Persistent pulmonary artery hypertension in patients undergoing balloon mitral valvotomy.
Pulmonary artery pressure (PAP) is known to regress after successful balloon mitral valvotomy (BMV). Data of persistent pulmonary artery hypertension (PPAH) following BMV is scarce. We analyzed the clinical, echocardiographic, and hemodynamic data of 701 consecutive patients who have undergone successful BMV in our institute from 1997 to 2003. Data of 287 patients who had PPAH (defined by pulmonary artery systolic pressure [PASP] of ≥ 40 mmHg at one year following BMV) were compared to the data of 414 patients who did not have PPAH. Patients who had PPAH were older (39.9 ± 9.9 years vs. 29.4 ± 10.1; P < 0.001). They had higher prevalence of atrial fibrillation (AF; 21.9 vs. 12.1%, P < 0.05), moderate or severe pulmonary artery hypertension (PAH) defined as PASP more than 50 mmHg (43.5 vs. 33.8%, P = 0.00), anatomically advanced mitral valve disease as assessed by Wilkin's echocardiographic score > 8 (33.7 vs. 23.2%, P < 0.001), and coexistent aortic valve disease (45.6 vs. 37.9%, P < 0.001) at the baseline. Those patients with PPAH had comparatively lower immediate postprocedural mitral valve area (MVA). On follow-up of more than five years, the occurrence of restenosis (39.3 vs. 10.1%, P = 0.000), new onset heart failure (14% vs. 4%, P < 0.05) and need for reinterventions (9.5% vs. 2.8%, P < 0.05) were higher in the PPAH group. Patients with PPAH were older, sicker, and had advanced rheumatic mitral valve disease. They had higher incidence of restenosis, new onset heart failure, and need for reinterventions on long term follow-up. PPAH represents an advanced stage of rheumatic valve disease and indicates chronicity of the disease, which may be the reason for the poorer prognosis of these patients. Patients with PPAH requires intense and more frequent follow-up.


A socioecological measurement of homophobia for all countries and its public health impact.
Measuring homophobia at country level is important to guide public health policy as reductions in stigma are associated with improved health outcomes among gay men and other men who have sex with men. Methods: We developed a Homophobic Climate Index incorporating institutional and social components of homophobia. Institutional homophobia was based on the level of enforcement of laws that criminalise, protect or recognise same-sex relations. Social homophobia was based on the level of acceptance and justifiability of homosexuality. We estimated the Index for 158 countries and assessed its robustness and validity. Western Europe is the most inclusive region, followed by Latin America. Africa and the Middle East are home to the most homophobic countries with two exceptions: South Africa and Cabo Verde. We found that a 1% decrease in the level of homophobia is associated with a 10% increase in the gross domestic product per capita. Countries whose citizens face gender inequality, human rights abuses, low health expenditures and low life satisfaction are the ones with a higher homophobic climate. Moreover, a 10% increase in the level of homophobia at country level is associated with a 1.7-year loss in life expectancy for males. A higher level of homophobia is associated with increased AIDS-related death among HIV-positive men. The socioecological approach of this index demonstrates the negative social, economic and health consequences of homophobia in low- and middle-income countries. It provides sound evidence for public health policy in favour of the inclusion of sexual minorities.


Selective induction of E2F1 in response to DNA damage, mediated by ATM-dependent phosphorylation.
Previous work has established a role for p53 in triggering apoptosis in response to DNA damage; p53 also induces apoptosis in response to deregulation of the Rb cell cycle pathway. The latter event is consistent with a role for the Rb-regulated E2F1 protein as a specific inducer of apoptosis and p53 accumulation. We now show that DNA damage leads to a specific induction of E2F1 accumulation, dependent on ATM kinase activity and that the specificity of E2F1 induction reflects a specificity in the phosphorylation of E2F1 by ATM as well as the related kinase ATR. We identify a site for ATM/ATR phosphorylation in the amino terminus of E2F1 and we show that this site is required for ATM-mediated stabilization of E2F1. Finally, we also show that E2F1 is required for DNA damaged induced apoptosis in mouse thymocytes. We conclude that the cellular response to DNA damage makes use of signals from the Rb/E2F cell cycle pathway.


Registration and analysis of white matter group differences with a multi-fiber model.
Diffusion magnetic resonance imaging has been used extensively to probe the white matter in vivo. Typically, the raw diffusion images are used to reconstruct a diffusion tensor image (DTI). The incapacity of DTI to represent crossing fibers leaded to the development of more sophisticated diffusion models. Among them, multi-fiber models represent each fiber bundle independently, allowing the direct extraction of diffusion features for population analysis. However, no method exists to properly register multi-fiber models, seriously limiting their use in group comparisons. This paper presents a registration and atlas construction method for multi-fiber models. The validity of the registration is demonstrated on a dataset of 45 subjects, including both healthy and unhealthy subjects. Morphometry analysis and tract-based statistics are then carried out, proving that multi-fiber models registration is better at detecting white matter local differences than single tensor registration.


High efficiency two-photon uncaging coupled by the correction of spontaneous hydrolysis.
Two-photon (TP) uncaging of neurotransmitter molecules is the method of choice to mimic and study the subtleties of neuronal communication either in the intact brain or in slice preparations. However, the currently available caged materials are just at the limit of their usability and have several drawbacks. The local and focal nature of their use may for example be jeopardized by a high spontaneous hydrolysis rate of the commercially available compounds with increased photochemical release rate. Here, using quantum chemical modelling we show the mechanisms of hydrolysis and two-photon activation, and synthesized more effective caged compounds. Furthermore, we have developed a new enzymatic elimination method removing neurotransmitters inadvertently escaping from their compound during experiment. This method, usable both in one and two-photon experiments, allows for the use of materials with an increased rate of photochemical release. The efficiency of the new compound and the enzymatic method and of the new compound are demonstrated in neurophysiological experiments.


Accurate vectorial finite element mode solver for magneto-optic and anisotropic waveguides.
In this work, a dielectric waveguide mode solver is presented considering a general nonreciprocal permittivity tensor. The proposed method allows us to investigate important cases of practical interest in the field of integrated optics, such as magneto-optical isolators and anisotropic waveguides. Unlike the earlier developed mode solver, our approach allows for the precise computation of both forward and backward propagating modes in the nonreciprocal case, ensuring high accuracy and computational efficiency. As a result, the nonreciprocal loss/phase shift can be directly computed, avoiding the use of the perturbation method. To compute the electromagnetic modes, the Rayleigh-Ritz functional is derived for the non-self adjoint case, it is discretized using the node-based finite element method and the penalty function is added to remove the spurious solutions. The resulting quadratic eigenvalue problem is linearized and solved in terms of the propagation constant for a given frequency (i.e., γ-formulation). The main benefits of this formulation are that it avoids the time-consuming iterations and preserves the matrix sparsity. Finally, the method is used to study two examples of integrated optical isolators based on nonreciprocal phase shift and nonreciprocal loss effect, respectively. The developed method is then compared with the perturbation approach and its simplified formulation based on semivectorial approximation.


Expression of Plasmodium berghei circumsporozoite antigen on the surface of exoerythrocytic schizonts and merozoites.
The intracellular distribution of circumsporozoite (CS) antigen was traced by immunoelectron microscopy in cultures of Plasmodium berghei exoerythrocytic (EE) schizonts with monoclonal antibody (Mab) 3D11 to the immunodominant repeat region of the P. berghei CS protein. CS antigen was localized on the parasitophorous vacuole (PV) membrane and pellicular complex of recently invaded sporozoites and on electron-dense masses of sloughed CS antigen in the host cell cytoplasm. CS antigen persisted throughout the complete EE cycle of P. berghei on the surface of EE schizonts and was incorporated into the plasma membrane of budding EE merozoites. Erythrocytic merozoites were not labeled by Mab 3D11, indicating that these 2 populations of merozoites differ in antigenic composition. Significant internal labeling occurred in 50 hr EE schizonts in association with the limiting membranes of peripheral vesicles and short, tube-like structures attached to their outer surfaces. These vesicles contained an electron-dense flocculent material also present in the PV space. Association of CS antigen with the limiting membranes of these vesicles suggests that they either develop as endocytotic invaginations of the schizont plasma membrane or transport newly synthesized CS antigen from the endoplasmic reticulum and Golgi of developing EE schizonts to the parasite surface.


Diet dominates host genotype in shaping the murine gut microbiota.
Mammals exhibit marked interindividual variations in their gut microbiota, but it remains unclear if this is primarily driven by host genetics or by extrinsic factors like dietary intake. To address this, we examined the effect of dietary perturbations on the gut microbiota of five inbred mouse strains, mice deficient for genes relevant to host-microbial interactions (MyD88(-/-), NOD2(-/-), ob/ob, and Rag1(-/-)), and >200 outbred mice. In each experiment, consumption of a high-fat, high-sugar diet reproducibly altered the gut microbiota despite differences in host genotype. The gut microbiota exhibited a linear dose response to dietary perturbations, taking an average of 3.5 days for each diet-responsive bacterial group to reach a new steady state. Repeated dietary shifts demonstrated that most changes to the gut microbiota are reversible, while also uncovering bacteria whose abundance depends on prior consumption. These results emphasize the dominant role that diet plays in shaping interindividual variations in host-associated microbial communities.


Genetic structure of the aphid, Chaetosiphon fragaefolii, and its role as a vector of the Strawberry Yellow Edge Virus to a native strawberry, Fragaria chiloensis in Chile.
The monoecious anholocyclical aphid, Chaetosiphon fragaefolii (Cockerell) (Homoptera: Aphididae), was collected on a native strawberry, Fragaria chiloensis (L.) Duchesne (Rosales: Rosaceae) from different sites in Chile. The presence of this aphid was recorded during two consecutive years. F. chiloensis plants were collected from seven natural and cultivated growing areas in central and southern Chile. Aphids were genotyped by cross-species amplification of four microsatellite loci from other aphid species. In addition, the aphid borne virus Strawberry mild yellow edge virus was confirmed in F. chiloensis plants by double-antibody sandwich ELISA and RT-PCR. Genetic variability and structure of the aphid populations was assessed from the geo-referenced individuals through AMOVA and a Bayesian assignment test. The presence of C. fragaefolii, during the two-year study was detected in only four of the seven sites (Curepto, Contulmo, Chilián and Cucao). Genetic variation among these populations reached 19% of the total variance. When assigning the individuals to groups, these were separated in three genetic clusters geographically disjunct. Of the seven sampled sites, six were positive for the virus by RT-PCR, and five by double-antibody sandwich ELISA . The incidence of the virus ranged from 0-100%. Presence of the virus corresponded with the presence of the aphid in all but two sites (Chilian and Vilches). The greatest incidence of Strawberry mild yellow edge virus was related to the abundance of aphids. On the other hand, sequences of the coat protein gene of the different virus samples did not show correspondence with either the genetic groups of the aphids or the sampling sites. The genetic structure of aphids could suggest that dispersal is mainly through human activities, and the spread to natural areas has not yet occurred on a great scale.


Cytosolic delivery of LDL nanoparticle cargo using photochemical internalization.
Following cellular delivery, most drugs must escape endosomes and lysosomes and reach the cytosol to be effective. This is particularly significant for nanoparticles, which can carry a large drug payload, but typically accumulate in endosomes and lysosomes. One attractive solution is to use light-triggered release, which can provide efficient endolysosomal membrane disruption and spatiotemporal control of cytosolic release. Here, we demonstrate the cytosolic release of cargo loaded into low density lipoprotein (LDL) nanoparticles using a photochemical internalization (PCI) approach. Three types of cargo-loaded LDL nanoparticles (CLLNPs) were generated by loading fluorescent dyes via (1) intercalation in the phospholipid monolayer exterior (surface loading), (2) conjugation to the amino acids of apoB-100 protein (protein loading) or (3) reconstitution into the hydrophobic core of LDL (core loading). Fluorescence imaging demonstrated the cellular uptake of CLLNPs was mediated by the LDL receptor and resulted in CLLNPs accumulation in endosomes. When cells were co-incubated with CLLNPs and AlPcS2a (a PCI agent), laser irradiation induced efficient cytosolic release of the surface-loaded and protein-labeled cargo, whereas the core-loaded hydrophobic dye could not readily be released. Thus, PCI is a useful cytosolic release method for CLLNPs, although the loading method must be considered.


Echocardiography is dispensable in uncomplicated Staphylococcus aureus bacteremia.
Current Staphylococcus aureus bacteremia (SAB) practice guidelines stratify treatment duration according to the likelihood of complications and recommend transesophageal echocardiography (TEE) in all cases. The benefit of TEE in uncomplicated SAB has not been validated. We performed a retrospective analysis of TEE and transthoracic echocardiography (TTE) among hospitalized adults with SAB in 3 prior observational studies (2002-2003, 2005-2006, and 2008-2009). Echocardiograms were ordered at the attending physician's discretion. SAB cases were stratified into the following types: complicated (persistent bacteremia [duration ≥3 d], relapse, and/or secondary foci); device-associated (intracardiac prosthetic devices); suspected endocarditis (the presence of murmurs or emboli); and uncomplicated (bacteremia duration ≤2 d, no device and/or secondary foci). We encountered 960 SAB cases; 83 were excluded (57 death/transfer/discharge within 48 h; 19 contaminants/no treatment; 7 care withdrawn). TEE and TTE were performed within 0-28 days of SAB onset in 177 (20.2%) and 321 (36.6%) instances, respectively. TEE was positive (with signs of endocarditis) in 42/177 (23.7%) cases: 7/39 (17.9%) community associated and 35/138 (25.4%) health care associated. It was positive in 29/120 (24.2%) complicated, 3/11 (27.3%) device-associated, 9/15 (60.0%) suspected endocarditis, and 1/31 (3.2%) uncomplicated cases of SAB. TTE was positive in 25/321 (7.8%) cases of SAB, 1 was uncomplicated; it was negative in 20/30 (66.7%) TEE-positive cases. Follow-up of ≥100 days was possible in 282/361 (78.1%) uncomplicated SAB; many (46.8%) received ≤15 days of therapy. None of them had relapses or secondary foci.These findings suggest that echocardiography is dispensable in cases of uncomplicated community-associated and health care-associated SAB. It should be limited to subsets with clinical findings of endocarditis, persistence, intracardiac devices, secondary foci, and relapse. The cost effectiveness of TTE prior to TEE among these patients is unknown.


Optical encryption system that uses phase conjugation in a photorefractive crystal.
We implement an optical encryption system based on double-random phase encoding of the data at the input and the Fourier planes. In our method we decrypt the image by generating a conjugate of the encrypted image through phase conjugation in a photorefractive crystal. The use of phase conjugation results in near-diffraction-limited imaging. Also, the key that is used during encryption can also be used for decrypting the data, thereby alleviating the need for using a conjugate of the key. The effect of a finite space-bandwidth product of the random phase mask on the encryption system's performance is discussed. A theoretical analysis is given of the sensitivity of the system to misalignment errors of a Fourier plane random phase mask.


Ex vivo and in vivo coronary ostial locations in humans.
Knowledge of the normal in vivo distribution and variation of coronary ostial locations is essential in the planning of various interventional and surgical procedures. However, all studies to date have reported the distribution of coronary ostia locations only in cadaver hearts. In this study, we sought to assess the distribution of coronary ostial locations in patients using cardiac dual-source computed tomography (CT) and compare these values to those of human cadaveric specimens. Measurements of the coronary ostia location were performed in 150 patients undergoing dual-source CT and in 75 cadavers using open measurement techniques. All 150 patients had a normal aortic valve function and no previous cardiac intervention or surgery. The location of the right and left coronary origin in relation to the aortic annulus and the height of the sinus of Valsalva were measured. Mean ostial locations at CT were 17.0 (+/-3.6) mm and 15.3 (+/-3.1) mm for the right and left coronary ostia, with large variations of both sides (right: 10.4-28.5 mm; left: 9.8-29.3 mm). In cadavers, mean locations were 14.9 (+/-4.3) mm [5-24 mm] for right and 16.0 (+/-3.6) mm [9-24 mm] for left coronary ostia. Comparison of CT and cadaver data showed statistically significant differences for right (P < 0.0001) but not left (P = 0.1675) coronary ostia. This study provides data of normal coronary ostial origins and demonstrates significant differences between in vivo and ex vivo measurements regarding the right coronary ostium. The observed large variations of coronary ostia origins emphasize the importance of considering such anatomic variations in the development of treatments.


Detection limits of an internal-reflection sensor for the optical beam deflection method.
The theoretical detection limit on angle deflection measurement when the quasi-critical internal-reflection method is used is calculated and compared with the more common method of using a bicell position-sensitive detector. Simple formulas for the sensitivity and resolution when the system is shot noise limited are given. It is shown that, even though the bicell detector is potentially much more sensitive for wide and well collimated beams, under typical laboratory restrictions, the internal reflection method may be more sensitive and have better resolution. It is argued that the internal-reflection method may be a tool in developing compact sensors based on the optical beam deflection method.


Molecular approaches to epidemiology and clinical aspects of malaria.
Malaria is a problem of global importance, responsible for 1-2 million deaths per year, mainly in African children, as well as considerable morbidity manifested as severe anaemia and encephalopathy in young children. Fundamental to the development of new tools for malaria control in humans is an increased understanding of key features of malaria infection, such as the diversity of outcome in different individuals, the understanding of different manifestations of the disease and of the mechanisms of immunity that allow clinical protection in the face of ongoing low-grade infection (concomitant immunity or premunition). Here, Graham Brown and colleagues review some of the ways in which molecular approaches might be used to increase our understanding of the epidemiology and clinical manifestations of malaria, as discussed at the Molecular Approaches to Malaria conference (MAM2000), Lorne, Australia, 2-5 February 2000.


10m/500 Mbps WDM visible light communication systems.
A wavelength-division-multiplexing (WDM) visible light communiction (VLC) system employing red and green laser pointer lasers (LPLs) with directly modulating data signals is proposed and experimentally demonstrated. With the assistance of preamplifier and adaptive filter at the receiving sites, low bit error rate (BER) at 10 m/500 Mbps operation is obtained for each wavelength. The use of preamplifier and adaptive filter offer significant improvements for free-space transmission performance. Improved performance of BER of <10(-9), as well as better and clear eye diagram were achieved in our proposed WDM VLC systems. LPL features create a new category of good performance with high-speed data rate, long transmission length (>5m), as well as easy handling and installation. This proposed WDM VLC system reveals a prominent one to present its advancement in simplicity and convenience to be installed.


Pertussis toxin analog with reduced enzymatic and biological activities is a protective immunogen.
Bordetella pertussis TOX3201 has a 12-base-pair insertion in the S1 subunit gene of pertussis toxin (PTX), which encodes for a 4-amino-acid insertion between residues 107 and 108 of the mature S1 subunit (Black et al., Science 240:656-659, 1988). This mutant strain has been shown to secrete a holotoxin analog of PTX, designated CRM3201, with reduced ADP-ribosyltransferase activity. In the present study, we evaluated the biochemical, biological, and immunoprotective activities of purified CRM3201. Assay of enzymatic activities showed that CRM3201 had 20 to 30% of the ADP-ribosyltransferase activity and 55 to 60% of the NAD glycohydrolase activity of native PTX. CRM3201, however, had only 2 to 6% of the activity of PTX in clustering CHO cells, promoting leukocytosis, inducing histamine sensitization, and potentiating an anaphylactic response to bovine serum albumin. In contrast, activities associated with the B oligomer (binding to fetuin, hemagglutination of goose erythrocytes, and lymphocyte mitogen activity) were comparable to those of native PTX. Injection of BALB/c mice with CRM3201 mixed with Al(OH)3 elicited high titers of antibody to PTX (as measured by enzyme-linked immunosorbent assay), which neutralized a leukocytosis-promoting dose of PTX in these mice and neutralized PTX in a CHO cell assay. Passive transfer of the anti-CRM3201 antibody protected 20-day-old Swiss-Webster mice against a lethal aerosol challenge with B. pertussis 18323. Active immunization with CRM3201 significantly reduced lung colonization in adult BALB/c mice with a B. pertussis respiratory infection. These results demonstrate (i) that the reduced ADP-ribosyltransferase activity of CRM3201 is associated with reductions in certain biological and toxic activities of PTX (the enzymatic and biological activities are not, however, totally concordant); (ii) that CRM3201 possesses a functional B oligomer; and (iii) that CRM3201 can induce toxin-neutralizing antibodies which protect mice against a respiratory challenge with B. pertussis. Our studies with CRM3201 show that recombinant analogs of PTX have the potential to be developed into safe, protective immunogens for use in new acellular pertussis vaccines.


Chromosome-level genome assembly, annotation, and phylogenomics of the gooseneck barnacle Pollicipes pollicipes.
The barnacles are a group of >2,000 species that have fascinated biologists, including Darwin, for centuries. Their lifestyles are extremely diverse, from free-swimming larvae to sessile adults, and even root-like endoparasites. Barnacles also cause hundreds of millions of dollars of losses annually due to biofouling. However, genomic resources for crustaceans, and barnacles in particular, are lacking. Using 62× Pacific Biosciences coverage, 189× Illumina whole-genome sequencing coverage, 203× HiC coverage, and 69× CHi-C coverage, we produced a chromosome-level genome assembly of the gooseneck barnacle Pollicipes pollicipes. The P. pollicipes genome is 770 Mb long and its assembly is one of the most contiguous and complete crustacean genomes available, with a scaffold N50 of 47 Mb and 90.5% of the BUSCO Arthropoda gene set. Using the genome annotation produced here along with transcriptomes of 13 other barnacle species, we completed phylogenomic analyses on a nearly 2 million amino acid alignment. Contrary to previous studies, our phylogenies suggest that the Pollicipedomorpha is monophyletic and sister to the Balanomorpha, which alters our understanding of barnacle larval evolution and suggests homoplasy in a number of naupliar characters. We also compared transcriptomes of P. pollicipes nauplius larvae and adults and found that nearly one-half of the genes in the genome are differentially expressed, highlighting the vastly different transcriptomes of larvae and adult gooseneck barnacles. Annotation of the genes with KEGG and GO terms reveals that these stages exhibit many differences including cuticle binding, chitin binding, microtubule motor activity, and membrane adhesion. This study provides high-quality genomic resources for a key group of crustaceans. This is especially valuable given the roles P. pollicipes plays in European fisheries, as a sentinel species for coastal ecosystems, and as a model for studying barnacle adhesion as well as its key position in the barnacle tree of life. A combination of genomic, phylogenetic, and transcriptomic analyses here provides valuable insights into the evolution and development of barnacles.


Textile-based wearable solid-contact flexible fluoride sensor: Toward biodetection of G-type nerve agents.
Rising global concerns posed by chemical and biological threat agents highlight the critical need to develop reliable strategies for the real-time detection of such threats. While wearable sensing technology is well suited to fulfill this task, the use of on-body devices for rapid and selective field identification of chemical agents is relatively a new area. This work describes a flexible printed textile-based solid-contact potentiometric sensor for the selective detection of fluoride anions liberated by the biocatalytic hydrolysis of fluorine-containing G-type nerve agents (such as sarin or soman). The newly developed solid-contact textile fluoride sensor relies on a fluoride-selective bis(fluorodioctylstannyl)methane ionophore to provide attractive analytical performance with near-Nernstian sensitivity and effective discrimination against common anions, along with excellent reversibility and repeatability for dynamically changing fluoride concentrations. By using stress-enduring printed inks and serpentine structures along with stretchable textile substrates, the resulting textile-based fluoride sensor exhibits robust mechanical resiliency under severe mechanical strains. Such realization of an effective textile-based fluoride-selective electrode allowed biosensing of the nerve-agent simulant diisopropyl fluorophosphate (DFP), in connection to immobilized organophosphorus acid anhydrolylase (OPAA) or organophosphorus hydrolase (OPH) enzymes. A user-friendly portable electronic module transmits data from the new textile-based potentiometric biosensor wirelessly to a nearby smartphone for alerting the wearer instantaneously about potential chemical threats. While expanding the scope of wearable solid-contact anion sensors, such a textile-based potentiometric fluoride electrode transducer offers particular promise for effective discrimination of G-type neurotoxins from organophosphate (OP) pesticides, toward specific field detection of these agents in diverse defense settings.


Minimum Threshold of Bariatric Surgical Weight Loss for Initial Diabetes Remission.
There are few studies testing the amount of weight loss necessary to achieve initial remission of type 2 diabetes mellitus (T2DM) following bariatric surgery and no published studies with use of weight loss to predict initial T2DM remission in sleeve gastrectomy (SG) patients. With Cox proportional hazards models we examined the relationship between initial T2DM remission and percent total weight loss (%TWL) after bariatric surgery. Categories of %TWL were included in the model as time-varying covariates. Of patients (N = 5,928), 73% were female; mean age was 49.8 ± 10.3 years and BMI 43.8 ± 6.92 kg/m2, and 57% had Roux-en-Y gastric bypass (RYGB). Over an average follow-up of 5.9 years, 71% of patients experienced initial remission of T2DM (mean time to remission 1.0 year). With 0-5% TWL used as the reference group in Cox proportional hazards models, patients were more likely to remit with each 5% increase in TWL until 20% TWL (hazard ratio range 1.97-2.92). When categories >25% TWL were examined, all patients had a likelihood of initial remission similar to that of 20-25% TWL. Patients who achieved >20% TWL were more likely to achieve initial T2DM remission than patients with 0-5% TWL, even if they were using insulin at the time of surgery. Weight loss after bariatric surgery is strongly associated with initial T2DM remission; however, above a threshold of 20% TWL, rates of initial T2DM remission did not increase substantially. Achieving this threshold is also associated with initial remission even in patients who traditionally experience lower rates of remission, such as patients taking insulin.


Shared decision making in the ED: ethical considerations.
The process of shared decision making (SDM) is an ethical imperative in the physician-patient relationship, especially in the emergency department (ED), where SDM can present unique challenges because patients and emergency physicians often have no established relationship and decisions about diagnosis, treatment, and disposition are time dependent. SDM should be guided by the ethical principles of autonomy, beneficence, nonmaleficence, and justice and the related principle of stewardship of finite resources. The objective of this article is to outline the ethical considerations of SDM in the ED in the context of diagnostic evaluations, therapeutic interventions, disposition decisions, and conflict resolution and to explore strategies for reaching decision consensus. Several cases are presented to highlight the ethical principles in SDM in the ED. SDM is an important approach to diagnostic testing in the ED. Achieving agreement regarding diagnostic evaluations requires a balance of respect for patient autonomy and stewardship of resources. SDM regarding ED therapeutic interventions is an important component of the balance of respect for patient autonomy and beneficence. While respecting patient autonomy, emergency physicians also recognize the importance of the application of professional judgment to achieve the best possible outcome for patients. SDM as an ethical imperative in the context of ED disposition is especially important because of the frequent ambiguity of equipoise in these situations. Unique clinical situations such as pediatric patients or patients who lack decisional capacity merit special consideration.


Zoonotic disease risk perceptions in the British veterinary profession.
In human and veterinary medicine, reducing the risk of occupationally-acquired infections relies on effective infection prevention and control practices (IPCs). In veterinary medicine, zoonoses present a risk to practitioners, yet little is known about how these risks are understood and how this translates into health protective behaviour. This study aimed to explore risk perceptions within the British veterinary profession and identify motivators and barriers to compliance with IPCs. A cross-sectional study was conducted using veterinary practices registered with the Royal College of Veterinary Surgeons. Here we demonstrate that compliance with IPCs is influenced by more than just knowledge and experience, and understanding of risk is complex and multifactorial. Out of 252 respondents, the majority were not concerned about the risk of zoonoses (57.5%); however, a considerable proportion (34.9%) was. Overall, 44.0% of respondents reported contracting a confirmed or suspected zoonoses, most frequently dermatophytosis (58.6%). In veterinary professionals who had previous experience of managing zoonotic cases, time or financial constraints and a concern for adverse animal reactions were not perceived as barriers to use of personal protective equipment (PPE). For those working in large animal practice, the most significant motivator for using PPE was concerns over liability. When assessing responses to a range of different "infection control attitudes", veterinary nurses tended to have a more positive perspective, compared with veterinary surgeons. Our results demonstrate that IPCs are not always adhered to, and factors influencing motivators and barriers to compliance are not simply based on knowledge and experience. Educating veterinary professionals may help improve compliance to a certain extent, however increased knowledge does not necessarily equate to an increase in risk-mitigating behaviour. This highlights that the construction of risk is complex and circumstance-specific and to get a real grasp on compliance with IPCs, this construction needs to be explored in more depth.


Normal growth hormone secretory reserve in men with idiopathic osteoporosis and reduced circulating levels of insulin-like growth factor-I.
Many men with idiopathic osteoporosis have reduced circulating insulin-like growth factor-I (IGF-I) levels. The major source of circulating IGF-I is GH-mediated production by the liver. The known anabolic effects of GH on the skeleton raised the possibility of GH deficiency in these men. We sought to test this hypothesis in this study. Fourteen men (mean age, 52.1 +/- 3.2 yr, range 31-68) with idiopathic osteoporosis were studied. Mean lumbar spine bone mineral density (BMD) was 0.723 g/cm2, T score -3.5; femoral neck BMD was 0.642 g/cm2, T score, -3.07; distal (1/3) radius BMD was 0.708 g/cm2, T score, -2.05. Eleven of 14 (79%) had frank reductions in serum IGF-I levels compared with age and sex-matched values (158.5 +/- 50 SD vs. 180 +/- 45 SD). GH secretion was stimulated by iv arginine infusion (30 g) over 30 min followed 1 h later by oral L-dopa (500 mg). Serum GH was measured at time (t) = -15, 0, 30, 45, 60, 90, 120, 150, and 180 min. All patients responded to at least one stimulus with the majority (n = 9) responding to both. Five patients responded either to arginine or to L-dopa but not to both. Baseline GH for the entire group was 0.77 + 0.08 ng/mL (SEM). Peak GH following arginine (t = 45-60 min) was 14.0 +/- 2.8 ng/mL, a 17.7 +/- 2.8-fold rise. Peak GH following L-dopa (t = 120-180 min) was 5.7 +/- 1.0 ng/mL, a 9.2 +/- 2.2-fold rise. No difference in maximal secretion was observed between those with low or normal IGF-I levels. Neither IGF-I nor IGF binding protein-3 concentrations changed significantly during the short period of GH stimulation. These data suggest that men with osteoporosis and reduced IGF-I levels do not appear to have a deficiency in the GH axis. Other hormonal or local factors may be important in regulating IGF-I expression. Deficiencies of IGF-I production at skeletal sites may be important in the pathogenesis of this syndrome.


Allele frequencies in Azuay Population in Ecuador.
One hundred and eighty-two samples of unrelated people who requested the paternity test at the Molecular Biology and Genetics Laboratory of the Catholic University of Cuenca-Ecuador in the province of Azuay were studied, except for the D1S1656 (180 samples) and SE33 (89 samples) markers. The STRs D22S1045, D3S1358, VWA, D16S539, D2S1338, D8S1179, D21S11, D18S51, D19S433, TH01, FGA, D1S1656, D12S391, D10S1248, D2S441, and SE33 were typed from blood samples, amplifying the DNA by polymerase chain reactions and electrophoresis. The allele frequencies were estimated by simple counting and the impartial heterozygosity was also calculated. The Hardy-Weinberg equilibrium theory was studied. In the results obtained with the analyzed markers, the largest number of alleles can be observed in the markers with the highest polymorphic information content (PIC): D21S11, D16S539, D2S1338, D19S433, D18S51, FGA, D1S1656, and D12S391. In addition, SE33 was analyzed in certain samples, showing as result a high PIC, in fact, the highest one because of its great polymorphisc characteristic. Likewise, these markers are the ones providing the highest probability of discrimination and the lowest probability of coincidence.


Exploratory analyses of the Danish Palliative Care Trial (DanPaCT): a randomized trial of early specialized palliative care plus standard care versus standard care in advanced cancer patients.
Early and integrated specialized palliative care is often recommended but has still only been investigated in relatively few randomized clinical trials. To investigate the effect of early specialized palliative care plus standard care versus standard care on the explorative outcomes in the Danish Palliative Care Trial (DanPaCT). We conducted a randomized multicentre, parallel-group clinical trial. Consecutive patients with metastatic cancer were included if they had symptoms or problems that exceeded a predefined threshold according to the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). Outcomes were estimated as the differences between the intervention and the control groups in the change from baseline to the weighted mean of the 3- and 8-week follow-ups measured as areas under the curve. In total, 145 patients were randomized to early specialized palliative care plus standard care versus 152 to standard care only. Early specialized palliative care had no significant effect on any of the symptoms or problems. Of the 21 items addressing satisfaction, specialized palliative care improved the item 'overall satisfaction with the help received from the health care system' with 9 points (95% confidence interval 3.8 to 14.2, p = 0.0006) and three other items (all p < 0.05). In line with the analyses of the primary and secondary outcomes in DanPaCT, we did not find that specialized palliative care, as provided in DanPaCT, affected symptoms and problems. However, patients in the intervention group seemed more satisfied with the health care received than those in the standard care group. NCT01348048.


Angiographic validation of eigenvolume to measure left ventricular size.
Radiopaque markers implanted in the left ventricle allow one to follow the motion of specific elements of myocardium and compute a measure of relative left ventricular volume, called "eigenvolume." Workers in our laboratory partially validated this measure in excised dog hearts by comparing eigenvolumes with volumes of balloons in the left ventricle. Perhaps because the balloon did not fully fill the left ventricle, there was a significant nonzero intercept in the relation between eigenvolume and balloon volume. Therefore, the results only partially confirmed the eigenvolume theory because eigenvolume should be proportional to cavity volume. This study compares eigenvolume with left ventricular volume measured by biplane angiography in intact beating hearts following hemodynamic interventions (atropine, phenylephrine, nitroprusside, volume loading, and propranolol). We performed 32 angiograms in five dogs. A high correlation (r = 0.958 +/- 0.029 [SD]) was found between eigenvolumes and left ventricular volumes. In contrast to earlier in vitro validations and consistent with theory, the intercept of the relation between eigenvolume and left ventricular cavity volume (angiovolume) was not significantly different from zero. These data strengthen the hypothesis that eigenvolume accurately reflects true left ventricular volume in vivo. These same data were used to assess the immediate (i.e., within a few beats) effect of angiography. Left ventricular volume loading associated with the angiogram modestly (6%) increases left ventricular end-diastolic and end-systolic eigenvolumes without changing stroke volume or pressures, consistent with a mild negative inotropic effect.


The Controlling Nutritional Status Score Is a Significant Independent Predictor of Poor Prognosis in Patients With Malignant Pleural Mesothelioma.
Malignant pleural mesothelioma (MPM) is a devastating neoplasm; however, some patients exhibit a good response to chemotherapy or multidisciplinary therapy, including surgery and chemotherapy. It is therefore important to discover the factors that can be used to select patients who will benefit from such treatment. Although the Controlling Nutritional Status (CONUT) score has been used to predict the prognosis in other types of malignancy, its utility in patients with MPM is unknown. The aim of this study was to clarify the clinical significance of the CONUT in patients with MPM. The data of 83 patients, who were treated with surgery, chemotherapy, or multidisciplinary therapy, were analyzed in the present study. A cut-off CONUT score of 2 was used to classify all of the patients into low or high CONUT groups. Fifty-two of the 83 patients were classified into the low CONUT group. A high CONUT score was significantly correlated with chemotherapy alone (P = .011). The high CONUT group had significantly poorer overall survival (OS) (P < .001) and disease- or progression-free survival (DFS/PFS) (P < .001). The clinical stage and the CONUT score were found to be independent predictive factors for the OS: clinical stage, I/II and III/IV; P = .001 and CONUT score, ≥ 3 and ≤ 2; P = .011, respectively. The clinical stage and the CONUT score were also independent predictive factors for DFS/PFS: clinical stage, I/II and III/IV; P = .006 and CONUT score, ≥ 3 and ≤ 2; P = .013, respectively. The CONUT score was an independent predictor of a poor prognosis in the patients with MPM. This score provides useful information for selecting patients who will benefit from the treatment.


Simvastatin effects on androgens, inflammatory mediators, and endogenous pituitary gonadotropins among patients with PCOS undergoing IVF: results from a prospective, randomized, placebo-controlled clinical trial.
To evaluate effects of simvastatin on selected biochemical parameters and reproductive outcome among patients with polycystic ovary syndrome (PCOS) who undergo in vitro fertilization (IVF). Patients with PCOS were randomized to receive either oral simvastatin, 20 mg/d (n = 32), or placebo (n = 32) in a prospective, double-blind, randomized clinical trial (NCT 005-75601) in parallel with controlled ovarian hyperstimulation for IVF. All patients were determined to be at average risk for cardiovascular disease, based on high-sensitivity C-reactive protein (hsCRP) measurement at entry. After an 8-week treatment interval concluding at periovulatory human chorionic gonadotropin administration, selected clinical and laboratory parameters were measured. Mean serum total testosterone level decreased by 25% in the simvastatin group, compared to a 10% reduction in the placebo group (P < 0.001). A trend of lower serum luteinizing hormone levels was noted in experimental and control groups (29% vs 22%, respectively), although this difference was not significant (P > 0.05). Neither fasting insulin nor quantitative insulin sensitivity check index were significantly impacted by simvastatin (P > 0.05). As expected, total cholesterol was not modified among placebo patients but was significantly reduced after simvastatin (P = 0.001). In addition, hsCRP and vascular cell adhesion protein-1 were both significantly lower after simvastatin therapy compared to controls (P ≤ 0.005 for both). At study completion, no important change in body mass index was observed in either group (P ≥ 0.60). Although oocyte maturation, fertilization, and clinical pregnancy rates were all higher after simvastatin, none of these improvements were statistically significant. This report presents data from the first prospective, randomized, placebo-controlled clinical investigation of simvastatin in the setting of PCOS and IVF. Simvastatin seems to be compatible with gonadotropin therapy for IVF and can offer beneficial endocrine and cardiovascular effects for patients with PCOS who undergo embryo transfer. Although the observed improvements in reproductive function were mild, the reductions in hsCRP and vascular cell adhesion protein-1 after simvastatin treatment were significant, suggesting the need for further clinical trials to clarify simvastatin's impact on reproductive physiology.


Endothelial cell storage and release of endothelin as a cardioregulatory mechanism.
Coronary vascular endothelial cells release substances into the coronary circulation that modify the contractile system of cardiac myocytes, and cardiac myocytes may release factors that modulate the secretion of cardioregulatory substances by endothelial cells. This regulatory loop is sensitive to the rate of coronary flow and tissue oxygen tension. In the present study, coronary venous effluent from isolated perfused hearts and the contents of the coronary vascular endothelial cells have been collected, the latter by disrupting the cells with coronary perfusion at high pressure. The relative amounts of upregulating and downregulating factors in both collections have been estimated by assaying their effects on the contractility of isolated cardiac trabeculas. The amount of upregulating factor stored in the endothelial cells is sensitive to the rate of coronary flow just before disruption of the cells. The quantity of endothelin in the coronary venous effluent and in the vascular endothelial cell contents was measured by radioimmunoassay and compared with the degree of upregulation of contractility produced by the two types of solutions. Upregulation was never produced in the absence of endothelin. The extent of the increase in contractility that was observed with endothelial cell contents correlated with the concentration of endothelin and was approximately the same as the increase in contractility from similar concentrations of endothelin added to standard Krebs' solution. The amount of the increase in contractility from coronary effluent could be accounted for by the concentration of endothelin in the effluent with the additional presence of some downregulating factor as well. The endothelin antagonist BQ123 inhibited the upregulation from coronary perfusate. It appears that endothelin alone can account for all of the upregulation of contractility produced by the vascular endothelial cells. Coronary flow, probably through shear forces, seems to regulate the production of endothelin possibly from an inactive precursor. Tissue oxygen tension appears to modulate the rate of release of the endothelin from endothelial cells though substances released by cardiac myocytes or other cells in the tissue. The downregulating factor is stored to a much smaller extent.


Expression of neurotrophins and their receptors in the mammalian ovary is developmentally regulated: changes at the time of folliculogenesis.
An emerging body of evidence suggests that neurotrophins not only promote neuronal survival and differentiation, but can also target nonneuronal cells for their actions. Neurotrophins initiate their biological effects by binding to cell membrane tyrosine kinase receptors of the trk protooncogene family. In addition, all neurotrophins recognize with similar affinity a different receptor molecule known as p75 nerve growth factor receptor (p75 NGFR) or low affinity NGFR, which appears to interact with the trk receptors to potentiate their response to neurotrophins. The mature mammalian ovary has been shown to synthesize several neurotrophins, including nerve growth factor (NGF), neurotrophin 3 (NT-3), and neurotrophin 4/5 (NT-4/5). The ovary also expresses some of the neurotrophin receptors, including p75 NGFR, trkB [the receptor for NT-4/5 and brain-derived neurotropic factor (BDNF)], and trkA (the NGF receptor). The present experiments were undertaken to determine whether neurotrophins and their receptors are expressed at the time of definitive ovarian histogenesis, and whether any of them exhibit a developmental pattern of expression related to the completion of folliculogenesis. Immunohistochemical identification of p75 NGFR in rat embryonic ovaries revealed that the receptor is predominantly expressed in mesenchymal cells. By gestational day 18, these cells have formed pockets that enclose presumptive pregranulosa cells and groups of oocytes into ovigerous cords. Immediately after birth, the ovigerous cords are subdivided, resulting in the abrupt formation of primordial follicles between 24-48 h after birth. Consistent with these observations, the p75 NGFR messenger RNA (mRNA) content increased after birth and remained elevated at the time of follicular assembly. The NGF and trkA genes showed a different pattern of expression, as the ovarian content of both NGF and trkA mRNA decreased at the time of folliculogenesis. In contrast to the drop in NGF and trkA mRNA expression, NT-4 mRNA levels increased at the time of follicular assembly, coinciding with the abrupt appearance of trkB mRNA. In situ hybridization showed that the increase in NT-4 mRNA expression occurred in a subpopulation of oocytes between 24-48 h after birth, and that the trkB gene became predominantly expressed at this time in epithelial pregranulosa cells. Substantial, but unchanging, levels of NT-3 mRNA and the mRNA encoding trkC, the preferred NT-3 receptor, were detected throughout the perinatal period examined. Very low and invariable levels of BDNF were also detected.(ABSTRACT TRUNCATED AT 400 WORDS)


Reproductive factors and menopausal hormone therapy and bladder cancer risk in the NIH-AARP Diet and Health Study.
The incidence of bladder cancer among women is at least one-third to one-fourth that observed among men in many countries. Even after accounting for known risk factors, the reason for this gender disparity remains unexplained. We conducted a comprehensive evaluation of reproductive factors and exogenous hormone use with a primary focus on menopausal hormone therapy use and risk of bladder cancer in women in the NIH-AARP Diet and Health Study. Reproductive and hormonal factors were ascertained on the baseline questionnaire in 1995-1996 among 201,492 females who were followed until December 31, 2006. During follow-up, 651 cases of bladder cancer were diagnosed. A subset of women provided detailed information on use of MHT in a second questionnaire in 1996-1997. In this analysis, 127,361 females were followed through June 30, 2002 and 198 incident bladder cancer cases were identified. Cox proportional hazard models, adjusted for smoking status, cigarettes per day and body mass index using age as the time metric, were used to obtain hazard ratios (HRs). A reduced risk was observed among parous women (HR=0.76; 95% CI 0.62-0.93) and women who reported late age at menarche (≥15 years) (HR=0.57; 95% CI 0.39-0.84). Women who reported ever using estrogen and progestin therapy had a decreased risk (HR=0.53; 95% CI: 0.34-0.83) compared with women who did not report MHT use. No association was observed for estrogen only users (HR=0.82; 95% CI: 0.58-1.15). Our results suggest a putative role for sex hormones in the etiology of bladder cancer among women.


Differences in non-Hodgkin lymphoma survival between young adults and children.
To examine differences in non-Hodgkin lymphoma (NHL) survival between young adults and children/adolescents. Survival analysis using 13 Surveillance, Epidemiology, and End Results registries. Cancer survival information from population-based cancer registries from 1992 through 2001. A total of 2442 cases of NHL among children/adolescents (aged 0-19 years) and young adults (aged 20-29 years). Differences in NHL survival between young adults and children. Comparison of 5-year survival by constructing Kaplan-Meier survival curves and modeling 5-year survival with multivariate Cox proportional hazards. Young adults were more likely to die compared with children/adolescents (hazard ratio = 2.06; 95% confidence interval, 1.65-2.56) even after accounting for NHL subtype and stage at diagnosis. Persons diagnosed with stage III disease (hazard ratio = 1.71; 95% confidence interval, 1.20-2.46) and stage IV disease (hazard ratio = 3.19; 95% confidence interval, 2.47-4.13) were more likely to die compared with persons diagnosed with stage I disease. Being a young adult at diagnosis and having a higher stage of disease at diagnosis were associated with higher risk of death from NHL. Increasing survival with NHL is dependent on receiving appropriate cancer therapy. Therefore, efforts to address survival should include improving enrollment in clinical trials as well as increasing access to care.


Epigenome-wide association studies without the need for cell-type composition.
In epigenome-wide association studies, cell-type composition often differs between cases and controls, yielding associations that simply tag cell type rather than reveal fundamental biology. Current solutions require actual or estimated cell-type composition--information not easily obtainable for many samples of interest. We propose a method, FaST-LMM-EWASher, that automatically corrects for cell-type composition without the need for explicit knowledge of it, and then validate our method by comparison with the state-of-the-art approach. Corresponding software is available from http://www.microsoft.com/science/.


Nuclear localisation of NOVH protein: a potential role for NOV in the regulation of gene expression.
To identify the NOV protein detected by immunofluorescence in the nucleus of human cancer cell lines to establish whether targeting to the nucleus reflects dual paracrine and intracrine biological functions of NOV, as has been reported previously for several signalling peptides and proteins. Nuclear and cytoplasmic fractions were prepared from 143 and HeLa cells in which nuclear NOV protein was detected. Western blotting analysis of NOV proteins in both types of fractions was performed using two NOV specific antibodies. Confocal microscopy was used to visualise the nuclear NOV protein in HeLa and 143 cells. A yeast two hybrid screening system was used to isolate cDNAs encoding proteins able to interact with the human NOV protein. A 31/32 kDa doublet of NOV protein was identified in the nuclear fraction of 143 and HeLa cells. Because the antibodies were directed against the C-terminus of NOV, the 31/32 kDa NOV isoform is probably truncated at the N-terminus and might correspond to the secreted 32 kDa NOV isoform detected in cell culture medium. Confocal microscopy indicated that in addition to the cytoplasmic NOV protein already identified, a nuclear NOV protein was present in both the nucleoplasm and nucleoli of Hela and 143 cells. Screening of cDNA libraries prepared from HeLa cells, Epstein-Barr virus transformed lymphocytes, and normal human brain showed that the NOV protein interacts with the rpb7 subunit of RNA polymerase in a yeast two hybrid system. The NOV protein detected in the nucleus of 143 and HeLa cells is probably an N-terminus truncated isoform of the secreted 48 kDa NOV protein. A growing body of evidence suggests that novH expression is closely associated with differentiation in normal human tissues and that the nov gene encodes a signalling protein that belongs to an emerging family of cell growth regulators. The nuclear localisation of a NOV isoform potentially provides an additional degree of signalling specificity. The interaction of the NOV protein and the rpb7 subunit of RNA polymerase II in the two hybrid system suggests that NOV might be involved in regulating gene expression at the transcriptional level. As has already been suggested for several other nuclearly located cytokines, the NOV protein does not contain a typical nuclear localisation signal. Therefore, it is possible that it combines with either a receptor or a chaperone during its translocation. Disruption of the balance between the secreted and nuclear NOV isoforms might affect the putative autocrine and paracrine functions of NOV and might be of considerable importance in the development of cancers in which the expression of novH has been shown to be impaired.


Initial quantitative proteomic map of 28 mouse tissues using the SILAC mouse.
Identifying the building blocks of mammalian tissues is a precondition for understanding their function. In particular, global and quantitative analysis of the proteome of mammalian tissues would point to tissue-specific mechanisms and place the function of each protein in a whole-organism perspective. We performed proteomic analyses of 28 mouse tissues using high-resolution mass spectrometry and used a mix of mouse tissues labeled via stable isotope labeling with amino acids in cell culture as a "spike-in" internal standard for accurate protein quantification across these tissues. We identified a total of 7,349 proteins and quantified 6,974 of them. Bioinformatic data analysis showed that physiologically related tissues clustered together and that highly expressed proteins represented the characteristic tissue functions. Tissue specialization was reflected prominently in the proteomic profiles and is apparent already in their hundred most abundant proteins. The proportion of strictly tissue-specific proteins appeared to be small. However, even proteins with household functions, such as those in ribosomes and spliceosomes, can have dramatic expression differences among tissues. We describe a computational framework with which to correlate proteome profiles with physiological functions of the tissue. Our data will be useful to the broad scientific community as an initial atlas of protein expression of a mammalian species.


Involvement of human cytochromes P450 (CYP) in the reductive metabolism of AQ4N, a hypoxia activated anthraquinone di-N-oxide prodrug.
To establish the role of the human cytochromes P450 (CYPs) in the reductive metabolism of the novel anthraquinone di-N-oxide prodrug AQ4N. Metabolism of AQ4N was conducted in a panel of 17 human phenotyped liver microsomes. AQ4N and metabolites were detected by reverse phase isocratic HPLC. CYP inhibitors and Spearman rank correlation were used to determine the significance of AQ4N metabolism versus specific CYP activity and/or expression. Anaerobic metabolism of AQ4N to the 2-electron reduction product, AQM, and the 4-electron reduced tertiary amine, AQ4, occurred in all 17 human liver microsome preparations. The range (+/- SE) for total AQ4N turnover was 14.26 +/- 1.43 nmol/incubate (highest) to 3.65 +/- 1.05 nmol/incubate (lowest). Metabolism was not detected in the absence of NADPH or microsomes. In aerobic incubates, AQM was less than 4% of anaerobic values whereas AQ4 was undetectable. CYP-mediated metabolism of AQ4N was inhibited completely by ketoconazole (KET) and carbon monoxide (CO), two global inhibitors of CYP-mediated metabolism. AQ4N metabolism correlated significantly with probes for CYP 3A, specifically benzoxylresorufin O-dealkylation [r(s) = 0.70,p <0.01] and tamoxifen N-demethylation (r(s) = 0.85, p < 0.01), but not with probes for CYPs 2C, 2D, and 1A. CYP 3A involvement was confirmed by the use of the CYP 3A specific inhibitor, triacetyloleandomycin (TAO), which repressed the formation of AQM to 13% of the uninhibited value and abolished completely the formation of AQ4. Alpha-naphthoflavone (ANF), an inhibitor of CYP 2C and 1A, had no significant effect on AQ4N metabolism. These data suggest that the human CYP 3A enzymes can contribute to the reductive metabolism of AQ4N. CYP 3A enzymes are highly expressed in a broad spectrum of human cancers. The results show that AQ4N requires anaerobic conditions for CYP 3A-mediated reduction and hence this subfamily of enzymes is likely to selectively activate AQ4N in hypoxic tumors.


The evolutionary pattern of mutations in glioblastoma reveals therapy-mediated selection.
Glioblastoma presents as a heterogeneous disease with poor prognosis despite the use of multimodal therapy. Analysis of genomic DNA changes between initial diagnosis and recurrence in response to standard treatment protocols would enhance understanding of disease progression and better inform new treatment strategies. A cohort of 21 patients with primary glioblastoma were examined between diagnosis and first recurrence. This study presented a rare opportunity to characterize molecular alterations in tumors observed in three patients who received no therapeutic intervention, other than surgery, offering a unique control. We focused this study by comparing the dynamic mutation profiles between the primary tumors and their matched recurrent counterparts. Molecular profiling of tumors was performed using multiplexed targeted deep sequencing of 409 well characterized cancer-associated genes, achieving a mean read depth of 1272 x. Three levels of evidence suggested an evolutionary pattern consistent with a response to therapy-mediated selection pressures exists in treated patients: 1) variant burden was reduced in recurrent tumors, 2) neutral evolutionary dynamics apparent in untreated tumors shifted toward a non-neutral mode of evolution in treated patients at recurrence, and 3) the recurrent tumor of one patient displayed an increased mutation rate attributable to a temozolomide-associated hypermutator phenotype. Our observations suggest that current treatment modalities are likely to fail in achieving long term remission with the majority of relapse samples containing distinct mutations when compared to primary diagnostic samples.


Pleural effusion in patients with acute lung injury: a CT scan study.
Pleural effusion is a frequent finding in patients with acute respiratory distress syndrome. To assess the effects of pleural effusion in patients with acute lung injury on lung volume, respiratory mechanics, gas exchange, lung recruitability, and response to positive end-expiratory pressure. A total of 129 acute lung injury or acute respiratory distress syndrome patients, 68 analyzed retrospectively and 61 prospectively, studied at two University Hospitals. Whole-lung CT was performed during two breath-holding pressures (5 and 45 cm H2O). Two levels of positive end-expiratory pressure (5 and 15 cm H2O) were randomly applied. Pleural effusion volume was determined on each CT scan section; respiratory system mechanics, gas exchange, and hemodynamics were measured at 5 and 15 cm H2O positive end-expiratory pressure. In 60 patients, elastances of lung and chest wall were computed, and lung and chest wall displacements were estimated. Patients were divided into higher and lower pleural effusion groups according to the median value (287 mL). Patients with higher pleural effusion were older (62±16 yr vs. 54±17 yr, p<0.01) with a lower minute ventilation (8.8±2.2 L/min vs. 10.1±2.9 L/min, p<0.01) and respiratory rate (16±5 bpm vs. 19±6 bpm, p<0.01) than those with lower pleural effusion. Both at 5 and 15 cm H2O of positive end-expiratory pressure PaO2/FIO2, respiratory system elastance, lung weight, normally aerated tissue, collapsed tissue, and lung and chest wall elastances were similar between the two groups. The thoracic cage expansion (405±172 mL vs. 80±87 mL, p<0.0001, for higher pleural effusion group vs. lower pleural effusion group) was greater than the estimated lung compression (178±124 mL vs. 23±29 mL, p<0.0001 for higher pleural effusion group vs. lower pleural effusion group, respectively). Pleural effusion in acute lung injury or acute respiratory distress syndrome patients is of modest entity and leads to a greater chest wall expansion than lung reduction, without affecting gas exchange or respiratory mechanics.


Role of tiotropium in the treatment of COPD.
Tiotropium is a potent, long-acting, selective anticholinergic bronchodilator. Treatment with tiotropium produces sustained improvements in lung function, particularly FEV1 (peak, trough, average, and area under the curve) compared with either placebo or ipratropium in patients with moderate to severe COPD. Preliminary evidence suggests that treatment with tiotropium may slow the rate of decline in FEV1, but this finding awaits confirmation. Tiotropium reduces lung hyperinflation, with associated improvements in exercise capacity. Tiotropium, compared with either placebo or ipratropium, improves a variety of patient-centered outcomes, including subjective dyspnea ratings and HRQL scores. Tiotropium reduces the frequency of COPD exacerbations and of hospitalizations due to exacerbations, but has not been shown to reduce all-cause mortality. Compared with the long-acting bronchodilators, tiotropium provides incrementally better bronchodilation, but it is not clearly superior in terms of patient-centered outcomes. Tiotropium has a good safety profile; however patients with severe cardiac disease, bladder outlet obstruction, or narrow angle glaucoma were excluded from all studies. Medico economic analyses suggest that treatment with tiotropium may also be cost-effective, primarily by reducing costs associated with hospitalizations.


Some simple rules for contrast, signal-to-noise and resolution in in-line x-ray phase-contrast imaging.
Simple analytical expressions are derived for the spatial resolution, contrast and signal-to-noise in X-ray projection images of a generic phase edge. The obtained expressions take into account the maximum phase shift generated by the sample and the sharpness of the edge, as well as such parameters of the imaging set-up as the wavelength spectrum and the size of the incoherent source, the source-to-object and object-to-detector distances and the detector resolution. Different asymptotic behavior of the expressions in the cases of large and small Fresnel numbers is demonstrated. The analytical expressions are compared with the results of numerical simulations using Kirchhoff diffraction theory, as well as with experimental X-ray measurements.


Practical model-based dose finding in early-phase clinical trials: optimizing tissue plasminogen activator dose for treatment of ischemic stroke in children.
A safe and effective tissue plasminogen activator (tPA) dose for childhood stroke has not been established. This article describes a Bayesian outcome-adaptive method for determining the best dose of an experimental agent and explains how this method was used to design a dose-finding trial for tPA in childhood. The method assigns doses to successive cohorts of patients on the basis of each dose's desirability, quantified in terms of the tradeoff between efficacy and toxicity. The tradeoff function is constructed from several pairs of equally desirable (efficacy, toxicity) probabilities specified by the physicians planning the trial. Each cohort's dose is chosen adaptively, based on dose-outcome data from the patients treated previously in the trial, to optimize the efficacy-toxicity tradeoff. Application of the method to design the tPA trial is described, including a computer simulation study to establish design properties. A hypothetical cohort-by-cohort example is given to illustrate how the method works during trial conduct. Because only a dose that is both safe and efficacious may be selected and the method combines phase I and phase II by integrating efficacy and toxicity to choose doses, it avoids the more time-consuming and expensive conventional approach of conducting a phase I trial based on toxicity alone followed by a phase II trial based on efficacy alone. This is especially useful in settings with low accrual rates, such as trials of tPA for pediatric acute ischemic stroke.


The helper NLR immune protein NRC3 mediates the hypersensitive cell death caused by the cell-surface receptor Cf-4.
Cell surface pattern recognition receptors (PRRs) activate immune responses that can include the hypersensitive cell death. However, the pathways that link PRRs to the cell death response are poorly understood. Here, we show that the cell surface receptor-like protein Cf-4 requires the intracellular nucleotide-binding domain leucine-rich repeat containing receptor (NLR) NRC3 to trigger a confluent cell death response upon detection of the fungal effector Avr4 in leaves of Nicotiana benthamiana. This NRC3 activity requires an intact N-terminal MADA motif, a conserved signature of coiled-coil (CC)-type plant NLRs that is required for resistosome-mediated immune responses. A chimeric protein with the N-terminal α1 helix of Arabidopsis ZAR1 swapped into NRC3 retains the capacity to mediate Cf-4 hypersensitive cell death. Pathogen effectors acting as suppressors of NRC3 can suppress Cf-4-triggered hypersensitive cell-death. Our findings link the NLR resistosome model to the hypersensitive cell death caused by a cell surface PRR.


Erythropoietin Restores Long-Term Neurocognitive Function Involving Mechanisms of Neuronal Plasticity in a Model of Hyperoxia-Induced Preterm Brain Injury.
Cerebral white and grey matter injury is the leading cause of an adverse neurodevelopmental outcome in prematurely born infants. High oxygen concentrations have been shown to contribute to the pathogenesis of neonatal brain damage. Here, we focused on motor-cognitive outcome up to the adolescent and adult age in an experimental model of preterm brain injury. In search of the putative mechanisms of action we evaluated oligodendrocyte degeneration, myelination, and modulation of synaptic plasticity-related molecules. A single dose of erythropoietin (20,000 IU/kg) at the onset of hyperoxia (24 hours, 80% oxygen) in 6-day-old Wistar rats improved long-lasting neurocognitive development up to the adolescent and adult stage. Analysis of white matter structures revealed a reduction of acute oligodendrocyte degeneration. However, erythropoietin did not influence hypomyelination occurring a few days after injury or long-term microstructural white matter abnormalities detected in adult animals. Erythropoietin administration reverted hyperoxia-induced reduction of neuronal plasticity-related mRNA expression up to four months after injury. Thus, our findings highlight the importance of erythropoietin as a neuroregenerative treatment option in neonatal brain injury, leading to improved memory function in adolescent and adult rats which may be linked to increased neuronal network connectivity.


Negotiated safety - components, context and use: an integrative literature review.
The aim of this study was to examine the components and use of negotiated safety in the context of HIV prevention and to identify reported factors associated with the concept. There is an emerging interest in dyadic approaches to address HIV transmission. Although there are theoretical foundations for how interpersonal relationships influence individual behaviour, how these dyadic processes influence on health is still not wholly understood. Integrative review of empirical and theoretical literature. The Cumulative Index for Nursing and Allied Health Literature (CINAHL) MEDLINE and PsychINFO electronic databases were accessed. Articles were read to gain a historical context of the term and identify varying interpretations of the concept. Factors warranting consideration in association with NS were identified and clinical and public health implications were noted. Forty-eight studies were reviewed. Negotiated safety included the following components: (i) HIV sero-negative concordant men within a primary relationship; (ii) joint HIV screening and mutual disclosure of their HIV status; (iii) explicit relationship boundaries which establish either nonexclusively that allows for the dispensing of condoms within the primary relationship and consistent condom use for extra-dyadic sex; or dispensing of condoms within a primary partnership and exclusivity; and (iv) a breach clause that allows communication to re-establish the agreement if needed. Negotiated safety is a prescriptive approach to HIV risk reduction among couples. Researchers and practitioners could benefit from promoting this approach to HIV prevention.


Dietary folate intake, MTHFR genetic polymorphisms, and the risk of endometrial cancer among Chinese women.
Folate plays an important role in carcinogenesis. The enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR), encoded by the MTHFR gene, is involved in this process. We investigated both the independent and joint effects of dietary folate and other methyl-related nutrients, as well as three polymorphisms of MTHFR (677C>T, 1298A>C, and 1793G>A), on endometrial cancer risk in a population-based case-control study. Between 1997 and 2003, 1,204 newly diagnosed endometrial cancer cases and 1,212 controls were recruited among women between the ages of 30 and 69 years in urban Shanghai, China. Information on dietary intake of folate and other methyl-related nutrients, including vitamin B2 (riboflavin), vitamin B6, vitamin B12, and methionine, was derived from a validated food frequency questionnaire. Genotyping was completed on 1,041 cases and 1,030 controls for MTHFR 677C>T (rs1801133), 1298A>C (rs1801131), and 1793 G>A (rs2274967) [corrected] Haplotype estimation of the three single-nucleotide polymorphisms was performed using PHASE software. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated to evaluate associations of nutrients, MTHFR genotypes, and haplotypes with endometrial cancer risk. A significant inverse association between dietary folate intake and endometrial cancer risk was observed among all subjects and non-B vitamin supplement users. The greatest reduction in endometrial cancer risk was observed among non-users of supplements in the highest quartile of dietary folate intake (OR, 0.5; 95% CI, 0.4-0.7) as compared with those in the lowest quartile. Dietary intake of folate cofactors (methionine, vitamin B2, vitamin B6, and vitamin B12) was not related to risk of endometrial cancer. No association was observed between endometrial cancer and the MTHFR 677C>T, 1298 A>C, and 1793G>A polymorphisms or derived haplotypes. Among non-users of supplements, however, the 1298C and 1793A alleles were associated with a lower risk of endometrial cancer among women with high dietary folate intake but related to a higher risk among those with low dietary folate intake (P(interaction) = 0.08 and 0.03, respectively). Further analysis showed that the lowest risk (OR, 0.6; 95% CI, 0.4-1.1) was among women with the 1298C allele and the highest intake of both folate and riboflavin (P(interaction) = 0.04). A similar association was observed for the 1793A allele (P(interaction) = 0.03). Our findings suggest that folate intake may decrease the risk of endometrial cancer and modify the effect of MTHFR polymorphisms on risk.


A systematic review of early rehabilitation methods following a rupture of the Achilles tendon.
Rupture of the Achilles tendon is a debilitating injury. Advances have led to the development of immediate weight bearing rehabilitation. A range of early rehabilitation methods exist, but further research is required into this new area. The first stage in the investigation of a complex intervention is to identify its defining components. The aim of this review was to systemically identify and summarise, from clinical studies, the individual components that define immediate weight bearing rehabilitation protocols for the treatment of acute Achilles tendon rupture's. The electronic databases MEDLINE, EMBASE, CINAHL, AMED and the register of current controlled trials were searched up to March 2010. All study designs and languages were included. Two independent reviewers used pre-defined inclusion and exclusion criteria to identify all eligible articles. Eligible articles were summarised and critically reviewed, using the extension of the CONSORT statement for non-pharmacological interventions. Two hundred and fifteen articles were screened, nine were included. These studies, presented the results of 424 patients; 236 who had surgery and 188 who were managed non-operatively. There were a range of rehabilitation protocols that were defined by four components. These components consisted of the degree of maintained plantarflexion, whether daily range of movement exercises were permitted, the type of orthotic and for how long it was worn. The efficacy of different immediate weight bearing rehabilitation protocols following an acute rupture of the Achilles tendon remains unclear. Further research is required to evaluate the identified components to optimise rehabilitation.


Species-specific synergistic effects of two plant growth-promoting microbes on green roof plant biomass and photosynthetic efficiency.
Rhizophagus irregularis, an arbuscular mycorrhizal fungus, and Bacillus amyloliquefaciens, a bacterium, are microorganisms that promote plant growth. They associate with plant roots and facilitate nutrient absorption by their hosts, increase resistance against pathogens and pests, and regulate plant growth through phytohormones. In this study, eight local plant species in Finland (Antennaria dioica, Campanula rotundifolia, Fragaria vesca, Geranium sanguineum, Lotus corniculatus, Thymus serpyllum, Trifolium repens, and Viola tricolor) were inoculated with R. irregularis and/or B. amyloliquefaciens in autoclaved substrates to evaluate the plant growth-promoting effects of different plant/microbe combinations under controlled conditions. The eight plant species were inoculated with R. irregularis, B. amyloliquefaciens, or both microbes or were not inoculated as a control. The impact of the microbes on the plants was evaluated by measuring dry shoot weight, colonization rate by the arbuscular mycorrhizal fungus, bacterial population density, and chlorophyll fluorescence using a plant phenotyping facility. Under dual inoculation conditions, B. amyloliquefaciens acted as a "mycorrhiza helper bacterium" to facilitate arbuscular mycorrhizal fungus colonization in all tested plants. In contrast, R. irregularis did not demonstrate reciprocal facilitation of the population density of B. amyloliquefaciens. Dual inoculation with B. amyloliquefaciens and R. irregularis resulted in the greatest increase in shoot weight and photosynthetic efficiency in T. repens and F. vesca.


Functional analysis of a CDKN2A 5'UTR germline variant associated with pancreatic cancer development.
CDKN2A coding region germline variants are associated with pancreatic adenocarcinoma (PC) susceptibility. Recently, we described functional germline 5'UTR CDKN2A variants from melanoma patients affecting the post-transcriptional regulation of p16INK4a mRNA that is dependent, at least in part, on an Internal Ribosome Entry Site (IRES) in the 5'UTR region. Here we describe a 5'UTR c.-201_-198delinsCTTT CDKN2A variant (frequency 0.0028 based on 350 PC patients), which seems to be private to PC, since it has never been found in public databases nor in thousands of melanoma patients tested. Functional analyses confirmed IRES activity of the 5'UTR in BX-PC3 PC cells and revealed a functional impact of the identified variant. Using gene reporter assays we observed reduced translation potential in cells treated with the mTOR inhibitor Torin1, a condition that favors the assessment of IRES activity. At the endogenous gene level we quantified allelic imbalance among polysome-associated mRNAs using a patient-derived cell line heterozygous for the c.-201_-198delinsCTTT. Overall, we conclude that this very rare private variant can be considered a potential mutation, specifically associated with PC. Our data indicate that sequencing of the entire 5'UTR of CDKN2A should be included in routine screening of PC cases with suspected inherited susceptibility.


A biophysical limit for quorum sensing in biofilms.
Bacteria grow on surfaces in complex immobile communities known as biofilms, which are composed of cells embedded in an extracellular matrix. Within biofilms, bacteria often interact with members of their own species and cooperate or compete with members of other species via quorum sensing (QS). QS is a process by which microbes produce, secrete, and subsequently detect small molecules called autoinducers (AIs) to assess their local population density. We explore the competitive advantage of QS through agent-based simulations of a spatial model in which colony expansion via extracellular matrix production provides greater access to a limiting diffusible nutrient. We note a significant difference in results based on whether AI production is constitutive or limited by nutrient availability: If AI production is constitutive, simple QS-based matrix-production strategies can be far superior to any fixed strategy. However, if AI production is limited by nutrient availability, QS-based strategies fail to provide a significant advantage over fixed strategies. To explain this dichotomy, we derive a biophysical limit for the dynamic range of nutrient-limited AI concentrations in biofilms. This range is remarkably small (less than 10-fold) for the realistic case in which a growth-limiting diffusible nutrient is taken up within a narrow active growth layer. This biophysical limit implies that for QS to be most effective in biofilms AI production should be a protected function not directly tied to metabolism.


Examining Predictive Validity of Oral Reading Fluency Slope in Upper Elementary Grades Using Quantile Regression.
Within multitiered instructional delivery models, progress monitoring is a key mechanism for determining whether a child demonstrates an adequate response to instruction. One measure commonly used to monitor the reading progress of students is oral reading fluency (ORF). This study examined the extent to which ORF slope predicts reading comprehension outcomes for fifth-grade struggling readers ( n = 102) participating in an intensive reading intervention. Quantile regression models showed that ORF slope significantly predicted performance on a sentence-level fluency and comprehension assessment, regardless of the students' reading skills, controlling for initial ORF performance. However, ORF slope was differentially predictive of a passage-level comprehension assessment based on students' reading skills when controlling for initial ORF status. Results showed that ORF explained unique variance for struggling readers whose posttest performance was at the upper quantiles at the end of the reading intervention, but slope was not a significant predictor of passage-level comprehension for students whose reading problems were the most difficult to remediate.


Individual and combined effects of cannabidiol and Δ9-tetrahydrocannabinol on striato-cortical connectivity in the human brain.
Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) are the two major constituents of cannabis with contrasting mechanisms of action. THC is the major psychoactive, addiction-promoting, and psychotomimetic compound, while CBD may have opposite effects. The brain effects of these drugs alone and in combination are poorly understood. In particular, the striatum is implicated in the pathophysiology of several psychiatric disorders, but it is unclear how THC and CBD influence striato-cortical connectivity. To examine effects of THC, CBD, and THC + CBD on functional connectivity of striatal sub-divisions (associative, limbic and sensorimotor). Resting-state functional Magnetic Resonance Imaging (fMRI) was used across two within-subjects, placebo-controlled, double-blind studies, with a unified analysis approach. Study 1 (N = 17; inhaled cannabis containing 8 mg THC, 8 mg THC + 10 mg CBD or placebo) showed strong disruptive effects of both THC and THC + CBD on connectivity in the associative and sensorimotor networks, but a specific effect of THC in the limbic striatum network which was not present in the THC + CBD condition. In Study 2 (N = 23, oral 600 mg CBD, placebo), CBD increased connectivity in the associative network, but produced only relatively minor disruptions in the limbic and sensorimotor networks. THC strongly disrupts striato-cortical networks, but this effect is mitigated by co-administration of CBD in the limbic striatum network. Oral CBD administered has a more complex effect profile of relative increases and decreases in connectivity. The insula emerges as a key region affected by cannabinoid-induced changes in functional connectivity, with potential implications for understanding cannabis-related disorders, and the development of cannabinoid therapeutics.


Socioeconomic disparities of periodontitis in Koreans based on the KNHANES IV.
The aim of this study was to identify the socioeconomic factors associated with the prevalence of periodontitis in Koreans. Cross-sectional data from 12 763 subjects, 15 years old and above, who underwent periodontal examinations were obtained from the Korean National Health and Nutrition Examination Survey IV (2007-209). Multivariate linear and logistic regression analyses were applied to estimate the association between socioeconomic indicators and prevalence of periodontitis. A significant association was found between increasing age and periodontitis. Participants with higher income were less likely to have periodontitis (aOR = 0.9 and 95% CI = 0.78-0.98, and aOR = 0.7 and 95% CI = 0.60-0.80 in the middle and highest quintiles of monthly household income, respectively). In addition, participants living in rural areas were less likely to have periodontitis (aOR = 0.9 and 95% CI = 0.81-0.99), and current smokers were more likely to have periodontitis (aOR = 1.7 and 95% CI = 1.49-1.89). The analysis of comorbidities revealed that individuals with diabetes mellitus (DM) were significantly more likely to have periodontitis (aOR = 1.4 and 95% CI = 1.18-1.68). In a rapidly increasing Korean population, the lower socioeconomic groups as well as individuals with DM were significantly more likely to present with periodontitis.


EEG-Neurofeedback as a Tool to Modulate Cognition and Behavior: A Review Tutorial.
Neurofeedback is attracting renewed interest as a method to self-regulate one's own brain activity to directly alter the underlying neural mechanisms of cognition and behavior. It not only promises new avenues as a method for cognitive enhancement in healthy subjects, but also as a therapeutic tool. In the current article, we present a review tutorial discussing key aspects relevant to the development of electroencephalography (EEG) neurofeedback studies. In addition, the putative mechanisms underlying neurofeedback learning are considered. We highlight both aspects relevant for the practical application of neurofeedback as well as rather theoretical considerations related to the development of new generation protocols. Important characteristics regarding the set-up of a neurofeedback protocol are outlined in a step-by-step way. All these practical and theoretical considerations are illustrated based on a protocol and results of a frontal-midline theta up-regulation training for the improvement of executive functions. Not least, assessment criteria for the validation of neurofeedback studies as well as general guidelines for the evaluation of training efficacy are discussed.


Resveratrol reduces infarct size and improves ventricular function after myocardial ischemia in rats.
The purpose of this study was to investigate the effect of resveratrol, a polyphenol present in grapes and red wine, on ventricular remodeling after myocardial infarction (MI) in rats. After permanent ligation of the left anterior descending artery, surviving rats were randomly allocated to three groups and treated with 1 mg/kg/day resveratrol (R-1 group), 0.1 mg/kg/day resveratrol (R-0.1 group), or vehicles (control group) administered by intraperitoneal injection once daily for four weeks. We examined the effects of resveratrol by echocardiography, hemodynamic studies, histologic examinations, and real-time quantitative polymerase chain reaction. The R-1 group had significantly increased fractional shortening of the left ventricle, ameliorated left ventricular dilatation, reduced left ventricular end-diastolic pressure, and reduced infarct size. In contrast, the R-0.1 group experienced no beneficial effects on myocardial infarction. The R-1 group also had significantly attenuated expression of myocardial atrial natriuretic peptide and transforming growth factor-beta1 mRNAs. This study indicates that resveratrol is a potent cardioprotective agent in MI rats. Its cardioprotective effects may be due to a reduction of atrial natriuretic peptide and transforming growth factor-beta1, which are known to protect the heart from detrimental remodeling.


Patients' own reasons and patient-perceived recommendations for orthognathic surgery.
In an attempt to learn more about patients' decision-making processes, an analysis was performed to examine patients' reasons for undergoing orthognathic surgery and their understanding of the reasons surgery was recommended. Before surgery, 105 females and 38 males completed an open-ended questionnaire in which they listed their reasons for choosing orthognathic surgery and their perceptions of their orthodontists' recommendations. Three raters classified the responses into 7 categories: esthetics, psychosocial, functional, TMJ/pain, authority, prevention, and other. Rater agreement ranged from a kappa of.55 to 1.00. Patients reported undergoing orthognathic surgery primarily for esthetic, functional, and TMJ improvements, 71%, 47%, and 28%, respectively. Females reported more TMJ-related reasons than males (P <.05). Patients reporting function (P <. 05), TMJ (P <.05), and prevention of future problems (P <.05) were older than patients not reporting these reasons. Mexican American patients indicated more psychosocial reasons (P <.05) than European Americans. Patients understood that orthognathic surgery was recommended primarily for esthetic, functional, and TMJ improvements, 52%, 44%, and 18%, respectively. Males reported receiving more preventative recommendations (23%) than females (10%). Mexican American patients reported receiving more psychosocial recommendations (P <.05) than European Americans. Agreement between each paired patient/patient-perceived reason was highest for TMJ problems (kappa = 0.588). In conclusion, patients underwent orthognathic surgery to improve esthetic, functional and TMJ problems and interpreted orthodontists' recommendations for similar reasons. On a case-to-case basis, agreement between patient and orthodontist-represented reasons was modest, suggesting differences between patients' own reasons and their perceptions of orthodontists' recommendations.


The Majority of Genotypes of the Virulence Gene inlA Are Intact among Natural Watershed Isolates of Listeria monocytogenes from the Central California Coast.
Internalin A is an essential virulence gene involved in the uptake of the foodborne pathogen Listeria monocytogenes into host cells. It is intact in clinical strains and often truncated due to Premature Stop Codons (PMSCs) in isolates from processed foods and processing facilities. Less information is known about environmental isolates. We sequenced the inlA alleles and did Multi Locus Variable Number Tandem Repeat Analysis (MLVA) on 112 L. monocytogenes isolates from a 3-year period from naturally contaminated watersheds near a leafy green growing area in Central California. The collection contained 14 serotype 1/2a, 12 serotype 1/2b, and 86 serotype 4b strains. Twenty-seven different inlA alleles were found. Twenty-three of the alleles are predicted to encode intact copies of InlA, while three contain PMSCs. Another allele has a 9-nucleotide deletion, previously described for a clinical strain, indicating that it is still functional. Intact inlA genes were found in 101 isolates, and 8 isolates contained the allele predicted to contain the 3-amino acid deletion. Both allele types were found throughout the 3-year sampling period. Three strains contained inlA alleles with PMSCs, and these were found only during the first 3 months of the study. SNP analysis of the intact alleles indicated clustering of alleles based on serotype and lineage with serotypes 1/2b and 4b (lineage I strains) clustering together, and serotype 1/2a (lineage II strains) clustering separately. The combination of serotype, MLVA types, and inlA allele types indicate that the 112 isolates reflect at least 49 different strains of L. monocytogenes. The finding that 90% of environmental L. monocytogenes isolates contain intact inlA alleles varies significantly from isolates found in processing plants. This information is important to public health labs and growers as to the varieties of L. monocytogenes that could potentially contaminate fresh produce in the field by various means.


Fiber genes of adenoviruses with tropism for the eye and the genital tract.
We have characterized the fibergenes of adenovirus type 19p (Ad19p), Ad19a, and Ad37 by sequencing. The fiber genes of Ad19a and Ad37 are identical and only five amino acids differ comparing Ad19a/Ad37 with Ad19p. Based on the translated sequences we calculated the isoelectrical points (Ips) and found that the fiber knobs of Ad19p, Ad19a, and Ad37 together with Ad8 display the highest Ips of all so far characterized. Two regions within the fiber knob with unusually basic characteristics have been identified. Sequence alignments revealed that the corresponding regions in other fiber knobs are highly antigenic in pepscan analysis and of importance for hemagglutination. Only two positions differ in the knobs comparing Ad19a/Ad37 with Ad19p. Hence, either of these or both amino acid residues should be expected to be responsible for the observed differences in hemagglutination between Ad19p and Ad19a/Ad37. Moreover, we have found two amino acids (Ala227 and Lys252) that are unique in their respective position in Ad19p, Ad19a, Ad37, and Ad8. Three amino acids (Lys236, Lys240, and Asn251) are unique in their respective position in Ad19a and Ad37, that manifest a tropism for the genital tract. All five amino acids colocalize within one of the two basic regions.


Reaction chemistry in rechargeable Li-O2 batteries.
The seemingly simple reaction of Li-O2 batteries involving lithium and oxygen makes this chemistry attractive for high-energy-density storage systems; however, achieving this reaction in practical rechargeable Li-O2 batteries has proven difficult. The reaction paths leading to the final Li2O2 discharge products can be greatly affected by the operating conditions or environment, which often results in major side reactions. Recent research findings have begun to reveal how the reaction paths may be affected by the surrounding conditions and to uncover the factors contributing to the difficulty in achieving the reactions of lithium and oxygen. This progress report describes the current state of understanding of the electrode reaction mechanisms in Li-O2 batteries; the factors that affect reaction pathways; and the effect of cell components such as solvents, salts, additives, and catalysts on the discharge product and its decomposition during charging. This comprehensive review of the recent progress in understanding the reaction chemistry of the Li-O2 system will serve as guidelines for future research and aid in the development of reliable high-energy-density rechargeable Li-O2 batteries.


NGS-Trex: Next Generation Sequencing Transcriptome profile explorer.
Next-Generation Sequencing (NGS) technology has exceptionally increased the ability to sequence DNA in a massively parallel and cost-effective manner. Nevertheless, NGS data analysis requires bioinformatics skills and computational resources well beyond the possibilities of many "wet biology" laboratories. Moreover, most of projects only require few sequencing cycles and standard tools or workflows to carry out suitable analyses for the identification and annotation of genes, transcripts and splice variants found in the biological samples under investigation. These projects can take benefits from the availability of easy to use systems to automatically analyse sequences and to mine data without the preventive need of strong bioinformatics background and hardware infrastructure. To address this issue we developed an automatic system targeted to the analysis of NGS data obtained from large-scale transcriptome studies. This system, we named NGS-Trex (NGS Transcriptome profile explorer) is available through a simple web interface http://www.ngs-trex.org and allows the user to upload raw sequences and easily obtain an accurate characterization of the transcriptome profile after the setting of few parameters required to tune the analysis procedure. The system is also able to assess differential expression at both gene and transcript level (i.e. splicing isoforms) by comparing the expression profile of different samples.By using simple query forms the user can obtain list of genes, transcripts, splice sites ranked and filtered according to several criteria. Data can be viewed as tables, text files or through a simple genome browser which helps the visual inspection of the data. NGS-Trex is a simple tool for RNA-Seq data analysis mainly targeted to "wet biology" researchers with limited bioinformatics skills. It offers simple data mining tools to explore transcriptome profiles of samples investigated taking advantage of NGS technologies.