a set of algorithms for the detection of transcription factor binding sites (TFBS). The MEET R package includes five motif searching algorithms: MEME/MAST(Multiple Expectation-Maximization for Motif Elicitation), Q-residuals, MDscan (Motif Discovery scan), ITEME (Information Theory Elements for Motif Estimation) and MATCH. In addition MEET allows the user to work with different alignment algorithms: MUSCLE (Multiple Sequence Comparison by Log-Expectation), ClustalW and MEME. The package can work in two modes, training and detection. The training mode allows the user to choose the best parameters of a detector. Once the parameters are chosen, the detection mode allows to analyze a genome looking for binding sites. Both modes can combine the different alignment and detection methods, offering multiple possibilities. Combining the alignments and the detection algorithms makes possible the comparison between detection models at the same level, without having to care about the differences produced during the alignment process. The MEET R package can be downloaded from http://sisbio.recerca.upc.edu/R/MEET_1.0. tar.gz.

Analysis of Incomplete Gene Expression Dataset Through Protein-protein Interaction Information

Conference Proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference. 2011  |  Pubmed ID: 22255911

This paper shows a graph based method to analyze proteomic expression data. The method allows the prediction of the expression of genes not measured by the gene expression technology based on the local connectivity properties of the measured differentially expressed gene set. The prediction of the expression jointly with the stability of this prediction as a function of the variation of the initial expressed set is computed. The method is able to correctly predict one third of the proteins with independence of variations on the selection of the initial set. The algorithm is validated through a Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometer (MALDI-TOF) protein expression experiment aiming the study of the protein expression patterns and post-translational modifications in human endothelial vascular cells exposed to atherosclerotic levels of Low Density Lipoproteins (LDL).

Mental Health Status and Risk Factors for Mental Health Problems in Left-behind Children of Women Migrant Workers in Sri Lanka

The Ceylon Medical Journal. Dec, 2011  |  Pubmed ID: 22298208

Many married Sri Lankan women annually migrate for employment overseas. Despite widely speculated psychological consequences in these children, their mental health status has not been systematically studied using validated instruments.

Scalp Metastasis in a Patient with Phaeochromocytoma

The Ceylon Medical Journal. Dec, 2011  |  Pubmed ID: 22298218

Measles, Mumps, Rubella (MMR) Vaccine - a Reply (1)

The Ceylon Medical Journal. Dec, 2011  |  Pubmed ID: 22298221

Glaucoma in a Patient with Nanophthalmos

Journal of Ophthalmic & Vision Research. Jul, 2011  |  Pubmed ID: 22454738

Sublineages of Beijing Strain of Mycobacterium Tuberculosis in Sri Lanka

Indian Journal of Microbiology. Jul, 2011  |  Pubmed ID: 22754025

Strains of the Beijing/W genotype of Mycobacterium tuberculosis have been responsible for large outbreaks of tuberculosis around the world, sometimes involving multi-drug resistance. It has been shown that more recently evolved Beijing sublineages are prone to cause outbreaks. Furthermore Beijing is the single predominant cluster in Sri Lanka. The present study identifies that recently evolved sublineages of Beijing strains are present in the study population. The majority of Beijing isolates (92.85%) were pan-susceptible. However, these findings may have important implications for the control and prevention of tuberculosis in Sri Lanka.

Genome-wide Meta-analysis Identifies Novel Multiple Sclerosis Susceptibility Loci

Annals of Neurology. Dec, 2011  |  Pubmed ID: 22190364

To perform a 1-stage meta-analysis of genome-wide association studies (GWAS) of multiple sclerosis (MS) susceptibility and to explore functional consequences of new susceptibility loci.

Malaria Infections Do Not Compromise Vaccine-induced Immunity Against Tuberculosis in Mice

PloS One. 2011  |  Pubmed ID: 22205939

Given the considerable geographic overlap in the endemic regions for malaria and tuberculosis, it is probable that co-infections with Mycobacterium tuberculosis and Plasmodium species are prevalent. Thus, it is quite likely that both malaria and TB vaccines may be used in the same populations in endemic areas. While novel vaccines are currently being developed and tested individually against each of these pathogens, the efficacy of these vaccines has not been evaluated in co-infection models. To further assess the effectiveness of these new immunization strategies, we investigated whether co-infection with malaria would impact the anti-tuberculosis protection induced by four different types of TB vaccines in a mouse model of pulmonary tuberculosis.

Changing Trends in Antimicrobial Resistance and Serotypes of Streptococcus Pneumoniae Isolates in Asian Countries: an Asian Network for Surveillance of Resistant Pathogens (ANSORP) Study

Antimicrobial Agents and Chemotherapy. Mar, 2012  |  Pubmed ID: 22232285

Antimicrobial resistance in Streptococcus pneumoniae remains a serious concern worldwide, particularly in Asian countries, despite the introduction of heptavalent pneumococcal conjugate vaccine (PCV7). The Asian Network for Surveillance of Resistant Pathogens (ANSORP) performed a prospective surveillance study of 2,184 S. pneumoniae isolates collected from patients with pneumococcal infections from 60 hospitals in 11 Asian countries from 2008 to 2009. Among nonmeningeal isolates, the prevalence rate of penicillin-nonsusceptible pneumococci (MIC, ≥ 4 μg/ml) was 4.6% and penicillin resistance (MIC, ≥ 8 μg/ml) was extremely rare (0.7%). Resistance to erythromycin was very prevalent in the region (72.7%); the highest rates were in China (96.4%), Taiwan (84.9%), and Vietnam (80.7%). Multidrug resistance (MDR) was observed in 59.3% of isolates from Asian countries. Major serotypes were 19F (23.5%), 23F (10.0%), 19A (8.2%), 14 (7.3%), and 6B (7.3%). Overall, 52.5% of isolates showed PCV7 serotypes, ranging from 16.1% in Philippines to 75.1% in Vietnam. Serotypes 19A (8.2%), 3 (6.2%), and 6A (4.2%) were the most prominent non-PCV7 serotypes in the Asian region. Among isolates with serotype 19A, 86.0% and 79.8% showed erythromycin resistance and MDR, respectively. The most remarkable findings about the epidemiology of S. pneumoniae in Asian countries after the introduction of PCV7 were the high prevalence of macrolide resistance and MDR and distinctive increases in serotype 19A.

Interactions of the Cytoplasmic Domain of Sindbis Virus E2 with Nucleocapsid Cores Promote Alphavirus Budding

Journal of Virology. Mar, 2012  |  Pubmed ID: 22190727

Alphavirus budding from the plasma membrane occurs through the specific interaction of the nucleocapsid core with the cytoplasmic domain of the E2 glycoprotein (cdE2). Structural studies of the Sindbis virus capsid protein (CP) have suggested that these critical interactions are mediated by the binding of cdE2 into a hydrophobic pocket in the CP. Several molecular genetic studies have implicated amino acids Y400 and L402 in cdE2 as important for the budding of alphaviruses. In this study, we characterized the role of cdE2 residues in structural polyprotein processing, glycoprotein transport, and capsid interactions. Along with hydrophobic residues, charged residues in the N terminus of cdE2 were critical for the effective interaction of cores with cdE2, a process required for virus budding. Mutations in the C-terminal signal sequence region of cdE2 affected E2 protein transport to the plasma membrane, while nonbudding mutants that were defective in cdE2-CP interaction accumulated E2 on the plasma membrane. The interaction of cdE2 with cytoplasmic cores purified from infected cells and in vitro-assembled core-like particles suggests that cdE2 interacts with assembled cores to mediate budding. We hypothesize that these cdE2 interactions induce a change in the organization of the nucleocapsid core upon binding leading to particle budding and priming of the nucleocapsid cores for disassembly that is required for virus infection.

Derivation and Validation of Age and Temperature Specific Reference Values and Centile Charts to Predict Lower Respiratory Tract Infection in Children with Fever: Prospective Observational Study

BMJ (Clinical Research Ed.). 2012  |  Pubmed ID: 22761088

To develop reference values and centile charts for respiratory rate based on age and body temperature, and to determine how well these reference values can predict the presence of lower respiratory tract infections (LRTI) in children with fever.

Follicular Dendritic Cells Emerge from Ubiquitous Perivascular Precursors

Cell. Jul, 2012  |  Pubmed ID: 22770220

The differentiation of follicular dendritic cells (FDC) is essential to the remarkable microanatomic plasticity of lymphoid follicles. Here we show that FDC arise from ubiquitous perivascular precursors (preFDC) expressing platelet-derived growth factor receptor β (PDGFRβ). PDGFRβ-Cre-driven reporter gene recombination resulted in FDC labeling, whereas conditional ablation of PDGFRβ(+)-derived cells abolished FDC, indicating that FDC originate from PDGFRβ(+) cells. Lymphotoxin-α-overexpressing prion protein (PrP)(+) kidneys developed PrP(+) FDC after transplantation into PrP(-) mice, confirming that preFDC exist outside lymphoid organs. Adipose tissue-derived PDGFRβ(+) stromal-vascular cells responded to FDC maturation factors and, when transplanted into lymphotoxin β receptor (LTβR)(-) kidney capsules, differentiated into Mfge8(+)CD21/35(+)FcγRIIβ(+)PrP(+) FDC capable of trapping immune complexes and recruiting B cells. Spleens of lymphocyte-deficient mice contained perivascular PDGFRβ(+) FDC precursors whose expansion required both lymphoid tissue inducer (LTi) cells and lymphotoxin. The ubiquity of preFDC and their strategic location at blood vessels may explain the de novo generation of organized lymphoid tissue at sites of lymphocytic inflammation. PAPERFLICK:

Molecular Characterization of Three 3-ketosteroid-Δ(1)-dehydrogenase Isoenzymes of Rhodococcus Ruber Strain Chol-4

The Journal of Steroid Biochemistry and Molecular Biology. Jul, 2012  |  Pubmed ID: 22771584

Rhodococcus ruber strain Chol-4 isolated from a sewage sludge sample is able to grow on minimal medium supplemented with steroids, showing a broad catabolic capacity. This paper reports the characterization of three different 3-ketosteroid-Δ(1)-dehydrogenases (KstDs) in the genome of R. ruber strain Chol-4. The genome of this strain does not contain any homologues of a 3-keto-5α-steroid-Δ(4)-dehydrogenase (Kst4d or TesI) that appears in the genomes of Rhodococcus erythropolis SQ1 or Comamonas testosteroni. Growth experiments with kstD2 mutants, either a kstD2 single mutant, kstD2 double mutants in combination with kstD1 or kstD3, or the triple kstD1,2,3 mutant, proved that KstD2 is involved in the transformation of 4-androstene-3,17-dione (AD) to 1,4-androstadiene-3,17-dione (ADD) and in the conversion of 9α-hydroxy-4-androstene-3,17-dione (9OHAD) to 9α-hydroxy-1,4-androstadiene-3,17-dione (9OHADD). kstD2,3 and kstD1,2,3 R. ruber mutants (both lacking KstD2 and KstD3) did not grow in minimal medium with cholesterol as the only carbon source, thus demonstrating the involvement of KstD2 and KstD3 in cholesterol degradation. In contrast, mutation of kstD1 does not alter the bacterial growth on the steroids tested in this study and therefore, the role of this protein still remains unclear. The absence of a functional KstD2 in R. ruber mutants provoked in all cases an accumulation of 9OHAD, as a branch product probably formed by the action of a 3-ketosteroid-9α-hydroxylase (KshAB) on the AD molecule. Therefore, KstD2 is a key enzyme in the AD catabolism pathway of R. ruber strain Chol-4 while KstD3 is involved in cholesterol catabolism.

Consumption Pattern of Iodised Salt in Households and Serum TSH Levels Among 5-9 Year Old Children in the Plantation Sector of Sri Lanka

The Ceylon Medical Journal. Jun, 2012  |  Pubmed ID: 22772784

Salt is the main source of iodine in areas with high rainfall and iodine deficiency is the main cause of preventable hypothyroidism. Iodisation of salt increases iodine intake, but will depend on how salt is handled. This study was carried out to assess the pattern of salt consumption in the estate population and to ascertain the relationship between household salt iodine concentration and TSH levels in children.

Conidiobolus Coranatus Infection of the Para-nasal Sinuses Masquerading As a Sino-nasal Tumour

The Ceylon Medical Journal. Jun, 2012  |  Pubmed ID: 22772789

Aqueous Tert-butanol Mixtures: A Model for Molecular-emulsions

The Journal of Chemical Physics. Jul, 2012  |  Pubmed ID: 22779659

By analogy with micro-emulsion, we introduce the molecular-emulsion picture to describe particular aqueous mixtures. The analogy is set by introducing the equivalent of the Teubner-Strey structure factor, the latter which is traditionally used to describe the structure of micro-emulsions. The main difference resides in the fact that the size of the oil and water domains are not in the micrometer, but in the nanometer scale. This implies that the molecular size and the molecular geometry cannot be neglected anymore. The introduction of this analogy is used to settle the problem of properly describing with computer simulations highly micro-heterogeneous aqueous mixtures. In particular, the issue of whether or not the Kirkwood-Buff integrals represent solely concentration fluctuations is settled by showing the contribution of the micro-heterogeneity to these integrals through the presence of an associated pre-peak in the structure factors. Both the Optimized Potentials for Liquid State (OPLS) and Transferable Potential for Phase Equilibria-United Atoms (TraPPE-UA) force fields for tert-butanol turn out to be remarkably good in describing the structure of the corresponding aqueous mixtures, when the above-mentioned analogy with micro-emulsion is introduced to correct for the computational artifacts in the Kirkwood-Buff integrals.

Comparison of Two Spectral Domain Optical Coherence Tomography Devices for Angle-closure Assessment

Investigative Ophthalmology & Visual Science. 2012  |  Pubmed ID: 22786910

Purpose. To compare two spectral domain optical coherence tomography (SD-OCT) devices for the identification of angle structures and the presence of angle closure. Methods. This was a prospective comparative study. Consecutive patients underwent gonioscopy and anterior segment imaging using two SD-OCT devices (iVue and Cirrus). Images were evaluated for the ability to detect angle structures such as Schwalbe's line (SL), trabecular meshwork (TM), Schlemm's canal (SC), and scleral spur (SS), and the presence of angle closure. Angle closure was defined as iris contact with the angle wall anterior to the SS on SD-OCT, and nonvisibility of the posterior TM on gonioscopy. Angle closure in an eye was defined as ≥two quadrants of closed angles. AC1 statistic was used to assess the agreement between devices. Results. Of the 69 subjects studied (46.4% male, 84.1% Chinese, mean age 64.0 ± 10.5 years), 40 subjects (40 eyes, 58.0%) had angle closure on gonioscopy. The most identifiable structure on Cirrus SD-OCT was the SS (82.2%) and SL on iVue SD-OCT (74.5%). Angle closure was indeterminable in 14.5% and 50.7% of Cirrus and iVue scans (P < 0.001), respectively. Interdevice agreement for angle closure was moderately strong (AC1 = 0.67), but agreement with gonioscopy was only fair (AC1 = 0.35 and 0.50 for Cirrus and iVue, respectively). Conclusions. It was more difficult to determine angle closure status with iVue compared with Cirrus SD-OCT. There was fair agreement between both devices with gonioscopy for identifying angle closure.

Regulatory T Cells Attenuate Neuropathic Pain Following Peripheral Nerve Injury and Experimental Autoimmune Neuritis

Pain. Sep, 2012  |  Pubmed ID: 22789131

Neuroimmune crosstalk in neuropathic pain is a key contributor to pain hypersensitivity following nervous system injury. CD4+CD25+Foxp3+ regulatory T cells (Tregs) are endogenous immune suppressors, reducing T-cell proliferation and proinflammatory cytokine production. Currently, the role of Tregs in neuropathic pain is unknown. In this study, we tested the effects of expanding Tregs on pain hypersensitivity and neuroinflammation in 2 models of neuropathy; sciatic nerve chronic constriction injury and experimental autoimmune neuritis in rats. Following chronic constriction injury, treatment with CD28 superagonist (CD28SupA), a Treg population expander, significantly increased Tregs in the lymphoid tissues, injured sciatic nerve, and lumbar spinal cord of rats. CD28SupA treatment led to a significant reduction in mechanical pain hypersensitivity, alongside a decrease in the numbers of infiltrating T cells, macrophages, and antigen-presenting cells in the sciatic nerve and dorsal root ganglia. In experimental autoimmune neuritis-affected rats, CD28SupA treatment resulted in a significant improvement in disease severity and in mechanical pain hypersensitivity. This was associated with a reduction in the numbers of T cells, macrophages, and antigen-presenting cells in the sciatic nerve and dorsal root ganglia, and reduced activation of microglia and infiltration of T cells in the spinal cord. Furthermore, depletion of Tregs by a CD25 antibody in mice with a partial sciatic nerve ligation resulted in prolonged mechanical pain hypersensitivity. These findings suggest that Tregs play a role in endogenous recovery from neuropathy-induced pain. Thus, this T-cell subset may be specifically targeted to alleviate chronic neuropathic pain.

Novel Method of Assessing Delamination of the Anterior Lens Capsule Using Spectral-domain Optical Coherence Tomography

Clinical Ophthalmology (Auckland, N.Z.). 2012  |  Pubmed ID: 22791977

BACKGROUND: Delamination of the anterior lens capsule producing a double-ring sign during continuous curvilinear capsulorhexis is commonly associated with true exfoliation syndrome. METHODS: Previous studies have concentrated on light- and transmission-electron microscopic features and correlated this with the histopathology of these anterior capsules. To our knowledge, this is the first report of the use of high-resolution spectral-domain optical coherence tomography to delineate delamination of the anterior lens capsule, incidentally detected during cataract surgery.

Knowledge and Practices on Breast and Cervical Cancer Screening Methods Among Female Health Care Workers: A Sri Lankan Experience

Asian Pacific Journal of Cancer Prevention : APJCP. 2012  |  Pubmed ID: 22799304

Breast and cervical cancer are the most common causes of cancer mortality among women worldwide, but they are largely preventable. There are limited data on knowledge and practices on screening methods of breast and cervical cancers among female health care workers in Sri Lanka, in spite of having an organized screening programme islandwide. A cross-sectional survey was conducted among 219 female health care workers including public health midwives (68.9%) selected from 6 districts in Sri Lanka using convenient sampling methods. A self-administered questionnaire was used as a pre-test in a capacity building training programme to collect the data. The mean (SD) duration of work experience of the respondents was 12 years and 52.5% were aged over 35 years. Most (76.7%) were married, and a family history of cancer was reported by 24.2%. Over 98% knew about self breast examination. Even though 84.1% practiced it, only 47.9% practiced it on a monthly basis. Clinical breast examination and mammography were known by 94.1% and 64.3% respectively. Only 19.2% had undergone a clinical breast examination within one year and 3.6% had ever undergone a mamography. Only 76.3% knew that a Pap smear detects precancerous stage of cervical cancer. Among 169 married workers, 73.4% had never had a Pap smear and only 17.2% had got it done within the preceding 5 years. Among the reasons for not doing a pap smear within 5 years, 47.0% believed it as not necessary, 17.3% due to fear/dislike, 23.2% as not having symptoms, 3% had not known about it and 3% not known about availability of services. The study findings suggest that the knowledge and practices on breast and cervical cancer screening methods among female health care workers need to be improved. Considering the role that health care workers play in communicating health behaviors to the general public, strengthening health education interventions for this group of females is essential.

Oral Health Status During Pregnancy: Rural-urban Comparisons of Oral Disease Burden Among Antenatal Women in Sri Lanka

Rural and Remote Health. Jul, 2012  |  Pubmed ID: 22799459

Sri Lanka is a middle income country and 80% of its population lives in rural areas. There is a well organized maternal and child health program and oral health care has recently been incorporated. The aim of this study was to report the oral disease burden of rural and urban antenatal women in the Western Province of Sri Lanka, thus highlighting the need to provide oral health care to this group.

Ganetespib (STA-9090), a Non-Geldanamycin HSP90 Inhibitor, Has Potent Antitumor Activity in In Vitro and In Vivo Models of Non-Small Cell Lung Cancer

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. Jul, 2012  |  Pubmed ID: 22806877

PURPOSE: We describe the anticancer activity of ganetespib, a novel non-geldanamycin heat shock protein 90 (HSP90) inhibitor, in non-small cell lung cancer (NSCLC) models. EXPERIMENTAL DESIGN: The activity of ganetespib was compared to that of the geldnamaycin 17-AAG in biochemical assays, cell lines and xenografts, and evaluated in an ERBB2 YVMA-driven mouse lung adenocarcinoma model. RESULTS: Ganetespib blocked the ability of HSP90 to bind to biotinylated geldanamycin and disrupted the association of HSP90 with its co-chaperone, p23, more potently than 17-AAG. In genomically-defined NSCLC cell lines, ganetespib caused depletion of receptor tyrosine kinases, extinguishing of downstream signaling, inhibition of proliferation and induction of apoptosis with IC50 values ranging 2-30 nM, substantially lower than those required for 17-AAG (20-3,500 nM). Ganetespib was also approximately 20-fold more potent in isogenic Ba/F3 pro-B cells rendered IL-3 independent by expression of EGFR and ERBB2 mutants. In mice bearing NCI-H1975 (EGFR L858R/T790M) xenografts, ganetespib was rapidly eliminated from plasma and normal tissues but was maintained in tumor with t1/2 58.3 hours, supporting once-weekly dosing experiments, in which ganetespib produced greater tumor growth inhibition than 17-AAG. However, after a single dose, re-expression of mutant EGFR occurred by 72 hours, correlating with reversal of anti-proliferative and pro-apoptotic effects. Consecutive day dosing resulted in xenograft regressions, accompanied by more sustained pharmacodynamic effects. Ganetespib also demonstrated activity against mouse lung adenocarcinomas driven by oncogenic ERBB2 YVMA.CONCLUSIONS: Ganetespib has greater potency than 17-AAG and potential efficacy against several NSCLC subsets, including those harboring EGFR or ERBB2 mutation.

Developmental Changes in the Metabolic Network of Snapdragon Flowers

PloS One. 2012  |  Pubmed ID: 22808147

Evolutionary and reproductive success of angiosperms, the most diverse group of land plants, relies on visual and olfactory cues for pollinator attraction. Previous work has focused on elucidating the developmental regulation of pathways leading to the formation of pollinator-attracting secondary metabolites such as scent compounds and flower pigments. However, to date little is known about how flowers control their entire metabolic network to achieve the highly regulated production of metabolites attracting pollinators. Integrative analysis of transcripts and metabolites in snapdragon sepals and petals over flower development performed in this study revealed a profound developmental remodeling of gene expression and metabolite profiles in petals, but not in sepals. Genes up-regulated during petal development were enriched in functions related to secondary metabolism, fatty acid catabolism, and amino acid transport, whereas down-regulated genes were enriched in processes involved in cell growth, cell wall formation, and fatty acid biosynthesis. The levels of transcripts and metabolites in pathways leading to scent formation were coordinately up-regulated during petal development, implying transcriptional induction of metabolic pathways preceding scent formation. Developmental gene expression patterns in the pathways involved in scent production were different from those of glycolysis and the pentose phosphate pathway, highlighting distinct developmental regulation of secondary metabolism and primary metabolic pathways feeding into it.

Forty Years of Sports Performance Research and Little Insight Gained

BMJ (Clinical Research Ed.). 2012  |  Pubmed ID: 22810388

Thiolated Particles As Effective Intravesical Drug Delivery Systems for Treatment of Bladder-related Diseases

Nanomedicine (London, England). Jul, 2012  |  Pubmed ID: 22812707

Aim: To prove in vivo mucoadhesiveness of thiolated and well-established polymeric microparticles and nanoparticles (NPs) as a promising nanomedical tool for the treatment of bladder-related diseases. Materials & methods: Spray drying and ionic gelation were used in order to generate microparticles and NPs. For particle detection, the fluorescent marker, fluorescein diacetate, was incorporated in microparticles and NPs, respectively. Mucoadhesive properties of the particles were pre-evaluated via rheological measurements and ex vivo in the porcine urinary bladder model to identify the most appropriate particles for in vivo application in female Sprague-Dawley rats. Results: Pretrials indicated that particles based on chitosan were most suitable as an intravesical drug delivery system for in vivo application. The retention time of thiolated chitosan NPs on the rat urinary bladder mucosa was approximately 170-fold higher in comparison with the pure fluorescent marker, fluorescein diacetate, having being applied as aqueous suspension without polymeric excipients. Conclusion: This advanced nanomedical tool based on thiolated chitosan seems to be a promising approach for the treatment of bladder-related diseases. Original submitted 20 January 2012; Revised submitted 20 April 2012.

Validation of Dynamic 3-dimensional Whole Heart Magnetic Resonance Myocardial Perfusion Imaging Against Fractional Flow Reserve for the Detection of Significant Coronary Artery Disease

Journal of the American College of Cardiology. Aug, 2012  |  Pubmed ID: 22818072

The goal of this study was to determine the diagnostic accuracy of dynamic 3-dimensional (3D) whole heart myocardial perfusion cardiovascular magnetic resonance (CMR) against invasively determined fractional flow reserve (FFR) and to establish the correlation between myocardium at risk defined by using the invasive Duke Jeopardy Score (DJS) and noninvasive 3D whole heart myocardial perfusion CMR.

Association of Levofloxacin Resistance with Mortality in Adult Patients with Invasive Pneumococcal Diseases: a Post Hoc Analysis of a Prospective Cohort

Infection. Jul, 2012  |  Pubmed ID: 22821428

OBJECTIVE: This study was conducted to identify risk factors for mortality and to evaluate the impact of antimicrobial resistance on outcome in adult patients with invasive pneumococcal disease (IPD). METHODS: A post hoc analysis of an observational cohort study on community-acquired pneumococcal infections was conducted and a total of 136 adult patients with IPD were analyzed in this study. RESULTS: Pneumonia was the most common type of infection (n = 84, 61.8 %), followed by primary bacteremia (n = 15, 11.0 %) and meningitis (n = 15, 11.0 %). One hundred and three patients (75.7 %) had concomitant pneumococcal bacteremia. The overall 30-day mortality rate was 26.5 % (36/136), and factors associated with 30-day mortality were corticosteroid use, presentation with septic shock, and development of acute respiratory distress syndrome (ARDS) (all P < 0.05). While penicillin and erythromycin resistance were associated with a lower mortality, an association between levofloxacin resistance and increased mortality was found in the univariate analysis; however, statistical significance was not reached (P = 0.083). Multivariable analysis showed that presentation with septic shock, corticosteroid use, development of ARDS, and levofloxacin resistance were independent factors associated with 30-day mortality. Of the five patients with IPD caused by levofloxacin-resistant Streptococcus pneumoniae, three (60 %) died within 30 days of diagnosis. CONCLUSION: Levofloxacin resistance was associated with increased mortality, along with septic shock, prior use of corticosteroids, and development of ARDS, in adult patients with IPD. Our data suggest that the emergence of levofloxacin resistance among invasive pneumococcal isolates is now becoming a challenge for clinicians managing community-acquired bacterial infections.

Does the Home Environment and the Sex of the Child Modify the Adverse Effects of Prenatal Exposure to Chlorpyrifos on Child Working Memory?

Neurotoxicology and Teratology. Jul, 2012  |  Pubmed ID: 22824009

Prenatal exposure to chlorpyrifos (CPF), an organophosphorus insecticide, has long been associated with delayed neurocognitive development and most recently with decrements in working memory at age 7. In the current paper, we expanded the previous work on CPF to investigate how additional biological and social environmental factors might create or explain differential neurodevelopmental susceptibility, focusing on main and moderating effects of the quality of the home environment (HOME) and child sex. We evaluate how the quality of the home environment (specifically, parental nurturance and environmental stimulation) and child sex interact with the adverse effects of prenatal CPF exposure on working memory at child age 7years. We did not observe a remediating effect of a high quality home environment (either parental nurturance or environmental stimulation) on the adverse effects of prenatal CPF exposure on working memory. However, we detected a borderline significant interaction between prenatal exposure to CPF and child sex (B (95% CI) for interaction term=-1.714 (-3.753 to 0.326)) suggesting males experience a greater decrement in working memory than females following prenatal CPF exposure. In addition, we detected a borderline interaction between parental nurturance and child sex (B (95% CI) for interaction term=1.490 (-0.518 to 3.499)) suggesting that, in terms of working memory, males benefit more from a nurturing environment than females. To our knowledge, this is the first investigation into factors that may inform an intervention strategy to reduce or reverse the cognitive deficits resulting from prenatal CPF exposure.

In Enterovirus 71 Encephalitis With Cardio-Respiratory Compromise, Elevated Interleukin 1β, Interleukin 1 Receptor Antagonist, and Granulocyte Colony-Stimulating Factor Levels Are Markers of Poor Prognosis

The Journal of Infectious Diseases. Aug, 2012  |  Pubmed ID: 22829643

Background. Enterovirus 71 (EV71) causes large outbreaks of hand, foot, and mouth disease (HFMD), with severe neurological complications and cardio-respiratory compromise, but the pathogenesis is poorly understood.Methods. We measured levels of 30 chemokines and cytokines in serum and cerebrospinal fluid (CSF) samples from Malaysian children hospitalized with EV71 infection (n = 88), comprising uncomplicated HFMD (n = 47), meningitis (n = 8), acute flaccid paralysis (n = 1), encephalitis (n = 21), and encephalitis with cardio-respiratory compromise (n = 11). Four of the latter patients died.Results. Both pro-inflammatory and anti-inflammatory mediator levels were elevated, with different patterns of mediator abundance in the CSF and vascular compartments. Serum concentrations of interleukin 1β (IL-1β), interleukin 1 receptor antagonist (IL-1Ra), and granulocyte colony-stimulating factor (G-CSF) were raised significantly in patients who developed cardio-respiratory compromise (P = .013, P = .004, and P < .001, respectively). Serum IL-1Ra and G-CSF levels were also significantly elevated in patients who died, with a serum G-CSF to interleukin 5 ratio of >100 at admission being the most accurate prognostic marker for death (P < .001; accuracy, 85.5%; sensitivity, 100%; specificity, 84.7%).Conclusions. Given that IL-1β has a negative inotropic action on the heart, and that both its natural antagonist, IL-1Ra, and G-CSF are being assessed as treatments for acute cardiac impairment, the findings suggest we have identified functional markers of EV71-related cardiac dysfunction and potential treatment options.

IDENTIFICATION OF THE WESTERN TARNISHED PLANT BUG (Lygus Hesperus) OLFACTORY CO-RECEPTOR ORCO: EXPRESSION PROFILE AND CONFIRMATION OF ATYPICAL MEMBRANE TOPOLOGY

Archives of Insect Biochemistry and Physiology. Jul, 2012  |  Pubmed ID: 22836832

Lygus hesperus (western tarnished plant bug) is an agronomically important pest species of numerous cropping systems. Similar to other insects, a critical component underlying behaviors is the perception and discrimination of olfactory cues. Consequently, the molecular basis of olfaction in this species is of interest. To begin to address this issue, we utilized homology-based PCR as a commonly accepted abbreviation but if necessary it is polymerase chain reaction methods to identify the L. hesperus olfactory receptor co-receptor (Orco) ortholog, a receptor that has been shown to be essential for olfaction. The L. hesperus Orco (LhOrco) shares significant sequence homology with known Orco proteins in other insects. Parallel experiments using the sympatric sister species, Lygus lineolaris (tarnished plant bug), revealed that the Lygus Orco gene was completely conserved. Surprisingly, a majority of the membrane topology prediction algorithms used in the study predicted LhOrco to have both the N and C terminus intracellular. In vitro immunofluorescent microscopy experiments designed to probe the membrane topology of transiently expressed LhOrco, however, refuted those predictions and confirmed that the protein adopts the inverted topology (intracellular N terminus and an extracellular C terminus) characteristic of Orco proteins. RT-PCR analyses indicated that LhOrco transcripts are predominantly expressed in adult antennae and to a lesser degree in traditionally nonolfactory chemosensory tissues of the proboscis and legs. Expression is not developmentally regulated because transcripts were detected in all nymphal stages as well as eggs. Taken together, the results suggest that LhOrco likely plays a critical role in mediating L. hesperus odorant perception and discrimination.

Benchmark Studies on the Building Blocks of DNA: II. Effect of Biological Environment on the Electronic Excitation Spectrum of Nucleobases

The Journal of Physical Chemistry. A. Jul, 2012  |  Pubmed ID: 22845884

In the first paper of this series (Szalay et al. {\it J. Phys. Chem. A}, {\bf 2012} DOI: 10.1021/jp300977a) we have investigated the excited states of nucleobases. It was shown that it is only the Equation of Motion Excitation Energy Coupled-Cluster (EOMEE-CC) methods which can give a balanced description for all type of the transitions of these molecules; if the goal is to obtain accurate results with uncertainty of about 0.1 eV only, triples corrections in the form of e.g. the EOMEE-CCSD(T) method needs to be included. In this second paper we extend this study to nucleobases in their biological environment, considering hydration, glycoside bond and base pairing. EOMEE-CCSD and EOMEE-CCSD(T) methods are used with aug-cc-pVDZ basis. The effect of surrounding water was systematically investigated by considering one to five water molecules at different positions. It was found that hydration can modify the order of the excited states: in particular \npi\ states get shifted above the neighboring \pipi\ ones. The glycoside bond's effect is smaller as has been shown by calculations on cytidine and guanosine. Here the loss of planarity causes some intensity shift from \pipi\ to \npi\ states. Finally the guanine-cytosine (GC) Watson-Crick pair was studied; most of the states could be identified as local excitations on one of the bases, but there is also a low lying charge-transfer state. Significant discrepancy with earlier CASPT2 and TDDFT studies was found for the GC pair and triples effects seem to be essential for all of these systems.

Reliability of Metatarsus Adductus Angle and Correlation with Hallux Valgus

Foot and Ankle Surgery : Official Journal of the European Society of Foot and Ankle Surgeons. Sep, 2012  |  Pubmed ID: 22857959

Metatarsus adductus is a common congenital foot deformity. Variable prevalence values were reported using different techniques in different populations. Numerous radiological measurements have been proposed to assess this deformity with a paucity of studies reporting the reliability of these methods. The metatarsus adductus angle was shown to correlate with the severity of hallux abductovalgus in normal feet and preselected populations of juvenile hallux valgus.

Antitumor Activity of Mushroom Polysaccharides: a Review

Food & Function. Aug, 2012  |  Pubmed ID: 22865023

Mushrooms were considered as a special delicacy by early civilizations and valued as a credible source of nutrients including considerable amounts of dietary fiber, minerals, and vitamins (in particularly, vitamin D). Mushrooms are also recognized as functional foods for their bioactive compounds offer huge beneficial impacts on human health. One of those potent bioactives is β-glucan, comprising a backbone of glucose residues linked by β-(1→3)-glycosidic bonds with attached β-(1→6) branch points, which exhibits antitumor and immunostimulating properties. The commercial pharmaceutical products from this polysaccharide source, such as schizophyllan, lentinan, grifolan, PSP (polysaccharide-peptide complex) and PSK (polysaccharide-protein complex), have shown evident clinical results. The immunomodulating action of mushroom polysaccharides is to stimulate natural killer cells, T-cells, B-cells, neutrophils, and macrophage dependent immune system responses via differing receptors involving dectin-1, the toll-like receptor-2 (a class of proteins that play a role in the immune system), scavengers and lactosylceramides. β-Glucans with various structures present distinct affinities toward these receptors to trigger different host responses. Basically, their antitumor abilities are influenced by the molecular mass, branching configuration, conformation, and chemical modification of the polysaccharides. This review aims to integrate the information regarding nutritional, chemical and biological aspects of polysaccharides in mushrooms, which will possibly be employed to elucidate the correlation between their structural features and biological functions.

The Future of Warfarin Pharmacogenetics in Under-represented Minority Groups

Future Cardiology. Jul, 2012  |  Pubmed ID: 22871196

Genotype-based dosing recommendations are provided in the US FDA-approved warfarin labeling. However, data that informed these recommendations were from predominately Caucasian populations. Studies show that variants contributing to warfarin dose requirements in Caucasians provide similar contributions to dose requirements in US Hispanics, but significantly lesser contributions in African-Americans. Further data demonstrate that variants occurring commonly in individuals of African ancestry, but rarely in other racial groups, significantly influence dose requirements in African-Americans. These data suggest that it is important to consider variants specific for African-Americans when implementing genotype-guided warfarin dosing in this population.

The Handling and Sampling of Radical Prostatectomy Specimens for Reporting and Research: the Oxford Approach

Journal of Clinical Pathology. Aug, 2012  |  Pubmed ID: 22872704

This article reviews previously described methods of fresh tissue sampling from radical prostatectomy specimens for research and describes a method used in Oxford which is simple, logical and cost effective. The method utilises a systematic zonal approach to tissue procurement in order to meet the increasing requirement for research samples with detailed morphological information such as zone of origin, tumour stage and Gleason grade.The described method involves punch biopsy sampling from a 4mm thick transverse slice cut 8mm superior to the apex. 9 biopsies are taken from each specimen in the following zonal distribution: Mid anterior, right lateral, right peripheral zone lateral, right peripheral zone mid, left peripheral zone mid, left peripheral zone lateral, left lateral, left transition zone and right transition zone.The method was validated by successfully sampling tumour in 7 out of 8 cases (88%). In 6 of the positive cases, tumour was present in more than 1 punch biopsy. The mean time from receipt of the specimen to completion of the biopsy freezing was 23.5 minutes. Tumour stage, zone and Gleason grade were determined for all positive biopsies. All cases were reported to RCPath guidelines with no compromising of margins.A logical systematic method of fresh tissue sampling from radical prostatectomy specimens is presented, which balances the need for accurate routine histopathological reporting with the requirement for increasingly complex research samples to be taken with attention to morphological details such as zone and stage.

Cancer Outcomes and All-cause Mortality in Adults Allocated to Metformin: Systematic Review and Collaborative Meta-analysis of Randomised Clinical Trials

Diabetologia. Aug, 2012  |  Pubmed ID: 22875195

AIMS/HYPOTHESIS: Observational studies suggest that metformin may reduce cancer risk by approximately one-third. We examined cancer outcomes and all-cause mortality in published randomised controlled trials (RCTs). METHODS: RCTs comparing metformin with active glucose-lowering therapy or placebo/usual care, with minimum 500 participants and 1-year follow-up, were identified by systematic review. Data on cancer incidence and all-cause mortality were obtained from publications or by contacting investigators. For two trials, cancer incidence data were not available; cancer mortality was used as a surrogate. Summary RRs, 95% CIs and I (2)statistics for heterogeneity were calculated by fixed effects meta-analysis. RESULTS: Of 4,039 abstracts identified, 94 publications described 14 eligible studies. RRs for cancer were available from 11 RCTs with 398 cancers during 51,681 person-years. RRs for all-cause mortality were available from 13 RCTs with 552 deaths during 66,447 person-years. Summary RRs for cancer outcomes in people randomised to metformin compared with any comparator were 1.02 (95% CI 0.82, 1.26) across all trials, 0.98 (95% CI 0.77, 1.23) in a subgroup analysis of active-comparator trials and 1.36 (95% CI 0.74, 2.49) in a subgroup analysis of placebo/usual care comparator trials. The summary RR for all-cause mortality was 0.94 (95% CI 0.79, 1.12) across all trials. CONCLUSIONS/INTERPRETATION: Meta-analysis of currently available RCT data does not support the hypothesis that metformin lowers cancer risk by one-third. Eligible trials also showed no significant effect of metformin on all-cause mortality. However, limitations include heterogeneous comparator types, absent cancer data from two trials, and short follow-up, especially for mortality.

The Effect of the Charge-Separating Interface on Exciton Dynamics in Photocatalytic Colloidal Heteronanocrystals

ACS Nano. Aug, 2012  |  Pubmed ID: 22881284

Ultrafast transient absorption spectroscopy was used to investigate the nature of photoinduced charge transfer processes taking place in ZnSe/CdS/Pt colloidal heteronanocrystals. These nanoparticles consist of a dot-in-a-rod semiconductor domain (ZnSe/CdS) coupled to a Pt tip. Together the three components are designed to dissociate an electron-hole pair by pinning the hole in the ZnSe domain while allowing the electron to transfer into the Pt tip. Separated charges can then induce a catalytic reaction, such as the light-driven hydrogen production. Present measurements demonstrate that the internal electron-hole separation is fast and results in the localization of both charges in nonadjacent parts of the nanoparticle. In particular, we show that photoinduced holes become confined within the ZnSe domain in less than 2 ps, while electrons take approximately 15 ps to transition into a Pt tip. More importantly, we demonstrate that the presence of the ZnSe dot within the CdS nanorods plays a key role both in enabling photoinduced separation of charges and in suppressing their backward recombination. The implications of the observed exciton dynamics to photocatalytic function of ZnSe/CdS/Pt heteronanocrystals are discussed.

Painting by Numbers: A Guide for Systematically Developing Indicators of Performance at Any Level of Health Care

Health Policy (Amsterdam, Netherlands). Aug, 2012  |  Pubmed ID: 22883386

OBJECTIVES: There is a need for methods to facilitate selection of robust indicators in health care settings. This research aims to determine the key steps in, and delineate a systematic process for, construction of health care performance indicators. METHODS: Information derived from a review of the published literature and analysis of key informant interviews was synthesised to derive key activities and concepts fundamental to, and essential for, the development of robust and meaningful indicators. These activities and concepts were ordered into a logical sequence. RESULTS: A sequence of six stages (prioritisation; intent; implementation requirements; measure specifications; indicator assessment; target development), with a series of steps within each stage, was delineated. This sequence comprises the Systematic Indicator Development (SID) Method, which may be utilised by health care policy decision makers, providers, or clinicians in a 'paint by numbers' manner to create robust and meaningful indicators, or to refine or amend existing indicators. CONCLUSIONS: The SID Method blends different aspects of indicator art and science and structures it in a logical way to provide transparency, consistency and rigour to indicator construction. The approach ensures that all health care sector stakeholders can make informed decisions when selecting indictors or interpreting obtained results.

Methemoglobinemia and Ascorbate Deficiency in Hemoglobin E β Thalassemia: Metabolic and Clinical Implications

Blood. Aug, 2012  |  Pubmed ID: 22885163

During investigations of the phenotypic diversity of hemoglobin E β thalassemia, the commonest form of severe thalassemia in many Asian countries, a patient was encountered with persistently high levels of methemoglobin associated with a left-shift in the oxygen dissociation curve, profound ascorbate deficiency and clinical features of scurvy; these abnormalities were corrected by treatment with vitamin C. Studies of erythropoietin production before and after treatment suggested that, as in an ascorbate-deficient murine model, the human hypoxia induction factor (HIF) pathway is not totally dependent on ascorbate levels. A follow-up study of 45 patients with HbE β thalassemia showed that methemoglobin levels were significantly raised and that there was also a significant reduction in plasma ascorbate levels, although not to those observed in the presenting patient. Haptoglobin levels were significantly reduced and the high frequency of the 2.2 haptoglobin genotype may place an additional pressure on ascorbate as a free-radical scavenger in this population. There was, in addition, a highly significant correlation between methemoglobin levels, splenectomy and factors that modify the degree of globin-chain imbalance. Since it is clear that methemoglobin levels are modified by several mechanisms, and because it may play a role in both adaptation to anemia and vascular damage, there is a strong case for its further study in other forms of thalassemia and sickle-cell anemia, particularly when splenic function is defective.

Treating Stiffness After Total Knee Arthroplasty: A Technical Note and Preliminary Results

The Open Orthopaedics Journal. 2012  |  Pubmed ID: 22888378

Total Knee Replacement is used to treat pain, stiffness and reduced range of movement. It has been estimated that a minimum of 90 degrees of range of motion in the knee is required for normal activities of daily living. In this article we demonstrate a technical note with a small patient series about the methods of treating knee stiffness after Total Knee Replacement.

Phlebotonics for Haemorrhoids

Cochrane Database of Systematic Reviews (Online). 2012  |  Pubmed ID: 22895941

Haemorrhoids are variceal dilatations of the anal and perianal venous plexus and often develop secondary to the persistently elevated venous pressure within the haemorrhoidal plexus (Kumar 2005). Phlebotonics are a heterogenous class of drugs consisting of plant extracts (i.e. flavonoids) and synthetic compounds (i.e. calcium dobesilate). Although their precise mechanism of action has not been fully established, they are known to improve venous tone, stabilize capillary permeability and increase lymphatic drainage. They have been used to treat a variety of conditions including chronic venous insufficiency, lymphoedema and haemorrhoids.Numerous trials assessing the effect of phlebotonics in treating the symptoms and signs of haemorrhoidal disease suggest that there is a potential benefit.

Corticosteroids for the Common Cold

Cochrane Database of Systematic Reviews (Online). 2012  |  Pubmed ID: 22895973

The common cold is a frequent illness, which, although benign and self-limiting, results in many consultations to primary care and considerable loss of school or work days. Current symptomatic treatments have limited benefit. Corticosteroids are an effective treatment in other upper respiratory tract infections and their anti-inflammatory effects may also be beneficial in the common cold.

Dengue Virus Infection Perturbs Lipid Homeostasis in Infected Mosquito Cells

PLoS Pathogens. 2012  |  Pubmed ID: 22457619

Dengue virus causes ∼50-100 million infections per year and thus is considered one of the most aggressive arthropod-borne human pathogen worldwide. During its replication, dengue virus induces dramatic alterations in the intracellular membranes of infected cells. This phenomenon is observed both in human and vector-derived cells. Using high-resolution mass spectrometry of mosquito cells, we show that this membrane remodeling is directly linked to a unique lipid repertoire induced by dengue virus infection. Specifically, 15% of the metabolites detected were significantly different between DENV infected and uninfected cells while 85% of the metabolites detected were significantly different in isolated replication complex membranes. Furthermore, we demonstrate that intracellular lipid redistribution induced by the inhibition of fatty acid synthase, the rate-limiting enzyme in lipid biosynthesis, is sufficient for cell survival but is inhibitory to dengue virus replication. Lipids that have the capacity to destabilize and change the curvature of membranes as well as lipids that change the permeability of membranes are enriched in dengue virus infected cells. Several sphingolipids and other bioactive signaling molecules that are involved in controlling membrane fusion, fission, and trafficking as well as molecules that influence cytoskeletal reorganization are also up regulated during dengue infection. These observations shed light on the emerging role of lipids in shaping the membrane and protein environments during viral infections and suggest membrane-organizing principles that may influence virus-induced intracellular membrane architecture.

Embryonic and Larval Development of Eugerres Mexicanus (Perciformes: Gerreidae) in Tenosique, Tabasco, Mexico

Revista De Biología Tropical. Mar, 2012  |  Pubmed ID: 22458231

Most studies on Eugerres mexicanus mainly consider biogeographic and systematic aspects and rarely address reproductive characteristics, which are useful for fishery population management plans. This study aimed at evaluating the ontogeny of E. mexicanus, based on 30 embryos and 30 larvae sampled by induced spawning of breeders, taken in February 2009 from the Usumacinta River in Tenosique, Tabasco, Mexico. All descriptions of the embryonic development were based on morphometric and meristic data and followed standard methods. Eggs, recovered at the gastrula stage, had an average diameter of 1.17mm (SD=0.08). The bud stage appeared during the first three hours of development, in which the posterior side was adhered to the vitellus; Kupffer's vesicle was visible. Yolk-sac larvae hatched 18 hours after fertilization, exhibiting a light brown color and an average total length of 2.94mm (SD=0.70); the preflexion stage was reached eight days after hatching, with a total average length of 4.67mm (SD=0.50) and a total notochord length of 4.45mm (SD=0.50). The flexion stage was reached on the 16th day, with an average total length of 6.66mm (SD=1.53), while postflexion was reached on the 24th day, with 10.33mm (SD=1.45). The pre-juvenile stage was reached on the 33rd day, with a total length of 14.30mm (SD=0.93), showing IX spines and 10 rays and III spines and eight rays in the dorsal and anal fins, respectively. The juvenile stage was reached by the 45th day, with an average length of 28.16mm (SD=1.93) and average weight of 4.75g (SD=1.49). Prejuveniles showed an initial pigmentation with dark colored dots in the superior and inferior jaw and dispersed on the head, while juveniles presented the same pigmentation pattern, decreasing towards the margin of the caudal peduncle. In conclusion, the embryonic developmental stages of E. mexicanus were typical for the Gerreidae group. However, their morphometric characters were slightly different since the diameter and size of the drop of oil were bigger than those reported for marine species. In addition, regarding pigmentation, the yolk-sac larvae of E. mexicanus were olive and yellow on the margin of the notochord, which differs from those reported for other species. This is the first recorded report on the reproductive biology and early life development of this species.

Molecular Screening of Nematodes in Lacertid Lizards from the Iberian Peninsula and Balearic Islands Using 18S RRNA Sequences

Journal of Helminthology. Apr, 2012  |  Pubmed ID: 22464729

The development of molecular methods is becoming a promising field in the analysis of parasite fauna in wildlife species. This is especially useful in the case of parasite species where developmental larval stages are difficult to assess using standard methods. In this study we screened for the presence of parasitic nematodes infecting lacertid lizards from the Iberian Peninsula and Balearic islands using nematode-specific 18S ribosomal RNA gene primers on host tissue samples. Sequencing of positive samples revealed the presence of different genera of nematodes. The detection of Strongyloides, a monoxenous genus reported for the first time in Podarcis lilfordi is probably the result of the amplification of larval stages present in the host circulatory system. Two spirurid nematodes, Synhimantus and a new unidentified clade, were also found, suggesting that reptiles might be paratenic hosts of several spirurid species. This study demonstrates the benefits of using specific molecular markers on tissue samples to identify infecting larval stages of nematodes, otherwise difficult to assess using traditional screening methods.

A Subspace Method for the Detection of Transcription Factor Binding Sites

Bioinformatics (Oxford, England). May, 2012  |  Pubmed ID: 22467907

MOTIVATION: The identification of the sites at which transcription factors (TFs) bind to Deoxyribonucleic acid (DNA) is an important problem in molecular biology. Many computational methods have been developed for motif finding, most of them based on position-specific scoring matrices (PSSMs) which assume the independence of positions within a binding site. However, some experimental and computational studies demonstrate that interdependences within the positions exist. RESULTS: In this article, we introduce a novel motif finding method which constructs a subspace based on the covariance of numerical DNA sequences. When a candidate sequence is projected into the modeled subspace, a threshold in the Q-residuals confidence allows us to predict whether this sequence is a binding site. Using the TRANSFAC and JASPAR databases, we compared our Q-residuals detector with existing PSSM methods. In most of the studied TF binding sites, the Q-residuals detector performs significantly better and faster than MATCH and MAST. As compared with Motifscan, a method which takes into account interdependences, the performance of the Q-residuals detector is better when the number of available sequences is small.

Biological Properties of Solid Free Form Designed Ceramic Scaffolds with BMP-2: in Vitro and in Vivo Evaluation

PloS One. 2012  |  Pubmed ID: 22470527

Porous ceramic scaffolds are widely studied in the tissue engineering field due to their potential in medical applications as bone substitutes or as bone-filling materials. Solid free form (SFF) fabrication methods allow fabrication of ceramic scaffolds with fully controlled pore architecture, which opens new perspectives in bone tissue regeneration materials. However, little experimentation has been performed about real biological properties and possible applications of SFF designed 3D ceramic scaffolds. Thus, here the biological properties of a specific SFF scaffold are evaluated first, both in vitro and in vivo, and later scaffolds are also implanted in pig maxillary defect, which is a model for a possible application in maxillofacial surgery. In vitro results show good biocompatibility of the scaffolds, promoting cell ingrowth. In vivo results indicate that material on its own conducts surrounding tissue and allow cell ingrowth, thanks to the designed pore size. Additional osteoinductive properties were obtained with BMP-2, which was loaded on scaffolds, and optimal bone formation was observed in pig implantation model. Collectively, data show that SFF scaffolds have real application possibilities for bone tissue engineering purposes, with the main advantage of being fully customizable 3D structures.

NSP4, an Elastase-related Protease in Human Neutrophils with Arginine Specificity

Proceedings of the National Academy of Sciences of the United States of America. Apr, 2012  |  Pubmed ID: 22474388

Neutrophil serine proteases (NSPs) in cytoplasmic granules of neutrophils are regarded as important antimicrobial defense weapons after engulfment and exposure of pathogens to the content of primary granules. Despite intensive studies on neutrophils during the last three decades, only three active serine proteases, neutrophil elastase (NE), cathepsin G (CG), and proteinase 3 (PR3) have been identified in these short-lived cells. Here, we report on the identification of a fourth serine protease (NSP4) with 39% identity to NE and PR3, but arginine specificity, yet sharing features like propeptide processing by dipeptidyl peptidase I, storage, and release as an active enzyme with the three active proteases. We established monoclonal antibodies against NSP4, excluded cross-reactivity to human granzymes, NE, CG, PR3, and azurocidin, and screened for NSP4 protein expression in various human tissues and blood leukocyte populations. Only granulocyte precursors and neutrophil populations from peripheral blood were positive. The content of NSP4 in neutrophil lysates, however, was about 20-fold lower compared with CG. Upon neutrophil activation, NSP4 was released into the supernatant. Profiling its specificity with peptide libraries from Escherichia coli revealed a preference for arginine in P1; it cleaved Tyr-Arg-Phe-Arg-AMC and Ala-Pro-Nva-thiobenzyl esters. NSP4 was inhibited by α(1)-proteinase inhibitor (α(1)-antitrypsin), C1 inhibitor, and most efficiently by antithrombin-heparin, but not by elafin, secretory leukocyte protease inhibitor, α(1)-antichymotrypsin, and monocyte-neutrophil elastase inhibitor. Functional specialization and preferred natural substrates of NSP4 remain to be determined to understand the biological interplay of all four NSPs during neutrophil responses.

The Sarcomeric Cytoskeleton As a Target for Pharmacological Intervention

Current Opinion in Pharmacology. Jun, 2012  |  Pubmed ID: 22483604

Many diseases of heart and skeletal muscle, from heart failure to muscle atrophy, pose unmet needs for specific and effective treatments. Recent advances suggest that sarcomeres, the smallest contractile units of heart and skeletal muscles, can be viable pharmacological targets. In sarcomeres, the contractile actin and myosin filaments are organised by a network of proteins combining structural and signalling functions, forming the sarcomeric cytoskeleton. This includes the giant proteins titin, obscurin and nebulin, which contain protein-binding sites along with signalling domains such as protein kinase, Rho activator, and Src-homology domains. These signalling domains have recently been implicated in sarcomere assembly, and the regulation of muscle contractile and metabolic adaptation. Although many functions of sarcomeric proteins remain to be discovered, their potential as pharmacological targets is now emerging. Here, we will review recent insight into the physiological and pathological signalling functions of sarcomeric cytoskeletal proteins and discuss new aspects and strategies in skeletal muscle signalling, pathomechanisms and therapy.

Evaluation of a Monoclonal Antibody-based Rapid Immunochromatographic Test for Direct Detection of Rabies Virus in the Brain of Humans and Animals

The American Journal of Tropical Medicine and Hygiene. Apr, 2012  |  Pubmed ID: 22492163

Rabies diagnosis uses a direct fluorescent antibody test (FAT) that is difficult, costly, and time-consuming, and requires trained personnel. We developed a rapid immunochromatographic test (RICT) for the diagnosis of rabies. The efficacy of the RICT was compared with that of the FAT. Brain samples were collected from humans, dogs, cats, and other animals in Sri Lanka (n = 248), Bhutan (n = 27), and Thailand (n = 228). The sensitivity (0.74-0.95), specificity (0.98-1.0), positive predictive value (0.98-1.0), negative predictive value (0.75-0.97), accuracy (0.91-0.98), and kappa measure of agreement (0.79-0.93) were all satisfactory for animal samples and samples preserved in 50% glycerol saline solution. Because the RICT showed high sensitivity but low specificity with human brain samples, it is unsuitable for confirming rabies in humans. No amino acid substitutions were found in the antibody attachment sites of the nucleoprotein gene with FAT-positive, RICT-negative samples. The RICT is reliable, user friendly, rapid, robust, and can be used in laboratories with a modest infrastructure.

Emerging Functional and Mechanistic Paradigms of Mammalian Long Non-coding RNAs

Nucleic Acids Research. Aug, 2012  |  Pubmed ID: 22492512

The recent discovery that the human and other mammalian genomes produce thousands of long non-coding RNAs (lncRNAs) raises many fascinating questions. These mRNA-like molecules, which lack significant protein-coding capacity, have been implicated in a wide range of biological functions through diverse and as yet poorly understood molecular mechanisms. Despite some recent insights into how lncRNAs function in such diverse cellular processes as regulation of gene expression and assembly of cellular structures, by and large, the key questions regarding lncRNA mechanisms remain to be answered. In this review, we discuss recent advances in understanding the biology of lncRNAs and propose avenues of investigation that may lead to fundamental new insights into their functions and mechanisms of action. Finally, as numerous lncRNAs are dysregulated in human diseases and disorders, we also discuss potential roles for these molecules in human health.

Bax and Bcl-xL Exert Their Regulation on Different Sites of the Ceramide Channel

The Biochemical Journal. Jul, 2012  |  Pubmed ID: 22494048

The present study demonstrates the important structural features of ceramide required for proper regulation, binding and identification by both pro-apoptotic and anti-apoptotic Bcl-2 family proteins. The C-4=C-5 trans-double bond has little influence on the ability of Bax and Bcl-xL to identify and bind to these channels. The stereochemistry of the headgroup and access to the amide group of ceramide is indispensible for Bax binding, indicating that Bax may interact with the polar portion of the ceramide channel facing the bulk phase. In contrast, Bcl-xL binding to ceramide channels is tolerant of stereochemical changes in the headgroup. The present study also revealed that Bcl-xL has an optimal interaction with long-chain ceramides that are elevated early in apoptosis, whereas short-chain ceramides are not well regulated. Inhibitors specific for the hydrophobic groove of Bcl-xL, including 2-methoxyantimycin A3, ABT-737 and ABT-263 provide insights into the region of Bcl-xL involved in binding to ceramide channels. Molecular docking simulations of the lowest-energy binding poses of ceramides and Bcl-xL inhibitors to Bcl-xL were consistent with the results of our functional studies and propose potential binding modes.

Identification of a Sex-linked Marker for Channel Catfish

Animal Genetics. Aug, 2012  |  Pubmed ID: 22497362

Sub-20 Nm Laser Ablation for Lithographic Dry Development

Nanotechnology. May, 2012  |  Pubmed ID: 22498667

Pattern collapse of small or high aspect ratio lines during traditional wet development is a major challenge for miniaturization in nanolithography. Here we report on a new dry process which combines high resolution resist exposure with selective laser ablation to achieve high resolution with high aspect ratios. Using a low power 532 nm laser, we dry develop a normally negative tone methyl acetoxy calix(6)arene in positive tone to reveal sub-20 nm half-pitch features in a ∼100 nm film at aspect ratios unattainable with conventional development with ablation time of 1-2 s per laser pixel (∼600 nm diameter spot). We also demonstrate superior negative tone wet development by combining electron beam exposure with subsequent laser exposure at a non-ablative threshold that requires far less electron beam exposure doses than traditional wet development.

Association of Childhood Obesity with Maternal Exposure to Ambient Air Polycyclic Aromatic Hydrocarbons During Pregnancy

American Journal of Epidemiology. Jun, 2012  |  Pubmed ID: 22505764

There are concerns that prenatal exposure to endocrine-disrupting chemicals increases children's risk of obesity. African-American and Hispanic children born in the Bronx or Northern Manhattan, New York (1998-2006), whose mothers underwent personal air monitoring for polycyclic aromatic hydrocarbon (PAH) exposure during pregnancy, were followed up to ages 5 (n = 422) and 7 (n = 341) years. At age 5 years, 21% of the children were obese, as were 25% of those followed to age 7 years. After adjustment for child's sex, age at measurement, ethnicity, and birth weight and maternal receipt of public assistance and prepregnancy obesity, higher prenatal PAH exposures were significantly associated with higher childhood body size. In adjusted analyses, compared with children of mothers in the lowest tertile of PAH exposure, children of mothers in the highest exposure tertile had a 0.39-unit higher body mass index z score (95% confidence interval (CI): 0.08, 0.70) and a relative risk of 1.79 (95% CI: 1.09, 2.96) for obesity at age 5 years, and they had a 0.30-unit higher body mass index z score (95% CI: 0.01, 0.59), a 1.93-unit higher percentage of body fat (95% CI: 0.33, 3.54), and a relative risk of 2.26 (95% CI: 1.28, 4.00) for obesity at age 7 years. The data indicate that prenatal exposure to PAHs is associated with obesity in childhood.

Neuraminidase Inhibitors for Preventing and Treating Influenza in Children (published Trials Only)

Cochrane Database of Systematic Reviews (Online). 2012  |  Pubmed ID: 22513907

During epidemics, influenza attack rates in children may exceed 40%. Options for prevention and treatment currently include the neuraminidase inhibitors zanamivir and oseltamivir. Laninamivir octanoate, the prodrug of laninamivir, is currently being developed.

Evaluation of an Improved Rapid Neutralizing Antibody Detection Test (RAPINA) for Qualitative and Semiquantitative Detection of Rabies Neutralizing Antibody in Humans and Dogs

Vaccine. Jun, 2012  |  Pubmed ID: 22516211

Using the principle of immunochromatography, we previously developed a method called RAPINA (Rapid Neutralizing Antibody detection test) that can measure the level of rabies virus -neutralizing antibody (VNA) in serum samples [Shiota S, Mannen K, Matsumoto T, Yamada K, Yasui T, Takayama K, et al. Development and evaluation of a rapid neutralizing antibody test for rabies. J Virol Methods 2009;161:58-62]. RAPINA is faster, simpler, and easier to perform compared with a virus-neutralizing test or enzyme-linked immunosorbent assay (ELISA). The improved version of RAPINA has greater positive and negative predictive values corresponding to a VNA level of 0.5 IU/mL, as recommended by the World Health Organization and the World Organization for Animal Health. To verify the efficacy of this improved method, serum samples were collected from humans and dogs before and after immunization against rabies and were tested in Japan, Sri Lanka, and Thailand. The results were compared between RAPINA and the true VNA levels measured by the Rapid Fluorescent Focus Inhibition Test (RFFIT). The improved RAPINA accurately predicted seropositivity for 182 of 183 seropositive human samples as assessed by RFFIT (99.5%) and for 138 of 140 RFFIT-negative human samples (98.6%). In dog serum samples, the positive and negative predictive values were 99.7% (345/355) and 95.6% (174/182), respectively. RAPINA was also used to estimate VNA levels in a semiquantitative manner by using serial dilution of serum samples. Our results show that RAPINA is an easy and rapid method for measuring VNA levels before and after immunization with the rabies vaccine and does not need a high skill level or sophisticated equipment. RAPINA can be used to monitor the success of preexposure prophylaxis in at-risk persons, vaccine coverage, and animal control. It can also be used in laboratories with modest facilities and where a large number of samples are screened.

Fear Avoidance Beliefs Predict Disability in Older Adults with Chronic Low Back Pain

PM & R : the Journal of Injury, Function, and Rehabilitation. Jul, 2012  |  Pubmed ID: 22516436

To determine whether fear avoidance beliefs (FABs) in older adults with chronic low back pain (CLBP) are significantly associated with gait speed decline and/or self-report of greater disability.

Effects of Cinnamomum Zeylanicum (Ceylon Cinnamon) on Blood Glucose and Lipids in a Diabetic and Healthy Rat Model

Pharmacognosy Research. Apr, 2012  |  Pubmed ID: 22518078

To evaluate short- and long-term effects of Cinnamomum zeylanicum on food consumption, body weight, glycemic control, and lipids in healthy and diabetes-induced rats.

Repeated Dengue Shock Syndrome and 'dengue Myocarditis' Responding Dramatically to a Single Dose of Methyl Prednisolone

International Journal of Infectious Diseases : IJID : Official Publication of the International Society for Infectious Diseases. Jul, 2012  |  Pubmed ID: 22521778

The place of steroids in the management of severe forms of dengue is unclear. A retrospective observational study showed the benefits of a single dose of intravenous methyl prednisolone in a highly selected group of patients who developed severe dengue during the febrile phase of infection. We report the case of a 14-year-old boy with dengue who developed three episodes of severe hemodynamic compromise while having high fever, 'myocarditis', third space fluid accumulation, progressive reduction in urine output, and altered mentation, who made a dramatic recovery following a single dose of intravenous methyl prednisolone. Results justify a well powered randomized controlled trial to evaluate the efficacy of this treatment in severe dengue.

Letter by Lumley Et Al Regarding Article, "arterial Pulse Wave Dynamics After Percutaneous Aortic Valve Replacement: Fall in Coronary Diastolic Suction with Increasing Heart Rate As a Basis for Angina Symptoms in Aortic Stenosis"

Circulation. Apr, 2012  |  Pubmed ID: 22529071

The Greater Sensitivity of Elderly APOE ε4 Carriers to Anticholinergic Medications is Independent of Cerebrovascular Disease Risk

The American Journal of Geriatric Pharmacotherapy. Jun, 2012  |  Pubmed ID: 22534472

Recent studies found use of anticholinergic medications to be associated with greater performance decrements in older persons who carry an ε4 allele of the apolipoprotein E (APOE) gene than in those carrying only ε2 or ε3 alleles.

Conventional and Emerging Treatments in the Management of Acute Primary Angle Closure

Clinical Ophthalmology (Auckland, N.Z.). 2012  |  Pubmed ID: 22536030

The management of acute primary angle closure is directed at lowering the intraocular pressure and relieving pupil block. Conventional treatment involves the use of medical treatment and laser peripheral iridotomy, respectively, as a means for achieving these aims. Newer therapeutic strategies have been described that are potentially useful adjuncts or alternatives to conventional treatment. Emerging strategies that lower intraocular pressure include anterior chamber paracentesis, as well as laser procedures such as iridoplasty and pupilloplasty. A possible alternative to relieving pupil block is lens extraction, and may be combined with adjunctive measures such as goniosynechiolysis and viscogoniosynechiolysis. Trabeculectomy has a limited role in the acute setting. This review paper reviews the current evidence regarding conventional and newer treatment modalities for acute primary angle closure.

A Novel Use of 2-Octyl-cyanoacrylate: Controlling Post-hemodialysis Site Hemorrhage

The Journal of Emergency Medicine. Apr, 2012  |  Pubmed ID: 22538121

BACKGROUND: A common complication of hemodialysis is bleeding from the dialysis site. DISCUSSION: To demonstrate the use of 2-octyl-cyanoacrylate in controlling venous bleeding associated with hemodialysis access. CONCLUSION: 2-octyl-cyanoacrylate is effective in stopping venous bleeding from hemodialysis sites.

Search for Signatures of Extra Dimensions in the Diphoton Mass Spectrum at the Large Hadron Collider

Physical Review Letters. Mar, 2012  |  Pubmed ID: 22540461

A search for signatures of extra spatial dimensions in the diphoton invariant-mass spectrum has been performed with the CMS detector at the LHC. No excess of events above the standard model expectation is observed using a data sample collected in proton-proton collisions at √s=7 TeV corresponding to an integrated luminosity of 2.2 fb(-1). In the context of the large-extra-dimensions model, lower limits are set on the effective Planck scale in the range of 2.3-3.8 TeV at the 95% confidence level. These limits are the most restrictive bounds on virtual-graviton exchange to date. The most restrictive lower limits to date are also set on the mass of the first graviton excitation in the Randall-Sundrum model in the range of 0.86-1.84 TeV, for values of the associated coupling parameter between 0.01 and 0.10.

Search for the Standard Model Higgs Boson in the Decay Channel H→ZZ→4ℓ in Pp Collisions at ˆ�s=7 TeV

Physical Review Letters. Mar, 2012  |  Pubmed ID: 22540464

A search for a Higgs boson in the four-lepton decay channel H→ZZ, with each Z boson decaying to an electron or muon pair, is reported. The search covers Higgs boson mass hypotheses in the range of 110100 GeV (with 13 below 160 GeV), while 67.1±6.0 (9.5±1.3) events are expected from background. The four-lepton mass distribution is consistent with the expectation of standard model background production of ZZ pairs. Upper limits at 95% confidence level exclude the standard model Higgs boson in the ranges of 134-158 GeV, 180-305 GeV, and 340-465 GeV. Small excesses of events are observed around masses of 119, 126, and 320 GeV, making the observed limits weaker than expected in the absence of a signal.

Using Latent Class Growth Analysis to Identify Childhood Wheeze Phenotypes in an Urban Birth Cohort

Annals of Allergy, Asthma & Immunology : Official Publication of the American College of Allergy, Asthma, & Immunology. May, 2012  |  Pubmed ID: 22541400

To advance asthma cohort research, we need a method that can use longitudinal data, including when collected at irregular intervals, to model multiple phenotypes of wheeze and identify both time-invariant (eg, sex) and time-varying (eg, environmental exposure) risk factors.

Calcaneal Osteotomy in the Treatment of Adult Acquired Flatfoot Deformity

Foot and Ankle Clinics. Jun, 2012  |  Pubmed ID: 22541523

Calcaneal osteotomies are an essential part of our current armamentarium in the treatment of AAFD. Soft tissue correction or bony realignment alone have failed to adequately correct the deformity; therefore, both procedures are used simultaneously to achieve long-term correction. Medial displacement and lateral column lengthening osteotomies in isolation or in combination and the Malerba osteotomy have been employed along with soft tissue balancing to good effect by various authors. The goal is to create a stable bony configuration with adequate soft tissue balance to maintain dynamic equilibrium in the hindfoot. In “pronatory syndromes,” the relation of the osteotomy to the posterior subtalar facet modifies the biomechanics of the hindfoot in different ways. Anterior calcaneal osteotomies correct deformities in the transverse plane (forefoot abduction), whereas posterior tuberosity osteotomies result in “varization” of the calcaneus and correct the frontal plane deformity. The choice of osteotomy depends on the plane of the dominant deformity. If the subtalar axis is more horizontal than normal, transverse plane movement is cancelled out and the frontal plane eversion–inversion is predominant. The patient presents with marked hindfoot valgus without significant forefoot abduction. Conversely, if the subtalar axis is more vertical than normal, transverse plane movement is predominant and the patient presents with forefoot abduction and instability of the medial midtarsal joints, although without significant hindfoot valgus. In this situation, a lateral column lengthening procedure is recommended to decrease the uncovering of the talar head and improve the height of the arch while correcting the forefoot abduction. With a predominant frontal plane deformity, medialization of the calcaneal tuberosity is used to displace the calcaneal weight bearing axis medially, aligning it with the tibial axis and restoring the function of the gastrosoleus as a heel invertor. An essential prerequisite for this is the absence of arthritis affecting the subtalar joint. The Achilles tendon may need to be lengthened at the same time.

In Vivo Evaluation of an Oral Drug Delivery System for Peptides Based on S-protected Thiolated Chitosan

Journal of Controlled Release : Official Journal of the Controlled Release Society. Jun, 2012  |  Pubmed ID: 22542699

The aim of the present study was the development and evaluation in vitro as well as in vivo of an oral delivery system based on a novel type of thiolated chitosan, so-called S-protected thiolated chitosan, for the peptide drug antide. The sulfhydryl ligand thioglycolic acid (TGA) was covalently attached to chitosan (CS) in the first step of modification. In the second step, these thiol groups of thiolated chitosan were protected by disulfide bond formation with the thiolated aromatic residue 6-mercaptonicotinamide (6-MNA). Absorptive transport studies of antide were evaluated ex vivo using rat intestinal mucosa. Matrix tablets of each polymer sample were prepared and their effect on the absorption of antide evaluated in vivo in male Sprague-Dawley rats. In addition, tablets were examined in terms of their disintegration, swelling and drug release behavior. The resulting S-protected thiomer (TGA-MNA) exhibited 840μmol of covalently linked 6-MNA per gram thiomer. Based on the implementation of this hydrophobic ligand on the thiolated backbone, the disintegration behavior was reduced greatly and a controlled release of the peptide could be achieved. Furthermore, permeation studies with TGA-MNA on rat intestine revealed a 4.5-fold enhanced absorptive transport of the peptide in comparison to antide in solution. Additional in vivo studies confirmed the potential of this novel conjugate. Oral administration of antide in solution led to only very small detectable quantities in plasma with an absolute and relative bioavailability (BA) of 0.003 and 0.03%, only. In contrast, with antide incorporated in TGA-MNA matrix tablets an absolute and relative BA of 1.4 and 10.9% could be reached, resulting in a 421-fold increased area under the plasma concentration time curve (AUC) compared to the antide solution. According to these results, S-protected thiolated chitosan as oral drug delivery system might be a valuable tool for improving the bioavailability of peptides.

Prenatal Bisphenol a Exposure and Child Behavior in an Inner-city Cohort

Environmental Health Perspectives. Aug, 2012  |  Pubmed ID: 22543054

Background: Experimental laboratory evidence suggests that bisphenol A (BPA), an endocrine disruptor, is a neurodevelopmental toxicant. However, there have been limited and inconclusive results with respect to sex-specific BPA effects on child behavior.Objective: We examined the association between prenatal BPA exposure and child behavior, adjusting for postnatal BPA exposure and hypothesizing sex-specific effects.Methods: We followed African-American and Dominican women and their children from pregnancy to child's age 5 years, collecting spot urine samples from the mothers during pregnancy (34 weeks on average) and from children between 3 and 4 years of age to estimate BPA exposure. We assessed child behavior between 3 and 5 years of age using the Child Behavior Checklist (CBCL) and used generalized linear models to test the association between BPA exposure and child behavior, adjusting for potential confounders.Results: The analysis was conducted on 198 children (87 boys and 111 girls). Among boys, high prenatal BPA exposure (highest quartile vs. the lowest three quartiles) was associated with significantly higher CBCL scores (more problems) on Emotionally Reactive [1.62 times greater; 95% confidence interval (CI): 1.13, 2.32] and Aggressive Behavior syndromes (1.29 times greater; 95% CI: 1.09, 1.53). Among girls, higher exposure was associated with lower scores on all syndromes, reaching statistical significance for Anxious/Depressed (0.75 times as high; 95% CI: 0.57, 0.99) and Aggressive Behavior (0.82 times as high; 95% CI: 0.70, 0.97).Conclusion: These results suggest that prenatal exposure to BPA may affect child behavior, and differently among boys and girls.

Fetal Window of Vulnerability to Airborne Polycyclic Aromatic Hydrocarbons on Proportional Intrauterine Growth Restriction

PloS One. 2012  |  Pubmed ID: 22545107

Although the entire duration of fetal development is generally considered a highly susceptible period, it is of public health interest to determine a narrower window of heightened vulnerability to polycyclic aromatic hydrocarbons (PAHs) in humans. We posited that exposure to PAHs during the first trimester impairs fetal growth more severely than a similar level of exposure during the subsequent trimesters.

Brain Anomalies in Children Exposed Prenatally to a Common Organophosphate Pesticide

Proceedings of the National Academy of Sciences of the United States of America. May, 2012  |  Pubmed ID: 22547821

Prenatal exposure to chlorpyrifos (CPF), an organophosphate insecticide, is associated with neurobehavioral deficits in humans and animal models. We investigated associations between CPF exposure and brain morphology using magnetic resonance imaging in 40 children, 5.9-11.2 y, selected from a nonclinical, representative community-based cohort. Twenty high-exposure children (upper tertile of CPF concentrations in umbilical cord blood) were compared with 20 low-exposure children on cortical surface features; all participants had minimal prenatal exposure to environmental tobacco smoke and polycyclic aromatic hydrocarbons. High CPF exposure was associated with enlargement of superior temporal, posterior middle temporal, and inferior postcentral gyri bilaterally, and enlarged superior frontal gyrus, gyrus rectus, cuneus, and precuneus along the mesial wall of the right hemisphere. Group differences were derived from exposure effects on underlying white matter. A significant exposure × IQ interaction was derived from CPF disruption of normal IQ associations with surface measures in low-exposure children. In preliminary analyses, high-exposure children did not show expected sex differences in the right inferior parietal lobule and superior marginal gyrus, and displayed reversal of sex differences in the right mesial superior frontal gyrus, consistent with disruption by CPF of normal behavioral sexual dimorphisms reported in animal models. High-exposure children also showed frontal and parietal cortical thinning, and an inverse dose-response relationship between CPF and cortical thickness. This study reports significant associations of prenatal exposure to a widely used environmental neurotoxicant, at standard use levels, with structural changes in the developing human brain.

Measurement of CYP1A2 Activity: a Focus on Caffeine As a Probe

Current Drug Metabolism. Jun, 2012  |  Pubmed ID: 22554278

The drug metabolising enzyme CYP1A2 contributes to the metabolism of a number of medicines including clozapine, olanzapine and theophylline. These medicines display a high degree of inter-individual variability in pharmacokinetics and response. Measuring CYP1A2 activity in vivo can be an important tool to identify the factors that influence variability in drug pharmacokinetics and inform dose selection. Caffeine is the only currently accepted probe to conduct in vivo phenotyping of CYP1A2. Despite the number of proposed matrices (biological fluid containing the drug and/or metabolite/s of interest) and metrics (mathematical formula relating the drug and/or metabolite/s to enzyme activity) proposed to measure CYP1A2 activity using caffeine, many of these are compromised by factors related to the specific metabolic pathway studied or pharmacokinetic characteristics of caffeine and its metabolites. Furthermore, questions regarding the appropriate study design and methodology to conduct studies to evaluate CYP1A2 activity have often been overlooked. These issues include the potential influence of a methylxanthine abstinence period prior to caffeine CYP1A2 phenotyping and the impact of caffeine formulation on determining CYP1A2 activity. This review aims to discuss the various CYP1A2 matrices and metrics with a particular focus on unresolved methodological issues.

The Helminth Community of the Skink Chalcides Sexlineatus from Gran Canaria (Canary Islands)

Journal of Helminthology. Jun, 2012  |  Pubmed ID: 22555048

A survey of the gastrointestinal helminth communities of a population of Chalcides sexlineatus Steindachner, a small skink endemic to Gran Canaria island (Canary Archipelago, Spain), was conducted to determine the prevalence, abundance and species diversity of intestinal parasites in these reptiles. Only three parasite species were found, one cestode, Oochoristica agamae Baylis, 1919 and two nematodes, Parapharyngodon micipsae (Seurat, 1917) and Pharyngodonidae gen. sp. Helminth infracommunities of C. sexlineatus showed low values of abundance and species richness and diversity, being more similar to the helminth community of Tarentola boettgeri boettgeri (Steindachner) rather than those of Gallotia stehlini (Schenkel), both syntopic with the sampled host.

Dynamics of Rye Chromosome 1R Regions with High or Low Crossover Frequency in Homology Search and Synapsis Development

PloS One. 2012  |  Pubmed ID: 22558456

In many organisms, homologous pairing and synapsis depend on the meiotic recombination machinery that repairs double-strand DNA breaks (DSBs) produced at the onset of meiosis. The culmination of recombination via crossover gives rise to chiasmata, which locate distally in many plant species such as rye, Secale cereale. Although, synapsis initiates close to the chromosome ends, a direct effect of regions with high crossover frequency on partner identification and synapsis initiation has not been demonstrated. Here, we analyze the dynamics of distal and proximal regions of a rye chromosome introgressed into wheat to define their role on meiotic homology search and synapsis. We have used lines with a pair of two-armed chromosome 1R of rye, or a pair of telocentrics of its long arm (1RL), which were homozygous for the standard 1RL structure, homozygous for an inversion of 1RL that changes chiasma location from distal to proximal, or heterozygous for the inversion. Physical mapping of recombination produced in the ditelocentric heterozygote (1RL/1RL(inv)) showed that 70% of crossovers in the arm were confined to a terminal segment representing 10% of the 1RL length. The dynamics of the arms 1RL and 1RL(inv) during zygotene demonstrates that crossover-rich regions are more active in recognizing the homologous partner and developing synapsis than crossover-poor regions. When the crossover-rich regions are positioned in the vicinity of chromosome ends, their association is facilitated by telomere clustering; when they are positioned centrally in one of the two-armed chromosomes and distally in the homolog, their association is probably derived from chromosome elongation. On the other hand, chromosome movements that disassemble the bouquet may facilitate chromosome pairing correction by dissolution of improper chromosome associations. Taken together, these data support that repair of DSBs via crossover is essential in both the search of the homologous partner and consolidation of homologous synapsis.

Met Signaling Regulates Growth, Repopulating Potential and Basal Cell-fate Commitment of Mammary Luminal Progenitors: Implications for Basal-like Breast Cancer

Oncogene. May, 2012  |  Pubmed ID: 22562252

Basal-like breast cancer is an aggressive subtype of mammary carcinoma. Despite expressing basal markers, typical of mammary stem cells, this tumor has been proposed to originate from luminal progenitors, which are downstream of stem cells along the mammary epithelial hierarchy. This suggests that committed luminal progenitors may reacquire basal, stem-like characteristics, but the mechanisms that regulate this transition remain unclear. Using mouse models, we found that luminal progenitors express high levels of the Met receptor for hepatocyte growth factor (HGF), as compared with the other mammary epithelial sub-populations. Constitutive activation of Met led luminal progenitors to attain stem cell properties, including enhanced clonogenic activity in vitro and de novo ability to reconstitute mammary glands in repopulation assays in vivo. Moreover, in response to Met signaling, luminal progenitors gave rise to hyperplastic ductal morphogenesis and preferentially underwent basal lineage commitment at the expense of luminal cell-fate specification. Opposite and symmetric results were produced by systemic pharmacological inhibition of Met. Hence, Met signaling targets luminal progenitors for expansion, impairs their differentiation toward the mature luminal phenotype and enables their commitment toward the basal lineage. These results emphasize a critical role for Met in promoting deregulated proliferation and basal plasticity of normal luminal progenitors in the mammary gland, a complex of events that may be required for sustaining the functional and phenotypic properties of basal-like breast tumors.Oncogene advance online publication, 7 May 2012; doi:10.1038/onc.2012.154.

Maternal Exposure to Polycyclic Aromatic Hydrocarbons and 5'-CpG Methylation of Interferon-γ in Cord White Blood Cells

Environmental Health Perspectives. Aug, 2012  |  Pubmed ID: 22562770

Background: Maternal factors are implicated in the onset of childhood asthma. Differentiation of naïve CD4+ T lymphocytes into pro-allergic T-helper 2 cells induces interleukin (IL)4 expression and inhibits interferon (IFN)γ expression accompanied by concordant methylation changes in the promoters of these genes. However, it has yet to be established whether maternal exposure to polycyclic aromatic hydrocarbons (PAHs) can alter these gene promoters epigenetically during fetal development.Objectives: In this study we sought to elucidate the relationship between maternal PAH exposure and promoter methylation status of IFNγ and IL4.Methods: We assessed the effects of benzo[a]pyrene (BaP), a representative airborne PAH, on the methylation status of the IFNγ and IL4 promoters in Jurkat cells and two lung adenocarcinoma cell lines, and on gene expression. In addition, we evaluated methylation status of the IFNγ promoter in cord white blood cells from 53 participants in the Columbia Center for Children's Environmental Health cohort. Maternal PAH exposure was estimated by personal air monitoring during pregnancy.Results: In vitro exposure of the cell models to low, noncytotoxic doses (0.1 and 1 nM) of BaP elicited increased promoter hypermethylation and reduced expression of IFNγ, but not IL4. IFNγ promoter methylation in cord white blood cells was associated with maternal PAH exposure in the cohort study subsample.Conclusion: Consistent with the results for the cell lines, maternal exposure to PAHs was associated with hypermethylation of IFNγ in cord blood DNA from cohort children. These findings support a potential role of epigenetics in fetal reprogramming by PAH-induced environmental diseases.

Classical Swine Fever Virus Isolates from Cuba Form a New Subgenotype 1.4

Veterinary Microbiology. Aug, 2012  |  Pubmed ID: 22902191

Identification and classification of classical swine fever virus (CSFV) on the basis of nucleotide sequencing and phylogenetic analysis have become an important tool to study the epidemiology and to control CSF disease. According to phylogenetic analyses of short sequences from the 5'nontranslated region (150nt) and the E2 (190nt), most CSFV isolates from South and Central America have been assorted to the subgenotypes 1.1 and 1.3, while CSFV isolates from Cuba have been allocated to subgenotype 1.2. Here we demonstrate that determination and comparison of full-length E2 sequences as well as of the sequences encoding for N(pro), C, E(rns), E1 and E2 (3361nt) do not support segregation of Cuban CSFV isolates to subgenotype 1.2. In fact, our analysis revealed that the Cuban isolates are more divergent from other so far known CSFV subgenotype 1 isolates and form a novel separate subgenotype that is proposed to be designated subgenotype 1.4.

Duplication of SOX9 is Not a Common Cause of 46,XX Testicular or 46,XX Ovotesticular DSD

Journal of Pediatric Endocrinology & Metabolism : JPEM. 2012  |  Pubmed ID: 22570960

Translocation of the SRY gene to the paternal X chromosome is the explanation for testis development in the majority of subjects with 46,XX testicular disorder of sexual development (DSD). However, nearly all subjects with 46,XX ovotesticular DSD and up to one third of subjects with 46,XX testicular DSD lack SRY. SRY-independent expression of SOX9 has been implicated in the etiology of testis development in some individuals.

Childhood Exposure to Fine Particulate Matter and Black Carbon and the Development of New Wheeze Between Ages 5 and 7 in an Urban Prospective Cohort

Environment International. Sep, 2012  |  Pubmed ID: 22572116

While exposures to urban fine particulate matter (PM(2.5)) and soot-black carbon (soot-BC) have been associated with asthma exacerbations, there is limited evidence on whether these pollutants are associated with the new development of asthma or allergy among young inner city children. We hypothesized that childhood exposure to PM(2.5) and the soot-BC component would be associated with the report of new wheeze and development of seroatopy in an inner city birth cohort.

Prevalence of Oral Mucosal Lesions in Adults Undergoing Highly Active Antiretroviral Therapy in Hong Kong

Journal of Investigative and Clinical Dentistry. Aug, 2012  |  Pubmed ID: 22573355

Aim:  Highly active antiretroviral therapy (HAART) has altered the prevalence and incidence of oral mucosal lesions of HIV infection. Recent reports show a variation in the prevalence of oral mucosal lesions in different population groups. Understanding the prevalence of these lesions is of paramount importance in the efficient delivery of dental care to such cohorts. The aim of the present study was to investigate the prevalence of oral mucosal lesions and salivary parameters during HAART in an ethnic Chinese cohort in Hong Kong. Methods:  A cross-sectional estimation of the prevalence of oral mucosal lesions was carried out in 101 HIV-infected ethnic Chinese in Hong Kong using the European Community-Clearinghouse classification. Results:  The prevalence of oral mucosal lesions was more common in patients who were classified at baseline as Centers for Disease Control (CDC) C3 category than CDC A2, A3, B2, and B3 (P < 0.05). An overall prevalence of 1.98% was observed for oral Kaposi's sarcoma. Additionally, the HIV group on HAART (0.37 ± 0.23 mL/min) had significantly lower salivary flow rates (P < 0.01) compared with the healthy group (0.49 ± 0.15 mL/min). Conclusions:  Although HAART appears to markedly reduce the prevalence of oral mucosal lesions during the course of HIV disease, regular systematic oral screening is still warranted for such populations for the early diagnosis and management of pathologies, such as Kaposi's sarcoma.

Urinary Naphthol Metabolites and Chromosomal Aberrations in 5-year-old Children

Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. Jul, 2012  |  Pubmed ID: 22573794

Exposure to naphthalene, an International Agency for Research on Cancer (IARC)-classified possible carcinogen and polycyclic aromatic hydrocarbon (PAH), is widespread, though resulting health effects are poorly understood. Metabolites of naphthalene, 1- and 2-naphthol, are measurable in urine and are biomarkers of personal exposure. Chromosomal aberrations, including translocations, are established markers of cancer risk and a biodosimeter of clastogenic exposures. Although prenatal (maternal) PAH exposure predicts chromosomal aberrations in cord blood, few studies have examined chromosomal aberrations in school-age children and none has examined their association with metabolites of specific PAHs.

Obscurin and KCTD6 Regulate Cullin-dependent Small Ankyrin-1 (sAnk1.5) Protein Turnover

Molecular Biology of the Cell. Jul, 2012  |  Pubmed ID: 22573887

Protein turnover through cullin-3 is tightly regulated by posttranslational modifications, the COP9 signalosome, and BTB/POZ-domain proteins that link cullin-3 to specific substrates for ubiquitylation. In this paper, we report how potassium channel tetramerization domain containing 6 (KCTD6) represents a novel substrate adaptor for cullin-3, effectively regulating protein levels of the muscle small ankyrin-1 isoform 5 (sAnk1.5). Binding of sAnk1.5 to KCTD6, and its subsequent turnover is regulated through posttranslational modification by nedd8, ubiquitin, and acetylation of C-terminal lysine residues. The presence of the sAnk1.5 binding partner obscurin, and mutation of lysine residues increased sAnk1.5 protein levels, as did knockdown of KCTD6 in cardiomyocytes. Obscurin knockout muscle displayed reduced sAnk1.5 levels and mislocalization of the sAnk1.5/KCTD6 complex. Scaffolding functions of obscurin may therefore prevent activation of the cullin-mediated protein degradation machinery and ubiquitylation of sAnk1.5 through sequestration of sAnk1.5/KCTD6 at the sarcomeric M-band, away from the Z-disk-associated cullin-3. The interaction of KCTD6 with ankyrin-1 may have implications beyond muscle for hereditary spherocytosis, as KCTD6 is also present in erythrocytes, and erythrocyte ankyrin isoforms contain its mapped minimal binding site.

Positive Selection Pressure on the B/C Domains of the E2-gene of Classical Swine Fever Virus in Endemic Areas Under C-strain Vaccination

Infection, Genetics and Evolution : Journal of Molecular Epidemiology and Evolutionary Genetics in Infectious Diseases. May, 2012  |  Pubmed ID: 22580241

In Cuba, classical swine fever (CSF) has become an endemic disease with several outbreaks each year, despite the implemented vaccination program. Interestingly, a trend towards a milder presentation of the disease has been observed among the animals during the last years. This study aimed to assess positive selection pressure acting on partial E2 gene of CSF viruses to gain insights into the mechanisms governing virulence and the driving forces of classical swine fever virus (CSFV) evolution in swine populations under regular vaccination. Selection pressure analysis were performed to detect positive selection acting on a particular lineage as well as among sites of the E2-B/C-domain of CSFV nucleotide sequences, reported in a previous study and in the present work, several models, available in the CODEML module of PAML 4.3, were used. In addition, a representative Cuban CSF isolate was assessed in an experimental infection trial for their clinical virulence in order to expand the knowledge regarding CSF viruses circulating in pig populations. The viral genomes sequenced in this study were grouped in a defined cluster within the genotype 1.2, as it has been reported previously for Cuban CSF viruses. The selection pressure analysis didn't find evidence of positive selection (dN/dS of>1) along any branch. The positive selective pressure analysis estimated six new sites under positive selection on E2 partial gene analysed. Besides, the clinical manifestations of the CSF-disease were related mainly to a mild course of the illness. The high number of positively selected sites suggests that these changes could be associated to viral evasion of the host-immune response. These observations highlight a possible association between escape viral variants and the alterations observed in the virulence and pathogenesis of the virus. Therefore, while the vaccination programs have not led to a genotype change, alterations in virulence were suggested to arise.

Fluctuations and Micro-heterogeneity in Aqueous Mixtures

The Journal of Chemical Physics. May, 2012  |  Pubmed ID: 22583258

The problem as to why water-water density correlations are systematically overestimated in computer simulation of aqueous mixtures is examined through an extensive molecular dynamics study of mixtures of the extended single point charge water model with a fully miscible weaker version of it, obtained by scaling down the site partial charges by a factor 2/3, thereby eliminating solute-solvent size differences. The study reveals that enhanced water correlations is a genuine physical effect, and are not an artifact of the simulations or the models, as previously suggested in the context of realistic aqueous mixtures. Rather, they correspond to the existence of strongly correlated water domains, for "weak-water" mole fraction x > 0.4, that modulate the spatial decay of the density correlations. These domains produce a prepeak in the structure factor, suggesting that simple aqueous mixture might behave just like micro-emulsions. The overestimated long range water correlations result from incorrect predictions of the asymptote of these correlations, which themselves arise from size limitations of the simulation box. However, by requiring consistency between thermodynamical and structural expressions of the concentration fluctuations, a method to predict the proper decay of the correlation function is obtained herein, inspired by the formal analogy with micro-emulsions. This study provides a new insight for the large values of the experimental Kirkwood-Buff integrals for many aqueous mixtures: these mixtures are in a Lifshitz-type regime, where concentration fluctuations compete with water domain formation.

'Optimum Threshold Estimation Based on Cost Function in a Multistate Diagnostic Setting' by K. Skaltsa, L. Jover, D. Fuster and J. L. Carrasco

Statistics in Medicine. May, 2012  |  Pubmed ID: 22585411

Intranasal Corticosteroids in Management of Acute Sinusitis: a Systematic Review and Meta-analysis

Annals of Family Medicine. May-Jun, 2012  |  Pubmed ID: 22585889

Acute sinusitis is a common condition in ambulatory care, where it is frequently treated with antibiotics, despite little evidence of their benefit. Intranasal corticosteroids might relieve symptoms; however, evidence for this benefit is currently unclear. We performed a systematic review and meta-analysis of the effects of intranasal corticosteroids on the symptoms of acute sinusitis.

Benchmark Studies on the Building Blocks of DNA. 1. Superiority of Coupled Cluster Methods in Describing the Excited States of Nucleobases in the Franck-condon Region

The Journal of Physical Chemistry. A. Jun, 2012  |  Pubmed ID: 22587574

Equation of motion excitation energy coupled-cluster (EOMEE-CC) methods including perturbative triple excitations have been used to set benchmark results for the excitation energy and oscillator strength of the building units of DNA, i.e., cytosine, guanine, adenine and thymine. In all cases the lowest twelve transitions have been considered including valence and Rydberg ones. Triple-ζ basis sets with diffuse functions have been used and the results are compared to CC2, CASPT2, TDDFT, and DFT/MRCI results from the literature. The results clearly show that it is only the EOMEE-CCSD(T) that is capable of providing accuracy of about 0.1 eV. EOMEE-CCSD systematically overshoots the energy of all types of transitions by 0.1-0.3 eV, whereas CC2 is surprisingly accurate for ππ* transitions but fails (often badly) for nπ* and Rydberg transitions. DFT and CASPT2 seem to give reliable results for the lowest transition, but the error increases fast with the excitation level. The differences in the excitation energies often change the energy ordering of the states, which should even influence the conclusions of excited state dynamics obtained with these approximate methods. The results call for further benchmark calculations on larger building blocks of DNA (nucleosides, basis pairs) at the CCSD(T) level.

Lobster (Panulirus Argus) Hepatopancreatic Trypsin Isoforms and Their Digestion Efficiency

The Biological Bulletin. Apr, 2012  |  Pubmed ID: 22589406

It is well known that crustaceans exhibit several isoforms of trypsin in their digestive system. Although the number of known crustacean trypsin isoforms continues increasing, especially those derived from cDNA sequences, the role of particular isoenzymes in digestion remains unknown. Among invertebrates, significant advances in the understanding of the role of multiple trypsins have been made only in insects. Since it has been demonstrated that trypsin isoenzyme patterns (phenotypes) in lobster differ in digestion efficiency, we used this crustacean as a model for assessing the biochemical basis of such differences. We demonstrated that the trypsin isoform known to be present in all individuals of Panulirus argus has a high catalytic efficiency (k(cat)/K(m) ) and is the most reactive toward native proteinaceous substrates, whereas one of the isoforms present in less efficient individuals has a lower k(cat) and a lower k(cat)/K(m), and it is less competent at digesting native proteins. A fundamental question in biology is how genetic differences produce different physiological performances. This work is the first to demonstrate that trypsin phenotypic variation in crustacean protein digestion relies on the biochemical properties of the different isoforms. Results are relevant for understanding trypsin polymorphism and protein digestion in lobster.

Symptomatic Treatment of the Cough in Whooping Cough

Cochrane Database of Systematic Reviews (Online). 2012  |  Pubmed ID: 22592689

The worldwide incidence of whooping cough (pertussis) has been estimated at 48.5 million cases and nearly 295,000 deaths per year. In low-income countries, the case-fatality rate among infants may be as high as 4%. Much of the morbidity of whooping cough in children and adults is due to the effects of the paroxysmal cough. Cough treatments proposed include corticosteroids, beta 2-adrenergic agonists, pertussis-specific immunoglobulin, antihistamines and possibly leukotriene receptor antagonists (LTRAs).

A Conserved Motif in the C-terminal Tail of DNA Polymerase α Tethers Primase to the Eukaryotic Replisome

The Journal of Biological Chemistry. Jul, 2012  |  Pubmed ID: 22593576

The DNA polymerase α-primase complex forms an essential part of the eukaryotic replisome. The catalytic subunits of primase and pol α synthesize composite RNA-DNA primers that initiate the leading and lagging DNA strands at replication forks. The physical basis and physiological significance of tethering primase to the eukaryotic replisome via pol α remain poorly characterized. We have identified a short conserved motif at the extreme C terminus of pol α that is critical for interaction of the yeast ortholog pol1 with primase. We show that truncation of the C-terminal residues 1452-1468 of Pol1 abrogates the interaction with the primase, as does mutation to alanine of the invariant amino acid Phe(1463). Conversely, a pol1 peptide spanning the last 16 residues binds primase with high affinity, and the equivalent peptide from human Pol α binds primase in an analogous fashion. These in vitro data are mirrored by experiments in yeast cells, as primase does not interact in cell extracts with pol1 that either terminates at residue 1452 or has the F1463A mutation. The ability to disrupt the association between primase and pol α allowed us to assess the physiological significance of primase being tethered to the eukaryotic replisome in this way. We find that the F1463A mutation in Pol1 renders yeast cells dependent on the S phase checkpoint, whereas truncation of Pol1 at amino acid 1452 blocks yeast cell proliferation. These findings indicate that tethering of primase to the replisome by pol α is critical for the normal action of DNA replication forks in eukaryotic cells.

Combined ω3 and ω6 Supplementation in Children with Attention-deficit Hyperactivity Disorder (ADHD) Refractory to Methylphenidate Treatment: a Double-blind, Placebo-controlled Study

Journal of Child Neurology. Jun, 2012  |  Pubmed ID: 22596014

Children (6-12 years) with attention-deficit hyperactivity disorder (ADHD) being treated with methylphenidate and standard behavior therapy for more than 6 months, whose parents reported no improvement in behavior and academic learning, were randomly assigned to receive supplementation with a combined ω3 and ω6 preparation or a placebo. Outcome was measured at 3 and 6 months after treatment using a self-assessment checklist completed by the parents. Statistically significant improvement was found in the treatment group compared with the placebo group (P < .01) in the following measures: restlessness, aggressiveness, completing work, and academic performance. Statistically significant improvement was not found at 3 months of treatment between groups but was evident at 6 months of treatment (P < .05) with inattention, impulsiveness, and cooperation with parents and teachers. Distractibility failed to show improvement. Effect sizes ranged from 0.3 to 1.1 at 3 months and 0.2 to 1.4 at 6 months for individual symptom variables.

Changes in Cortical Thickness in the Frontal Lobes in Schizophrenia Are a Result of Thinning of Pyramidal Cell Layers

European Archives of Psychiatry and Clinical Neuroscience. May, 2012  |  Pubmed ID: 22610045

Decreased cortical thickness and reduced activity as measured by fMRI in the grey matter of the subgenual cingulate cortex have been reported in schizophrenia and bipolar disorder, and cortical grey matter loss has been reliably reported in the frontal and temporal lobes in schizophrenia. The aim of this study was to examine the thickness of each of the six cortical layers in the subgenual cingulate cortex, five frontal lobe and four temporal lobe gyri. We examined two separate cohorts. Cohort 1 examines the subgenual cingulate cortex (SCC) in schizophrenia (n = 10), bipolar disorder (n = 15) and major depressive disorder (n = 20) against control subjects (n = 19). Cohort two examines frontal and temporal gyri in schizophrenia (n = 16), major depressive disorder (n = 6) against matched controls (n = 32). The cohorts were selected with identical clinical criteria, but underwent different tissue processing to contrast the effect of chemical treatment on tissue shrinkage. Measurements of layer I-VI thickness were taken from cresyl-violet- and haematoxylin-stained sections in cohort one and from cresyl-violet- and H&E-stained sections in cohort two. SCC cortical thickness decreased in male subjects with bipolar disorder (p = 0.048), and male schizophrenia cases showed a specific decrease in the absolute thickness of layer V (p = 0.003). Compared to controls, the relative thickness of layer V in the crown of the SCC decreased in schizophrenia (p < 0.001). A significant decrease in total cortical thickness was observed across the frontal lobe in schizophrenia (p < 0.0001), with specific pyramidal layer thinning in layers III (p = 0.0001) and V (p = 0.005). There was no effect of lateralization. No changes were noted in temporal lobe cortical thickness. This study demonstrates diminished pyramidal layer thickness resulting in decreased frontal lobe thickness in schizophrenia.

Studying Current Status of Intensive Care Services in Sri Lanka

International Journal of Critical Illness and Injury Science. Jan, 2012  |  Pubmed ID: 22624096

To describe intensive care unit (ICU) facilities in Sri Lanka; to describe the pattern of admissions, case-mix and mortality; compare patient outcome against the various types of ICUs; and determine the adequacy and standards of training received by medical and nursing staff.

Asymptomatic Transmission of Treponema Pallidum (syphilis) Through Deceased Donor Liver Transplantation

Transplant Infectious Disease : an Official Journal of the Transplantation Society. Jun, 2012  |  Pubmed ID: 22624823

A 55-year-old woman underwent liver transplantation (LT) with a graft from a deceased donor. Mandatory pre-donation investigations showed positive syphilis serology that was available only after the transplant, with high Treponema pallidum particle agglutination assay titer compatible with donor syphilis infection. Despite the institution of appropriate post-exposure prophylaxis, the recipient demonstrated latent seroconversion; however, liver graft function improved without evidence of syphilitic hepatitis or other manifestations of the disease. Through this first reported case of asymptomatic transmission of syphilis following LT, we highlight the investigations and treatment strategies for donor-derived syphilis in liver transplant recipients. This report supplements the existing limited evidence on safe use of infected grafts from syphilitic donors through appropriate post-exposure prophylaxis.

Fibrous Pseudotumor of the Testis: Case 1

Ultrasound Quarterly. Jun, 2012  |  Pubmed ID: 22634789

Hypertrophied Anterior Division of Ascending Pharyngeal Artery Simulating Internal Carotid Artery

Ultrasound Quarterly. Jun, 2012  |  Pubmed ID: 22634793

Metabolomics As a Hypothesis-Generating Functional Genomics Tool for the Annotation of Arabidopsis Thaliana Genes of "Unknown Function"

Frontiers in Plant Science. 2012  |  Pubmed ID: 22645570

Metabolomics is the methodology that identifies and measures global pools of small molecules (of less than about 1,000 Da) of a biological sample, which are collectively called the metabolome. Metabolomics can therefore reveal the metabolic outcome of a genetic or environmental perturbation of a metabolic regulatory network, and thus provide insights into the structure and regulation of that network. Because of the chemical complexity of the metabolome and limitations associated with individual analytical platforms for determining the metabolome, it is currently difficult to capture the complete metabolome of an organism or tissue, which is in contrast to genomics and transcriptomics. This paper describes the analysis of Arabidopsis metabolomics data sets acquired by a consortium that includes five analytical laboratories, bioinformaticists, and biostatisticians, which aims to develop and validate metabolomics as a hypothesis-generating functional genomics tool. The consortium is determining the metabolomes of Arabidopsis T-DNA mutant stocks, grown in standardized controlled environment optimized to minimize environmental impacts on the metabolomes. Metabolomics data were generated with seven analytical platforms, and the combined data is being provided to the research community to formulate initial hypotheses about genes of unknown function (GUFs). A public database (www.PlantMetabolomics.org) has been developed to provide the scientific community with access to the data along with tools to allow for its interactive analysis. Exemplary datasets are discussed to validate the approach, which illustrate how initial hypotheses can be generated from the consortium-produced metabolomics data, integrated with prior knowledge to provide a testable hypothesis concerning the functionality of GUFs.

A Role for Phosphoinositides in Regulating Plant Nuclear Functions

Frontiers in Plant Science. 2012  |  Pubmed ID: 22645589

Nuclear localized inositol phospholipids and inositol phosphates are important for regulating many essential processes in animal and yeast cells such as DNA replication, recombination, RNA processing, mRNA export and cell cycle progression. An overview of the current literature indicates the presence of a plant nuclear phosphoinositide (PI) pathway. Inositol phospholipids, inositol phosphates, and enzymes of the PI pathway have been identified in plant nuclei and are implicated in DNA replication, chromatin remodeling, stress responses and hormone signaling. In this review, the potential functions of the nuclear PI pathway in plants are discussed within the context of the animal and yeast literature. It is anticipated that future research will help shed light on the functional significance of the nuclear PI pathway in plants.

Isolated Trigeminal Nerve Palsy with Motor Involvement As a Presenting Manifestation of Multiple Sclerosis in an Equatorial Region - a Case Report

International Archives of Medicine. 2012  |  Pubmed ID: 22647398

ABSTRACT: INTRODUCTION: Isolated cranial nerve palsies are considered to be an uncommon presenting feature of multiple sclerosis. Involvement of the trigeminal nerve, particularly its motor component as part of a clinically isolated syndrome of multiple sclerosis has rarely been reported in equatorial regions and no cases have been described in Sri Lanka thus far. CASE PRESENTATION: We report a case of isolated right sided trigeminal nerve palsy (Motor and Sensory) in a 34 year old previously well lady from urban Sri Lanka who was found to have characteristic lesions on Magnetic Resonance Imaging highly suggestive of multiple sclerosis. CONCLUSIONS: Multiple sclerosis should be considered in the differential diagnosis of patients who present with isolated cranial nerve palsies. Clinicians should have a high index of suspicion when evaluating such patients especially in low prevalence regions close to the equator. Early recognition and treatment of such a "Clinically Isolated Syndrome" may prevent early relapse.

Spatial Coordination of Kindlin-2 with Talin Head Domain in Interaction with Integrin β Cytoplasmic Tails

The Journal of Biological Chemistry. Jul, 2012  |  Pubmed ID: 22648415

Both talin head domain and kindlin-2 interact with integrin β cytoplasmic tails, and they function in concert to induce integrin activation. Binding of talin head domain to β cytoplasmic tails has been characterized extensively, but information on the interaction of kindin-2 with this integrin segment is limited. In this study, we systematically examine the interactions of kindlin-2 with integrin β tails. Kindlin-2 interacted well with β(1) and β(3) tails but poorly with the β(2) cytoplasmic tail. This binding selectivity was determined by the non-conserved residues, primarily the three amino acids at the extreme C terminus of the β(3) tail, and the sequence in β(2) was non-permissive. The region at the C termini of integrin β(1) and β(3) tails recognized by kindlin-2 was a binding core of 12 amino acids. Kindlin-2 and talin head do not interact with one another but can bind simultaneously to the integrin β(3) tail without enhancing or inhibiting the interaction of the other binding partner. Kindlin-2 itself failed to directly unclasp integrin α/β tail complex, indicating that kindlin-2 must cooperate with talin to support the integrin activation mechanism.

Functional Herbal Food Ingredients Used in Type 2 Diabetes Mellitus

Pharmacognosy Reviews. Jan, 2012  |  Pubmed ID: 22654403

From many reports it is clear that diabetes will be one of the major diseases in the coming years. As a result there is a rapidly increasing interest in searching new medicines, or even better searching prophylactic methods. Based on a large number of chemical and pharmacological research work, numerous bioactive compounds have been found in functional herbal food ingredients for diabetes. The present paper reviews functional herbal food ingredients with regards to their anti-diabetic active principles and pharmacological test results, which are commonly used in Asian culinary system and medical system and have demonstrated clinical or/and experimental anti-diabetic effectiveness. Our idea of reviewing this article is to give more attention to these functional food ingredients as targets medicinal foods in order to prevent or slow down the development of type 2 diabetes mellitus.

Surgical Resection of Hepatic Metastases from Neuroendocrine Neoplasms: A Systematic Review

Surgical Oncology. Sep, 2012  |  Pubmed ID: 22658833

Neuroendocrine tumours (NET) most commonly metastasize to the liver. Hepatic resection of NET hepatic metastases (NETHM) has been shown to improve symptomology and survival.

On Oncogenes and Tumor Suppressor Genes in the Mammary Gland

Cold Spring Harbor Perspectives in Biology. Jun, 2012  |  Pubmed ID: 22661637

A Protocol for a Randomized Clinical Trial of Interactive Video Dance: Potential for Effects on Cognitive Function

BMC Geriatrics. 2012  |  Pubmed ID: 22672287

ABSTRACT:

Surveillance for Ocular Hypertension: an Evidence Synthesis and Economic Evaluation

Health Technology Assessment (Winchester, England). Jun, 2012  |  Pubmed ID: 22687263

To determine effective and efficient monitoring criteria for ocular hypertension [raised intraocular pressure (IOP)] through (i) identification and validation of glaucoma risk prediction models; and (ii) development of models to determine optimal surveillance pathways.

What is the Role of Intra-aortic Balloon Counterpulsation in Acute Myocardial Infarction Presenting Without Shock?

Heart International. Feb, 2012  |  Pubmed ID: 22690294

New Monodentate Amidine Superbasic Ligands with a Single Configuration in Fac-[Re(CO)(3)(5,5'- or 6,6'-Me(2)bipyridine)(amidine)]BF(4) Complexes

Inorganic Chemistry. Jul, 2012  |  Pubmed ID: 22691073

Treatment of two precursors, fac-[Re(CO)(3)(L)(CH(3)CN)]BF(4) [L = 5,5'-dimethyl-2,2'-bipyridine (5,5'-Me(2)bipy) (1) and 6,6'-dimethyl-2,2'-bipyridine (6,6'-Me(2)bipy) (2)], with five C(2)-symmetrical saturated heterocyclic amines yielded 10 new amidine complexes, fac-[Re(CO)(3)(L)(HNC(CH(3))N(CH(2)CH(2))(2)Y)]BF(4) [Y = CH(2), (CH(2))(2), (CH(2))(3), NH, or O]. All 10 complexes possess the novel feature of having only one isomer (amidine E configuration), as established by crystallographic and (1)H NMR spectroscopic methods. We are confident that NMR signals of the other possible isomer (amidine Z configuration) would have been detected, if it were present. Isomers are readily detected in closely related amidine complexes because the double-bond character of the amidine C-N3 bond (N3 is bound to Re) leads to slow E to Z isomer interchange. The new fac-[Re(CO)(3)(L)(HNC(CH(3))N(CH(2)CH(2))(2)Y)]BF(4) complexes have C-N3 bonds with essentially identical double-bond character. However, the reason that the Z isomer is so unstable as to be undetectable in the new complexes is undoubtedly because of unfavorable clashes between the equatorial ligands and the bulky N(CH(2)CH(2))(2)Y ring moiety of the axial amidine ligand. The amidine formation reactions in acetonitrile (25 °C) proceeded more easily with 2 than with 1, indicating that the distortion in 6,6'-Me(2)bipy resulting from the proximity of the methyl substituents to the inner coordination sphere enhanced the reactivity of the coordinated CH(3)CN. Reaction times for 1 and 2 exhibited a similar dependence on the basicity and ring size of the heterocyclic amine reactants. Moreover, when the product of the reaction of 1 with piperidine, fac-[Re(CO)(3)(5,5'-Me(2)bipy)(HNC(CH(3))N(CH(2)CH(2))(2)CH(2))]BF(4), was challenged in acetonitrile-d(3) or CDCl(3) with a 5-fold excess of the strong 4-dimethylaminopyridine ligand, there was no evidence for replacement of the amidine ligand after two months, thus establishing that the piperidinylamidine ligand is a robust ligand. This chemistry offers promise as a suitable means for preparing isomerically pure conjugated fac-[(99m)Tc(CO)(3)L](n±) imaging agents, including conjugates with known bioactive heterocyclic amines.

Cardiovascular Physiology in Premotor Parkinson's Disease: A Neuroepidemiologic Study

Movement Disorders : Official Journal of the Movement Disorder Society. Jul, 2012  |  Pubmed ID: 22700356

Changes in cardiovascular physiology in Parkinson's disease (PD) are common and may occur prior to diagnostic parkinsonian motor signs. We investigated associations of electrocardiographic (ECG) abnormalities, orthostasis, heart rate variability, and carotid stenosis with the risk of PD diagnosis in the Cardiovascular Health Study, a community-based cohort of older adults. ECG abnormality, orthostasis (symptomatic or asymptomatic), heart rate variability (24-hour Holter monitoring), and any carotid stenosis (≥1%) by ultrasound were modeled as primary predictors of incident PD diagnosis using multivariable logistic regression. Incident PD cases were identified by at least 1 of the following: self-report, antiparkinsonian medication use, and ICD-9. If unadjusted models were significant, they were adjusted or stratified by age, sex, and smoking status, and those in which predictors were still significant (P ≤ .05) were also adjusted for race, diabetes, total cholesterol, low-density lipoprotein, blood pressure, body mass index, physical activity, education level, stroke, and C-reactive protein. Of 5888 participants, 154 incident PD cases were identified over 14 years of follow-up. After adjusting models with all covariates, those with any ECG abnormality (odds ratio [OR], 1.45; 95% CI, 1.02-2.07; P = .04) or any carotid stenosis (OR, 2.40; 95% CI, 1.40-4.09; P = .001) at baseline had a higher risk of incident PD diagnosis. Orthostasis and heart rate variability were not significant predictors. This exploratory study suggests that carotid stenosis and ECG abnormalities occur prior to motor signs in PD, thus serving as potential premotor features or risk factors for PD diagnosis. Replication is needed in a population with more thorough ascertainment of PD onset. © 2012 Movement Disorder Society.

A Novel Membrane-dependent On/off Switch Mechanism of Talin FERM Domain at Sites of Cell Adhesion

Cell Research. Jun, 2012  |  Pubmed ID: 22710802

The activation of heterodimeric (α/β) integrin transmembrane receptors by cytosolic protein talin is crucial for regulating diverse cell-adhesion-dependent processes, including blood coagulation, tissue remodeling, and cancer metastasis. This process is triggered by the coincident binding of N-terminal FERM (four-point-one-protein/ezrin/radixin/moesin) domain of talin (talin-FERM) to the inner membrane surface and integrin β cytoplasmic tail, but how these binding events are spatiotemporally regulated remains obscure. Here we report the crystal structure of a dormant talin, revealing how a C-terminal talin rod segment (talin-RS) self-masks a key integrin-binding site on talin-FERM via a large interface. Unexpectedly, the structure also reveals a distinct negatively charged surface on talin-RS that electrostatically hinders the talin-FERM binding to the membrane. Such a dual inhibitory topology for talin is consistent with the biochemical and functional data, but differs significantly from a previous model. We show that upon enrichment with phosphotidylinositol-4,5-bisphosphate (PIP2) - a known talin activator, membrane strongly attracts a positively charged surface on talin-FERM and simultaneously repels the negatively charged surface on talin-RS. Such an electrostatic "pull-push" process promotes the relief of the dual inhibition of talin-FERM, which differs from the classic "steric clash" model for conventional PIP2-induced FERM domain activation. These data therefore unravel a new type of membrane-dependent FERM domain regulation and illustrate how it mediates the talin on/off switches to regulate integrin transmembrane signaling and cell adhesion.Cell Research advance online publication 19 June 2012; doi:10.1038/cr.2012.97.

Current Opinion on the Role of Resection and Liver Transplantation for Hepatocellular Cancer

Indian Journal of Gastroenterology : Official Journal of the Indian Society of Gastroenterology. Jun, 2012  |  Pubmed ID: 22711364

Hepatocellular carcinoma (HCC) represents one of the most common cancers worldwide with rising incidence in developed countries. The best treatment options with curative intent for patients with HCC are liver resection or transplantation, although the role of hepatic ablative therapies has also been recognized. Surgical resection has emerged as the primary treatment in carefully selected patients of HCC. With the advances in surgical and radiological techniques, the perioperative mortality has been reduced to less than 5 % depending on the extent of resection and hepatic reserve. The role of liver transplantation (LT) as the mainstay of treatment for the majority of patients with HCC has evolved in the last few decades. Historically, the Milan criteria have been considered the gold standard for selecting patients; more expanded selection criteria to include those with more advanced tumors have been implemented in recent years. Living donor liver transplantation (LDLT) has emerged as a way to expand the donor pool and has influenced the role of transplantation for HCC, especially in communities with little access to cadaveric transplantation. Salvage transplantation is an alternative option as it allows a window for the biologically less favorable lesions to declare tumor behavior. Salvage transplantation also decreases the burden on transplant resources. Sirolimus, a novel immunosuppressant drug with anti-tumor effect, may have a role in limiting the severity of recurrent disease after transplantation for HCC, and play an important role in the future management of transplant recipients. This article examines the literature on current status of management of HCC.

Geographical Profile of RpoB Gene Mutations in Rifampicin Resistant Mycobacterium Tuberculosis Isolates in Sri Lanka

Microbial Drug Resistance (Larchmont, N.Y.). Jun, 2012  |  Pubmed ID: 22731859

The nature and frequency of mutations in the rpoB gene of rifampicin (RIF) resistant Mycobacterium tuberculosis clinical isolates varies considerably between different geographical regions. The objective of the present study was the identification of rpoB gene mutations responsible for RIF resistance in M. tuberculosis isolates in Sri Lanka. Three regions of the rpoB gene of M. tuberculosis, one corresponding to a 437-bp region, including the rifampicin resistance-determining region (RRDR) and two other regions (1395 bp and 872 bp) spanning the RRDR, were polymerase chain reaction amplified, and were subjected to DNA sequencing. The two mutations found within the RRDR in the 31 RIF resistant strains isolated in this study were at codon 526 (n=15, 48.4%) CAC (His)→TAC (Tyr) and codon 531 (n=3, 9.7%) TCG (Ser)→TTG (Leu). A significant proportion (n=15, 48.3%) showed mutations spanning the RRDR, including two novel mutations at codon 626 (n=13, 41.9%) GAC (Asp)→GAG (Glu) and 184 (n=2, 6.4%) GAC (Asp)→GAT (Asp), a silent mutation. Two isolates revealed double mutations (codons 626+526 and 626+184). The presence of a high frequency of new mutations, and the different frequencies of the universally prevailing mutations, as reported here, emphasizes the need for expanding the geographical database of mutations for effective application of an rpoB-based diagnosis of multidrug resistant tuberculosis.

Prenatal Exposure to Butylbenzyl Phthalate and Early Eczema in an Urban Cohort

Environmental Health Perspectives. Jun, 2012  |  Pubmed ID: 22732598

Background: Recent cross-sectional studies suggest a link between butylbenzyl phthalate (BBzP) in house dust and childhood eczema. Objectives: To evaluate whether monobenzyl phthalate (MBzP), the main BBzP metabolite in urine, during pregnancy is associated prospectively with eczema in young children, and whether this association varies by the child's sensitization to indoor allergens or serological evidence of any allergies. Methods: MBzP was measured in spot urine samples during the 3rd trimester of pregnancy from n=407 African American and Dominican women residing in New York City in 1999-2006. Repeated questionnaires asked mothers whether their doctor ever said their child had eczema. Child blood samples at ages 24, 36, and 60 months were analyzed for total, anti-cockroach, dust mite, and mouse IgE. Relative risks (RR) were estimated with multivariable modified Poisson regression. Analyses included a multinomial logistic regression model for early and late onset eczema versus no eczema through age 60 months. Results: MBzP was detected in >99% of samples (geometric mean 13.6, interquartile range 5.7, 31.1 ng/ml). By 24 months, 30% of children developed eczema, with the proportion higher among African Americans (48%) than Dominicans (21%) (p<0.001). An interquartile range increase in log MBzP concentration was associated positively with early onset eczema (RR 1.52 for eczema by 24 months, 95%CI: 1.21, 1.91, p=0.0003, n=113 reporting eczema / 376 total sample), adjusting for urine specific gravity, sex, and race/ethnicity. MBzP was not associated with allergic sensitization, nor did seroatopy modify consistently the MBzP and eczema association. Conclusions: Prenatal exposure to BBzP may influence the risk of developing eczema in early childhood.

Quality in the Provision of Headache Care. 2: Defining Quality and Its Indicators

The Journal of Headache and Pain. Aug, 2012  |  Pubmed ID: 22733141

The objective of this study was to define "quality" of headache care, and develop indicators that are applicable in different settings and cultures and to all types of headache. No definition of quality of headache care has been formulated. Two sets of quality indicators, proposed in the US and UK, are limited to their localities and/or specific to migraine and their development received no input from people with headache. We first undertook a literature review. Then we conducted a series of focus-group consultations with key stakeholders (doctors, nurses and patients) in headache care. From the findings we proposed a large number of putative quality indicators, and refined these and reduced their number in consultations with larger international groups of stakeholder representatives. We formulated a definition of quality from the quality indicators. Five main themes were identified: (1) headache services; (2) health professionals; (3) patients; (4) financial resources; (5) political agenda and legislation. An initial list of 160 putative quality indicators in 14 domains was reduced to 30 indicators in 9 domains. These gave rise to the following multidimensional definition of quality of headache care: "Good-quality headache care achieves accurate diagnosis and individualized management, has appropriate referral pathways, educates patients about their headaches and their management, is convenient and comfortable, satisfies patients, is efficient and equitable, assesses outcomes and is safe." Quality in headache care is multidimensional and resides in nine essential domains that are of equal importance. The indicators are currently being tested for feasibility of use in clinical settings.

Quality in the Provision of Headache Care. 1: Systematic Review of the Literature and Commentary

The Journal of Headache and Pain. Aug, 2012  |  Pubmed ID: 22736100

Widely accepted quality indicators for headache care would provide a basis not only for assessment of care but also, and more importantly, for its improvement. The objective of the study was to identify and summarize existing information on such indicators: specifically, did indicators exist, how had they been developed, what aspects of headache care did they relate to and how and with what utility were they being used? A systematic review of the medical literature was performed. A total of 32 articles met criteria for inclusion. We identified 55 existing headache quality indicators of which 37 evaluated processes of headache care. Most were relevant only to specific populations of patients and to care delivered in high-resource settings. Indicators had been used to describe overall quality of headache care at a national level, but not systematically applied to the evaluation and improvement of headache services in other settings. Some studies had evaluated the use of existing disability and quality of life instruments, but their findings had not been incorporated into quality indicators. Existing headache care quality indicators are incomplete and inadequate for purpose. They emphasize processes of care rather than structure or outcomes, and are not widely applicable to different levels and locations of headache care. Furthermore, they do not fully incorporate accepted evidence regarding optimal methods of care. There is a clear need for consensus-based indicators that fully reflect patients' and public-health priorities. Ideally, these will be valid across cultures and health-care settings.

In Vivo Magnetic Resonance Imaging for Investigating the Development and Distribution of Experimental Brain Metastases Due to Breast Cancer

Translational Oncology. Jun, 2012  |  Pubmed ID: 22741041

The overall goal of this study was to assess the utility of three-dimensional magnetic resonance imaging (MRI) for monitoring the temporal and spatial development of experimental brain metastasis in mice.

Letter to the Editor Re: 'Smartphones to Join Scalpels and Stethoscopes?'

Neurosurgery. Jun, 2012  |  Pubmed ID: 22743363

Interpreting the Need for Initial Support to Perform Tandem Stance Tests of Balance

Physical Therapy. Aug, 2012  |  Pubmed ID: 22745198

BackgroundGeriatric rehabilitation reimbursement increasingly requires documented deficits on standardized measures. Tandem stance performance can characterize balance, but protocols are not standardized.ObjectiveThe purpose of this study was to explore the impact of: (1) initial support to stabilize in position and (2) maximum hold time on tandem stance tests of balance in older adults.DesignA cross-sectional secondary analysis of observational cohort data was conducted. METHODS:/b>One hundred seventeen community-dwelling older adults (71% female, 12% black) were assigned to 1 of 3 groups based on the need for initial support to perform tandem stance: (1) unable even with support, (2) able only with support, and (3) able without support. The able without support group was further stratified on hold time in seconds: (1) <10 (low), (2) 10 to 29, (medium), and (3) 30 (high). Groups were compared on primary outcomes (gait speed, Timed "Up & Go" Test performance, and balance confidence) using analysis of variance. RESULTS: /b>Twelve participants were unable to perform tandem stance, 14 performed tandem stance only with support, and 91 performed tandem stance without support. Compared with the able without support group, the able with support group had statistically or clinically worse performance and balance confidence. No significant differences were found between the able with support group and the unable even with support group on these same measures. Extending the hold time to 30 seconds in a protocol without initial support eliminated ceiling effects for 16% of the study sample.LimitationsSmall comparison groups, use of a secondary analysis, and lack of generalizability of results were limitations of the study. CONCLUSIONS:/b>Requiring initial support to stabilize in tandem stance appears to reflect meaningful deficits in balance-related mobility measures, so failing to consider support may inflate balance estimates and confound hold time comparisons. Additionally, 10-second maximum hold times limit discrimination of balance in adults with a higher level of function. For community-dwelling older adults, we recommend timing for at least 30 seconds and documenting initial support for consideration when interpreting performance.

Molecular Survey of Apicomplexa in Podarcis Wall Lizards Detects Hepatozoon , Sarcocystis , and Eimeria Species

The Journal of Parasitology. Jun, 2012  |  Pubmed ID: 22746392

Abstract : The occurrence of apicomplexan parasites in Podarcis sp. wall lizards from the Iberian Peninsula and Balearic islands was studied by amplification and sequencing of the 18S rRNA gene. Species from 3 genera, Hepatozoon , Sarcocystis , and Eimeria , were found. The phylogenetic analysis of the 18S rRNA gene provides unexpected insights into the evolutionary history of these parasites. All Hepatozoon spp. specimens were recovered as part of a clade already identified in lizards from North Africa. The Sarcocystis species, detected in Podarcis lilfordi from Cabrera Island in the Balearic Islands, appears related to Sarcocystis gallotiae , known only from endemic Gallotia sp. lizards from the Canary Islands. Based on the lack of snake predators on this island, this parasite presumably presents an atypical transmission cycle that uses the same host species as both intermediate and final host through cannibalism, like S. gallotiae . Eimeria sp. is reported for the first time from Podarcis spp. lizards. This study shows the power of detecting multiple different apicomplexan parasites through screening of tail tissue samples and blood drops that are often collected in reptiles for other purposes.

Clinically Meaningful Change in Stair Negotiation Performance in Older Adults

Gait & Posture. Jul, 2012  |  Pubmed ID: 22748468

Stair negotiation is a key marker for independence among older adults; however, clinically meaningful change has not been established. Our objective was to establish the values of clinically meaningful change in stair negotiation time using distribution- and anchor-based approaches. Study participants were 371 community residing older adults (age≥70) in the Einstein Aging Study with time to ascend and descend 3 steps measured at baseline and at one-year follow-up. Anchor-based estimates were obtained using functional decline (defined as one-point increment in disability score) and change in self-reported walking ability over the one-year follow-up period. Small, moderate, and large meaningful change estimates were 0.28, 0.71, and 1.15s for stair ascent time (0.31, 0.78, and 1.25s for stair descent time) using the distribution-based approach of effect size. The estimates of meaningful decline range from 0.47 to 0.53s for stair ascent time (0.33-0.53s for stair descent time) using the anchor-based approach. The estimates of meaningful improvement were smaller (0.13-0.18s for stair ascent, 0.06-0.15 for stair descent) compared to those for decline. Based on general consistency between distribution- and anchor-based approaches, preliminary criteria suggested for stair negotiation time is 0.5s for meaningful decline and 0.2s for meaningful improvement.

Gene-environment Interactions on Growth Trajectories

Genetic Epidemiology. Apr, 2012  |  Pubmed ID: 22311237

It has been suggested that children with larger brains tend to perform better on IQ tests or cognitive function tests. Prenatal head growth and head growth in infancy are two crucial periods for subsequent intelligence. Studies have shown that environmental exposure to air pollutants during pregnancy is associated with fetal growth reduction, developmental delay, and reduced IQ. Meanwhile, genetic polymorphisms may modify the effect of environment on head growth. However, studies on gene-environment or gene-gene interactions on growth trajectories have been quite limited partly due to the difficulty to quantitatively measure interactions on growth trajectories. Moreover, it is known that assessing the significance of gene-environment or gene-gene interactions on cross-sectional outcomes empirically using the permutation procedures may bring substantial errors in the tests. We proposed a score that quantitatively measures interactions on growth trajectories and developed an algorithm with a parametric bootstrap procedure to empirically assess the significance of the interactions on growth trajectories under the likelihood framework. We also derived a Wald statistic to test for interactions on growth trajectories and compared it to the proposed parametric bootstrap procedure. Through extensive simulation studies, we demonstrated the feasibility and power of the proposed testing procedures. We applied our method to a real dataset with head circumference measures from birth to age 7 on a cohort currently being conducted by the Columbia Center for Children's Environmental Health (CCCEH) in Krakow, Poland, and identified several significant gene-environment interactions on head circumference growth trajectories.

FRAX or Fiction: Determining Optimal Screening Strategies for Treatment of Osteoporosis in Residents in Long-Term Care Facilities

Journal of the American Geriatrics Society. Feb, 2012  |  Pubmed ID: 22316237

OBJECTIVES: To examine screening strategies for osteoporosis and fractures for treatment of long-term care residents. DESIGN: Cross-sectional analysis to examine screening strategies for treatment. SETTING: Assisted living and skilled care facilities. PARTICIPANTS: Two hundred two frail women aged 65 and older (mean 85), excluding those receiving bisphosphonates. MEASUREMENTS: Clinical fractures of the hip or spine (Clin Fx); Clin Fx or bone mineral density (BMD); Clin Fx, BMD, or vertebral fractures (VF) assessed according to dual-energy X-ray absorptiometry-based vertebral fracture assessments; fracture risk algorithm using femoral neck BMD (FRAX-FN); fracture risk algorithm using body mass index (FRAX-BMI); or Clin Fx or heel ultrasound (heel US). RESULTS: Treatment eligibility ranged from 17% (Clin Fx) to 98% (FRAX-BMI). VFs were found in 47%, 74% of which were silent. Criteria with Clin Fx, BMD, or VF identified 73% of study participants for treatment. FRAX-FN suggested treatment in 81% but would have missed approximately 10% of individuals with silent VFs. Clin Fx or heel US suggested that 39% of participants were eligible for treatment. CONCLUSION: Long-term care residents eligible for osteoporosis treatment ranged from fewer than 20% to roughly all residents depending on screening criteria. VFs are common and identify a subset of residents missed by conventional BMD scans or FRAX-FN. A reasonable clinical approach could consider treatment for those with Clin Fx of the hip or spine, radiological evidence of a VF, or osteoporosis according to BMD classification. Prospective studies are needed to determine optimal screening strategies for treatment in this cohort.

Development of Toxoplasma Gondii Calcium-dependent Protein Kinase 1 (TgCDPK1) Inhibitors with Potent Anti-toxoplasma Activity

Journal of Medicinal Chemistry. Mar, 2012  |  Pubmed ID: 22320388

Toxoplasmosis is a disease of prominent health concern that is caused by the protozoan parasite Toxoplasma gondii. Proliferation of T. gondii is dependent on its ability to invade host cells, which is mediated in part by calcium-dependent protein kinase 1 (CDPK1). We have developed ATP competitive inhibitors of TgCDPK1 that block invasion of parasites into host cells, preventing their proliferation. The presence of a unique glycine gatekeeper residue in TgCDPK1 permits selective inhibition of the parasite enzyme over human kinases. These potent TgCDPK1 inhibitors do not inhibit the growth of human cell lines and represent promising candidates as toxoplasmosis therapeutics.

Comparison of Scanning Laser Ophthalmoscopy and High-definition Optical Coherence Tomography Measurements of Optic Disc Parameters

The British Journal of Ophthalmology. Apr, 2012  |  Pubmed ID: 22322203

To investigate the agreement between scanning laser ophthalmoscopy (Heidelberg retinal tomograph 3; HRT-3) and high-definition optical coherence tomography (HD-OCT) for measurements of optic nerve head (ONH) parameters.

Dietary Protein Quality Differentially Regulates Trypsin Enzymes at the Secretion and Transcription Level in Panulirus Argus by Distinct Signaling Pathways

The Journal of Experimental Biology. Mar, 2012  |  Pubmed ID: 22323208

The effects of pelleted diets with different protein composition (fish, squid or soybean meals as main protein sources) on trypsin secretion and expression were studied in the lobster Panulirus argus. Trypsin secretion was shown to be maximal 4 h after ingestion. At this time, fish- and squid-based diets induced trypsin secretion, as well as up-regulation of the major trypsin isoform at the transcription level. While fish- and squid-based diets elicited a prandial response, soybean-based diet failed to stimulate the digestive gland to secrete trypsin into the gastric fluid or induce trypsin expression above the levels observed in fasting lobsters. In vitro assays showed that intact proteins rather than protein hydrolysates stimulate trypsin secretion in the lobster. However, the signal for trypsin transcription appears to be different to that for secretion and is probably mediated by the appearance of free amino acids in the digestive gland, suggesting a stepwise regulation of trypsin enzymes during digestion. We conclude that trypsin enzymes in P. argus are regulated at the transcription and secretion level by the quality of dietary proteins through two distinct signaling pathways. Our results indicate that protein digestion efficiency in spiny lobsters can be improved by selecting appropriated protein sources. However, other factors like the poor solubility of dietary proteins in dry diets could hamper further enhancement of digestion efficiency.

Radiological Assessment of Metatarsus Adductus

Foot and Ankle Surgery : Official Journal of the European Society of Foot and Ankle Surgeons. Mar, 2012  |  Pubmed ID: 22325995

Metatarsus adductus is the most common congenital foot abnormality. Whilst there is a growing body of evidence describing many aspects of this condition, basic questions regarding aetiology, management and treatment remain controversial. Diagnosis is achieved with clinical and radiological examination. The latter is particularly important for the diagnosis of mild cases. An extensive literature review is presented outlining the development of various radiological methods of angular measurement used in the diagnosis and classification of metatarsus adductus. In addition, the review highlights a spectrum of values obtained for each angle and the validity were reported.

The Super-rapid Technique in Maastricht Category III Donors: Has It Developed Enough for Marginal Liver Grafts from Donors After Cardiac Death?

Current Opinion in Organ Transplantation. Apr, 2012  |  Pubmed ID: 22327912

Follow-up data from donors following cardiac death (DCD) liver transplants suggest an increased risk of graft failure and morbid complications, and the risk increased with grafts from marginal donors. Donor warm ischaemia (dWIT) stands out as the common aetiological factor. Aim of this review is to examine if super-rapid technique had developed sufficiently enough to improve the effects of dWIT that had been started since treatment withdrawal in category III DCD marginal donors.

Prohypertensive Effect of Gestational Personal Exposure to Fine Particulate Matter. Prospective Cohort Study in Non-smoking and Non-obese Pregnant Women

Cardiovascular Toxicology. Sep, 2012  |  Pubmed ID: 22328329

Exposure to fine particulate matter (PM) is a recognized risk factor for elevated blood pressure (BP) and cardiovascular disease in adults, and this prospective cohort study was undertaken to evaluate whether gestational exposure to PM(2.5) has a prohypertensive effect. We measured personal exposure to fine particulate matter (PM(2.5)) by personal air monitoring in the second trimester of pregnancy among 431 women, and BP values in the third trimester were obtained from medical records of prenatal care clinics. In the general estimating equation model, the effect of PM(2.5) on BP was adjusted for relevant covariates such as maternal age, education, parity, gestational weight gain (GWG), prepregnancy BMI, environmental tobacco smoke (ETS), and blood lead level. Systolic blood pressure (SBP) increased in a linear fashion across a dosage of PM(2.5) and on average augmented by 6.1 mm Hg (95% CI, 0.6-11.6) with log unit of PM(2.5) concentration. Effects of age, maternal education, prepregnancy BMI, blood lead level, and ETS were insignificant. Women with excessive gestational weight gain (>18 kg) had higher mean SBP parameters by 5.5 mmHg (95% CI, 2.7-8.3). In contrast, multiparous women had significantly lower SBP values (coeff. = -4.2 mm Hg; 95% CI, -6.8 to -1.6). Similar analysis performed for diastolic blood pressure (DBP) has demonstrated that PM(2.5) also affected DBP parameters (coeff. = 4.1; 95% CI, -0.02 to 8.2), but at the border significance level. DBP values were positively associated with the excessive GWG (coeff. = 2.3; 95% CI, 0.3-4.4) but were inversely related to parity (coeff. = -2.7; 95% CI, -4.6 to -0.73). In the observed cohort, the exposure to fine particulate matter during pregnancy was associated with increased maternal blood pressure.

Epigenetic Regulation of MiRNA Genes and Their Role in Human Melanomas

Epigenomics. Feb, 2012  |  Pubmed ID: 22332660

Melanoma is a leading cause of death from cancers in the USA. While exposure to UV radiation has long been identified as a primary risk factor for melanoma, molecular mechanisms directly linking UV radiation to the development of melanoma, especially metastatic melanoma, are poorly understood. Besides abnormality in several signal transduction pathways important for normal melanocyte development, a number of ncRNAs, including miRNAs, are emerging as important causal factors to melanoma initiation and progression. The recent discovery of altered patterns of epigenetic regulation in ncRNA genes adds further complexity. Since miRNA precursor genes are usually nested within other protein-coding genes, the abnormal regulation of these protein-coding genes by epigenetic mechanisms is expected to cause aberrant regulation of the miRNA target genes. We discuss recent findings that link epigenetic regulation of ncRNA genes to melanoma, and speculate on a possible connection between UV irradiation and epigenetic regulation that might be important for this disease.

Clinical Presentation, Risk Factors and Treatment Outcomes of First Allograft Rejection After Penetrating Keratoplasty in Early and Late Postoperative Period

Eye (London, England). May, 2012  |  Pubmed ID: 22344190

Corneal graft rejection is the most common reason for the failure of an allograft corneal transplant. We undertook this study to identify and compare risk factors and treatment outcomes for early and late corneal graft rejections after optical penetrating keratoplasty.

The Limits of Genome-wide Methods for Pharmacogenomic Testing

Pharmacogenetics and Genomics. Apr, 2012  |  Pubmed ID: 22344246

The goal of pharmacogenomics is the translation of genomic discoveries into individualized patient care. Recent advances in the means to survey human genetic variation are fundamentally transforming our understanding of the genetic basis of interindividual variation in therapeutic response. The goal of this study was to systematically evaluate high-throughput genotyping technologies for their ability to assay variation in pharmacogenetically important genes (pharmacogenes). These platforms are either being proposed for or are already being widely used for clinical implementation; therefore, knowledge of coverage of pharmacogenes on these platforms would serve to better evaluate current or proposed pharmacogenetic association studies.

A Review of Telemedicine Interventions in Diabetes Care

Journal of Telemedicine and Telecare. 2012  |  Pubmed ID: 22362832

We reviewed the literature concerning the use of telemedicine interventions in diabetes care. The PubMed database was searched for randomized controlled trials concerning the use of telemedicine for patients with type 1 or type 2 diabetes. A total of 27 articles (studies) met the inclusion criteria. The interventions concerned videoconferencing (n = 8), mobile phones (n = 10) and telephone calls (n = 9). There was metabolic improvement in 23 studies, which was significant in 12 out of 23 (44%). Only two studies (8%) reported a negative clinical outcome. The majority of the studies (n = 19; 70%) employed behavioural therapy as the key intervention. The medium used for interaction in behavioural therapy intervention was videoconferencing (n = 7), mobile phone (n = 4), telephone calls (n = 8), feedback letters (n = 2). Telemedicine appears to be a promising alternative to conventional therapy.

Ceramide Channels: Influence of Molecular Structure on Channel Formation in Membranes

Biochimica Et Biophysica Acta. May, 2012  |  Pubmed ID: 22365970

The sphingolipid, ceramide, self-assembles in the mitochondrial outer membrane (MOM), forming large channels capable of translocating proteins. These channels are believed to be involved in protein release from mitochondria, a key decision-making step in cell death. Synthetic analogs of ceramide, bearing modifications in each of the major structural features of ceramide were used to probe the molecular basis for the stability of ceramide channels. Channel stability and mitochondrial permeabilization were disrupted by methylation of the C1-hydroxyl group whereas modifications of the C3 allylic hydroxyl group were well tolerated. A change in chirality at C2 that would influence the orientation of the C1-hydroxyl group resulted in a strong reduction of channel-forming ability. Similarly, methylation of the amide nitrogen is also detrimental to channel formation. Many changes in the degree, location and nature of the unsaturation of ceramide had little effect on mitochondrial permeabilization. Competition experiments between ceramide and analogs resulted in synergy with structures compatible with the ceramide channel model and antagonism with incompatible structures. The results are consistent with ceramide channels being highly organized structures, stabilized by specific inter-molecular interactions, similar to the interactions responsible for protein folding.

Coupling Solid-phase Microextraction and Laser Desorption Ionization for Rapid Identification of Biological Material

Rapid Communications in Mass Spectrometry : RCM. Apr, 2012  |  Pubmed ID: 22368066

Solid phase microextraction (SPME) use small fibers directly plunged in the solution under investigation to quickly extract and quantify by different techniques the amount of selected dissolved compounds.

Multiple Determinants for Selective Inhibition of Apicomplexan Calcium-dependent Protein Kinase CDPK1

Journal of Medicinal Chemistry. Mar, 2012  |  Pubmed ID: 22369268

Diseases caused by the apicomplexan protozoans Toxoplasma gondii and Cryptosporidium parvum are a major health concern. The life cycle of these parasites is regulated by a family of calcium-dependent protein kinases (CDPKs) that have no direct homologues in the human host. Fortuitously, CDPK1 from both parasites contains a rare glycine gatekeeper residue adjacent to the ATP-binding pocket. This has allowed creation of a series of C3-substituted pyrazolopyrimidine compounds that are potent inhibitors selective for CDPK1 over a panel of human kinases. Here we demonstrate that selectivity is further enhanced by modification of the scaffold at the C1 position. The explanation for this unexpected result is provided by crystal structures of the inhibitors bound to CDPK1 and the human kinase c-SRC. Furthermore, the insight gained from these studies was applied to transform an alternative ATP-competitive scaffold lacking potency and selectivity for CDPK1 into a low nanomolar inhibitor of this enzyme with no activity against SRC.

Biosynthetic Approach for Functional Protein Microarrays

Analytical Biochemistry. May, 2012  |  Pubmed ID: 22370272

Protein microarrays have emerged as an indispensable research tool for providing information about protein functions and interactions through high-throughput screening. Traditional methods for immobilizing biomolecules onto solid surfaces have been based on covalent and noncovalent binding, entrapment in semipermeable membranes, microencapsulation, sol gel, and hydrogel methods. Each of these techniques has its own strengths but fails to combine the most important tenets of a functional protein microarray such as covalent attachment, native protein conformation, homogeneity of the protein monolayer, control over active site orientation, and retention of protein activity. Here we present a selective and site-directed covalent immobilization technique for proteins via a benzoxazine ring formation through a Diels-Alder reaction in water and a genetically encoded 3-amino-L-tyrosine (3-NH(2)Tyr) amino acid. Fully functional protein microarrays, with monolayer arrangements and complete control over their orientations, were generated using this strategy.

Meta-analysis of Individual Patient Data in Randomised Trials of Self Monitoring of Blood Glucose in People with Non-insulin Treated Type 2 Diabetes

BMJ (Clinical Research Ed.). 2012  |  Pubmed ID: 22371867

To assess the effectiveness of self monitoring blood glucose levels in people with non-insulin treated type 2 diabetes compared with clinical management without self monitoring, and to explore the effects in specific patient groups.

Spontaneous Remission After a Year of Romiplostim in an Adult Patient with Refractory Primary Immune Thrombocytopenia

Annals of Hematology. Sep, 2012  |  Pubmed ID: 22373551

PTEN Protein Phosphatase Activity Correlates with Control of Gene Expression and Invasion, a Tumor-suppressing Phenotype, but Not with AKT Activity

Science Signaling. Feb, 2012  |  Pubmed ID: 22375056

The tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) has a well-characterized lipid phosphatase activity and a poorly characterized protein phosphatase activity. We show that both activities are required for PTEN to inhibit cellular invasion and to mediate most of its largest effects on gene expression. PTEN appears to dephosphorylate itself at threonine 366, and mutation of this site makes lipid phosphatase activity sufficient for PTEN to inhibit invasion. We propose that the dominant role for PTEN's protein phosphatase activity is autodephosphorylation-mediated regulation of its lipid phosphatase activity. Because PTEN's regulation of invasion and these changes in gene expression required lipid phosphatase activity, but did not correlate with the total cellular abundance of its phosphatidylinositol 3,4,5-trisphosphate (PIP₃) lipid substrate or AKT activity, we propose that localized PIP₃ signaling may play a role in those PTEN-mediated processes that depend on both its protein and lipid phosphatase activities. Finally, we identified a tumor-derived PTEN mutant selectively lacking protein phosphatase activity, indicating that in some circumstances the regulation of invasion and not that of AKT can correlate with PTEN-mediated tumor suppression.

Domestic Airborne Black Carbon and Exhaled Nitric Oxide in Children in NYC

Journal of Exposure Science & Environmental Epidemiology. May-Jun, 2012  |  Pubmed ID: 22377682

Differential exposure to combustion by-products and allergens may partially explain the marked disparity in asthma prevalence (3-18%) among New York City neighborhoods. Subclinical changes in airway inflammation can be measured by fractional exhaled nitric oxide (FeNO). FeNO could be used to test independent effects of these environmental exposures on airway inflammation. Seven- and eight-year-old children from neighborhoods with lower (range 3-9%, n=119) and higher (range 11-18%, n=121) asthma prevalence participated in an asthma case-control study. During home visits, FeNO was measured, and samples of bed dust (allergens) and air (black carbon; BC) were collected. Neighborhood built-environment characteristics were assessed for the 500 m surrounding participants' homes. Airborne BC concentrations in homes correlated with neighborhood asthma prevalence (P<0.001) and neighborhood densities of truck routes (P<0.001) and buildings burning residual oil (P<0.001). FeNO concentrations were higher among asthmatics with than in those without frequent wheeze (≥4 times/year) (P=0.002). FeNO concentrations correlated with domestic BC among children without seroatopy (P=0.012) and with dust mite allergen among children with seroatopy (P=0.020). The association between airborne BC in homes and both neighborhood asthma prevalence and FeNO suggest that further public health interventions on truck emissions standards and residual oil use are warranted.

Crystal Structure of Human Enterovirus 71

Science (New York, N.Y.). Jun, 2012  |  Pubmed ID: 22383808

Enterovirus 71 is a picornavirus associated with fatal neurological illness in infants and young children. Here, we report the crystal structure of enterovirus 71 and show that, unlike in other enteroviruses, the "pocket factor," a small molecule that stabilizes the virus, is partly exposed on the floor of the "canyon." Thus, the structure of antiviral compounds may require a hydrophilic head group designed to interact with residues at the entrance of the pocket.

A Whole-Chromosome Analysis of Meiotic Recombination in Drosophila Melanogaster

G3 (Bethesda, Md.). Feb, 2012  |  Pubmed ID: 22384403

Although traditional genetic assays have characterized the pattern of crossing over across the genome in Drosophila melanogaster, these assays could not precisely define the location of crossovers. Even less is known about the frequency and distribution of noncrossover gene conversion events. To assess the specific number and positions of both meiotic gene conversion and crossover events, we sequenced the genomes of male progeny from females heterozygous for 93,538 X chromosomal single-nucleotide and InDel polymorphisms. From the analysis of the 30 F1 hemizygous X chromosomes, we detected 15 crossover and 5 noncrossover gene conversion events. Taking into account the nonuniform distribution of polymorphism along the chromosome arm, we estimate that most oocytes experience 1 crossover event and 1.6 gene conversion events per X chromosome pair per meiosis. An extrapolation to the entire genome would predict approximately 5 crossover events and 8.6 conversion events per meiosis. Mean gene conversion tract lengths were estimated to be 476 base pairs, yielding a per nucleotide conversion rate of 0.86 × 10(-5) per meiosis. Both of these values are consistent with estimates of conversion frequency and tract length obtained from studies of rosy, the only gene for which gene conversion has been studied extensively in Drosophila. Motif-enrichment analysis revealed a GTGGAAA motif that was enriched near crossovers but not near gene conversions. The low-complexity and frequent occurrence of this motif may in part explain why, in contrast to mammalian systems, no meiotic crossover hotspots have been found in Drosophila.

Effects of Prenatal Polycyclic Aromatic Hydrocarbon Exposure and Environmental Tobacco Smoke on Child IQ in a Chinese Cohort

Environmental Research. Apr, 2012  |  Pubmed ID: 22386727

This study of a birth cohort in the city of Tongliang in Chongqing, China, evaluated the relationship between two prenatal exposures (polycyclic aromatic hydrocarbons(PAH) and environmental tobacco smoke(ETS)) and child intelligence quotient (IQ) as measured by the Wechsler Preschool and Primary Scale of Intelligence at age 5 years. A coal-fired power plant was the major source of ambient PAH in this city. We tested the hypothesis that, after adjusting for potential confounders, prenatal exposure to these pollutants would be associated with lower IQ scores at 5 years of age.

Solution Structure of the Dickerson DNA Dodecamer Containing a Single Ribonucleotide

Biochemistry. Mar, 2012  |  Pubmed ID: 22390730

Ribonucleotides are frequently incorporated into DNA during replication. They are recognized and processed by several cellular enzymes, and their continued presence in the yeast nuclear genome results in replicative stress and genome instability. Thus, it is important to understand the effects of isolated ribonucleotide incorporation on DNA structure. With this goal in mind, we describe the nuclear magnetic resonance structure of the self-complementary Dickerson dodecamer sequence [d(CGC)rGd(AATTCGCG)](2) containing two symmetrically positioned riboguanosines. The absence of an observable H(1)-H(2) scalar coupling interaction indicates a C3'-endo conformation for the ribose. Longer-range structural perturbations resulting from the presence of the ribonucleotide are limited to the adjacent and transhelical nucleotides, while the global B-form DNA structure is maintained. Because crystallographic studies have indicated that isolated ribonucleotides promote global B → A transitions, we also performed molecular modeling analyses to evaluate the structural consequences of higher ribonucleotide substitution levels. Increasing the ribonucleotide content increased the minor groove width toward values more similar to that of A-DNA, but even 50% ribonucleotide substitution did not fully convert the B-DNA to A-DNA. Comparing our structure with the structure of an RNase H2-bound DNA supports the conclusion that, as with other DNA-protein complexes, the DNA conformation is strongly influenced by the interaction with the protein.

Prospective Study of 2-[¹⁸F]fluorodeoxyglucose Positron Emission Tomography in the Assessment of Regional Nodal Spread of Disease in Patients with Breast Cancer: an Ontario Clinical Oncology Group Study

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. Apr, 2012  |  Pubmed ID: 22393089

2-[(18)F]fluorodeoxyglucose (FDG) positron emission tomography (PET) is potentially useful in assessing lymph nodes and detecting distant metastases in women with primary breast cancer.

Does Left Ventricular Function Continue to Influence Mortality Following Contemporary Percutaneous Coronary Intervention?

Coronary Artery Disease. May, 2012  |  Pubmed ID: 22395238

Left ventricular (LV) dysfunction was associated with adverse outcome after percutaneous coronary intervention (PCI) in the balloon-angioplasty and bare-metal stent era. Technological advances have reduced complications after PCI. The impact of left ventricular ejection fraction (LVEF) on outcomes in current clinical practice is unknown, with commonly used risk stratification models not consistently incorporating preprocedural LVEF.

Imaging of the Iridocorneal Angle with the RTVue Spectral Domain Optical Coherence Tomography

Investigative Ophthalmology & Visual Science. 2012  |  Pubmed ID: 22395882

To determine the ability of the RTVue spectral domain optical coherence tomography (SDOCT) to image the anterior chamber angle (ACA).

Sensitivity of Tumor Cells Towards CIGB-300 Anticancer Peptide Relies on Its Nucleolar Localization

Journal of Peptide Science : an Official Publication of the European Peptide Society. Apr, 2012  |  Pubmed ID: 22407768

CIGB-300 is a novel anticancer peptide that impairs the casein kinase 2-mediated phosphorylation by direct binding to the conserved phosphoacceptor site on their substrates. Previous findings indicated that CIGB-300 inhibits tumor cell proliferation in vitro and induces tumor growth delay in vivo in cancer animal models. Interestingly, we had previously demonstrated that the putative oncogene B23/nucleophosmin (NPM) is the major intracellular target for CIGB-300 in a sensitive human lung cancer cell line. However, the ability of this peptide to target B23/NPM in cancer cells with differential CIGB-300 response phenotype remained to be determined. Interestingly, in this work, we evidenced that CIGB-300's antiproliferative activity on tumor cells strongly correlates with its nucleolar localization, the main subcellular localization of the previously identified B23/NPM target. Likewise, using CIGB-300 equipotent doses (concentration that inhibits 50% of proliferation), we demonstrated that this peptide interacts and inhibits B23/NPM phosphorylation in different cancer cell lines as evidenced by in vivo pull-down and metabolic labeling experiments. Moreover, such inhibition was followed by a fast apoptosis on CIGB-300-treated cells and also an impairment of cell cycle progression mainly after 5 h of treatment. Altogether, our data not only validates B23/NPM as a main target for CIGB-300 in cancer cells but also provides the first experimental clues to explain their differential antiproliferative response. Importantly, our findings suggest that further improvements to this cell penetrating peptide-based drug should entail its more efficient intracellular delivery at such subcellular localization.

Acute Exacerbations of COPD in the United States: Inpatient Burden and Predictors of Costs and Mortality

COPD. Apr, 2012  |  Pubmed ID: 22409371

Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are a leading cause of hospitalizations in the United States and the major cost driver of COPD. This study determined the national inpatient burden of AECOPD and assessed the association of co-morbidities and hospital characteristics with inpatient costs and mortality. Discharge records from the Agency for Healthcare Research and Quality (AHRQ) Healthcare Cost and Utilization Project (HCUP) Nationwide Inpatient Sample for 2006 was utilized. Outcomes of costs and mortality were assessed for AECOPD hospitalizations in cases ≥40 years of age. Multivariate regression analyses using a generalized linear model framework were conducted to determine predictors of inpatient costs and mortality controlling for patient demographics, primary payer, co-morbidity index, length of stay, hospital region, mechanical ventilation, and admission period. Overall, 1,254,703 hospitalizations for AECOPD were observed with mean costs of $9545(±12,700) and total costs of $11.9 billion. In-hospital mortality was 4.3% (N = 53,748). Discharges averaged 70.6 (±11.9) years of age. The majority were female (52.8%) and of white race (83.6% of reported race). Several co-morbidities were significantly associated with both costs and mortality (p < 0.001): acute myocardial infarction; congestive heart failure; cerebrovascular disease; lung cancer; cardiac arrhythmias; pulmonary circulation disorders; and weight loss. Significantly higher costs (p < 0.001) were associated with large and urban hospitals. The importance of co-morbidities in AECOPD is indicated in their association with prognosis and inpatient costs. Future research should determine if better management of these conditions can favorably impact the COPD disease burden.

Reproducibility and Intraindividual Variation over Days in Buccal Cell DNA Methylation of Two Asthma Genes, Interferon γ (IFNγ) and Inducible Nitric Oxide Synthase (iNOS)

Clinical Epigenetics. 2012  |  Pubmed ID: 22414378

ABSTRACT: The biological mechanisms responsible for the onset and exacerbation of asthma symptoms in children may involve the epigenetic regulation of inflammatory genes after environmental exposures. Using buccal cells, we hypothesized that DNA methylation in promoter regions of two asthma genes, inducible nitric oxide synthase (iNOS) and interferon γ (IFNγ), can vary over several days. Repeat buccal samples were collected 4 to 7 days apart from 34 children participating in the Columbia Center for Children's Environmental Health (CCCEH) birth cohort study. Several field duplicates (sequential collection of two samples in the field) and replicates (one sample pyrosequenced twice) also were collected to ensure consistency with collection and laboratory procedures. DNA methylation was assessed by pyrosequencing a PCR of bisulfite-treated DNA. We found that replicate and field duplicate samples were correlated strongly (r = 0.86 to 0.99, P < 0.05), while repeat samples demonstrated low within-subject correlations (r = 0.19 to 0.56, P = 0.06 to 0.30). Our data reveal DNA methylation as a dynamic epigenetic mechanism that can be accessed safely and reproducibly in an inner city pediatric cohort using non-invasive buccal swabs and pyrosequencing technology.

The Role of Bedside Ultrasound in the Diagnosis of Pericardial Effusion and Cardiac Tamponade

Journal of Emergencies, Trauma, and Shock. Jan, 2012  |  Pubmed ID: 22416160

This review article discusses two clinical cases of patients presenting to the emergency department with pericardial effusions. The role of bedside ultrasound in the detection of pericardial effusions is investigated, with special attention to the specific ultrasound features of cardiac tamponade. Through this review, clinicians caring for patients with pericardial effusions will learn to rapidly diagnose this condition directly at the bedside. Clinicians will also learn to differentiate between simple pericardial effusions in contrast to more complicated effusions causing cardiac tamponade. Indications for emergency pericardiocentesis are covered, so that clinicians can rapidly determine which group of patients will benefit from an emergency procedure to drain the effusion.

A Cancer Screening Intervention for Underserved Latina Women by Lay Educators

Journal of Women's Health (2002). May, 2012  |  Pubmed ID: 22416791

Inadequate screening adherence for breast, cervical, and colorectal cancer among Latinas places them at greater risk for poor survival rates, once diagnosed. The purpose of this study was to examine two delivery methods of lay health educators (promotoras de salud) to increase screening behavior and evaluate costs.

AGEs-RAGE Mediated Up-regulation of Connexin43 in Activated Human Microglial CHME-5 Cells

Neurochemistry International. May, 2012  |  Pubmed ID: 22417726

Microglial activation is a significant contributor to the pathogenesis of many neurodegenerative diseases. Microglia respond to a range of stimuli including pathogenic protein deposits such as advanced glycation endproducts (AGEs). AGEs are prominent inflammatory stimuli that accumulate in the ageing brain. AGEs can activate microglia, leading to the production of excessive amounts of inflammatory cytokines and coupling via gap junction proteins especially connexin43 (Cx43). The literature on the expression of microglial Cx43 during inflammation is controversial. Many cellular effects of AGEs are thought to be mediated by the receptor RAGE. There is however, no evidence suggesting Cx43 is a downstream effector of AGEs-RAGE interaction in microglia. In addition, most of the AGEs-related studies have been undertaken using rodent microglia; the information on human microglia is sparse. Microglia of human and rodent origin respond differently to certain stimuli. The aims of this study were to investigate the AGEs-RAGE-mediated activation of human microglia and establish if Cx43 is one of the downstream effectors of AGEs-RAGE interaction in these cells. Human microglial CHME-5 cells were treated with different doses of AGEs for a selected time-period and microglial activation studied using specific markers. The protein expression of RAGE, Cx43 and TNF-α-receptors (RI and RII) was analysed in response to AGEs in the absence/presence of various doses of anti-RAGE Fabs. TNF-α levels in media were measured using ELISA. TNF-α-induced opening of gap junctional channels was assessed by dye uptake assays and the effect of neutralising TNFRII on Cx43 levels was also studied. CHME-5 cells showed an up-regulation of RAGE, TNF-α, TNFRs (especially TNFRII) and Cx43 upon AGEs treatment and a significant dose-dependent drop in the levels of TNF-α, TNFRII and Cx43 in the presence of anti-RAGE Fabs. TNF-α induced gap junctional/hemichannel opening whereas blocking TNFRII inhibited TNF-α-induced increase in Cx43 levels. Results suggested that TNF-α, TNFRII and Cx43 are downstream effectors of the AGEs-RAGE interaction in human microglial CHME-5 cells.

Thiolated Chitosan Nanoparticles for the Nasal Administration of Leuprolide: Bioavailability and Pharmacokinetic Characterization

International Journal of Pharmaceutics. May, 2012  |  Pubmed ID: 22421322

The purpose of this study was to develop thiolated nanoparticles to enhance the bioavailability for the nasal application of leuprolide. Thiolated chitosan-thioglycolic acid (chitosan-TGA) and unmodified chitosan nanoparticles (NPs) were developed via ionic gelation with tripolyphosphate (TPP). Leuprolide was incorporated during the formulation process of NPs. The thiolated (chitosan-TGA) NPs had a mean size of 252 ± 82 nm, a zeta potential of +10.9 ± 4 mV, and payload of leuprolide was 12 ± 2.8. Sustained release of leuprolide from thiolated NPs was demonstrated over 6h, which might be attributed to inter- and/or intramolecular disulfide formation within the NPs network. Ciliary beat frequency (CBF) study demonstrated that thiolated NPs can be considered as suitable additives for nasal drug delivery systems. Compared to leuprolide solution, unmodified NPs and thiolated NPs provoked increased leuprolide transport through porcine nasal mucosa by 2.0 and 5.2 folds, respectively. The results of a pharmacokinetic study in male Sprague-Dawley rats showed improved transport of leuprolide from thiolated NPs as compared to leuprolide solution. Thiolated NPs had a 6.9-fold increase in area under the curve, more than 4-fold increase in elimination half-life, and a ∼3.8-fold increase in maximum plasma concentration compared to nasal solution alone. The relative nasal bioavailability (versus s.c. injection) of leuprolide thiolated NPs calculated on the basis of AUC((0-6)) was about 19.6% as compared to leuprolide solution 2.8%. The enhanced bioavailability of leuprolide is likely due to facilitated transport by thiolated NPs rather than improved release.

An SYBR Green-based Real-time RT-PCR Assay for the Detection of H5 Hemagglutinin Subtype Avian Influenza Virus

Molecular and Cellular Probes. Jun, 2012  |  Pubmed ID: 22421464

Increasing diversity among H5 hemagglutinin (HA) subtype avian influenza (AI) viruses has resulted in the need of novel sensitive and specific molecular assays. In this study, an SYBR Green-based real-time reverse transcription-PCR (RRT-PCR) assay was developed for the detection of H5 subtype AI virus. Sequence analysis of the Mexican lineage H5N2 isolates (subgroup B) revealed several mismatches in the primer/hydrolysis probe set reported in the commonly used RRT-PCR assay for the detection of H5 North American lineage. The present assay was designed to circumvent the challenge that these viruses represent for the specific detection of H5 subtype AI viruses. This RRT-PCR assay successfully detected a range of different H5 subtype AI strains from both Eurasian and North American lineages representing different avian H5 HA clades from diverse geographical locations. The sensitivity of the present method was determined by using in vitro-transcribed RNA and 10-fold serial dilutions of titrated AI viruses. High sensitivity levels were obtained, with limits of detection of 10(0) 50% egg infectious dose (EID50)/mL and 4.2 gene copies/μl. The linear ranges of the assay span within 10(6)-10(0) EID50/mL and 10(6)-10(0) gene copies/μl. The results obtained from this method were directly compared with those of the H5 RRT-PCR assay recommended by the OIE. The comparison was performed with 110 tracheal and cloacal swabs from various bird species collected during field and laboratory investigations in Eurasia and Africa in 2006 and 2008 and showed 100% agreement. This assay is recommended as an alternative method, also allowing a 'double check' approach detection, to be use mainly in outbreak scenarios with higher risk of poultry infections by Central American/Caribbean H5 AI viruses.

Heel Ultrasound Can Assess Maintenance of Bone Mass in Women with Breast Cancer

Journal of Clinical Densitometry : the Official Journal of the International Society for Clinical Densitometry. Jul-Sep, 2012  |  Pubmed ID: 22425507

Postmenopausal women with early stage breast cancer are at increased risk for bone loss and fractures. Bisphosphonates can prevent bone loss, but little data are available on changes in bone mass assessed by heel quantitative ultrasound (QUS). Our objectives were to determine if (1) heel QUS would provide a reliable and accessible method for evaluation of changes in bone mass in women with breast cancer when compared with the current standard of bone mass measurement, dual-energy X-ray absorptiometry (DXA) and (2) oral risedronate could affect these changes. Eighty-six newly postmenopausal (up to 8yr) women with nonmetastatic breast cancer were randomized to risedronate, 35mg once weekly or placebo. Outcomes were changes in heel QUS bone mass measurements and conventional DXA-derived bone mineral density (BMD). Over 2yr, bone mass assessed by heel QUS remained stable in women on risedronate, whereas women on placebo had a 5.2% decrease (p≤0.05) in heel QUS bone mass. Both total hip BMD and femoral neck BMD assessed by DXA decreased by 1.6% (p≤0.05) in the placebo group and remained stable with risedronate. Spine BMD remained stable in both groups. Heel QUS was moderately associated with BMD measured by DXA at the total hip (r=0.50), femoral neck (r=0.40), and spine (r=0.46) at baseline (all p≤0.001). In conclusion, risedronate helps to maintain skeletal integrity as assessed by heel QUS for women with early stage breast cancer. Heel QUS is associated with DXA-derived BMD at other major axial sites and may be used to follow skeletal health and bone mass changes in these women.

Developmental Regulation of MURF E3 Ubiquitin Ligases in Skeletal Muscle

Journal of Muscle Research and Cell Motility. Jun, 2012  |  Pubmed ID: 22426552

The striated muscle-specific tripartite motif (TRIM) proteins TRIM63/MURF1, TRIM55/MURF2 and TRIM54/MURF3 can function as E3 ubiquitin ligases in ubiquitin-mediated muscle protein turnover. Despite the well-characterised role of MURF1 in skeletal muscle atrophy, the dynamics of MURF isogene expression in the development and early postnatal adaptation of skeletal muscle is unknown. Here, we show that MURF2 is the isogene most highly expressed in embryonic skeletal muscle at E15.5, with the 50 kDa A isoform predominantly expressed. MURF1 and MURF3 are upregulated only postnatally. Knockdown of MURF2 p50A by isoform-specific siRNA results in delayed myogenic differentiation and myotube formation in vitro, with perturbation of the stable, glutamylated microtubule population. This underscores that MURF2 plays an important role in the earliest stages of skeletal muscle differentiation and myofibrillogenesis. During further development, there is a shift towards the 60 kDa A isoform, which dominates postnatally. Analysis of the fibre-type expression shows that MURF2 A isoforms are predominantly slow-fibre associated, whilst MURF1 is largely excluded from these fibres, and MURF3 is ubiquitously distributed in both type I and II fibres.

Classification Algorithms Enhance the Discrimination of Glaucoma from Normal Eyes Using High-definition Optical Coherence Tomography

Investigative Ophthalmology & Visual Science. Apr, 2012  |  Pubmed ID: 22427583

To evaluate the diagnostic performance of classification algorithms based on Linear Discriminant Analysis (LDA) and Classification And Regression Tree (CART) methods, compared with optic nerve head (ONH) and retinal nerve fiber layer (RNFL) parameters measured by high-definition optical coherence tomography (Cirrus HD-OCT) for discriminating glaucoma subjects.

Prenatal Polycyclic Aromatic Hydrocarbon (PAH) Exposure and Child Behavior at Age 6-7 Years

Environmental Health Perspectives. Jun, 2012  |  Pubmed ID: 22440811

Airborne polycyclic aromatic hydrocarbons (PAH) are widespread urban air pollutants from fossil fuel burning and other combustion sources. We previously reported that a broad spectrum of combustion-related DNA adducts in cord blood was associated with attention problems at 6-7 years of age in the Columbia Center for Children's Environmental Health (CCCEH) longitudinal cohort study.

A Sri Lankan Infant with Vaccine Associated Acute Flaccid Paralysis

The Ceylon Medical Journal. Mar, 2012  |  Pubmed ID: 22453711

Rapid Onset Obesity, Hypoventilation, Hypothalamic, Autonomic and Thermal Dysregulation, and Neural Tumour (ROHHADNET) Syndrome Presenting with Cushing Syndrome

The Ceylon Medical Journal. Mar, 2012  |  Pubmed ID: 22453714

A Case Series of Domestic Pressure Cooker Burns

The Ceylon Medical Journal. Mar, 2012  |  Pubmed ID: 22453715

Prenatal Exposure to Polycyclic Aromatic Hydrocarbons, Benzo[a]pyrene-DNA Adducts, and Genomic DNA Methylation in Cord Blood

Environmental Health Perspectives. May, 2012  |  Pubmed ID: 22256332

Polycyclic aromatic hydrocarbons (PAHs) are carcinogenic environmental pollutants generated during incomplete combustion. After exposure and during metabolism, PAHs can form reactive epoxides that can covalently bind to DNA. These PAH-DNA adducts are established markers of cancer risk. PAH exposure has been associated with epigenetic alterations, including genomic cytosine methylation. Both global hypomethylation and hypermethylation of specific genes have been associated with cancer and other diseases in humans. Experimental evidence suggests that PAH-DNA adduct formation may preferentially target methylated genomic regions. Early embryonic development may be a particularly susceptible period for PAH exposure, resulting in both increased PAH-DNA adducts and altered DNA methylation.Objective: We explored whether prenatal exposure to PAHs is associated with genomic DNA methylation in cord blood and whether methylation levels are associated with the presence of detectable PAH-DNA adducts.

Neuraminidase Inhibitors for Preventing and Treating Influenza in Children

Cochrane Database of Systematic Reviews (Online). 2012  |  Pubmed ID: 22258949

During epidemics, influenza attack rates in children may exceed 40%. Options for prevention and treatment currently include the neuraminidase inhibitors zanamivir and oseltamivir. Laninamivir octanoate, the prodrug of laninamivir, is currently being developed.

Imaging in the Management of Ischemic Cardiomyopathy: Special Focus on Magnetic Resonance

Journal of the American College of Cardiology. Jan, 2012  |  Pubmed ID: 22261158

Heart failure of ischemic origin has become increasingly common over the last decade because of the improved survival of patients with acute myocardial infarction. Revascularization with coronary bypass grafting or percutaneous coronary intervention plays a pivotal role in patients with ischemic cardiomyopathy, although these interventions are often associated with relatively high peri-procedural risk. The pathophysiological substrate of ischemic cardiomyopathy is heterogeneous, varying from predominantly hibernating myocardium to irreversible scarring. There is evidence to suggest that patients with hibernating myocardium benefit most from revascularization, whereas medical therapy is associated with an adverse prognosis. Therefore, noninvasive testing is recommended by relevant guidelines to guide optimal management in these patients. However, the role of noninvasive testing has recently been challenged. There are various imaging modalities available that provide information on different aspects of the disease, and therefore, they differ significantly in sensitivity and specificity. In clinical practice, choosing among the different imaging modalities can be difficult. Cardiac magnetic resonance has evolved into a comprehensive modality that can accurately determine the amount of hibernating myocardium as well as the presence and degree of myocardial ischemia and the extent of the scar. This paper reviews the indications, accuracy, and clinical utility of the available imaging techniques, with a special focus on cardiac magnetic resonance in ischemic cardiomyopathy, and provides an outlook on how this field might evolve in the future.

Megakaryocyte Development is Normal in Mice with Targeted Disruption of Tescalcin

Experimental Cell Research. Mar, 2012  |  Pubmed ID: 22285131

Tescalcin is an EF-hand calcium-binding protein that interacts with the Na+/H+ exchanger 1 (NHE1). Levay and Slepak recently proposed a role for tescalcin in megakaryopoiesis that was independent of NHE1 activity. Their studies using K562 and HEL cell lines, and human CD34+ hematopoietic stem cells suggested an essential role for tescalcin in megakaryocyte differentiation.

Pupil Dynamics in Chinese Subjects with Angle Closure

Graefe's Archive for Clinical and Experimental Ophthalmology = Albrecht Von Graefes Archiv Fur Klinische Und Experimentelle Ophthalmologie. Jan, 2012  |  Pubmed ID: 22290071

OBJECTIVE: To evaluate the speed of pupil constriction (SPC) in response to a standardized change in illumination from dark to light using anterior segment optical coherence tomography (AS-OCT) in eyes with closed angles, compared to those with open angles. METHODS: This was a prospective, comparative, observational study. Study subjects with primary angle-closure glaucoma (PACG) and/or primary angle-closure (PAC) were recruited along with a group of normal as controls. Videos of iris and anterior segment changes in response to illumination were captured with real-time video recording from AS-OCT and analysed frame by frame, beginning from a dilated to a constricted pupil. Customized software was used to measure speed of iris constriction, anterior chamber depth (ACD), anterior chamber width (ACW), iris thickness, and pupil diameter (PD). SPC was defined as the rate of pupil diameter change in response to illumination. RESULTS: One hundred and sixty three Chinese subjects were recruited in this study. A total of 137 of 163 eligible videos (82.5%) were available for analysis, comprising 87 subjects with closed angles (all had undergone laser peripheral iridotomies before) and 50 with open angles. SPC was less in eyes with closed angles (1.22 mm/sec vs 1.56 mm/sec, p < 0.001), after adjusting for age and ACW, and was positively correlated with axial length, ACD, anterior chamber angle status, PD in the dark, and iris thickness in the dark, (all r > 0.2, all p < 0.05). In multivariate analysis, SPC was independently associated with anterior chamber angle status (closed angle vs open angle) (β = 0.276, p = 0.016) and PD in dark (β = 0.129, p = 0.009), after adjusting for age, ACW, ACD, iris thickness and vertical cup-to-disc ratio. CONCLUSIONS: Compared to those with open angles, eyes with closed angles in Chinese subjects have slower speed of pupil constriction in response to dark-light change, even after adjusting for biometric factors associated with angle closure. The results suggest that differences in irido-pupillary dynamics may play a role in the pathogenesis of angle closure.

A New Sentinel Surveillance System for Severe Influenza in England Shows a Shift in Age Distribution of Hospitalised Cases in the Post-pandemic Period

PloS One. 2012  |  Pubmed ID: 22291929

The World Health Organization and European Centre for Disease Prevention and Control have highlighted the importance of establishing systems to monitor severe influenza. Following the H1N1 (2009) influenza pandemic, a sentinel network of 23 Trusts, the UK Severe Influenza Surveillance System (USISS), was established to monitor hospitalisations due to confirmed seasonal influenza in England. This article presents the results of the first season of operation of USISS in 2010/11.

Bilateral Delayed Nonpupillary Block Angle Closure After Insertion of Phakic Intraocular Lens

Journal of Cataract and Refractive Surgery. Apr, 2012  |  Pubmed ID: 22296844

Probe Functionalization with a Rhop-3 Antibody: Toward a Rhop-3 Antigen Immunosensor for Detection of Malaria

Analytical and Bioanalytical Chemistry. Mar, 2012  |  Pubmed ID: 22297859

The antibody specific for the malaria protein, Rhop-3, and FL-Rhop-3, were immobilized on the surface of a gold electrode modified with cysteamine. Colloidal gold was used to enhance the detection signal for Rhop-3 antigens. The Rhop-3 antibody was also immobilized on gold electrodes preactivated with dithiobis(succinimidyl proprionate) (DSP). Immobilization was performed at room temperature and at 37 °C. Cyclic voltammetry (CV) was used to monitor the interaction between the immobilized antibody and its cognate antigen in solution, using ferricyanide, K3Fe(CN)6, as reporting electroactive probe. Tests indicate recognition of Rhop-3 protein by the immobilized antibody. Antigen recognition was enhanced by incubation at 37 °C compared with room-temperature incubation. Our results suggest that an immunosensor can be developed and optimized to aid detection of Rhop-3 antigens in samples from malaria patients. As far as we are aware, this is the first amperometric immunosensor targeting Rhop-3 antigen as a malaria biomarker.

The Association of Recombination Events in the Founding and Emergence of Subgenogroup Evolutionary Lineages of Human Enterovirus 71

Journal of Virology. Mar, 2012  |  Pubmed ID: 22205739

Enterovirus 71 (EV71) is responsible for frequent large-scale outbreaks of hand, foot, and mouth disease worldwide and represent a major etiological agent of severe, sometimes fatal neurological disease. EV71 variants have been classified into three genogroups (GgA, GgB, and GgC), and the latter two are further subdivided into subgenogroups B1 to B5 and C1 to C5. To investigate the dual roles of recombination and evolution in the epidemiology and transmission of EV71 worldwide, we performed a large-scale genetic analysis of isolates (n = 308) collected from 19 countries worldwide over a 40-year period. A series of recombination events occurred over this period, which have been identified through incongruities in sequence grouping between the VP1 and 3Dpol regions. Eleven 3Dpol clades were identified, each specific to EV71 and associated with specific subgenogroups but interspersed phylogenetically with clades of coxsackievirus A16 and other EV species A serotypes. The likelihood of recombination increased with VP1 sequence divergence; mean half-lives for EV71 recombinant forms (RFs) of 6 and 9 years for GgB and GgC overlapped with those observed for the EV-B serotypes, echovirus 9 (E9), E30, and E11, respectively (1.3 to 9.8 years). Furthermore, within genogroups, sporadic recombination events occurred, such as the linkage of two B4 variants to RF-W instead of RF-A and of two C4 variants to RF-H. Intriguingly, recombination events occurred as a founding event of most subgenogroups immediately preceding their lineage expansion and global emergence. The possibility that recombination contributed to their subsequent spread through improved fitness requires further biological and immunological characterization.

Adult Right Lobe Live Donor Liver Transplant with Reconstruction of Retro-portal Accessory Right Hepatic Artery

Transplant International : Official Journal of the European Society for Organ Transplantation. Mar, 2012  |  Pubmed ID: 22188165

Travel-related Disseminated Penicillium Marneffei Infection in a Renal Transplant Patient

Transplant Infectious Disease : an Official Journal of the Transplantation Society. Aug, 2012  |  Pubmed ID: 22188555

Penicillium marneffei is a thermally dimorphic fungus that causes severe human immunodeficiency virus-related opportunistic infection in endemic areas of Southeast Asia and has rarely been reported in solid organ transplant (SOT) recipients. We report here the case of an Australian renal transplant patient who presented with disseminated P. marneffei infection shortly after a 10-day holiday to Vietnam, and review all previously published cases of penicilliosis associated with renal transplantation. This is the first reported case, to our knowledge, of P. marneffei infection in an SOT recipient acquired during travel to an endemic country, and highlights the importance of an accurate travel history when opportunistic infection is suspected, as well as giving appropriate health advice to transplant patients who travel.

The GDI-like Solubilizing Factor PDEδ Sustains the Spatial Organization and Signalling of Ras Family Proteins

Nature Cell Biology. Feb, 2012  |  Pubmed ID: 22179043

We identify a role for the GDI-like solubilizing factor (GSF) PDEδ in modulating signalling through Ras family G proteins by sustaining their dynamic distribution in cellular membranes. We show that the GDI-like pocket of PDEδ binds and solubilizes farnesylated Ras proteins, thereby enhancing their diffusion in the cytoplasm. This mechanism allows more effective trapping of depalmitoylated Ras proteins at the Golgi and polycationic Ras proteins at the plasma membrane to counter the entropic tendency to distribute these proteins over all intracellular membranes. Thus, PDEδ activity augments K/Hras signalling by enriching Ras at the plasma membrane; conversely, PDEδ down-modulation randomizes Ras distributions to all membranes in the cell and suppresses regulated signalling through wild-type Ras and also constitutive oncogenic Ras signalling in cancer cells. Our findings link the activity of PDEδ in determining Ras protein topography to Ras-dependent signalling.

Synergistic Effects of Conjugating Cell Penetrating Peptides and Thiomers on Non-viral Transfection Efficiency

Biomaterials. Mar, 2012  |  Pubmed ID: 22169137

Nanoparticles generated by complex coacervation of plasmid DNA (pDNA) and modified chitosans namely chitosan-thioglycolic acid (TGA) conjugate and chitosan-HIV-1 Tat peptide conjugate were evaluated as gene delivery systems. In order to optimize transfection efficiency, chitosan-HIV-1 Tat peptide conjugate was combined with chitosan-TGA before its complexation with pDNA. Particle size and zeta potential measurements were performed to characterize the generated nanoparticles. The nanoparticles transfection efficiencies were assessed by exploitation of the green fluorescent protein (GFP) reporter gene. HEK293 cells were incubated for 24 h with the nanoparticles and the GFP positive cells were observed by fluorescence microscopy. The nanoparticles in the size range of 200-300 nm could transfect HEK293 cells as a model cell line with different transfection efficiencies. Unlike chitosan-TGA, chitosan-HIV-1 Tat peptide led to increased zeta potential of nanoparticles as compared to unmodified chitosan. The transfection efficiency of the nanoparticles generated by combination of chitosan-HIV-1 Tat peptide with chitosan-TGA was comparatively higher than that of the nanoparticles generated by either chitosan-TGA or the combination of chitosan-HIV-1 Tat peptide with unmodified chitosan. After 72 h of incubation, the combination of chitosan-HIV-1 Tat peptide with chitosan-TGA was found to be 7.12- and 67.37 times more efficient than unmodified chitosan and pDNA alone, respectively and showed a synergistic effect in transfection of pDNA into the cells. Moreover, none of the nanoparticles showed any severe cytotoxicity. Accordingly, this strategy might result in a potent carrier for gene delivery.

Targeting Diverse Signaling Interaction Sites Allows the Rapid Generation of Bivalent Kinase Inhibitors

ACS Chemical Biology. Mar, 2012  |  Pubmed ID: 22148755

The identification of potent and selective modulators of protein kinase function remains a challenge, and new strategies are needed for generating these useful ligands. Here, we describe the generation of bivalent inhibitors of three unrelated protein kinases: the CAMK family kinase Pim1, the mitogen-activated protein kinase (MAPK) p38α, and the receptor tyrosine kinase (RTK) epidermal growth factor receptor (EGFR). These bivalent inhibitors consist of an ATP-competitive inhibitor that is covalently tethered to an engineered form of the self-labeling protein O(6)-alkylguanine-DNA alkyltransferase (SNAP-tag). In each example, SNAP-tag is fused to a peptide ligand that binds to a signaling interaction site of the kinase being targeted. These interactions increase the overall selectivity and potency of the bivalent inhibitors that were generated. The ability to exploit disparate binding sites in diverse kinases points to the generality of the method described. Finally, we demonstrate that ATP-competitive inhibitors that are conjugated to the bio-orthogonal tag O(4)-benzyl-2-chloro-6-aminopyrimidine (CLP) are cell-permeable. The selective labeling of SNAP-tag with CLP conjugates allows the rapid assembly of bivalent inhibitors in living cells.

Lessons Learned from an Osteoporosis Clinical Trial in Frail Long-term Care Residents

Clinical Trials (London, England). 2012  |  Pubmed ID: 22157987

Although osteoporosis affects women of all ages, the impact is most pronounced in frail residents in long-term care. Nevertheless, few interventional trials have been performed in this population, and few data on therapeutic alternatives are available in this cohort.

Association of the GGCX (CAA)16/17 Repeat Polymorphism with Higher Warfarin Dose Requirements in African Americans

Pharmacogenetics and Genomics. Feb, 2012  |  Pubmed ID: 22158446

Little is known about genetic contributors to higher than usual warfarin dose requirements, particularly for African Americans. This study tested the hypothesis that the γ-glutamyl carboxylase (GGCX) genotype contributes to warfarin dose requirements greater than 7.5 mg/day in an African American population.

Self-monitoring of Oral Anticoagulation: Systematic Review and Meta-analysis of Individual Patient Data

Lancet. Jan, 2012  |  Pubmed ID: 22137798

Uptake of self-testing and self-management of oral anticoagulation [corrected] has remained inconsistent, despite good evidence of their effectiveness. To clarify the value of self-monitoring of oral anticoagulation, we did a meta-analysis of individual patient data addressing several important gaps in the evidence, including an estimate of the effect on time to death, first major haemorrhage, and thromboembolism.

HPAM: Hirshfeld Partitioned Atomic Multipoles

Computer Physics Communications. Feb, 2012  |  Pubmed ID: 22140274

An implementation of the Hirshfeld (HD) and Hirshfeld-Iterated (HD-I) atomic charge density partitioning schemes is described. Atomic charges and atomic multipoles are calculated from the HD and HD-I atomic charge densities for arbitrary atomic multipole rank l(max) on molecules of arbitrary shape and size. The HD and HD-I atomic charges/multipoles are tested by comparing molecular multipole moments and the electrostatic potential (ESP) surrounding a molecule with their reference ab initio values. In general, the HD-I atomic charges/multipoles are found to better reproduce ab initio electrostatic properties over HD atomic charges/multipoles. A systematic increase in precision for reproducing ab initio electrostatic properties is demonstrated by increasing the atomic multipole rank from l(max) = 0 (atomic charges) to l(max) = 4 (atomic hexadecapoles). Both HD and HD-I atomic multipoles up to rank l(max) are shown to exactly reproduce ab initio molecular multipole moments of rank L for L ≤ l(max). In addition, molecular dipole moments calculated by HD, HD-I, and ChelpG atomic charges only (l(max) = 0) are compared with reference ab initio values. Significant errors in reproducing ab initio molecular dipole moments are found if only HD or HD-I atomic charges used.