Human alpha-thrombin inhibition by the highly selective compounds N-ethoxycarbonyl-D-Phe-Pro-alpha-azaLys p-nitrophenyl ester and N-carbobenzoxy-Pro-alpha-azaLys p-nitrophenyl ester: a kinetic, thermodynamic and X-ray crystallographic study.
Kinetics, thermodynamics and structural aspects of human alpha-thrombin (thrombin) inhibition by newly synthesized low molecular weight derivatives of alpha-azalysine have been investigated. The thrombin catalyzed hydrolysis of N-ethoxycarbonyl-D-Phe-Pro-alpha-azaLys p-nitrophenyl ester (Eoc-D-Phe-Pro-azaLys-ONp) and N-carbobenzoxy-Pro-alpha-azaLys p-nitrophenyl ester (Cbz-Pro-azaLys-ONp) was investigated at pH 6.2 and 21.0 degrees C, and analyzed in parallel with that of N-alpha-(N,N-dimethylcarbamoyl)-alpha-azalysine p-nitrophenyl ester (Dmc-azaLys-ONp). Decarboxylation following the enzymatic hydrolysis of these p-nitrophenyl esters gave the corresponding 1-peptidyl-2(4-aminobutyl) hydrazines (peptidyl-Abh) showing properties of thrombin competitive inhibitors. Therefore, thermodynamics for the reversible binding of D-Phe-Pro-Abh, Cbz-Pro-Abh and Dmc-Abh to thrombin was examined. These results are consistent with the minimum four-step catalytic mechanism for product inhibition of serine proteinases. Eoc-D-Phe-Pro-azaLys-ONp and Eoc-D-Phe-Pro-Abh display a sub-micromolar affinity for thrombin together with a high selectivity versus homologous plasmatic and pancreatic serine proteinases acting on cationic substrates. The three-dimensional structures of the reversible non-covalent thrombin:Eoc-D-Phe-Pro-Abh and thrombin:Cbz-Pro-Abh complexes have been determined by X-ray crystallography at 2.0 A resolution (R-factor = 0.169 and 0.179, respectively), and analyzed in parallel with that of the thrombin:Dmc-azaLys acyl-enzyme adduct. Both Eoc-D-Phe-Pro-Abh and Cbz-Pro-Abh competitive inhibitors are accommodated in the thrombin active center, spanning the region between the aryl binding site and the S1 primary specificity subsite.


Antifungal activity of four weedy plant extracts against selected mycotoxigenic fungi.
To investigate the antifungal activity of aqueous and organic extracts of four weedy plant species viz. Tagetes minuta, Lippia javanica, Amaranthus spinosus and Vigna unguiculata against isolates of four agriculturally important fungi, i.e. Fusarium verticillioides, F. proliferatum, Aspergillus flavus and A. parasiticus. Dried powdered aerial parts of the plants were extracted sequentially with hexane, dichloromethane, methanol and water and tested for activity using a serial microdilution assay. Results were read every day over 120 h. All extracts except for the water extracts showed growth inhibitory activity against most isolates of the Fusarium spp. The most active were the methanol and hexane extracts of V. unguiculata and A. spinosus with minimum inhibitory concentration (MIC) values of <0.5 mg ml(-1) after 48 h against Fusarium spp. No inhibition of the Aspergillus spp. tested was observed, but conidium formation was stimulated on plates treated with plant extracts when visually compared to the growth controls. The results obtained from this study indicated that chemical constituents from these plant species may be developed as potential agrochemical fungicides. SIGNIFICANCE AND IMPACT OF THE RESEARCH: Food and feed are subject to infection by a variety of micro-organisms that can induce spoilage and/or produce metabolites that are toxic to humans and animals. Extracts of V. unguiculata and A. spinosus were most active and maybe developed into environmentally friendly fungicides, which are affordable to rural farmers in developing countries.


Principal component trajectories for modeling spectrally continuous dynamics as forced linear systems.
Delay embeddings of time series data have emerged as a promising coordinate basis for data-driven estimation of the Koopman operator, which seeks a linear representation for observed nonlinear dynamics. Recent work has demonstrated the efficacy of dynamic mode decomposition (DMD) for obtaining finite-dimensional Koopman approximations in delay coordinates. In this paper we demonstrate how nonlinear dynamics with sparse Fourier spectra can be (i) represented by a superposition of principal component trajectories and (ii) modeled by DMD in this coordinate space. For continuous or mixed (discrete and continuous) spectra, DMD can be augmented with an external forcing term. We present a method for learning linear control models in delay coordinates while simultaneously discovering the corresponding exogenous forcing signal in a fully unsupervised manner. This extends the existing DMD with control (DMDc) algorithm to cases where a control signal is not known a priori. We provide examples to validate the learned forcing against a known ground truth and illustrate their statistical similarity. Finally, we offer a demonstration of this method applied to real-world power grid load data to show its utility for diagnostics and interpretation on systems in which somewhat periodic behavior is strongly forced by unknown and unmeasurable environmental variables.


TMD symptoms and vertical mandibular symmetry in young adult orthodontic patients in North Sumatra, Indonesia: a cross-sectional study.
Background: Temporomandibular joint disorder (TMD) includes symptoms of pain and dysfunction in the muscles of mastication and the temporomandibular joint. Differences in vertical condylar height, observed in the assessment of mandibular asymmetry, is a structural alteration that represents a risk factor for TMD. The study aimed to evaluate the association between TMD symptoms and vertical mandibular symmetry in young adult orthodontic patients in North Sumatra, Indonesia. Methods: The cross-sectional study included 18-25-year-old (mean ± SD, 21.9 ± 2.0 years) old orthodontic patients admitted to the Dental Hospital of Universitas Sumatera Utara, Medan, between June 2016 and March 2017. Vertical mandibular asymmetry was assessed from all 106 subjects using Kjellberg's technique from pre-treatment panoramic radiographs. The TMD symptoms were assessed by structural interviews using modified questionnaires based on Temporomandibular Disorder Diagnostic Index and Fonseca's Anamnestic Index. Results: Of the 106 subjects, 26 (24.5% of the total) with vertical mandibular symmetry and 39 (36.8%) with vertical mandibular asymmetry were positive for TMD symptoms. By contrast, 17 patients (16.0% of the total) with vertical condylar symmetry and 24 patients (22.6%) with vertical mandibular asymmetry were regarded negative for TMD symptoms. There was no significant difference (p=0.520) in TMD symptoms based on vertical mandibular symmetry. Conclusion: The results from this studied Sumatran population indicate that there are common TMD symptoms in young adult orthodontic patients, but there is no significant association between vertical mandibular asymmetry and TMD symptoms. Further study on the development of TMD, mandibular asymmetry and treatment planning for growing patients is suggested, using longitudinal and transitional approaches.


Comparison of different risk perception measures in predicting seasonal influenza vaccination among healthy Chinese adults in Hong Kong: a prospective longitudinal study.
Risk perception is a reported predictor of vaccination uptake, but which measures of risk perception best predict influenza vaccination uptake remain unclear. During the main influenza seasons (between January and March) of 2009 (Wave 1) and 2010 (Wave 2),505 Chinese students and employees from a Hong Kong university completed an online survey. Multivariate logistic regression models were conducted to assess how well different risk perceptions measures in Wave 1 predicted vaccination uptake against seasonal influenza in Wave 2. The results of the multivariate logistic regression models showed that feeling at risk (β = 0.25, p = 0.021) was the better predictor compared with probability judgment while probability judgment (β = 0.25, p = 0.029 ) was better than beliefs about risk in predicting subsequent influenza vaccination uptake. Beliefs about risk and feeling at risk seemed to predict the same aspect of subsequent vaccination uptake because their associations with vaccination uptake became insignificant when paired into the logistic regression model. Similarly, to compare the four scales for assessing probability judgment in predicting vaccination uptake, the 7-point verbal scale remained a significant and stronger predictor for vaccination uptake when paired with other three scales; the 6-point verbal scale was a significant and stronger predictor when paired with the percentage scale or the 2-point verbal scale; and the percentage scale was a significant and stronger predictor only when paired with the 2-point verbal scale. Beliefs about risk and feeling at risk are not well differentiated by Hong Kong Chinese people. Feeling at risk, an affective-cognitive dimension of risk perception predicts subsequent vaccination uptake better than do probability judgments. Among the four scales for assessing risk probability judgment, the 7-point verbal scale offered the best predictive power for subsequent vaccination uptake.


Single-molecule real-time transcript sequencing facilitates common wheat genome annotation and grain transcriptome research.
The large and complex hexaploid genome has greatly hindered genomics studies of common wheat (Triticum aestivum, AABBDD). Here, we investigated transcripts in common wheat developing caryopses using the emerging single-molecule real-time (SMRT) sequencing technology PacBio RSII, and assessed the resultant data for improving common wheat genome annotation and grain transcriptome research. We obtained 197,709 full-length non-chimeric (FLNC) reads, 74.6 % of which were estimated to carry complete open reading frame. A total of 91,881 high-quality FLNC reads were identified and mapped to 16,188 chromosomal loci, corresponding to 13,162 known genes and 3026 new genes not annotated previously. Although some FLNC reads could not be unambiguously mapped to the current draft genome sequence, many of them are likely useful for studying highly similar homoeologous or paralogous loci or for improving chromosomal contig assembly in further research. The 91,881 high-quality FLNC reads represented 22,768 unique transcripts, 9591 of which were newly discovered. We found 180 transcripts each spanning two or three previously annotated adjacent loci, suggesting that they should be merged to form correct gene models. Finally, our data facilitated the identification of 6030 genes differentially regulated during caryopsis development, and full-length transcripts for 72 transcribed gluten gene members that are important for the end-use quality control of common wheat. Our work demonstrated the value of PacBio transcript sequencing for improving common wheat genome annotation through uncovering the loci and full-length transcripts not discovered previously. The resource obtained may aid further structural genomics and grain transcriptome studies of common wheat.


Positive and negative nano-electrospray mass spectrometry of ruthenated serum albumin supported by docking studies: an integrated approach towards defining metallodrug binding sites on proteins.
Binding of three ruthenium(ii) compounds of general formula mer-[Ru(L3)(N-N)X][Y] (where L3 = 4'-chloro-2,2':6',2''-terpyridine (Cl-tpy); N-N = 1,2-diaminoethane (en), 1,2-diaminocyclohexane (dach) or 2,2'-bipyridine (bipy); X = Cl; Y = Cl) to human serum albumin (HSA) has been investigated by nano-LC/nano-ESI MS and docking studies. A bottom-up proteomics approach has been applied for the structural characterization of metallated proteins and the data were analyzed in both the positive and negative ion mode. The negative ion mode was achieved after the post-column addition of an isopropanol solution of formaldehyde that enabled sample ionization at micro-flow rates. The negative ion mode MS has been proved to be beneficial for the analysis of binding sites on ruthenated protein in terms of ion charge reduction and consequent simplification of target sequence identification based on isotopic differences between ruthenated and non-ruthenated peptides. Moreover, the negative ion mode ESI MS shows the advantage of singly charged ion formation and, unlike MALDI MS, it does not cause complete ligand fragmentation, merging the benefits of each method into a single experiment. Six target sequences were identified for the binding of en and dach compounds, and four sequences for the binding of bipy. All compounds have been found to bind histidine and one aspartate residue. Docking studies showed that the identified sequences are the constituents of five distinct binding sites for en and dach, or two sites for the bipy complex. The selection of binding sites seems to be dependent on the chelate ligand and the form of the complex prior or after hydrolysis of the leaving chloride ligand.


Long-term evaluation of survival, continence and potency (SCP) outcomes after robot-assisted radical prostatectomy (RARP).
To report combined oncological and functional outcome in a series of patients who underwent robot-assisted radical prostatectomy (RARP) for clinically localised prostate cancer in a single European centre after 5-year minimum follow-up according to survival, continence and potency (SCP) outcomes. We extracted from our prostate cancer database all consecutive patients with a minimum follow-up of 5 years after RARP. Biochemical failure was defined as a confirmed PSA concentration of >0.2 ng/mL. All patients alive at the last follow-up were evaluated for functional outcomes using the Expanded Prostate Cancer Index Composite (EPIC) and Sexual Health Inventory for Men (SHIM) questionnaires. Oncological and functional outcomes were reported according to the SCP system. Specifically, patients were classified as using no pad (C0), using one pad for security (C1), and using ≥1 pad (C2) (not including the prior definition). Patients potent (SHIM score of >17) without any aids were classified as P0 category; patients potent (SHIM score of >17) with use of phosphodiesterase type 5 inhibitorsas P1; and patients with erectile dysfunction (SHIM score of <17) as P2 category. Patients who did not undergo a nerve-sparing technique, who were not potent preoperatively, who were not interested in erections, or who did not have sexual partners were classified as Px category. The 3-, 5- and 7-year biochemical recurrence-free survival rates were 96.3%; 89.6% and 88.3%, respectively. At follow-up, 146 (79.8%) were fully continent (C0), 20 (10.9%) still used a safety pad (C1) and 17 (9.3%) were incontinent using ≥1 pad (C2). Excluding Px patients, 52 patients (47.3%) were classified as P0; 41 patients (37.3%) were classified as P1 and 17 patients (15.5%) were P2. In patients preoperatively continent and potent, who received a nerve-sparing technique and did not require any adjuvant therapy, oncological and functional success was attained by 77 (80.2%) patients. In the subgroup of 67 patients not evaluable for potency recovery (Px), oncological and continence outcomes were attained in 46 patients (68.7%). Oncological and functional success was attained in a high percentage of patients who underwent RARP at ≥5 years follow-up. Interestingly, this study confirmed that excellent oncological and functional outcomes can be obtained in the 'best' category of patients, i.e. those preoperatively continent and potent and with tumour characteristics suitable for a nerve-sparing technique.


Global gene expression analysis of human erythroid progenitors.
Understanding the pattern of gene expression during erythropoiesis is crucial for a synthesis of erythroid developmental biology. Here, we isolated 4 distinct populations at successive erythropoietin-dependent stages of erythropoiesis, including the terminal, pyknotic stage. The transcriptome was determined using Affymetrix arrays. First, we demonstrated the importance of using defined cell populations to identify lineage and temporally specific patterns of gene expression. Cells sorted by surface expression profile not only express significantly fewer genes than unsorted cells but also demonstrate significantly greater differences in the expression levels of particular genes between stages than unsorted cells. Second, using standard software, we identified more than 1000 transcripts not previously observed to be differentially expressed during erythroid maturation, 13 of which are highly significantly terminally regulated, including RFXAP and SMARCA4. Third, using matched filtering, we identified 12 transcripts not previously reported to be continuously up-regulated in maturing human primary erythroblasts. Finally, using transcription factor binding site analysis, we identified potential transcription factors that may regulate gene expression during terminal erythropoiesis. Our stringent lists of differentially regulated and continuously expressed transcripts containing many genes with undiscovered functions in erythroblasts are a resource for future functional studies of erythropoiesis. Our Human Erythroid Maturation database is available at https://cellline.molbiol.ox.ac.uk/eryth/index.html. [corrected].


Insertion polymorphisms of SINE200 retrotransposons within speciation islands of Anopheles gambiae molecular forms.
SINEs (Short INterspersed Elements) are homoplasy-free and co-dominant genetic markers which are considered to represent useful tools for population genetic studies, and could help clarifying the speciation processes ongoing within the major malaria vector in Africa, Anopheles gambiae s.s. Here, we report the results of the analysis of the insertion polymorphism of a nearly 200 bp-long SINE (SINE200) within genome areas of high differentiation (i.e. "speciation islands") of M and S A. gambiae molecular forms. A SINE-PCR approach was carried out on thirteen SINE200 insertions in M and S females collected along the whole range of distribution of A. gambiae s.s. in sub-Saharan Africa. Ten specimens each for Anopheles arabiensis, Anopheles melas, Anopheles quadriannulatus A and 15 M/S hybrids from laboratory crosses were also analysed. Eight loci were successfully amplified and were found to be specific for A. gambiae s.s.: 5 on 2L chromosome and one on X chromosome resulted monomorphic, while two loci positioned respectively on 2R (i.e. S200 2R12D) and X (i.e. S200 X6.1) chromosomes were found to be polymorphic. S200 2R12D was homozygote for the insertion in most S-form samples, while intermediate levels of polymorphism were shown in M-form, resulting in an overall high degree of genetic differentiation between molecular forms (Fst = 0.46 p < 0.001) and within M-form (Fst = 0.46 p < 0.001). The insertion of S200 X6.1 was found to be fixed in all M- and absent in all S-specimens. This led to develop a novel easy-to-use PCR approach to straightforwardly identify A. gambiae molecular forms. This novel approach allows to overcome the constraints associated with markers on the rDNA region commonly used for M and S identification. In fact, it is based on a single copy and irreversible SINE200 insertion and, thus, is not subjected to peculiar evolutionary patterns affecting rDNA markers, e.g. incomplete homogenization of the arrays through concerted evolution and/or mixtures of M and S IGS-sequences among the arrays of single chromatids. The approach utilized allowed to develop new easy-to-use co-dominant markers for the analysis of genetic differentiation between M and S-forms and opens new perspectives in the study of the speciation process ongoing within A. gambiae.


A computer-automated, multi-center, multi-blinded, randomized control trial evaluating hypothesized spirit presence and communication.
The gold standard in biomedical research is the multi-center, multi-blinded, randomized control trial (RCT). In pharmacological research the RCT is termed a Phase III clinical trial. This paper presents the core goals and RCT methods developed to investigate automated spirit presence and communication. The goals are: (1) to use currently available, reliable, and affordable technology (total hardware cost per system less than $4,000; these systems will be provided free to collaborating laboratories), (2) to automate data collection and real-time analyses employing specially designed software, (3) to only require a quiet space (used at night) in collaborating laboratories, (4) to not necessitate human subjects committee approvals at collaborating institutions (because the participants are hypothesized spirit participants), and (5) to enable international collaboration regardless of the investigator's personal beliefs about the hypothesis. The research design and methods meet a phrase popularized by Carl Sagan: "Extraordinary claims require extraordinary evidence." The design minimizes false positives and false negatives. University affiliated investigators in established laboratories who regularly publish in peer reviewed journals, and are interested in collaborating in this RCT, are invited to contact the author.


Quality of life after Nissen fundoplication in patients with gastroesophageal reflux disease: Comparison between long- and short-term follow-up.
Nissen fundoplication is the golden standard for surgical treatment of gastroesophageal reflux disease (GERD). Numerous studies report excellent short-term results. However, data regarding long-term quality of life are lacking. The aim of this study is to investigate the long-term quality of life after Nissen fundoplication in patients with GERD and to compare this with the short-term results. We retrospectively analysed all patients who underwent laparoscopic Nissen fundoplication for GERD between January 2004 and January 2016. All patients received a validated GERD-Health-Related Quality of Life questionnaire by mail to assess post-operative quality of life. Maximum quality of life is represented by a score of 75. Secondary outcome measures were complications and recurrence rate. One hundred and seventy-five (77.1%) of the 227 operated patients returned the questionnaire. The median follow-up was 3.7 (0.1-10.3) years. Mean age was 51.6 (range 15-85) and 72 patients were male. We report an excellent quality of life with a median total score of 70 (range 2-75). Re-operation rate was 13.6% (23/169); the re-operation was due to recurrent reflux in 12 patients and due to persistent dysphagia in 11 patients. 91.3% of the re-operations were performed within the first 5 years after surgery. Mortality rate was zero. We report a large series of single-centre, single-surgeon laparoscopic Nissen fundoplication. Despite the re-operation rate of 13.6%, we found excellent long-term symptomatic outcome. There was no difference between short- and long-term results.


Prominent positioning and food swaps are effective interventions to reduce the saturated fat content of the shopping basket in an experimental online supermarket: a randomized controlled trial.
Interventions to reduce the saturated fat (SFA) content of food purchases may help reduce SFA consumption and lower cardiovascular risk. This factorial RCT aimed to examine the effect of altering the default order of foods and being offered a swap on the SFA content of food selected during an online shopping experiment. UK adults who were the primary grocery shoppers for their household were recruited online and invited to select items in a custom-made experimental online supermarket using a 10-item shopping list. Participants were randomly allocated to one of four groups (i) to see products within a category ranked in ascending order of SFA content, (ii) receive an offer to swap to a product with less SFA, (iii) a combination of both interventions, or (iv) no intervention. The primary outcome was the difference in percentage energy from SFA in the shopping basket between any of the four groups. The outcome assessors and statistician were blinded to intervention allocation. Between March and July 2018, 1240 participants were evenly randomised and 1088 who completed the task were analysed (88%). Participants were 65% female and aged 38y (SD 12). Compared with no intervention (n = 275) where the percentage energy from SFA was 25.7% (SD 5.6%), altering the order of foods (n = 261) reduced SFA by [mean difference (95%CI)] -5.0% (- 6.3 to - 3.6) and offering swaps (n = 279) by - 2.0% (- 3.3 to - 0.6). The combined intervention (n = 273) was significantly more effective than swaps alone (- 3.4% (- 4.7 to - 2.1)) but not different than altering the order alone (- 0.4% (- 1.8 to 0.9)), p = 0.04 for interaction. Altering the default order to show foods in ascending order of SFA and offering a swap with lower SFA reduced percentage energy from SFA in an experimental online supermarket. Environmental-level interventions, such as altering the default order, may be a more promising way to improve food purchasing than individual-level ones, such as offering swaps. ISRCTN13729526 https://doi.org/10.1186/ISRCTN13729526 26th February 2018.


Early-onset aging and mitochondrial defects associated with loss of histone acetyltransferase 1 (Hat1).
Histone acetyltransferase 1 (Hat1) is responsible for the acetylation of newly synthesized histone H4 on lysines 5 and 12 during the process of chromatin assembly. To understand the broader biological role of Hat1, we have generated a conditional mouse knockout model of this enzyme. We previously reported that Hat1 is required for viability and important for mammalian development and genome stability. In this study, we show that haploinsufficiency of Hat1 results in a significant decrease in lifespan. Defects observed in Hat1+/- mice are consistent with an early-onset aging phenotype. These include lordokyphosis (hunchback), muscle atrophy, minor growth retardation, reduced subcutaneous fat, cancer, and paralysis. In addition, the expression of Hat1 is linked to the normal aging process as Hat1 mRNA and protein becomes undetectable in many tissues in old mice. At the cellular level, fibroblasts from Hat1 haploinsufficient embryos undergo early senescence and accumulate high levels of p21. Hat1+/- mouse embryonic fibroblasts (MEFs) display modest increases in endogenous DNA damage but have significantly higher levels of reactive oxygen species (ROS). Consistently, further studies show that Hat1-/- MEFs exhibit mitochondrial defects suggesting a critical role for Hat1 in mitochondrial function. Taken together, these data show that loss of Hat1 induces multiple hallmarks of early-onset aging.


The hospitalist perspective on treatment of community-acquired bacterial pneumonia.
Community-acquired bacterial pneumonia (CABP) is an important health care concern in the United States and worldwide, and is associated with significant morbidity, mortality, and health care expenditure. Streptococcus pneumoniae is the most frequent causative pathogen of CABP. Other common pathogens include Staphylococcus aureus, Haemophilus influenzae, Enterobacteriaceae, Legionella pneumophila, Mycoplasma pneumoniae, and Chlamydophila pneumoniae. However, in clinical practice, the causative pathogen of CABP is most often not identified. Therefore, a common treatment approach for patients hospitalized with CABP is empiric antibiotic therapy with a β-lactam in combination with a macrolide, respiratory fluoroquinolones, or tetracyclines. An increase in the incidence of S. pneumoniae that is resistant to frequently used antibiotics, including β-lactams, macrolides, and tetracyclines, provides a challenge for the physician when selecting empiric antimicrobial therapy. When patients with CABP do not respond to initial therapy, they must be adequately reevaluated with further diagnostic testing, change in antimicrobial regimen, and/or transfer of the patient to a higher level of care. The role of hospital medicine physicians is crucial in treating patients who are hospitalized with CABP. An important focus of hospitalists is to provide care improvement in a way that addresses both patient and hospital needs. It is essential that the hospitalist provides best possible patient care, including adherence to quality measures, optimizing the patient's hospital length of stay, and arranging adequate post-discharge care in an effort to prevent readmission and provide appropriate ongoing outpatient care.


Escherichia coli intracellular pH, membrane potential, and cell growth.
We studied the changes in various cell functions during the shift to alkaline extracellular pH in wild-type Escherichia coli and in strain DZ3, a mutant defective in pH homeostasis. A rapid increase in membrane potential (delta psi) was detected in both the wild type and the mutant immediately upon the shift, when both cell types failed to control intracellular pH. Upon reestablishment of intracellular pH - extracellular pH and growth in the wild type, delta psi decreased to a new steady-state value. The electrochemical proton gradient (delta muH+) was similar in magnitude to that observed before the pH shift. In the mutant DZ3, delta psi remained elevated, and even though delta muH+ was higher than in the wild type, growth was impaired. Cessation of growth in the mutant is not a result of cell death. Hence, the mutant affords an interesting system to explore the intracellular-pH-sensitive steps that arrest growth without affecting viability. In addition to delta muH+, we measured respiration rates, protein synthesis, cell viability, induction of beta-galactosidase, DNA synthesis, and cell elongation upon failure of pH homeostasis. Cell division was the only function arrested after the shift in extracellular pH. The cells formed long chains with no increase in colony-forming capacity.


Safe intravenous antibiotic therapy at home: experience of a UK based programme.
Outpatient i.v. antibiotic therapy is well developed in the United States, largely because of pressures from third-party payers to reduce costs of medical care. We have developed an outpatient i.v. antibiotic programme in Oxford, that has evolved from a desire to provide high quality i.v. therapy to AIDS patients with cytomegalovirus retinitis. We describe the rationale of the service and report on our first two years' experience. We treated 67 consecutive patients (eight with HIV infection) at home with i.v. antibiotics. This resulted in a saving of 2275 hospital days for those patients without HIV infection. HIV positive patients received 69 months of home i.v. therapy. Minor intravascular catheter complications occurred in only five patients (7.5%). The only serious complications were three episodes of catheter-related sepsis (4.5%), all occurring in AIDS patients who had lines in for more than six months. We have shown that home i.v. antibiotic therapy can be delivered safely to patients with a wide variety of infectious problems using the existing network of community nurses in the National Health Service. Essential components to the programme include a multidisciplinary team working between the hospital and community and a written shared care protocol. Such a programme can result in reduced lengths of hospital stay and patient, community nurse and physician satisfaction.


Anger Expression and the Risk of Cardiovascular Disease Among Urban and Rural Japanese Residents: The Circulatory Risk in Communities Study.
It has been suggested that urbanization, which has been expanding rapidly for the past several decades, increases the risk of cardiovascular disease (CVD) associated with psychological factors such as anger, but the evidence is limited. We examined the hypothesis that urbanicity modifies the association of anger expression with the risk of CVD. A prospective study was conducted in 5936 residents of urban and rural communities aged 40 to 79 years who had completed an annual health checkup including a questionnaire on anger expression between 1995 and 1998. Associations of anger expression with the risk of CVDs were examined using Cox proportional hazards models, after adjusting for classical cardiovascular risk factors. During a median follow-up of 16.6 years, we identified 312 incident CVDs. The means (SDs) of anger expression were 24.7 (5.8) among urban residents and 24.6 (5.7) among rural participants (p = .87). Among urban residents, anger expression was positively associated with the risk of total CVD: the multivariable hazard ratio (95% confidence interval) was 1.27 (1.05-1.54). In contrast, no association was found among rural residents: the corresponding ratio (interval) was 0.96 (0.85-1.09), with a significant interaction between urban and rural residency with anger expression for incident CVD (p = .047). Similar associations were observed with the risk of CVD subtypes, including ischemic stroke and ischemic CVD. We found a positive association between anger expression and the risk of CVD among urban residents but not rural residents, suggesting that urbanicity enhances the anger-CVD association.


Characterising the Profile of Everyday Executive Functioning and Relation to IQ in Adults with Williams Syndrome: Is the BRIEF Adult Version a Valid Rating Scale?
Although there is evidence of a distinct profile of executive dysfunction in Williams syndrome (WS), a rare genetically based neurodevelopmental disorder, the utility of informant reports of everyday executive function (EF) impairments and their relation to intelligence is not yet clear. Here we aimed to evaluate the functional impact of executive dysfunction in adults with WS and to establish the validity of child and adult versions of the most commonly used rating scale for EF assessment, the Behaviour Rating Inventory of Executive Function (BRIEF). We were also interested in whether distinct components of everyday EF relate to intelligence in WS. Parent report child (BRIEF-C) and adult (BRIEF-A) ratings were collected on 20 adults with WS (aged 18.5 to 53 years), with a mean IQ of 60.95 (SD = 17.67). Neuropsychological measures of EF included: The Shape School Test (Espy, 2007); select subdomains of EF from the Woodcock-Johnson III Tests of Cognitive Abilities, Australian Adaptation (WJ III COG); and select subdomains from the Vineland Adaptive Behaviour Scales, Second Edition-Parent Survey (Vineland-II). Results showed that the BRIEF-A, but not the BRIEF-C, was the most highly correlated with neuropsychological measures of EF, suggesting that it was a valid measure of the profile of EF impairments in adults with WS. The profile of everyday EF dysfunction revealed relative impairments in monitoring, working memory, planning and organisation in WS. In addition, both neuropsychological and rating scale measures showed an association between the shifting component of EF and intelligence. These findings indicate that the BRIEF-A is a valid measure of the multidimensional nature of real-world impairments in EF, and highlight its utility as a less labor intensive and low-cost screening tool for measuring specific EF impairments that could become the focus of targeted intervention in adults with WS.


Rett syndrome phenotype following infantile acute encephalopathy.
Rett syndrome is a progressive neurodevelopmental disorder with a well-defined clinical spectrum and course. Recently, mutations in the gene encoding X-linked methyl-CpG binding protein 2 (MECP2) have been identified as the cause of Rett syndrome. Along with the classic form, variant forms of Rett syndrome and Rett syndrome phenotypes are also recognized. We report on a girl who, at age 2 months, developed an acute encephalopathy with destructive brain damage 12 hours after acellular pertussis vaccination. Peripheral lymphocyte subset analysis revealed the existence of T lymphocytes double positive for CD4 and CD8 markers. This pattern normalized over the following 3 months. Months later, the girl manifested a Rett syndrome phenotype. DNA screening of the MECP2 gene was unrevealing in the child and her parents. This previously unreported association emphasizes the notion that Rett syndrome phenotypes can result from different (either genetic or environmental) causes.


Purification and characterization of cytochrome P450 reductase from liver microsomes of feral leaping mullet (Liza saliens).
NADPH-cytochrome P450 reductase was purified to electrophoretic homogeneity from detergent-solubilized liver microsomes from the leaping mullet (Liza saliens). The purified reductase was characterized with respect to spectral, electrophoretic, and biocatalytic properties. In addition, effects of pH, ionic strength, and the substrate concentration on the NADPH-dependent cytochrome c reductase activity of the purified fish liver cytochrome P450 reductase were studied. Cytochrome P450 reductase was purified 438-fold with a yield of 17.5% with respect to the initial amount present in the fish liver microsomes. The specific activity of the enzyme was found to be 52.6 mumol cytochrome c reduced per minute per mg protein. The monomer molecular weight of the purified enzyme was calculated to be 77,000 +/- 1000 when electrophoresed on polyacrylamide gels under the denaturing conditions in the presence of SDS. The absorption spectrum of fish reductase showed two peaks at 378 and 455 nm. NADPH-dependent cytochrome c reductase activity of the purified Liza saliens liver cytochrome P450 reductase was found to be maximal when pH was between 7.4 and 7.8. The apparent K(m) of the purified enzyme was found to be 7.69 microM for cytochrome c when the enzyme activity was measured in 0.3 M potassium phosphate buffer, pH 7.7, at room temperature, and the enzyme was fully saturated by its substrate, cytochrome c, when the substrate concentration was at or above the 70 microM. Furthermore, the purified enzyme was biocatalytically active in reconstituting the 7-ethoxyresorufin O-deethylase activity in the reconstituted system containing purified mullet liver cytochrome P4501A1 and lipid. These results suggested that the purified fish liver cytochrome P450 reductase is similar to its mammalian counterparts with respect to spectral, electrophoretic, and biocatalytic properties.


The association between ankle-brachial index and asymptomatic cranial-carotid stenosis: a population-based, cross-sectional study of 5440 Han Chinese.
Routine screening for asymptomatic cranial-carotid stenosis (ACCS) is controversial and recommendation in clinical practice is vague. The ankle-brachial index (ABI) is reported as a predictor for cardiovascular disease. However, there is a scarcity of data about the association between abnormal ABI and ACCS. A population-based cross-sectional study was conducted to explore the relationship between ABI and ACCS. A sample of 5440 Chinese adults aged 40-94 years old was recruited from 2010 to 2011. The ABI was measured using a portable Doppler device and ACCS was evaluated by bilateral carotid duplex ultrasound and portable examination devices. A logistic regression model was used to analyse the association between ABI and ACCS after adjusting for potential confounding factors. A low ABI was associated with ACCS [odds ratio (OR) 1.95, 95% confidence interval (CI) 1.42-2.67] after adjusting for potential confounders. When the data were stratified by age and sex, the correlation remained statistically significant in the male (OR 2.32, 95% CI 1.60-3.37) and elderly (OR 3.07, 95% CI 1.97-4.78) subgroups compared to the female (OR 1.26, 95% CI 0.67-2.39) and middle-aged groups (OR 1.27, 95% CI 0.77-2.12), respectively. This study demonstrated that low ABI is a significant risk factor for ACCS in male and elderly Chinese adults.


An enzyme-centric approach for modelling non-linear biological complexity.
The current challenge of Systems Biology is to integrate high throughput data sets for simulating the complexity of biological networks, exploit the evolution of nature-designed networks that maintain the robustness of a biological system, and thereby generate novel, experimentally testable hypotheses. In order to simulate non-linear biological complexities, we have previously developed an Enzyme-Centric mechanistic modeling approach and validated it using metabolic network in E. coli. The idea is to use prior knowledge of catalytic and regulatory mechanisms of each enzyme within the metabolic network to build a dynamic model for investigating the network level regulation and thus understand the nature design principle behind the network. In this paper, we further demonstrate the application of complex enzyme catalytic and regulatory modules to simulate nonlinear network regulatory patterns vs. simple linear conversion model. We learned and validated that it is essential to incorporate prior knowledge from the literature to simulate non-linear biological complexities. The network expandability is demonstrated and validated with the complex amino acid biosynthetic network with multi-regulations. Also, we demonstrated the compatibility of mechanistic models within close species. Furthermore, the eukaryotic protein factory model for insuring steady mRNA production is simulated and the coupling of RNA transcription and splicing is validated by both mathematical simulation and experimental analysis. We demonstrated the importance of modeling complex enzyme catalytic and regulatory mechanisms to further understand nonlinear network regulatory patterns. The simulations presented in this paper reveal how a living system maintains homeostasis and its robustness to continue functioning while facing environmental stresses or genetic mutations.


Identification of a Potent Microbial Lipid Antigen for Diverse NKT Cells.
Semi-invariant/type I NKT cells are a well-characterized CD1d-restricted T cell subset. The availability of potent Ags and tetramers for semi-invariant/type I NKT cells allowed this population to be extensively studied and revealed their central roles in infection, autoimmunity, and tumor immunity. In contrast, diverse/type II NKT (dNKT) cells are poorly understood because the lipid Ags that they recognize are largely unknown. We sought to identify dNKT cell lipid Ag(s) by interrogating a panel of dNKT mouse cell hybridomas with lipid extracts from the pathogen Listeria monocytogenes. We identified Listeria phosphatidylglycerol as a microbial Ag that was significantly more potent than a previously characterized dNKT cell Ag, mammalian phosphatidylglycerol. Further, although mammalian phosphatidylglycerol-loaded CD1d tetramers did not stain dNKT cells, the Listeria-derived phosphatidylglycerol-loaded tetramers did. The structure of Listeria phosphatidylglycerol was distinct from mammalian phosphatidylglycerol because it contained shorter, fully-saturated anteiso fatty acid lipid tails. CD1d-binding lipid-displacement studies revealed that the microbial phosphatidylglycerol Ag binds significantly better to CD1d than do counterparts with the same headgroup. These data reveal a highly potent microbial lipid Ag for a subset of dNKT cells and provide an explanation for its increased Ag potency compared with the mammalian counterpart.


Structure and function of the calcium-selective TRP channel TRPV6.
Epithelial calcium channel TRPV6 is a member of the vanilloid subfamily of TRP channels that is permeable to cations and highly selective to Ca2+ ; it shows constitutive activity regulated negatively by Ca2+ and positively by phosphoinositol and cholesterol lipids. In this review, we describe the molecular structure of TRPV6 and discuss how its structural elements define its unique functional properties. High Ca2+ selectivity of TRPV6 originates from the narrow selectivity filter, where Ca2+ ions are directly coordinated by a ring of anionic aspartate side chains. Divalent cations Ca2+ and Ba2+ permeate TRPV6 pore according to the knock-off mechanism, while tight binding of Gd3+ to the aspartate ring blocks the channel and prevents Na+ from permeating the pore. The iris-like channel opening is accompanied by an α-to-π helical transition in the pore-lining transmembrane helix S6. As a result of this transition, the intracellular halves of the S6 helices bend and rotate by about 100 deg, exposing different residues to the channel pore in the open and closed states. Channel opening is also associated with changes in occupancy of the transmembrane domain lipid binding sites. The inhibitor 2-aminoethoxydiphenyl borate (2-APB) binds to TRPV6 in a pocket formed by the cytoplasmic half of the S1-S4 transmembrane helical bundle and shifts open-closed channel equilibrium towards the closed state by outcompeting lipids critical for activation. Ca2+ inhibits TRPV6 via binding to calmodulin (CaM), which mediates Ca2+ -dependent inactivation. The TRPV6-CaM complex exhibits 1:1 stoichiometry; one TRPV6 tetramer binds both CaM lobes, which adopt a distinct head-to-tail arrangement. The CaM C-terminal lobe plugs the channel through a unique cation-π interaction by inserting the side chain of lysine K115 into a tetra-tryptophan cage at the ion channel pore intracellular entrance. Recent studies of TRPV6 structure and function described in this review advance our understanding of the role of this channel in physiology and pathophysiology and inform new therapeutic design.


Adult Neural Stem Cell Regulation by Small Non-coding RNAs: Physiological Significance and Pathological Implications.
The adult neurogenic niches are complex multicellular systems, receiving regulatory input from a multitude of intracellular, juxtacrine, and paracrine signals and biological pathways. Within the niches, adult neural stem cells (aNSCs) generate astrocytic and neuronal progeny, with the latter predominating in physiological conditions. The new neurons generated from this neurogenic process are functionally linked to memory, cognition, and mood regulation, while much less is known about the functional contribution of aNSC-derived newborn astrocytes and adult-born oligodendrocytes. Accumulating evidence suggests that the deregulation of aNSCs and their progeny can impact, or can be impacted by, aging and several brain pathologies, including neurodevelopmental and mood disorders, neurodegenerative diseases, and also by insults, such as epileptic seizures, stroke, or traumatic brain injury. Hence, understanding the regulatory underpinnings of aNSC activation, differentiation, and fate commitment could help identify novel therapeutic avenues for a series of pathological conditions. Over the last two decades, small non-coding RNAs (sncRNAs) have emerged as key regulators of NSC fate determination in the adult neurogenic niches. In this review, we synthesize prior knowledge on how sncRNAs, such as microRNAs (miRNAs) and piwi-interacting RNAs (piRNAs), may impact NSC fate determination in the adult brain and we critically assess the functional significance of these events. We discuss the concepts that emerge from these examples and how they could be used to provide a framework for considering aNSC (de)regulation in the pathogenesis and treatment of neurological diseases.


Requirement for CD28 co-stimulation is lower in SHP-1-deficient T cells.
This study provides biochemical and functional evidence pertaining to the role of the intracellular protein tyrosine phosphatase, SHP-1, in influencing thresholds for TCR activation. Although the loss of SHP-1 in thymocytes from motheaten mice had minimal effects on the initial rise of cytosolic Ca(2+) concentration following TCR triggering, the post-stimulation equilibrium levels of Ca(2+) were consistently elevated. In keeping with a SHP-1 effect on PLCgamma function, IP3 generation was increased in SHP-1 deficient thymocytes. Importantly, we demonstrate that loss of SHP-1 results in a relaxation of the normally stringent co-stimulatory requirements for IL-2 production. SHP-1 deficient single-positive CD4(+) thymocytes revealed a significantly enhanced capacity to produce IL-2 in response to anti-CD3 stimulation alone. In contrast, the simultaneous triggering of CD3 and CD28 was required for equivalent IL-2 production in control single-positive CD4(+) thymocytes. Furthermore, SHP-1 deficient thymocytes generated an increased and prolonged proliferative response to anti-CD3 stimulation alone. In addition, the simultaneous triggering of CD28 and CD3 resulted in equivalent proliferative responses in SHP-1-deficient and control thymocytes, suggesting that a strong co-stimulatory signal is able to override the effect of SHP-1 loss on TCR hyperresponsiveness. Collectively, these results suggest that SHP-1, rather than acting directly on TCR signaling, may indirectly raise thresholds for TCR triggering by modulating co-stimulatory signals.


Computed tomographic features of feline sino-nasal and sino-orbital aspergillosis.
Feline upper respiratory tract aspergillosis (URTA) occurs as two distinct anatomical forms, namely, sino-nasal aspergillosis (SNA) and sino-orbital aspergillosis (SOA). An emerging pathogen, Aspergillus felis, is frequently involved. The pathogenesis of URTA, in particular the relationship between the infecting isolate and outcome, is poorly understood. In this study, computed tomography was used to investigate the route of fungal infection and extension in 16 cases (SNA n = 7, SOA n = 9) where the infecting isolate had been identified by molecular testing. All cases had nasal cavity involvement except for one cat with SNA that had unilateral frontal sinus changes. There was a strong association between the infecting species and anatomic form (P = 0.005). A. fumigatus infections remained within the sino-nasal cavity, while cryptic species infections were associated with orbital and paranasal soft-tissue involvement and with orbital lysis. Cryptic species were further associated with a mass in the nasal cavity, paranasal sinuses or nasopharynx. Orbital masses showed heterogeneous contrast enhancement, with central coalescing hypoattenuating foci and peripheral rim enhancement. Severe, cavitated turbinate lysis, typical of canine SNA, was present only in cats with SNA. These findings support the hypothesis that the nasal cavity is the portal of entry for fungal spores in feline URTA and that the route of extension to involve the orbit is via direct naso-orbital communication from bone lysis. Additionally, a pathogenic role for A. wyomingensis and a sinolith in a cat with A. udagawae infection are reported for the first time.


Ototoxicity in children with high-risk neuroblastoma: prevalence, risk factors, and concordance of grading scales--a report from the Children's Oncology Group.
Platinum-based therapy is the mainstay for management of high-risk neuroblastoma. Prevalence of platinum-related ototoxicity has ranged from 13% to 95% in previous reports; variability is attributable to small samples and disparate grading scales. There is no consensus regarding optimal ototoxicity grading. Furthermore, prevalence and predictors of hearing loss in a large uniformly treated high-risk neuroblastoma population are unknown. We address these gaps in our study. Audiologic testing was completed after administration of cisplatin alone (< 400 mg/m(2); exposure one) or after cisplatin (400 mg/m(2)) plus carboplatin (1,700 mg/m(2); exposure two). Hearing loss was graded using four scales (American Speech-Language-Hearing Association; Brock; Chang; and Common Terminology Criteria for Adverse Events, version 3 [CTCAEv3]). Of 489 eligible patients, 333 had evaluable audiologic data. Median age at diagnosis was 3.3 years. Prevalence of severe hearing loss differed by scale. For those in the exposure-one group, prevalence ranged from 8% per Brock to 47% per CTCAEv3 (Brock v CTCAEv3 and Chang, P < .01; CTCAEv3 v Chang, P = .16); for those in the exposure-two group, prevalence ranged from 30% per Brock to 71% per CTCAEv3 (all pair-wise comparisons, P < .01). In patients requiring hearing aids, hearing loss was graded as severe in 49% (Brock), 91% (Chang), and 100% (CTCAEv3). Risk factors for severe hearing loss included exposure to cisplatin and carboplatin compared with cisplatin alone and hospitalization for infection. Severe hearing loss is prevalent among children with high-risk neuroblastoma. Exposure to cisplatin combined with myeloablative carboplatin significantly increases risk. The Brock scale underestimates severe hearing loss and should be used with caution in this setting.


A combinatorial model for effective estrus detection in Murrah buffalo.
Buffaloes are silent heat animals and lacunae in their estrus detection results a substantial economic loss in developing countries. Many advanced tools to aid heat detection have been developed but are neither affordable nor easily interpretable by marginal farmers. The present investigation was made to develop a cost-effective estrus detection model by combining several known estrus predicting parameters. Various signs of estrus were classified under major parameters such as visual, cow behavioral, bull behavioral, biochemical, and gyneco-clinical. Expression of those parameters was observed in buffaloes, and the percentage of positive estrus detection was calculated for each combination of estrus prediction parameters. The present result concludes that the model comprises of five parameters group with several signals with twenty-six different combinations. It was observed that the expression of individual combinations and their corresponding estrus detection efficiency varies significantly, i.e., detection efficiency rises as the number of combination increases. Combination of three parameters would provide an estrus detection efficiency >70% and suggested for an easy estrus detection. This would be a cost-effective model for farmers and benefits in enhancing buffalo population/reproduction.


Spotlight on Pimavanserin Tartrate and Its Therapeutic Potential in the Treatment of Major Depressive Disorder: The Evidence to Date.
Major depressive disorder (MDD) is widely prevalent and one of the leading causes of disability. Treatment outcomes remain suboptimal with 1 in 3 patients with MDD responding inadequately to commonly used antidepressants. Pimavanserin, an atypical antipsychotic that modulates serotonergic neurotransmission by selectively binding to serotonin receptor (2A and 2C) subtypes and without dopaminergic activity, may have the potential as an adjunctive treatment for MDD. In a phase 2 trial (n=203), addition of pimavanserin, as compared to placebo, to stable treatment with antidepressants was associated with greater reduction in 17-item Hamilton Depression Rating Scale score [HAMD, least square means (95% confidence interval) of -1.7 (-0.03, -3.37), p=0.039]. Furthermore, treatment with pimavanserin was associated with significantly greater improvement in specific symptoms associated with depression such as impaired sexual function, anxiety, sleepiness, and irritability. However, the availability of pimavanserin for clinical care of patients with MDD remains uncertain. Top-line results of phase 3 studies (n=298) that were announced by the sponsor found similar reductions in HAMD (mean baseline-to-week-5 reduction of 9.0 and 8.1, p=0.296) and rates of adverse events (58.1% and 54.7%) with addition of pimavanserin and placebo respectively to stable treatment with antidepressants. Given the potential benefit for specific symptoms such as impaired sexual function, anxiety and sleep/wakefulness disturbances, future studies that enrich for these symptoms may be needed to clarify the utility of adjunctive pimavanserin in treatment of patients with MDD.


Human brain evolution and the "Neuroevolutionary Time-depth Principle:" Implications for the Reclassification of fear-circuitry-related traits in DSM-V and for studying resilience to warzone-related posttraumatic stress disorder.
The DSM-III, DSM-IV, DSM-IV-TR and ICD-10 have judiciously minimized discussion of etiologies to distance clinical psychiatry from Freudian psychoanalysis. With this goal mostly achieved, discussion of etiological factors should be reintroduced into the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V). A research agenda for the DSM-V advocated the "development of a pathophysiologically based classification system". The author critically reviews the neuroevolutionary literature on stress-induced and fear circuitry disorders and related amygdala-driven, species-atypical fear behaviors of clinical severity in adult humans. Over 30 empirically testable/falsifiable predictions are presented. It is noted that in DSM-IV-TR and ICD-10, the classification of stress and fear circuitry disorders is neither mode-of-acquisition-based nor brain-evolution-based. For example, snake phobia (innate) and dog phobia (overconsolidational) are clustered together. Similarly, research on blood-injection-injury-type-specific phobia clusters two fears different in their innateness: 1) an arguably ontogenetic memory-trace-overconsolidation-based fear (hospital phobia) and 2) a hardwired (innate) fear of the sight of one's blood or a sharp object penetrating one's skin. Genetic architecture-charting of fear-circuitry-related traits has been challenging. Various, non-phenotype-based architectures can serve as targets for research. In this article, the author will propose one such alternative genetic architecture. This article was inspired by the following: A) Nesse's "Smoke-Detector Principle", B) the increasing suspicion that the "smooth" rather than "lumpy" distribution of complex psychiatric phenotypes (including fear-circuitry disorders) may in some cases be accounted for by oligogenic (and not necessarily polygenic) transmission, and C) insights from the initial sequence of the chimpanzee genome and comparison with the human genome by the Chimpanzee Sequencing and Analysis Consortium published in late 2005. Neuroevolutionary insights relevant to fear circuitry symptoms that primarily emerge overconsolidationally (especially Combat related Posttraumatic Stress Disorder) are presented. Also introduced is a human-evolution-based principle for clustering innate fear traits. The "Neuroevolutionary Time-depth Principle" of innate fears proposed in this article may be useful in the development of a neuroevolution-based taxonomic re-clustering of stress-triggered and fear-circuitry disorders in DSM-V. Four broad clusters of evolved fear circuits are proposed based on their time-depths: 1) Mesozoic (mammalian-wide) circuits hardwired by wild-type alleles driven to fixation by Mesozoic selective sweeps; 2) Cenozoic (simian-wide) circuits relevant to many specific phobias; 3) mid Paleolithic and upper Paleolithic (Homo sapiens-specific) circuits (arguably resulting mostly from mate-choice-driven stabilizing selection); 4) Neolithic circuits (arguably mostly related to stabilizing selection driven by gene-culture co-evolution). More importantly, the author presents evolutionary perspectives on warzone-related PTSD, Combat-Stress Reaction, Combat-related Stress, Operational-Stress, and other deployment-stress-induced symptoms. The Neuroevolutionary Time-depth Principle presented in this article may help explain the dissimilar stress-resilience levels following different types of acute threat to survival of oneself or one's progency (aka DSM-III and DSM-V PTSD Criterion-A events). PTSD rates following exposure to lethal inter-group violence (combat, warzone exposure or intentionally caused disasters such as terrorism) are usually 5-10 times higher than rates following large-scale natural disasters such as forest fires, floods, hurricanes, volcanic eruptions, and earthquakes. The author predicts that both intentionally-caused large-scale bioevent-disasters, as well as natural bioevents such as SARS and avian flu pandemics will be an exception and are likely to be followed by PTSD rates approaching those that follow warzone exposure. During bioevents, Amygdala-driven and locus-coeruleus-driven epidemic pseudosomatic symptoms may be an order of magnitude more common than infection-caused cytokine-driven symptoms. Implications for the red cross and FEMA are discussed. It is also argued that hospital phobia as well as dog phobia, bird phobia and bat phobia require re-taxonomization in DSM-V in a new "overconsolidational disorders" category anchored around PTSD. The overconsolidational spectrum category may be conceptualized as straddling the fear circuitry spectrum disorders and the affective spectrum disorders categories, and may be a category for which Pitman's secondary prevention propranolol regimen may be specifically indicated as a "morning after pill" intervention. Predictions are presented regarding obsessive-compulsive disorder (OCD) (e.g., female-pattern hoarding vs. male-pattern hoarding) and "culture-bound" acute anxiety symptoms (taijin-kyofusho, koro, shuk yang, shook yong, suo yang, rok-joo, jinjinia-bemar, karoshi, gwarosa, Voodoo death). Also discussed are insights relevant to pseudoneurological symptoms and to the forthcoming Dissociative-Conversive disorders category in DSM-V, including what the author terms fright-triggered acute pseudo-localized symptoms (i.e., pseudoparalysis, pseudocerebellar imbalance, psychogenic blindness, pseudoseizures, and epidemic sociogenic illness). Speculations based on studies of the human abnormal-spindle-like, microcephaly-associated (ASPM) gene, the microcephaly primary autosomal recessive (MCPH) gene, and the forkhead box p2 (FOXP2) gene are made and incorporated into what is termed "The pre-FOXP2 Hypothesis of Blood-Injection-Injury Phobia." Finally, the author argues for a non-reductionistic fusion of "distal (evolutionary) neurobiology" with clinical "proximal neurobiology," utilizing neurological heuristics. It is noted that the value of re-clustering fear traits based on behavioral ethology, human-phylogenomics-derived endophenotypes and on ontogenomics (gene-environment interactions) can be confirmed or disconfirmed using epidemiological or twin studies and psychiatric genomics.


In vivo MRSI of hyperpolarized [1-(13)C]pyruvate metabolism in rat hepatocellular carcinoma.
Hepatocellular carcinoma (HCC), the primary form of human adult liver malignancy, is a highly aggressive tumor with average survival rates that are currently less than 1 year following diagnosis. Most patients with HCC are diagnosed at an advanced stage, and no efficient marker exists for the prediction of prognosis and/or response(s) to therapy. We have reported previously a high level of [1-(13)C]alanine in an orthotopic HCC using single-voxel hyperpolarized [1-(13)C]pyruvate MRS. In the present study, we implemented a three-dimensional MRSI sequence to investigate this potential hallmark of cellular metabolism in rat livers bearing HCC (n = 7 buffalo rats). In addition, quantitative real-time polymerase chain reaction was used to determine the mRNA levels of lactate dehydrogenase A, nicotinamide adenine (phosphate) dinucleotide dehydrogenase quinone 1 and alanine transaminase. The enzyme levels were significantly higher in tumor than in normal liver tissues within each rat, and were associated with the in vivo MRSI signal of [1-(13)C]alanine and [1-(13)C]lactate after a bolus intravenous injection of [1-(13)C]pyruvate. Histopathological analysis of these tumors confirmed the successful growth of HCC as a nodule in buffalo rat livers, revealing malignancy and hypervascular architecture. More importantly, the results demonstrated that the metabolic fate of [1-(13)C]pyruvate conversion to [1-(13)C]alanine significantly superseded that of [1-(13)C]pyruvate conversion to [1-(13)C]lactate, potentially serving as a marker of HCC tumors.


Prevalence of Sensorineural Hearing Loss in Children with Palliated or Repaired Congenital Heart Disease.
Background Children with congenital heart disease (CHD) are at increased risk of neurodevelopmental deficits, and the presence of sensorineural hearing loss (SNHL) may further lead to poor language skills acquisition and speech delays. Prevalence of SNHL in the general pediatric population is estimated to be 0.2% at birth to 0.35% during adolescence. Very few studies have attempted to estimate SNHL prevalence in children who have undergone congenital heart surgery. Methods This retrospective study aimed to estimate SNHL prevalence in children who underwent congenital heart surgery in our institution and were followed up in our high-risk pediatric cardiology clinics for four years from 2009 to 2013. Data were collected on demographics, preoperative variables, surgical variables, and post-operative variables. Results SNHL prevalence in asymptomatic, palliated/repaired CHD patients followed in our high-risk clinics and undergoing routine surveillance was 11.6% (20 of 172 patients with hearing impairment). SNHL prevalence was not statistically higher in single-ventricle patients (17.2%) compared to biventricular patients (14.7%). Inotropic score in the first 24 hours of postoperative period (p=0.05), lowest arterial PaO2 (p=0.003), duration of Lasix drip (p=0), and bolus dose in days (p=0.03) were all found to be statistically significant in the hearing-impaired group. However, using logistic regression, we identified no statistically significant predictors for hearing loss. Conclusion The results suggest the need for routine audiology screening of all patients with complex CHD, especially those who have undergone neonatal cardiac repair/palliation at less than one year of age, irrespective of risk factors.


TRPC Channels: Dysregulation and Ca2+ Mishandling in Ischemic Heart Disease.
Transient receptor potential canonical (TRPC) channels are ubiquitously expressed in excitable and non-excitable cardiac cells where they sense and respond to a wide variety of physical and chemical stimuli. As other TRP channels, TRPC channels may form homo or heterotetrameric ion channels, and they can associate with other membrane receptors and ion channels to regulate intracellular calcium concentration. Dysfunctions of TRPC channels are involved in many types of cardiovascular diseases. Significant increase in the expression of different TRPC isoforms was observed in different animal models of heart infarcts and in vitro experimental models of ischemia and reperfusion. TRPC channel-mediated increase of the intracellular Ca2+ concentration seems to be required for the activation of the signaling pathway that plays minor roles in the healthy heart, but they are more relevant for cardiac responses to ischemia, such as the activation of different factors of transcription and cardiac hypertrophy, fibrosis, and angiogenesis. In this review, we highlight the current knowledge regarding TRPC implication in different cellular processes related to ischemia and reperfusion and to heart infarction.


Frost trends and their estimated impact on yield in the Australian wheatbelt.
Radiant spring frosts occurring during reproductive developmental stages can result in catastrophic yield loss for wheat producers. To better understand the spatial and temporal variability of frost, the occurrence and impact of frost events on rain-fed wheat production was estimated across the Australian wheatbelt for 1957-2013 using a 0.05 ° gridded weather data set. Simulated yield outcomes at 60 key locations were compared with those for virtual genotypes with different levels of frost tolerance. Over the last six decades, more frost events, later last frost day, and a significant increase in frost impact on yield were found in certain regions of the Australian wheatbelt, in particular in the South-East and West. Increasing trends in frost-related yield losses were simulated in regions where no significant trend of frost occurrence was observed, due to higher mean temperatures accelerating crop development and causing sensitive post-heading stages to occur earlier, during the frost risk period. Simulations indicated that with frost-tolerant lines the mean national yield could be improved by up to 20% through (i) reduced frost damage (~10% improvement) and (ii) the ability to use earlier sowing dates (adding a further 10% improvement). In the simulations, genotypes with an improved frost tolerance to temperatures 1 °C lower than the current 0 °C reference provided substantial benefit in most cropping regions, while greater tolerance (to 3 °C lower temperatures) brought further benefits in the East. The results indicate that breeding for improved reproductive frost tolerance should remain a priority for the Australian wheat industry, despite warming climates.


The changing face of P300 BCIs: a comparison of stimulus changes in a P300 BCI involving faces, emotion, and movement.
One of the most common types of brain-computer interfaces (BCIs) is called a P300 BCI, since it relies on the P300 and other event-related potentials (ERPs). In the canonical P300 BCI approach, items on a monitor flash briefly to elicit the necessary ERPs. Very recent work has shown that this approach may yield lower performance than alternate paradigms in which the items do not flash but instead change in other ways, such as moving, changing colour or changing to characters overlaid with faces. The present study sought to extend this research direction by parametrically comparing different ways to change items in a P300 BCI. Healthy subjects used a P300 BCI across six different conditions. Three conditions were similar to our prior work, providing the first direct comparison of characters flashing, moving, and changing to faces. Three new conditions also explored facial motion and emotional expression. The six conditions were compared across objective measures such as classification accuracy and bit rate as well as subjective measures such as perceived difficulty. In line with recent studies, our results indicated that the character flash condition resulted in the lowest accuracy and bit rate. All four face conditions (mean accuracy >91%) yielded significantly better performance than the flash condition (mean accuracy = 75%). Objective results reaffirmed that the face paradigm is superior to the canonical flash approach that has dominated P300 BCIs for over 20 years. The subjective reports indicated that the conditions that yielded better performance were not considered especially burdensome. Therefore, although further work is needed to identify which face paradigm is best, it is clear that the canonical flash approach should be replaced with a face paradigm when aiming at increasing bit rate. However, the face paradigm has to be further explored with practical applications particularly with locked-in patients.


Traps in displaying optical performances of a progressive-addition lens.
Typical traps when displaying the partial optical performances of a progressive-addition lens (PAL) are presented. The PAL is briefly described first. Then the ray-tracing software is described in detail. It permits the computation of the optical performance of the PAL in typical cases. For a reference PAL optical partial performances, which are computed in different cases, are displayed. The plots show that the performance depends on the computation conditions, that displaying only some areas of the partial performance may lead to traps for the characterization of the PAL, and that coma must be taken into account to obtain a precise measurement.


Glucose decouples intracellular Ca2+ activity from glucagon secretion in mouse pancreatic islet alpha-cells.
The mechanisms of glucagon secretion and its suppression by glucose are presently unknown. This study investigates the relationship between intracellular calcium levels ([Ca(2+)](i)) and hormone secretion under low and high glucose conditions. We examined the effects of modulating ion channel activities on [Ca(2+)](i) and hormone secretion from ex vivo mouse pancreatic islets. Glucagon-secreting α-cells were unambiguously identified by cell specific expression of fluorescent proteins. We found that activation of L-type voltage-gated calcium channels is critical for α-cell calcium oscillations and glucagon secretion at low glucose levels. Calcium channel activation depends on K(ATP) channel activity but not on tetrodotoxin-sensitive Na(+) channels. The use of glucagon secretagogues reveals a positive correlation between α-cell [Ca(2+)](i) and secretion at low glucose levels. Glucose elevation suppresses glucagon secretion even after treatment with secretagogues. Importantly, this inhibition is not mediated by K(ATP) channel activity or reduction in α-cell [Ca(2+)](i). Our results demonstrate that glucose uncouples the positive relationship between [Ca(2+)](i) and secretory activity. We conclude that glucose suppression of glucagon secretion is not mediated by inactivation of calcium channels, but instead, it requires a calcium-independent inhibitory pathway.


Conversion of bacteriorhodopsin into a chloride ion pump.
In the light-driven proton pump bacteriorhodopsin, proton transfer from the retinal Schiff base to aspartate-85 is the crucial reaction of the transport cycle. In halorhodopsin, a light-driven chloride ion pump, the equivalent of residue 85 is threonine. When aspartate-85 was replaced with threonine, the mutated bacteriorhodopsin became a chloride ion pump when expressed in Halobacterium salinarium and, like halorhodopsin, actively transported chloride ions in the direction opposite from the proton pump. Chloride was bound to it, as revealed by large shifts of the absorption maximum of the chromophore, and its photointermediates included a red-shifted state in the millisecond time domain, with its amplitude and decay rate dependent on chloride concentration. Bacteriorhodopsin and halorhodopsin thus share a common transport mechanism, and the interaction of residue 85 with the retinal Schiff base determines the ionic specificity.


Electrophysiologic properties of the myocardial infarction border zone: effects of transient aortic occlusion.
This study used transmural multipolar electrodes, ventricular pressure monitoring, and cardiac electrical stimulation techniques to examine the effects of transient aortic occlusion on ventricular refractoriness in a canine model of recent myocardial infarction. Six previously instrumented resting awake dogs were atrially paced, followed by timed premature extrastimuli inserted at epicardial pacing sites adjacent to an apical left ventricular (LV) myocardial infarction or in an LV control zone remote from the myocardial infarction. Electrophysiologic and pressure recordings were obtained before and during periods of transient aortic occlusion. Aortic occlusion was applied before the last beat of an eight-beat atrial pacing sequence and resulted in increased peak LV pressure (92.8 +/- 27.7 mm Hg, p = 0.003). Aortic occlusion shortened LV effective refractory period (ERP) recorded from the myocardial infarction border zone in both the subepicardial (-17.0 +/- 11.8 msec, p = 0.019) and subendocardial (-17.7 +/- 10.9 msec, p = 0.011) regions, whereas LVERP of the control zone was unchanged. Conduction latency of premature beats at equivalent coupling intervals and maximum latency observed were unchanged by aortic occlusion. atrioventricular conduction interval shortened in association with aortic occlusion. Thus transient aortic occlusion reduced ventricular refractoriness in the border zone adjacent to the myocardial infarction while control zone refractoriness was minimally or not changed. Heterogeneity of ventricular myocardial refractoriness may result from mechanical dysfunction, potentially increasing susceptibility to arrhythmias.


The eucaryotic aminoacyl-tRNA synthetase complex: suggestions for its structure and function.
Aminoacyl-tRNA synthetases from eucaryotic cells generally are isolated as high molecular weight complexes comprised of multiple synthetase activities, and often containing other components as well. A model is proposed for the synthetase complex in which hydrophobic extensions on the proteins serve to maintain them in their high molecular weight form, but are not needed for catalytic activity. The structural similarity of these enzymes to certain membrane-bound proteins, and its implications for synthetase localization and function in vivo, are discussed.


Antibody to ras proteins in patients with colon cancer.
The current study examined sera from 160 colon cancer patients and 60 normal individuals to determine whether antibody to mutated p21 ras protein was present. Studies focused on the aspartic acid substitution at amino acid position 12 (denoted D12), one of the most common mutations in colon adenocarcinoma. IgA antibodies directed against mutated p21 ras-D12 protein were detected in 51 (32%) of 160 colon cancer patients, but only in 1 (2.5%) of 40 normal individuals. The greater incidence of antibody in cancer patients provides presumptive evidence that immunization to the ras proteins occurred as a result of the malignancy. Examination of sera for antibody reactivity to wild-type p21 ras protein (denoted p21 ras-G12) as well as p21 ras proteins bearing the D12, V12, S12, or L61 mutations showed that antibody detected was largely to normal segments of the p21 ras protein. Epitope mapping, using peptide neutralization assays with mutated or normal ras peptides as competitors, demonstrated that in 10 (67%) of 15 sera examined the antibody reactivity to p21 ras-G12 protein was neutralized by peptides near the carboxyl terminus of p21 ras protein, but not by peptides spanning the specific point mutation region. Antibody reactivities correlated with peripheral blood lymphocyte count, but did not correlate with patient age, sex, histology, stage, tumor locus, lymph node metastasis, or serum carcinoembryonic antigen.


Clinical consequences of iron overload in patients with myelodysplastic syndromes: the case for iron chelation therapy.
Patients with myelodysplastic syndromes (MDS) are at increased risk of iron overload due to ineffective erythropoiesis and chronic transfusion therapy. The clinical consequences of iron overload include cardiac and/or hepatic failure, endocrinopathies, and infection risk. Areas covered: Iron chelation therapy (ICT) can help remove excess iron and ultimately reduce the clinical consequences of iron overload. The authors reviewed recent (last five years) English-language articles from PubMed on the topic of iron overload-related complications and the use of ICT (primarily deferasirox) to improve outcomes in patients with MDS. Expert commentary: While a benefit of ICT has been more firmly established in other transfusion-dependent conditions, such as thalassemia, its role in reducing iron overload in MDS remains controversial due to the lack of prospective controlled data demonstrating a survival benefit. Orally administered chelation agents (e.g. deferasirox) are now available, and observational and/or retrospective data support a survival benefit of using ICT in MDS. The placebo-controlled TELESTO trial (NCT00940602) is currently examining the use of deferasirox in MDS patients with iron overload, and is evaluating specifically whether use of ICT to alleviate iron overload can also reduce iron overload-related complications in MDS and improve survival.


From delivery science to discovery science: realising the full potential of global mental health.
The discipline of global mental health has been singularly associated with the generation of knowledge which seeks to reduce the treatment gap for mental disorders. Its priority research agenda has focused on delivery science, i.e. the science of implementing evidence-based interventions. Considerable new resources have furthered this agenda, leading to a flowering of innovations to address barriers to the delivery of interventions while also contributing to the growth and consolidation of research capacity in low and middle income countries. A significant, but as yet under-recognised, opportunity of this global mental health initiative is its potential contribution to discovery science, notably research aimed at identifying the aetiology of mental disorders and the development of novel interventions. This editorial considers a range of potential themes for such discovery science and its guiding principles. Given the limited knowledge that we currently possess about the nature of mental disorders or their effective prevention and treatment, this may well be the most important ultimate contribution of global mental health, i.e. generating knowledge which not only reduces the treatment gap but the actual global burden of mental disorders, and will finally do justice to the 'global' of this discipline.


Pretreatment clinical and laboratory findings in dogs with primary hyperparathyroidism: 210 cases (1987-2004).
To evaluate pretreatment clinical and laboratory findings in dogs with naturally occurring primary hyperparathyroidism. Retrospective study. 210 dogs with primary hyperparathyroidism and 200 randomly selected, age-matched control dogs that did not have primary hyperparathyroidism. Medical records for dogs with primary hyperparathyroidism were reviewed for signalment; clinical features; and results of clinicopathologic testing, serum parathyroid hormone assays, and diagnostic imaging. Mean age of the dogs with primary hyperparathyroidism was 11.2 years (range, 6 to 17 years). The most common clinical signs were attributable to urolithiasis or urinary tract infection (ie, straining to urinate, increased frequency of urination, and hematuria). Most dogs (149 [71%]) did not have any observable abnormalities on physical examination. All dogs had hypercalcemia, and most (136 [65%]) had hypophosphatemia. Overall, 200 of the 210 (95%) dogs had BUN and serum creatinine concentrations within or less than the reference range, and serum parathyroid hormone concentration was within reference limits in 135 of 185 (73%) dogs in which it was measured. Urolithiasis was identified in 65 (31 %) dogs, and urinary tract infection was diagnosed in 61 (29%). Mean serum total calcium concentration for the control dogs-was significantly lower than mean concentration for the dogs with primary hyperparathyroidism, but mean BUN and serum creatinine concentrations for the control dogs were both significantly higher than concentrations for the dogs with primary hyperparathyroidism. Results suggest that urolithiasis and urinary tract infection may be associated with hypercalcemia in dogs-with primary hyperparathyroidism, but that development of renal insufficiency is uncommon.


A population-based incidence study of chronic fatigue.
Most research on syndromes of chronic fatigue has been conducted in clinical settings and is therefore subject to selection biases. We report a population-based incidence study of chronic fatigue (CF) and chronic fatigue syndrome (CFS). Questionnaires assessing fatigue and emotional morbidity were sent to 695 adult men and women who had replied to a postal questionnaire survey 1 year earlier. Possible CFS cases, subjects with probable psychiatric disorder and normal controls were interviewed. Baseline fatigue score, the level of emotional morbidity and a physical attribution for fatigue were risk factors for developing CF. However, after adjusting for confounding, premorbid fatigue score was the only significant predictor. A minority of CF subjects, all female, had consulted their general practitioner; higher levels of both fatigue and emotional morbidity were associated with consultation. Possible CFS cases reported similar rates of current and past psychiatric disorder to psychiatric controls, but after controlling for fatigue or a diagnosis of neurasthenia the current rates were more similar to those of normal controls. Two new cases of CFS were confirmed. Both fatigue and emotional morbidity are integral components of chronic fatigue syndromes. The demographic and psychiatric associations of CFS in clinical studies are at least partly determined by selection biases. Given that triggering and perpetuating factors may differ in CFS, studies that examine the similarities and differences between chronic fatigue syndromes and psychiatric disorder should consider both the stage of the illness and the research setting.


Systematic Review and Meta-Analysis of Posttransplant Hepatic Artery and Biliary Complications in Patients Treated With Transarterial Chemoembolization Before Liver Transplantation.
Hepatic artery complications are feared complications after liver transplantation and may compromise the biliary tract, graft, and patient survival. The objective of this systematic review and meta-analysis was to compare risk of hepatic artery and biliary complications after liver transplantation in patients who underwent neoadjuvant transarterial chemoembolization (TACE) versus no TACE. Comprehensive searches were performed in Embase, MEDLINE OvidSP, Web of Science, Google Scholar, and Cochrane databases to identify studies concerning hepatocellular cancer patients undergoing preliver transplantation TACE. Quality assessment of studies was done by the validated checklist of Downs and Black. Meta-analyses were performed to evaluate the incidence of all hepatic artery complications, hepatic artery thrombosis, and biliary tract complications, using binary random-effect models. Fourteen retrospective studies, representing 1122 TACE patients, met the inclusion criteria. Postoperative hepatic artery complications consisted of hepatic artery thrombosis, stenosis, and (pseudo)-aneurysms. Preliver transplantation TACE was significantly associated with occurrence of posttransplant hepatic artery complications (odds ratio, 1.57; 95% confidence interval, 1.09-2.26; P = 0.02). No significant association between neoadjuvant TACE and hepatic artery thrombosis alone or biliary tract complications was found. Patients treated with TACE before liver transplantation may be at increased risk for development of hepatic artery complications after liver transplantation.


First Report of Bacterial Streak of Fennel (Foeniculum vulgare) in California Caused by Pseudomonas syringae pv. apii.
A previously undescribed disease appeared on commercially grown fennel (Foeniculum vulgare) in Salinas (Monterey County), CA in March 2010. Initial symptoms consisted of small, dark brown-to-black lesions on leaves and stems. As disease progressed, lesions expanded in a linear fashion and eventually spread down the stems and into the bulbs. Once the disease reached the fennel bulbs, the plants were unmarketable. Eighteen, gram-negative, blue-fluorescing bacterial isolates were obtained on sucrose peptone agar from individual plants of two outbreaks from different fields in Salinas. The isolates were dome shaped on sucrose-amended media and produced necrotic lesions when injected into tobacco. Isolates were oxidase negative and did not rot potatoes or hydrolyze arginine. These reactions corresponded to Lelliot's group 1, which includes Pseudomonas syringae (2). The fennel isolates were identical to recently characterized isolates of P. syringae pv. apii from parsley grown in coastal California (1) and similar to the pathotype strain of P. syringae pv. apii according to DNA fragment banding patterns of amplicons generated from repetitive extragenic palindromic sequence (rep)-PCR using the BOXA1R primer. The isolates were distinct from the pathotype strain P. syringae pv. coriandricola. Like P. syringae pv. apii, the fennel isolates did not nucleate ice but did hydrolyze gelatine. Six isolates were tested for pathogenicity in each of two independent experiments with a total of six replications per isolate. Healthy, potted fennel plant stems of a proprietary cultivar were pierced once with insect display pins that had been dipped into bacterial colonies grown for 48 h on nutrient agar. Control stems were inoculated with sterile pins. Plants were incubated for 48 h at 100% relative humidity and then held in a greenhouse. After 4 to 6 days, inoculated fennel plants developed symptoms similar to those originally observed in the field. Bacteria isolated from surface-disinfested symptomatic tissue were fluorescent and identical to strains used to inoculate plants as evaluated by rep-PCR, thus fulfilling Koch's postulates. Control plants remained symptomless. To our knowledge, this is the first report of this pathogen causing a disease on fennel; the disease has been named bacterial streak. The disease occurred in three fields in 2010 and incidence was <1% in each case. Similar symptoms were also observed on fennel in the 2011 season in at least two fields. Previously, the host range of P. syringae pv. apii was reported to be restricted to celery. This research expands the natural host range of P. syringae pv. apii; thus, care should be taken in choosing Apiaceae crops for plantings subsequent to the occurrence of this pathogen. References: (1) C. T. Bull et al. Phytopathology 101:847, 2011. (2) R. A. Lelliott. J. Appl. Bacteriol. 29:470, 1966.


Evidence of cue synergism in termite corpse response behavior.
Subterranean termites of the genus Reticulitermes are known to build walls and tubes and move considerable amounts of soil into wood but the causes of this behavior remain largely unexplored. In laboratory assays, we tested the hypothesis that Reticulitermes virginicus (Banks) would carry more sand into wooden blocks containing corpses compared to corpse-free controls. We further predicted that the corpses of predatory ants would elicit a stronger response than those of a benign beetle species or nestmates. As hypothesized, significantly more sand was carried into blocks containing corpses and this material was typically used to build partitions separating the dead from the rest of the colony. Contrary to expectations, however, this behavior did not vary among corpse types. We then tested the hypothesis that oleic acid, an unsaturated fatty acid released during arthropod decay and used by ants and other arthropod taxa in corpse recognition, would induce a similar building response in R. virginicus. To additionally determine the role of foreign objects in giving rise to this behavior, the experiment was carried out with and without imitation corpses (i.e., small glass beads). As predicted, oleic acid induced building (a tenfold increase) but only when applied to beads, suggesting strong synergism between tactile and chemical cues. Oleic acid also significantly reduced the amount of wood consumed by R. virginicus and may possess useful repellent properties.


Genomic and Phenotypic Variability in Neisseria gonorrhoeae Antimicrobial Susceptibility, England.
Antimicrobial resistance (AMR) in Neisseria gonorrhoeae is a global concern. Phylogenetic analyses resolve uncertainties regarding genetic relatedness of isolates with identical phenotypes and inform whether AMR is due to new mutations and clonal expansion or separate introductions by importation. We sequenced 1,277 isolates with associated epidemiologic and antimicrobial susceptibility data collected during 2013-2016 to investigate N. gonorrhoeae genomic variability in England. Comparing genetic markers and phenotypes for AMR, we identified 2 N. gonorrhoeae lineages with different antimicrobial susceptibility profiles and 3 clusters with elevated MICs for ceftriaxone, varying mutations in the penA allele, and different epidemiologic characteristics. Our results indicate N. gonorrhoeae with reduced antimicrobial susceptibility emerged independently and multiple times in different sexual networks in England, through new mutation or recombination events and by importation. Monitoring and control for AMR in N. gonorrhoeae should cover the entire population affected, rather than focusing on specific risk groups or locations.


Association of insulin resistance with distance to wealthy areas: the multi-ethnic study of atherosclerosis.
Little is known about environmental determinants of type 2 diabetes. The authors hypothesized that insulin resistance is positively related to distance to a wealthy area and to local neighborhood poverty. Data were derived from The Multi-Ethnic Study of Atherosclerosis, a study of adults aged 45-84 years in six US locales, and the 2000 US Census. The homeostasis model assessment (HOMA) index was used to measure insulin resistance. Linear regression was used to estimate associations between area characteristics and insulin resistance after adjustment for age, sex, income, education, and race/ethnicity and for the potential mediators diet, physical activity, and body mass index (n = 4,821). Among persons not treated for diabetes, distance to a wealthy area was associated with HOMA independent of local poverty and person-level covariates: per 4.4-km change, the relative increase in HOMA was 13% (95% confidence interval: 7%, 19%), similar to the effect of a body mass index increase of 1.7 kg/m(2) on HOMA. This association was reduced after adjustment for physical activity, diet, and body mass index (relative increase = 9%, 95% confidence interval: 3%, 15%). Local neighborhood poverty was also positively, but more weakly associated with insulin resistance, with no association after adjustment for race/ethnicity. This study shows that proximity to resources in high-income areas is related to insulin resistance.


Phase II study of ispinesib in recurrent or metastatic squamous cell carcinoma of the head and neck.
Ispinesib (SB-715992) inhibits the mitotic kinesin spindle protein (KSP), a novel target for anticancer therapy. A phase II study was conducted to examine the efficacy of ispinesib in recurrent or metastatic head and neck squamous cell carcinoma (RMHNSC). Patients with up to one prior line of chemotherapy for RMHNSC were treated with ispinesib 18 mg/m2 IV over 1 hour every 21 days. Twenty-one patients were enrolled onto this study with a target stage I sample size of 19. Of 20 evaluable patients, no objective responses were seen and stable disease > 2 cycles was observed in five patients (25%). The median time to progression was 1.4 (95% CI 1.3-2.3) months, median survival was 3.5 (95% CI 2.8-7.8) months, and 1 year overall survival was 20% (95% CI 8.3-48.1%). The most frequent attributable grades III-V adverse events were neutropenia (60% of patients) and leukopenia (55%). The pharmacokinetic profile was consistent with results from phase I studies. Archival tissues (n = 14) demonstrated low to moderate KSP expression by immunohistochemistry. In addition, no pharmacodynamic changes were observed in peripheral blood mononuclear cells. We detected no antitumor activity of ispinesib in RMHNSC on this dosing schedule.


Improving HIV test uptake and case finding with assisted partner notification services.
Despite the enormous expansion of HIV testing services (HTS), an estimated 40% of people with HIV infection remain undiagnosed. To enhance the efficiency of HTS, new approaches are needed. The WHO conducted a systematic review on the effectiveness of assisted partner notification in improving HIV test uptake and diagnosis, and the occurrence of adverse events, to inform the development of normative guidelines. We systematically searched five electronic databases through June 2016. We also contacted experts in the field and study authors for additional information where needed. Eligible studies compared assisted HIV partner notification services to passive or no notification. Where multiple studies reported comparable outcomes, meta-analysis was conducted using a random-effects model to produce relative risks (RRs) or risk ratios and 95% confidence intervals (CIs). Of 1742 citations identified, four randomized controlled trials and six observational studies totalling 5150 index patients from eight countries were included. Meta-analysis of three individually randomized trials showed that assisted partner notification services resulted in a 1.5-fold increase in HTS uptake among partners compared with passive referral (RR = 1.46; 95% CI: 1.22-1.75; I = 0%). The proportion of HIV-positive partners was 1.5 times higher with assisted partner notification than with passive referral (RR = 1.47; 95% CI: 1.12-1.92; I = 0%). Few instances of violence or harm occurred. Assisted partner notification improved partner testing and diagnosis of HIV-positive partners, with few reports of harm. WHO strongly recommends voluntary assisted HIV partner notification services to be offered as part of a comprehensive package of testing and care.


A review on the use of statins and tocotrienols, individually or in combination for the treatment of osteoporosis.
Skeletal tissue undergoes continuous remodeling which makes it unique among other body tissues. Osteoporosis is a common bone metabolic disorder affecting both men and women. Osteoporosis and its complications mainly osteoporotic fractures, have a high impact on health and economy. Current approved medications are associated with numerous side effects, which limit their use. Identification of a new and safe therapy is mandatory. Statins, also known as HMGCoA reductase inhibitors, are frequently used for the treatment of hypercholesterolemia and for the prevention of morbidity and mortality associated with cardiovascular disease. Statins improved bone health status in intact and ovariectomised rodents following high clinically intolerable oral doses. However, this beneficial effect of statins could not be significantly demonstrated in humans. The reason behind this discrepancy might be due to the safety and bioavailability of the currently used oral statins. Vitamin E, especially the tocotrienols at the dose 60 mg/kg/day provided significant antiosteoporotic effects in different animal models of osteoporosis. The use of the aforementioned dose of tocotrienols was shown to be safe in both humans and animals. Enhancement of bone formation and reduction of bone resorption were achieved more effectively by a combination of tocotrienols and statins than by either treatment when supplemented separately at clinically tolerable doses. Therefore, the adverse effects associated with high statin doses might be avoided with the coadministration of tocotrienols. Moreover, the combination therapy strategy might be useful for patients who are at high risk of osteoporosis, cardiovascular events and hypercholesterolaemia.