Monthly administration of long-acting injectable risperidone and striatal dopamine D2 receptor occupancy for the management of schizophrenia.
Long-acting risperidone administered intramuscularly biweekly is approved for the management of schizophrenia. However, dosing of long-acting antipsychotics is frequently extended in clinical practice, and a recent clinical trial has lent support to monthly dosing of long-acting risperidone. The objective of this positron emission tomography (PET) study was to examine the striatal dopamine D(2) binding of long-acting risperidone administered intramuscularly once a month. Following at least 3 maintenance monthly injections of 50 mg long-acting risper-idone, 7 patients with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder under-went PET using [(11)C]raclopride to measure D(2) binding potential within 4 days of the next scheduled injection. Data were collected from May to October 2003. This PET study was part of a larger 52-week clinical study wherein individuals received long-acting risperidone once monthly over a 1-year interval. One-year follow-up data were obtained from the 52-week parent investigation. The mean +/- SD D(2) receptor occupancy was 56% +/- 24% (range, 29%-82%). Of note, there were 4 subjects with less than 60% D(2) occupancy, none of whom relapsed over the course of the 1-year follow-up. The mean +/- SD total plasma level of risperidone plus 9-hydroxyrisperidone was 16.6 +/- 12.3 ng/mL (range, 5.7-40.8). As with plasma levels, there was considerable variability in D(2) occupancy levels for individuals receiving long-acting risperidone. This work suggests a possibility that sustained D(2) occupancy at or above the accepted threshold with acute clinical response may not be necessary to maintain response, a hypothesis with important clinical implications as we consider antipsychotic dosing and future antipsychotic development. clinicaltrials.gov Identifier: NCT00236353.


Preparation of synaptoneurosomes from mouse cortex using a discontinuous percoll-sucrose density gradient.
Synaptoneurosomes (SNs) are obtained after homogenization and fractionation of mouse brain cortex. They are resealed vesicles or isolated terminals that break away from axon terminals when the cortical tissue is homogenized. The SNs retain pre- and postsynaptic characteristics, which makes them useful in the study of synaptic transmission. They retain the molecular machinery used in neuronal signaling and are capable of uptake, storage, and release of neurotransmitters. The production and isolation of active SNs can be problematic using medias like Ficoll, which can be cytotoxic and require extended centrifugation due to high density, and filtration and centrifugation methods, which can result in low activity due to mechanical damage of the SNs. However, the use of discontinuous Percoll-sucrose density gradients to isolate SNs provides a rapid method to produce good yields of translationally active SNs. The Percoll-sucrose gradient method is quick and gentle as it employs isotonic conditions, has fewer and shorter centrifugation spins and avoids centrifugation steps that pellet SNs and cause mechanical damage.


Duration of gestation, size at birth and later childhood behaviour.
Although many previous studies have reported an association between preterm birth or small size at birth and later behaviour, multiple methodological limitations threaten the validity of causal inferences from reported associations. The authors have examined the association between gestational age and gestational age-specific size at birth (weight, length and head circumference) and behaviour in a large sample of children born healthy at term. The data were from the 6.5-year follow-up of 13,889 Belarusian children who participated in the Promotion of Breastfeeding Intervention Trial, a cluster-randomised trial of a breast-feeding promotion intervention. Child behaviour was measured using the parent and teacher versions of the Strengths and Difficulties Questionnaire (SDQ). Differences in SDQ scores by gestational age and by birthweight, birth length and birth head circumference standardised for gestational age and sex (z-scores) were analysed after controlling for potentially confounding maternal and family factors. There was no association between gestational age and child behaviour after adjusting for potential confounding factors. Lower birthweight-for-gestational age was associated with higher scores in problem behaviours including total difficulties, conduct problems, hyperactivity, emotional symptoms and peer problems. Similar but smaller differences were observed with birth length and birth head circumference, but those differences were attenuated with adjustment for birthweight. The patterns of association were consistent in both parent and teacher assessments. Among school-age children born at term within normal range of birthweight, fetal growth, but not gestational age, was associated with behavioural problem scores.


Incidence of cancer among patients with knee implants in Sweden, 1980-1994.
As knee implants become more common, it is important to study their potential health risks. We investigated cancer occurrence in a nationwide population-based cohort of 30,011 patients who underwent knee replacement surgery in Sweden from 1980 to 1994. Patients were followed from 1 year after the date of their surgery through December 31, 1995, accruing 122,616 person-years of observation. The average follow-up time was 4.3 years, with 2365 patients followed for 10 years or more. Overall cancer incidence was not elevated compared with the general population of Sweden (standardized incidence ratio [SIR] = 1.03; 95% confidence interval [CI] = 0.98-1.08). A reduced rate for all respiratory cancers (SIR = 0.73; 95% CI = 0.59-0.91) and for lung cancer (SIR = 0.73; 95% CI = 0.58-0.91) was found among both men and women. Elevated rates were found for prostate (SIR = 1.20; 95% CI = 1.06-1.34) and bone cancer (SIR = 6.00; 95% CI = 1.24-17.52) in men. The bone cancer excess was based on three observed cases, two of which occurred at a site unrelated to the implant and the site of the third tumor is unknown. Rates of connective tissue cancer and leukemia-lymphoma were not elevated significantly among knee implant recipients. Long-term follow-up (>or= 10 years) did not show a significant excess risk for all cancer (SIR = 1.10; 95% CI = 0.86-1.38) or for any site-specific cancer, including bone cancer, lymphoma, or leukemia. Subgroup analyses for patients with rheumatoid arthritis produced results similar to the overall results. This epidemiologic study of cancer risk among patients with knee implants is the largest to date. It provides evidence that the incidence of cancer among patients with knee implants is similar to that of the general population. Continued follow-up of this cohort is warranted to evaluate further potential long-term effects of these implants.


The binding of echinomycin to deoxyribonucleic acid.
Echinomycin is a peptide antibiotic which binds strongly to double-helical DNA up to a limit of approximately one molecule per five base-pairs. There is no detectable interaction with rRNA and only extremely feeble non-specific interaction with poly(rA)-poly(rU). Heat denaturation of DNA greatly decreases the binding, and similarly limited interaction is observed with naturally occurring single-stranded DNA. Association constants for binding to nine double-helical DNA species from different sources are presented; they vary by a factor of approximately 10, but are not simply related to the gross base composition. The interaction with DNA is ionic-strength-dependent, the binding constant falling by a factor of 4 when the ionic strength is raised from 0.01 to 0.10mol/litre. From the effect of temperature on the association constant for calf thymus DNA, the enthalpy of interaction is calculated to be about -13kJ/mol (-3kcal/mol). Binding of echinomycin persists in CsCl gradients and the buoyant density of nicked bacteriophage PM2 DNA is decreased by 25 mg/ml. Echinomycin interacts strongly with certain synthetic poly-deoxynucleotides, the binding constant decreasing in the order poly(dG)-poly(dC) greater than poly(dG-dC) greater than poly(dA-dT). For the latter two polymers the number of base-pairs occluded per bound antibiotic molecule is calculated to be three, whereas for poly(dG)-poly(dC) it is estimated to be four to five. Poly(dA)-poly(dT) and poly(dI)-poly(dC) interact only very weakly with the antibiotic. Poly(dI-dC) interacts to a slightly greater extent, but the binding curve is quite unlike that seen with the three strongly binding synthetic polynucleotides. Echinomycin affects the supercoiling of closed circular duplex bacteriophage PM2 DNA in the characteristic fashion of intercalating drugs. At low ionic strength the unwinding angle is almost twice that of ethidium. Likewise the extension of the helix, determined from changes in the viscosity of rod-like sonicated DNA fragments, is nearly double that expected for a simple (monofunctional) intercalation process. On this basis the interaction process is characterized as bifunctional intercalation. At higher ionic strength the unwinding angle relative to that of ethidium and the helix extension per bound echinomycin molecule fall, indicating a smooth progression towards more nearly monofunctional intercalation. Two simpler compounds which act as analogues of the quinoxaline chromophores of echinomycin, quinoxaline-2-carboxamide and the trypanocidal drug Bayer 7602, interact with DNA very much more weakly than does echinomycin, showing that the peptide portion of the antibiotic plays an essential role in determining the strength and specificity of the interaction.


Durable responses to thalidomide-based drug therapy for myelofibrosis with myeloid metaplasia.
To present the results of a long-term analysis of 2 sequential phase 2 trials of thalidomide (alone or in combination) for palliation of myelofibrosis with myeloid metaplasia (MMM). We analyzed (March 1999 to August 2003) initial and long-term outcomes from 36 patients with symptomatic MMM who had enrolled in either our thalidomide single-agent trial (n=15) or our trial of low-dose thalidomide (50 mg/d) combined with prednisone (n=21). Among the 36 study patients, 20 (56%) showed some improvement in their clinical course. Response rates for specific end points included improvements in anemia (15 of 36 [42%]), thrombocytopenia (10 of 13 [77%]), or splenomegaly (5 of 30 [17%]). The combination of low-dose thalidomide and prednisone, as opposed to single-agent thalidomide, was better tolerated and more efficacious. After a median follow-up of 25 months (range, 20-56 months), 10 of 36 patients (28%) showed an ongoing response, including 8 patients in whom protocol treatment has been discontinued for a median of 21 months (range, 16-31 months). Durable treatment responses were documented for only anemia and thrombocytopenia. Treatment response was not affected by the baseline status of bone marrow fibrosis, angiogenesis, osteosclerosis, cytogenetics, or circulating myeloid progenitor (CD34) cell count. Unusual drug effects, all reversible, included leukocytosis (8 patients) and/or thrombocytosis (6 patients). Thalidomide (alone or combined with prednisone) is an effective first-line treatment of symptomatic anemia or thrombocytopenia in MMM. Thalidomide-based therapy has the potential to produce durable responses in MMM-associated cytopenias, even after discontinuation of the drug.


Electron transfer dynamics and excited state branching in a charge-transfer platinum(II) donor-bridge-acceptor assembly.
A linear asymmetric Pt(ii) trans-acetylide donor-bridge-acceptor triad designed for efficient charge separation, NAP[triple bond, length as m-dash]Pt(PBu3)2[triple bond, length as m-dash]Ph-CH2-PTZ (), containing strong electron acceptor and donor groups, 4-ethynyl-N-octyl-1,8-naphthalimide (NAP) and phenothiazine (PTZ) respectively, has been synthesised and its photoinduced charge transfer processes characterised in detail. Excitation with 400 nm, ∼50 fs laser pulse initially populates a charge transfer manifold stemming from electron transfer from the Pt-acetylide centre to the NAP acceptor and triggers a cascade of charge and energy transfer events. A combination of ultrafast time-resolved infrared (TRIR) and transient absorption (TA) spectroscopies, supported by UV-Vis/IR spectroelectrochemistry, emission spectroscopy and DFT calculations reveals a self-consistent photophysical picture of the excited state evolution from femto- to milliseconds. The characteristic features of the NAP-anion and PTZ-cation are clearly observed in both the TRIR and TA spectra, confirming the occurrence of electron transfer and allowing the rate constants of individual ET-steps to be obtained. Intriguingly, has three separate ultrafast electron transfer pathways from a non-thermalised charge transfer manifold directly observed by TRIR on timescales ranging from 0.2 to 14 ps: charge recombination to form either the intraligand triplet (3)NAP with 57% yield, or the ground state, and forward electron transfer to form the full charge-separated state (3)CSS ((3)[PTZ(+)-NAP(-)]) with 10% yield as determined by target analysis. The (3)CSS decays by charge-recombination to the ground state with ∼1 ns lifetime. The lowest excited state is (3)NAP, which possesses a long lifetime of 190 μs and efficiently sensitises singlet oxygen. Overall, molecular donor-bridge-acceptor triad demonstrates excited state branching over 3 different pathways, including formation of a long-distant (18 Å) full charge-separated excited state from a directly observed vibrationally hot precursor state.


Are seedlings from small seeds always inferior to seedlings from large seeds? Effects of seed biomass on seedling growth in Pastinaca sativa L.
Previous field studies of recruitment in Pastinaca sativa L. indicate that more seedlings from small seeds than from large seeds survive short-term droughts. To explore this phenomenon, the effects of variation in seed biomass in Pastinaca sativa on embryo size and seedling characteristics 10, 20, 30 and 40 days after emergence were investigated. On the basis of most characteristics, seedlings from large seeds should be superior to seedlings from small seeds. Embryo length and cotyledon area were positively related to seed biomass, as were above ground biomass, total leaf area, and root biomass in all harvests. Total seedling biomass was positively related to seed biomass in the 10, 20, and 30 day harvests, but not the 40 day harvest. However, the ratio of maximum root length/total leaf area was negatively related to seed biomass in the 10 and 20 day harvests, suggesting that, under drought conditions, seedlings from small seeds may transpire less water than those from large seeds relative to their ability to reach water supplies. Although seedlings from larger seeds had greater root biomass, this may be of little advantage under drought conditions since approximately 90% of the root biomass is in the upper 10 cm of soil which dries out quickly. The advantage that seedlings from small seeds have under drought conditions is short-lived, lasting about 20 days in the glasshouse and an estimated 60-90 days in the field. This advantage is short-term because the relationship between seed biomass and resource allocation patterns changes during early seedling development.


The METEX study: methotrexate versus expectant management in women with ectopic pregnancy: a randomised controlled trial.
Patients with ectopic pregnancy (EP) and low serum hCG concentrations and women with a pregnancy of unknown location (PUL) and plateauing serum hCG levels are commonly treated with systemic methotrexate (MTX). However, there is no evidence that treatment in these particular subgroups of women is necessary as many of these early EPs may resolve spontaneously. The aim of this study is whether expectant management in women with EP or PUL and with low but plateauing serum hCG concentrations is an alternative to MTX treatment in terms of treatment success, future pregnancy, health related quality of life and costs. A multicentre randomised controlled trial in The Netherlands. Hemodynamically stable patients with an EP visible on transvaginal ultrasound and a plateauing serum hCG concentration < 1,500 IU/L or with a persisting PUL with plateauing serum hCG concentrations < 2,000 IU/L are eligible for the trial. Patients with a viable EP, signs of tubal rupture/abdominal bleeding, or a contra-indication for MTX will not be included. Expectant management is compared with systemic MTX in a single dose intramuscular regimen (1 mg/kg) in an outpatient setting. Serum hCG levels are monitored weekly; in case of inadequately declining, systemic MTX is installed or continued. In case of hemodynamic instability and/or signs of tubal rupture, surgery is performed. The primary outcome measure is an uneventful decline of serum hCG to an undetectable level by the initial intervention. Secondary outcomes are (re)interventions (additional systemic MTX injections and/or surgery), treatment complications, health related quality of life, financial costs, and future fertility. Analysis is performed according to the intention to treat principle. Quality of life is assessed by questionnaires before and at three time points after randomisation. Costs are expressed as direct costs with data on costs and used resources in the participating centres. Fertility is assessed by questionnaires after 6, 12, 18 and 24 months. Patients' preferences will be assessed using a discrete choice experiment. This trial will provide guidance on the present management dilemmas in women with EPs and PULs with low and plateauing serum hCG concentrations. Current Controlled Trials ISRCTN 48210491.


Interactions between zebrafish pigment cells responsible for the generation of Turing patterns.
The reaction-diffusion system is one of the most studied nonlinear mechanisms that generate spatially periodic structures autonomous. On the basis of many mathematical studies using computer simulations, it is assumed that animal skin patterns are the most typical examples of the Turing pattern (stationary periodic pattern produced by the reaction-diffusion system). However, the mechanism underlying pattern formation remains unknown because the molecular or cellular basis of the phenomenon has yet to be identified. In this study, we identified the interaction network between the pigment cells of zebrafish, and showed that this interaction network possesses the properties necessary to form the Turing pattern. When the pigment cells in a restricted region were killed with laser treatment, new pigment cells developed to regenerate the striped pattern. We also found that the development and survival of the cells were influenced by the positioning of the surrounding cells. When melanophores and xanthophores were located at adjacent positions, these cells excluded one another. However, melanophores required a mass of xanthophores distributed in a more distant region for both differentiation and survival. Interestingly, the local effect of these cells is opposite to that of their effects long range. This relationship satisfies the necessary conditions required for stable pattern formation in the reaction-diffusion model. Simulation calculations for the deduced network generated wild-type pigment patterns as well as other mutant patterns. Our findings here allow further investigation of Turing pattern formation within the context of cell biology.


Developing health and social care planning in collaboration.
Collaboration between different professions in community care for older people is often both difficult and complex. In this project, a participatory action research (PAR) was conducted in order to support the professions involved in the care for older people to develop individualized health and social care plans. Cases from daily work were discussed in different professional groups over a period of one year. A key finding was that lack of knowledge regarding the other professions' field of expertise and their underlying professional culture and values was a barrier in their collaboration. However, as the continuous reflective dialogue process progressed, the participants began to reflect more about the importance of collaboration as a prerequisite to achieve the best possible care for the recipient. This process of reflection led to the often complex needs of the care recipients being given a more central position and thus care plans being better tailored to each person's needs.


Testosterone use in men with sexual dysfunction: a systematic review and meta-analysis of randomized placebo-controlled trials.
To conduct a systematic review and meta-analysis of randomized placebo-controlled trials to measure the effect of testosterone use on sexual function in men with sexual dysfunction and varying testosterone levels. Librarian-designed search strategies were used to search the MEDLINE (1966 to October 2004), EMBASE (1988 to October 2004), and Cochrane CENTRAL (inception to October 2004) databases. The MEDLINE search was rerun in March 2005. We also reviewed reference lists from included studies and content expert files. We selected randomized placebo-controlled trials of testosterone vs placebo that enrolled men with sexual dysfunction and measured satisfaction with erectile function and libido and overall sexual satisfaction. We included 17 trials (N = 862 participants) in this review. Trials that enrolled participants with low testosterone levels showed (1) a moderate nonsignificant and inconsistent effect of testosterone use on satisfaction with erectile function (random-effects pooled effect size, 0.80; 95% confidence interval [CI], -0.10 to 1.60), (2) a large effect on libido (pooled effect size, 1.31; 95% CI, 0.40 to 2.25), and (3) no significant effect on overall sexual satisfaction. Trials that enrolled patients with low-normal and normal testosterone levels at baseline showed testosterone that caused (1) a small effect on satisfaction with erectile function (pooled effect size, 0.34; 95% CI, 0.03 to 0.65), (2) moderate nonsignificant effect on libido (pooled effect size, 0.41; 95% CI, -0.01 to 0.83), and (3) no significant effect on overall sexual satisfaction. Testosterone use in men is associated with small improvements in satisfaction with erectile function and moderate improvements in libido. Unexplained inconsistent results across trials, wide CIs, and possible reporting bias weaken these inferences.


Cloning and comparative studies of seaweed trehalose-6-phosphate synthase genes.
The full-length cDNA sequence (3219 base pairs) of the trehalose-6-phosphate synthase gene of Porphyra yezoensis (PyTPS) was isolated by RACE-PCR and deposited in GenBank (NCBI) with the accession number AY729671. PyTPS encodes a protein of 908 amino acids before a stop codon, and has a calculated molecular mass of 101,591 Daltons. The PyTPS protein consists of a TPS domain in the N-terminus and a putative TPP domain at the C-terminus. Homology alignment for PyTPS and the TPS proteins from bacteria, yeast and higher plants indicated that the most closely related sequences to PyTPS were those from higher plants (OsTPS and AtTPS5), whereas the most distant sequence to PyTPS was from bacteria (EcOtsAB). Based on the identified sequence of the PyTPS gene, PCR primers were designed and used to amplify the TPS genes from nine other seaweed species. Sequences of the nine obtained TPS genes were deposited in GenBank (NCBI). All 10 TPS genes encoded peptides of 908 amino acids and the sequences were highly conserved both in nucleotide composition (>94%) and in amino acid composition (>96%). Unlike the TPS genes from some other plants, there was no intron in any of the 10 isolated seaweed TPS genes.


Molecular basis of polymorphisms of human complement component C3.
C3 exhibits two common allotypic variants that may be separated by gel electrophoresis and are called C3 fast (C3 F) and C3 slow (C3 S). C3 F, the less common variant, occurs at appreciable frequencies only in Caucasoid populations (gene frequency = 0.20). An increased prevalence of the C3 F allele has been reported in patients with partial lipodystrophy, IgA nephropathy, and Indian childhood hepatic cirrhosis. Studies of the genomic organization of the human C3 gene led to the identification of a single change (C to G) between C3 S and C3 F at nucleotide 364 in exon 3. This leads, at the translation level, to the substitution of an arginine residue (positively charged) in C3 S for a glycine residue (neutral) in C3 F. This substitution results in a polymorphic restriction site for the enzyme HhaI. The resulting restriction fragment length polymorphism (RFLP) was investigated using genomic DNA, amplified using the polymerase chain reaction; there was absolute concordance between the genomic polymorphism and the distribution of C3 S and C3 F in 50 normal subjects. The molecular basis of a second structural polymorphism, defined by the monoclonal antibody HAV 4-1, was also characterized. The polymorphic determinant was identified at codon 314 in the exon 9 of the beta chain where a leucine residue (HAV 4-1+) is substituted for a proline residue (HAV 4-1-). Identification of the amino acid sequences of these polymorphic variants will facilitate characterization of possible functional differences between different allotypes of C3. Three RFLPs (BamHI, EcoRI, and SstI) were located to introns in the C3 gene. There was no allelic association between these three RFLPs, or between the RFLPs and the C3 F/S polymorphic site. Genetic equilibration of these polymorphisms has occurred within a gene of 41 kb.


Emotional intelligence assessment in a graduate entry medical school curriculum.
The management of emotions in the workplace is a skill related to the ability to demonstrate empathic behaviour towards patients; to manage emotional reactions in oneself and to lead others as part of a team. This ability has been defined as emotional intelligence (EI) and doctor's EI may be related to communication skills and to patient satisfaction levels. This study reports on the use of two assessments of EI as part of a course on Personal and Professional Development (PPD) in a graduate medical school curriculum. Fifty one graduate entry medical students completed an eight session course on PPD between December 2005 and January 2006. Students completed two measures of EI: self-report (EQ-i) and ability (MSCEIT V2.0) over a two year study period. The data gathered were used to explore the relationship between self-report and ability EI and between EI and student demographics, academic performance and change over time. Analysis of the EI data demonstrated that self-report EI did not change over time and was not related to ability EI. Females scored higher than males on a number of self-report and ability EI scores. Self-reported self-awareness was found to deteriorate in males and females over time. High self-reported EI was found to be associated with poor performance on clinical competency assessments but with good performance on a number of bio-medical knowledge based assessments. This report concludes that assessments of EI can be incorporated into a medical school curriculum as part of a PPD programme and that the concept of EI may be associated with performance in medical school.


5,10-Dimesityldiindeno[1,2-a:2',1'-i]phenanthrene: a stable biradicaloid derived from Chichibabin's hydrocarbon.
A diindenophenanthrene biradicaloid, formally derived from Chichibabin's hydrocarbon, is obtained in a short, scalable synthesis. The present system is electron-rich and devoid of conjugated substituents, and still exhibits very good stability under ambient conditions. The introduction of the diindeno[1,2-a:2',1'-i] phenanthrene ring framework results in a singlet biradicaloid system with an easily accessible triplet state (ΔE S-T = -1.30 kcal mol-1) and a small electronic bandgap (1.39 V). The stability limits of the title hydrocarbon were explored systematically in the solid state, to reveal an unusual thermally initiated hydrogen-scrambling oligomerization process.


Metastability in lipid based particles exhibits temporally deterministic and controllable behavior.
The metastable-to-stable phase-transition is commonly observed in many fields of science, as an uncontrolled independent process, highly sensitive to microscopic fluctuations. In particular, self-assembled lipid suspensions exhibit phase-transitions, where the underlying driving mechanisms and dynamics are not well understood. Here we describe a study of the phase-transition dynamics of lipid-based particles, consisting of mixtures of dilauroylphosphatidylethanolamine (DLPE) and dilauroylphosphatidylglycerol (DLPG), exhibiting a metastable liquid crystalline-to-stable crystalline phase transition upon cooling from 60°C to 37°C. Surprisingly, unlike classically described metastable-to-stable phase transitions, the manner in which recrystallization is delayed by tens of hours is robust, predetermined and controllable. Our results show that the delay time can be manipulated by changing lipid stoichiometry, changing solvent salinity, adding an ionophore, or performing consecutive phase-transitions. Moreover, the delay time distribution indicates a deterministic nature. We suggest that the non-stochastic physical mechanism responsible for the delayed recrystallization involves several rate-affecting processes, resulting in a controllable, non-independent metastability. A qualitative model is proposed to describe the structural reorganization during the phase transition.


The bradykinin-forming cascade and its role in hereditary angioedema.
To review the mechanisms by which bradykinin is generated in hereditary angioedema (HAE) (C1 inhibitor deficiency), including the role of human plasma proteins and endothelial cells. Published articles in reviewed journals that address (1) the fundamentals of bradykinin formation, (2) interactions between kinin-forming proteins and endothelial cells, (3) clinical evidence that bradykinin causes swelling in HAE, and (4) therapeutic options focused on inhibition of the plasma kallikrein-kinin cascade. Historical articles that have made fundamental observations. Recent articles that address evolving concepts of disease pathogenesis and treatment. C1 inhibitor deficiency causes dysregulation of the plasma bradykinin-forming cascade with overproduction of bradykinin due to uninhibited effects of activated factor XII and plasma kallikrein. Swelling in HAE and production of bradykinin are localized (and may then disseminate); activation along the endothelial cell surface involves cell membrane ligands of factor XII and high-molecular-weight kininogen, release of endothelial cell heat shock protein 90, activation of the high-molecular-weight kininogen-prekallikrein complex, and endothelial cell activation at the B2 receptor. Attacks of swelling may be terminated by treatment with a kallikrein inhibitor or B2 receptor blockade. Replenishing C1 inhibitor can abort attacks of swelling and provide prophylaxis with intravenous administration. Bradykinin is the mediator of swelling in types I and II HAE and is overproduced because of a deficiency in C1 inhibitor. Inhibition of bradykinin formation by novel agentscan provide targeted therapeutic approaches that address the pathophysiologic abnormalities.


Experimental cross-species infection of common marmosets by titi monkey adenovirus.
Adenoviruses are DNA viruses that infect a number of vertebrate hosts and are associated with both sporadic and epidemic disease in humans. We previously identified a novel adenovirus, titi monkey adenovirus (TMAdV), as the cause of a fulminant pneumonia outbreak in a colony of titi monkeys (Callicebus cupreus) at a national primate center in 2009. Serological evidence of infection by TMAdV was also found in a human researcher at the facility and household family member, raising concerns for potential cross-species transmission of the virus. Here we present experimental evidence of cross-species TMAdV infection in common marmosets (Callithrix jacchus). Nasal inoculation of a cell cultured-adapted TMAdV strain into three marmosets produced an acute, mild respiratory illness characterized by low-grade fever, reduced activity, anorexia, and sneezing. An increase in virus-specific neutralization antibody titers accompanied the development of clinical signs. Although serially collected nasal swabs were positive for TMAdV for at least 8 days, all 3 infected marmosets spontaneously recovered by day 12 post-inoculation, and persistence of the virus in tissues could not be established. Thus, the pathogenesis of experimental inoculation of TMAdV in common marmosets resembled the mild, self-limiting respiratory infection typically seen in immunocompetent human hosts rather than the rapidly progressive, fatal pneumonia observed in 19 of 23 titi monkeys during the prior 2009 outbreak. These findings further establish the potential for adenovirus cross-species transmission and provide the basis for development of a monkey model useful for assessing the zoonotic potential of adenoviruses.


Does bathymetry drive coastal whale shark (Rhincodon typus) aggregations?
The whale shark (Rhincodon typus) is known to aggregate in a number of coastal locations globally, however what causes these aggregations to form where they do is largely unknown. This study examines whether bathymetry is an important driver of coastal aggregation locations for R. typus through bathymetry's effect on primary productivity and prey availability. This is a global study taking into account all coastal areas within R. typus' range. R. typus aggregation locations were identified through an extensive literature review. Global bathymetric data were compared at R. typus aggregation locations and a large random selection of non-aggregation areas. Generalised linear models were used to assess which bathymetric characteristic had the biggest influence on aggregation presence. Aggregation sites were significantly shallower than non-aggregation sites and in closer proximity to deep water (the mesopelagic zone) by two orders of magnitude. Slope at aggregation sites was significantly steeper than non-aggregation sites. These three bathymetric variables were shown to have the biggest association with aggregation sites, with up to 88% of deviation explained by the GLMs. The three key bathymetric characteristics similar at the aggregation sites are known to induce upwelling events, increase primary productivity and consequently attract numerous other filter feeding species. The location of aggregation sites in these key areas can be attributed to this increased prey availability, thought to be the main reason R. typus aggregations occur, extensively outlined in the literature. The proximity of aggregations to shallow areas such as reefs could also be an important factor why whale sharks thermoregulate after deep dives to feed. These findings increase our understanding of whale shark behaviour and may help guide the identification and conservation of further aggregation sites.


Nanoindentation of injection molded PLA and self-reinforced composite PLA after in vitro conditioning for three months.
Poly(lactic acid) (PLA) is used for medical devices such as sutures or orthopedic screws. A standard way to determine the loss of mechanical properties of a degradable polymer would be to soak the polymer in phosphate buffered saline (PBS) and test the desired property as a function of immersion time. This method is not sensitive enough to discern changes in mechanical properties through the cross-section of the polymer and neglects the degradation that is occurring at the molecular level. This article presents results of a nanoindentation study carried out with PLA. The modulus and hardness of PLA is characterized as a function of processing method, immersion time in PBS, and location of the indent. Measuring local properties with the nanoindenter allowed detection of differences in material properties as a function of all three of these variables. The mechanical properties on the edge were lower than the interior of the sample after in vitro degradation, and changes were seen earlier for nanoindentation than for traditional flexural or tensile tests. The nanoindenter is a valuable tool for quantifying changes in material properties and may have applicability for accelerated tests to screen biomaterials.


Method for appraising model validity of randomised controlled trials of homeopathic treatment: multi-rater concordance study.
A method for assessing the model validity of randomised controlled trials of homeopathy is needed. To date, only conventional standards for assessing intrinsic bias (internal validity) of trials have been invoked, with little recognition of the special characteristics of homeopathy. We aimed to identify relevant judgmental domains to use in assessing the model validity of homeopathic treatment (MVHT). We define MVHT as the extent to which a homeopathic intervention and the main measure of its outcome, as implemented in a randomised controlled trial (RCT), reflect 'state-of-the-art' homeopathic practice. Using an iterative process, an international group of experts developed a set of six judgmental domains, with associated descriptive criteria. The domains address: (I) the rationale for the choice of the particular homeopathic intervention; (II) the homeopathic principles reflected in the intervention; (III) the extent of homeopathic practitioner input; (IV) the nature of the main outcome measure; (V) the capability of the main outcome measure to detect change; (VI) the length of follow-up to the endpoint of the study. Six papers reporting RCTs of homeopathy of varying design were randomly selected from the literature. A standard form was used to record each assessor's independent response per domain, using the optional verdicts 'Yes', 'Unclear', 'No'. Concordance among the eight verdicts per domain, across all six papers, was evaluated using the kappa (κ) statistic. The six judgmental domains enabled MVHT to be assessed with 'fair' to 'almost perfect' concordance in each case. For the six RCTs examined, the method allowed MVHT to be classified overall as 'acceptable' in three, 'unclear' in two, and 'inadequate' in one. Future systematic reviews of RCTs in homeopathy should adopt the MVHT method as part of a complete appraisal of trial validity.


High-Frequency Oscillatory Ventilation Use and Severe Pediatric ARDS in the Pediatric Hematopoietic Cell Transplant Recipient.
The effectiveness of high-frequency oscillatory ventilation (HFOV) in the pediatric hematopoietic cell transplant patient has not been established. We sought to identify current practice patterns of HFOV, investigate parameters during HFOV and their association with mortality, and compare the use of HFOV to conventional mechanical ventilation in severe pediatric ARDS. This is a retrospective analysis of a multi-center database of pediatric and young adult allogeneic hematopoietic cell transplant subjects requiring invasive mechanical ventilation for critical illness from 2009 through 2014. Twelve United States pediatric centers contributed data. Continuous variables were compared using a Wilcoxon rank-sum test or a Kruskal-Wallis analysis. For categorical variables, univariate analysis with logistic regression was performed. The database contains 222 patients, of which 85 subjects were managed with HFOV. Of this HFOV cohort, the overall pediatric ICU survival was 23.5% (n = 20). HFOV survivors were transitioned to HFOV at a lower oxygenation index than nonsurvivors (25.6, interquartile range 21.1-36.8, vs 37.2, interquartile range 26.5-52.2, P = .046). Survivors were transitioned to HFOV earlier in the course of mechanical ventilation, (day 0 vs day 2, P = .002). No subject survived who was transitioned to HFOV after 1 week of invasive mechanical ventilation. We compared subjects with severe pediatric ARDS treated only with conventional mechanical ventilation versus early HFOV (within 2 d of invasive mechanical ventilation) versus late HFOV. There was a trend toward difference in survival (conventional mechanical ventilation 24%, early HFOV 30%, and late HFOV 9%, P = .08). In this large database of pediatric allogeneic hematopoietic cell transplant subjects who had acute respiratory failure requiring invasive mechanical ventilation for critical illness with severe pediatric ARDS, early use of HFOV was associated with improved survival compared to late implementation of HFOV, and the subjects had outcomes similar to those treated only with conventional mechanical ventilation.


Assessment of Heavy Metal and Trace Element Levels in Patients with Telogen Effluvium.
Despite a multitude of studies, etiology of primary chronic telogen effluvium (TE) remains incompletely understood. Essential heavy metals are associated with beneficial effects in humans as well as in other living organisms. However, they may lead to toxic effects when the exposure exceeds the higher tolerable limits. We wanted to assess the heavy metal and trace element levels in patients with chronic TE. A total of 40 subjects with chronic TE were included in the study, and 30 healthy women served as control. General and dermatological examinations were taken up in all individuals. Those patients with positive hair pull test were evaluated with the help of a trichogram. The presence of >20% telogen hair as documented by trichogram was a requirement for the study inclusion. UNICAM-929 spectrophotometry device was used for determining serum trace element and heavy metal concentrations. In spite of an absence of significant differences in terms of average Zn concentration, weight, or height between patients and controls, significant differences were noted for Cd, Fe, Mg, Mn, Pb, Co, and Cu (P <0.05). Our results suggest that heavy metals may play a causative role in the development of chronic TE. However, contrary to previous reports, zinc did not appear to play an important etiological role, while these patients had elevated serum iron levels.


Direct quantification of circulating miRNAs in different stages of nasopharyngeal cancerous serum samples in single molecule level with total internal reflection fluorescence microscopy.
MicroRNAs (miRNAs) are small noncoding RNAs that regulate human gene expression at the post-transcriptional level. Growing evidence indicates that the expression profile of miRNAs is highly correlated with the occurrence of human diseases including cancers. Playing important roles in complex gene regulation processes, the aberrant expression pattern of various miRNAs is implicated in different types and even stages of cancer. Besides localizing in cells, many of these miRNAs are found circulating around the body in a wide variety of fluids such as urine, serum and saliva. Surprisingly, these extracellular circulating miRNAs are highly stable and resistant to degradation, and therefore, are considered as promising biomarkers for early cancer diagnostic via noninvasive extraction from body fluids. Unfortunately, the abundance of these small RNAs is ultralow in the body fluids, making it challenging to quantify them in complex sample matrixes. Establishing a sensitive, specific yet simple assay for an accurate quantification of circulating miRNAs is therefore desirable. Our group previously reported a sensitive and specific detection assay of miRNAs in single molecule level with the aid of total internal reflection fluorescence microscopy. In this work, we advanced the assay to differentiate the expression of a nasopharyngeal carcinoma (NPC) up-regulator hsa-mir-205 (mir-205) in serum collected from patients of different stages of NPC. To overcome the background matrix interference in serum, a locked nucleic acid-modified molecular beacon (LNA/MB) was applied as the detection probe to hybridize, capture and detect target mir-205 in serum matrix with enhanced sensitivity and specificity. A detection limit of 500 fM was achieved. The as-developed method was capable of differentiating NPC stages by the level of mir-205 quantified in serum with only 10 μL of serum and the whole assay can be completed in 1 h. The experimental results agreed well with those previously reported whereas the quantity of miR-205 determined by our assay was found comparable to that of quantitative reverse transcription polymerase chain reaction (qRT-PCR), supporting that this assay can be served as a promising noninvasive detection tool for early NPC diagnosis, monitoring and staging.


Male-specific association between MT-ND4 11719 A/G polymorphism and ulcerative colitis: a mitochondria-wide genetic association study.
Ulcerative colitis (UC) is a chronic inflammatory disorder of still unknown pathogenesis. Increasing evidence indicates that alterations in mitochondrial respiration and thus adenosine triphosphate (ATP) production are involved. This may contribute to mucosal energy deficiency and subsequently intestinal barrier malfunction, which is accepted to be a major hallmark of UC. Genetic alterations of the mitochondrial genome are one cause of mitochondrial dysfunction. However, less is known about mitochondrial gene polymorphisms in UC. Therefore, we aimed at identifying genetic associations between mitochondrial polymorphisms and UC. German UC cases (n = 1062) and German healthy controls (n = 3030) were genotyped using the Affymetrix Genome-Wide Human SNP Array 6.0. The primary association analysis was to test for associations between mitochondrial single nucleotide polymorphisms (SNPs) and UC using Fisher's exact test in the total sample and stratified by sex. In addition, we tested for associations between mitochondrial haplogroups and UC and for interactions between the most promising mitochondrial SNPs and nuclear SNPs. An independent set of German subjects with 1625 UC cases and 3575 controls was used for replication. We identified a genetic association between the MT-ND4 11719 A/G polymorphism and UC in the subgroup of males (rs2853495; odds ratio, 1.40; 95 % confidence interval, 1.13 to 1.73; p = 0.002). This association was replicated in the second independent cohort. In the association analysis based on mitochondrial haplogroups the lowest p values were reached for haplogroups HV and T (p = 0.029 and 0.035). Haplogroup HV is determined by the mitochondrial 11719 A/G polymorphism. Accordingly, this association was only found in the subgroup of males (p = 0.009). For the first time, we observed an association between the MT-ND4 11719 A/G polymorphism and UC. The gene MT-ND4 encodes for a subunit of the mitochondrial electron transport chain complex I, which is pivotal for ATP production and might therefore contribute to mucosal energy deficiency. The male-specific association indicates differences between males and females concerning the impact of mitochondrial gene polymorphisms on the development of UC. Further investigations of the functional mechanism underlying this association and the relevance of the gender-specificity are highly warranted.


Diversity of Salmonella enterica serovar Derby isolated from pig, pork and humans in Germany.
Salmonella enterica serovar Derby (S. Derby) is one of the most prevalent serovars in pigs in Europe and in the U.S. and ranks among the 10 most frequently isolated serovars in humans. Therefore, a set of 82 epidemiologically unrelated S. Derby strains isolated between 2006 and 2008 from pigs, pork and humans in Germany was selected and investigated in respect to the transmission of clonal groups of the serovar along the food chain. Various phenotypic and genotypic methods were applied and the pathogenicity and resistance gene repertoire was determined. Phenotypically 72% of the strains were susceptible to all 17 antimicrobials tested while the others were monoresistant to tetracycline or multi-resistant with different resistance profiles. Four major clonal groups were identified based on PFGE, sequence data of the virulence genes sopA, sopB and sopD, VNTR-locus STTR5 and MLST revealing also the new sequence type ST774. Thirty different PFGE profiles were detected resulting in four clusters representing the four groups. The pathogenicity gene repertoire of 32 representative S. Derby strains analyzed by microarray showed six types with differences in the Salmonella pathogenicity islands, pathogenicity genes on smaller islets or prophages and fimbriae coding genes. The pathogenicity gene repertoire of the predominant types PAT DE1 and DE2 were most similar to the ones of S. Paratyphi B (dT+, O5-) and to a minor degree to S. Infantis and S. Virchow PATs. Overall this study showed that in Germany currently one major S. Derby clone is frequently isolated from pigs and humans. Contaminated pork was identified as one vehicle and consequently is a risk for human health. To prevent this serovar from entering the food chain, control measurements should be applied at the farm level.


Green Tea (Camellia Sinensis): Chemistry and Oral Health.
Green tea is a widely consumed beverage worldwide. Numerous studies have suggested about the beneficial effects of green tea on oral conditions such as dental caries, periodontal diseases and halitosis. However, to date there have not been many review articles published that focus on beneficial effects of green tea on oral disease. The aim of this publication is to summarize the research conducted on the effects of green tea on oral cavity. Green tea might help reduce the bacterial activity in the oral cavity that in turn, can reduce the aforementioned oral afflictions. Furthermore, the antioxidant effect of the tea may reduce the chances of oral cancer. However, more clinical data is required to ascertain the possible benefits of green tea consumption on oral health.


The Qatar Biobank: background and methods.
The Qatar Biobank aims to collect extensive lifestyle, clinical, and biological information from up to 60,000 men and women Qatari nationals and long-term residents (individuals living in the country for ≥15 years) aged ≥18 years (approximately one-fifth of all Qatari citizens), to follow up these same individuals over the long term to record any subsequent disease, and hence to study the causes and progression of disease, and disease burden, in the Qatari population. Between the 11(th)-December-2012 and 20(th)-February-2014, 1209 participants were recruited into the pilot study of the Qatar Biobank. At recruitment, extensive phenotype information was collected from each participant, including information/measurements of socio-demographic factors, prevalent health conditions, diet, lifestyle, anthropometry, body composition, bone health, cognitive function, grip strength, retinal imaging, total body dual energy X-ray absorptiometry, and measurements of cardiovascular and respiratory function. Blood, urine, and saliva were collected and stored for future research use. A panel of 66 clinical biomarkers was routinely measured on fresh blood samples in all participants. Rates of recruitment are to be progressively increased in the coming period and the recruitment base widened to achieve a cohort of consented individuals broadly representative of the eligible Qatari population. In addition, it is planned to add additional measures in sub-samples of the cohort, including Magnetic Resonance Imaging (MRI) of the brain, heart and abdomen. The mean time for collection of the extensive phenotypic information and biological samples from each participant at the baseline recruitment visit was 179 min. The 1209 pilot study participants (506 men and 703 women) were aged between 28-80 years (median 39 years); 899 (74.4%) were Qatari nationals and 310 (25.6%) were long-term residents. Approximately two-thirds of pilot participants were educated to graduate level or above. The pilot has proven that recruitment of volunteers into the Qatar Biobank project with intensive baseline measurements of behavioural, physical, and clinical characteristics is well accepted and logistically feasible. Qatar Biobank will provide a powerful resource to investigate the major determinants of ill-health and well-being in Qatar, providing valuable insights into the current and future public health burden that faces the country.


Bayesian Nonparametric Methods for Partially-Observable Reinforcement Learning.
Making intelligent decisions from incomplete information is critical in many applications: for example, robots must choose actions based on imperfect sensors, and speech-based interfaces must infer a user's needs from noisy microphone inputs. What makes these tasks hard is that often we do not have a natural representation with which to model the domain and use for choosing actions; we must learn about the domain's properties while simultaneously performing the task. Learning a representation also involves trade-offs between modeling the data that we have seen previously and being able to make predictions about new data. This article explores learning representations of stochastic systems using Bayesian nonparametric statistics. Bayesian nonparametric methods allow the sophistication of a representation to scale gracefully with the complexity in the data. Our main contribution is a careful empirical evaluation of how representations learned using Bayesian nonparametric methods compare to other standard learning approaches, especially in support of planning and control. We show that the Bayesian aspects of the methods result in achieving state-of-the-art performance in decision making with relatively few samples, while the nonparametric aspects often result in fewer computations. These results hold across a variety of different techniques for choosing actions given a representation.


A simple serum-free freezing medium for serum-free cultured cells.
Because the presence of serum in cell culture raises safety problems for the production of biologicals, we have developed a serum-free medium (SFM) for the cryopreservation of animal cells. This medium is based of the SFM MDSS2, to which 10% dimethylsulfoxide (DMSO) and 0.1% methylcellulose or 3% polyvinyl pyrrolidone or no other additive than DMSO were added. Both, Vero and BHK-21 cells regularly cultivated in MDSS2, could be cryopreserved in the three serum-free freezing media and could be thawed without any cell loss. No differences could be found between the cells in the standard freezing medium (DMEM containing 10% fetal calf serum and 10% DMSO) and those frozen in SFM, with respect to cell growth and viability. In the case of the Vero cells no differences were observed with respect to their attachment. This medium represents the last step in fulfilling a complete serum-free animal cell based bioprocess.


Post-translational modification of genetically encoded polypeptide libraries.
The genetic encoding of polypeptides with biological display systems enables the facile generation and screening of very large combinatorial libraries of molecules. By post-translationally modifying the encoded polypeptides, chemically and structurally more diverse molecules beyond linear amino acid polymers can be generated. The first post-translational modification applied to encoded polypeptides, the oxidation of cysteine residues to form disulfide bridges, is a natural one and was used to cyclise short peptides soon after the invention of phage display. Recently a range of non-natural chemical strategies for the post-translational modification of encoded polypeptide repertoires were applied to generate optical biosensors, semisynthetic polypeptides, peptide-drug conjugates, redox-insensitive monocyclic peptides or multicyclic peptides, and these strategies are reviewed in this article.


Structure and activity associated with multiple forms of Schizosaccharomyces pombe DNA polymerase delta.
DNA polymerase delta (Pol delta) isolated from Schizosaccharomyces pombe (sp) consists of at least four subunits, Pol3, Cdc1, Cdc27, and Cdm1. We have reconstituted the four-subunit complex by simultaneously expressing these polypeptides in baculovirus-infected insect cells. The properties of the purified cloned spPol delta were identical to the native spPol delta isolated from S. pombe cells. In addition, we also isolated a three-subunit complex containing Pol3, Cdc1, and Cdm1. Both three- and four-subunit complexes required replication factor C and proliferating cell nuclear antigen for DNA replication. However, in the presence of low levels of polymerase complexes, the three-subunit complex was less efficient than the four-subunit complex in supporting DNA replication. The inefficient synthesis of DNA by the three-subunit complex can be remedied by the addition of Cdc27, the subunit missing in the three-subunit complex. Gel filtration analysis demonstrated that the three-subunit complex is a monomer of the heterotrimer (Pol3, Cdc1, and Cdm1) and that the four-subunit complex is a dimer of the heterotetramer (Pol3, Cdc1, Cdc27, and Cdm1), similar to the structure of native spPol delta. We have further shown that Cdc1 and Cdc27 interact to form a heterodimeric complex. Gel filtration studies indicate that the structure of this complex is dimeric. These observations suggest that the Cdc27 subunit may play an important role contributing to the dimerization of Pol delta.


Attitudes to mode of hysterectomy--a survey-based study among Swedish gynecologists.
To determine gynecologists' attitudes to mode of hysterectomy on benign indication. Cross-sectional study. Sweden. Members of the Swedish Society of Obstetrics and Gynecology. A postal questionnaire. Questions examined attitudes to mode of hysterectomy based on three clinical scenarios with different conditions of the uterus. Gynecologists were also asked to estimate how the distribution of the different modes of benign hysterectomy should be overall. The modes to choose were total abdominal, subtotal abdominal, laparoscopic or vaginal hysterectomy (VH). Analyses were performed with multiple logistic regression and multivariate analysis of covariance. Preferred mode of hysterectomy in the three scenarios and distribution of modes of hysterectomy. VH was the most preferred method in general as well as when the uterus was of normal size, whereas subtotal and total abdominal hysterectomy were the most favored methods when the uterus was enlarged. VH was more often preferred by male compared to female gynecologists as a personal preference. The choice and distribution of mode varied significantly between place of work, seniority and in the quantity of yearly performed hysterectomies. The minimal invasive methods, vaginal and laparoscopic hysterectomy, were recommended in more than 50% of the overall suggested distribution. Personal choice of mode of hysterectomy does not seem to strictly follow evidence-based recommendations, but varies significantly between gynecologist's gender, type of clinical setting in which the gynecologist works, seniority and by how many hysterectomies the gynecologist does annually.


Astrocytic water channel aquaporin-4 modulates brain plasticity in both mice and humans: a potential gliogenetic mechanism underlying language-associated learning.
The role of astrocytes in brain plasticity has not been extensively studied compared with that of neurons. Here we adopted integrative translational and reverse-translational approaches to explore the role of an astrocyte-specific major water channel in the brain, aquaporin-4 (AQP4), in brain plasticity and learning. We initially identified the most prevalent genetic variant of AQP4 (single nucleotide polymorphism of rs162008 with C or T variation, which has a minor allele frequency of 0.21) from a human database (n=60 706) and examined its functionality in modulating the expression level of AQP4 in an in vitro luciferase reporter assay. In the following experiments, AQP4 knock-down in mice not only impaired hippocampal volumetric plasticity after exposure to enriched environment but also caused loss of long-term potentiation after theta-burst stimulation. In humans, there was a cross-sectional association of rs162008 with gray matter (GM) volume variation in cortices, including the vicinity of the Perisylvian heteromodal language area (Sample 1, n=650). GM volume variation in these brain regions was positively associated with the semantic verbal fluency. In a prospective follow-up study (Sample 2, n=45), the effects of an intensive 5-week foreign language (English) learning experience on regional GM volume increase were modulated by this AQP4 variant, which was also associated with verbal learning capacity change. We then delineated in mice mechanisms that included AQP4-dependent transient astrocytic volume changes and astrocytic structural elaboration. We believe our study provides the first integrative evidence for a gliogenetic basis that involves AQP4, underlying language-associated brain plasticity.


Minimal within-host dengue models highlight the specific roles of the immune response in primary and secondary dengue infections.
In recent years, the within-host viral dynamics of dengue infections have been increasingly characterized, and the relationship between aspects of these dynamics and the manifestation of severe disease has been increasingly probed. Despite this progress, there are few mathematical models of within-host dengue dynamics, and the ones that exist focus primarily on the general role of immune cells in the clearance of infected cells, while neglecting other components of the immune response in limiting viraemia. Here, by considering a suite of mathematical within-host dengue models of increasing complexity, we aim to isolate the critical components of the innate and the adaptive immune response that suffice in the reproduction of several well-characterized features of primary and secondary dengue infections. By building up from a simple target cell limited model, we show that only the innate immune response is needed to recover the characteristic features of a primary symptomatic dengue infection, while a higher rate of viral infectivity (indicative of antibody-dependent enhancement) and infected cell clearance by T cells are further needed to recover the characteristic features of a secondary dengue infection. We show that these minimal models can reproduce the increased risk of disease associated with secondary heterologous infections that arises as a result of a cytokine storm, and, further, that they are consistent with virological indicators that predict the onset of severe disease, such as the magnitude of peak viraemia, time to peak viral load, and viral clearance rate. Finally, we show that the effectiveness of these virological indicators to predict the onset of severe disease depends on the contribution of T cells in fuelling the cytokine storm.


Angiogenesis and angiocrines regulating heart growth.
Endothelial cells (ECs) line the inner surface of all blood and lymphatic vessels throughout the body, making endothelium one of the largest tissues. In addition to its transport function, endothelium is now appreciated as a dynamic organ actively participating in angiogenesis, permeability and vascular tone regulation, as well as in the development and regeneration of tissues. The identification of endothelial-derived secreted factors, angiocrines, has revealed non-angiogenic mechanisms of endothelial cells in both physiological and pathological tissue remodeling. In the heart, ECs play a variety of important roles during cardiac development as well as in growth, homeostasis and regeneration of the adult heart. To date, several angiocrines affecting cardiomyocyte growth in response to physiological or pathological stimuli have been identified. In this review, we discuss the effects of angiogenesis and EC-mediated signaling in the regulation of cardiac hypertrophy. Identification of the molecular and metabolic signals from ECs during physiological and pathological cardiac growth could provide novel therapeutic targets to treat heart failure, as endothelium is emerging as one of the potential target organs in cardiovascular and metabolic diseases.


Inflammatory markers among adolescents and young adults with bipolar spectrum disorders.
Despite burgeoning literature in middle-aged adults, little is known regarding proinflammatory markers (PIMs) among adolescents and young adults with bipolar disorder. Similarly, few prior studies have considered potential confounds when examining the association between PIMs and bipolar disorder characteristics. We therefore retrospectively examined these topics in the Course and Outcome of Bipolar Youth (COBY) study. Subjects were 123 adolescents and young adults (mean [SD] = 20.4 ± 3.8 years; range, 13.4-28.3 years) in COBY, enrolled between October 2000 and July 2006. DSM-IV diagnoses were determined using the Schedule for Affective Disorders and Schizophrenia for School-Age Children (K-SADS). Clinical characteristics during the preceding 6 months, including mood, comorbidity, and treatment, were evaluated using the Longitudinal Interval Follow-Up Evaluation (LIFE). Serum levels of interleukin (IL)-6, tumor necrosis factor (TNF)-α, and high-sensitivity C-reactive protein (hsCRP) were assayed. Primary analyses examined the association of PIMs with bipolar disorder characteristics during the preceding 6 months. Several lifetime clinical characteristics were significantly associated with PIMs in multivariable analyses, including longer illness duration (P = .005 for IL-6; P = .0004 for hsCRP), suicide attempts (P = .01 for TNF-α), family history of suicide attempts or completion (P = .01 for hsCRP), self-injurious behavior (P =.005 for TNF-α), substance use disorder (SUD) (P < .0001 for hsCRP), and family history of SUD (P = .02 for TNF-α; P = .01 for IL-6). The following bipolar disorder characteristics during the preceding 6 months remained significantly associated with PIMs in multivariable analyses that controlled for differences in comorbidity and treatment: for TNF-α, percentage of weeks with psychosis (χ(2) = 5.7, P =.02); for IL-6, percentage of weeks with subthreshold mood symptoms (χ(2)= 8.3, P = .004) and any suicide attempt (χ(2) = 6.1, P = .01); for hsCRP, maximum severity of depressive symptoms (χ(2) = 8.3, P =.004). Proinflammatory markers may be relevant to bipolar disorder characteristics as well as other clinical characteristics among adolescents and young adults with bipolar disorder. Traction toward validating PIMs as clinically relevant biomarkers in bipolar disorder will require repeated measures of PIMs and incorporation of relevant covariates.


Occurrence and fate modeling of MTBE and BTEX compounds in a Swiss Lake used as drinking water supply.
Emissions of fuel components from boating use on multiple-use lakes and reservoirs are of high concern with regard to the drinking water supply from such water bodies. We report results of a detailed study on the occurrence, sources and fate of aromatic hydrocarbons and methyl tert-butyl ether (MTBE) in a typical holomictic lake, Lake Zurich, that supplies drinking water for the largest Swiss city. Emphasis of the investigation was on the fuel oxygenate MTBE, which was found in concentrations up to 1.4 microg/L in the epilimnion and up to 0.05microg/L in the hypolimnion of the lake. The concentration difference was due to the stratification of the lake during the boating season with very limited water exchange across the thermocline. MTBE and BTEX nearly completely volatilized before vertical lake mixing occurred in winter. Spatial and temporal variations of MTBE concentrations in the lake were observed and successfully predicted using two complementary box models (MASAS Light and Aquasim). The drinking water supply from holomictic lakes is not at risk for the scenarios studied if water is extracted from well below the thermocline. Since emissions of unburned gasoline into such water bodies are caused predominantly by boating activities, restrictions of highly emitting two-stroke engines could substantially reduce the MTBE and BTEX load of the epilimnion during the boating season.


Parkinson's disease tremor is diminished with relaxation guided imagery.
Patients with Parkinson's disease (PD) may have pronounced tremor that exacerbates during stress. To determine whether PD tremor improves with relaxation guided imagery (RGI) and relaxing music. Twenty patients with PD with moderate to severe tremor participated in sessions where relaxation techniques were implemented. Tremor was objectively monitored using an accelerometer. RGI dramatically decreased tremor in all 20 patients (baseline 270.38 +/- 85.82 vs. RGI 35.57 +/- 43.90 movements per minute P < 0.0001). In 15 patients, RGI completely abolished tremor for 1-13 min. Average tremor activity remained significantly below baseline both 15 min and 30 min after RGI was discontinued (P < 0.001). Patients reported improvement lasting 2-14 hours (mean 6.8 +/- 3.8). Relaxing music significantly reduced tremor but to a lesser degree than RGI (220.04 +/- 106.53 movements per minute P = 0.01). Self-relaxation had no significant effect on tremor. RGI can supplement conventional medical treatments for tremor in patients with PD on best medical treatment.


Anthropogenic climate change drives shift and shuffle in North Atlantic phytoplankton communities.
Anthropogenic climate change has shifted the biogeography and phenology of many terrestrial and marine species. Marine phytoplankton communities appear sensitive to climate change, yet understanding of how individual species may respond to anthropogenic climate change remains limited. Here, using historical environmental and phytoplankton observations, we characterize the realized ecological niches for 87 North Atlantic diatom and dinoflagellate taxa and project changes in species biogeography between mean historical (1951-2000) and future (2051-2100) ocean conditions. We find that the central positions of the core range of 74% of taxa shift poleward at a median rate of 12.9 km per decade (km⋅dec(-1)), and 90% of taxa shift eastward at a median rate of 42.7 km⋅dec(-1) The poleward shift is faster than previously reported for marine taxa, and the predominance of longitudinal shifts is driven by dynamic changes in multiple environmental drivers, rather than a strictly poleward, temperature-driven redistribution of ocean habitats. A century of climate change significantly shuffles community composition by a basin-wide median value of 16%, compared with seasonal variations of 46%. The North Atlantic phytoplankton community appears poised for marked shift and shuffle, which may have broad effects on food webs and biogeochemical cycles.


Robotic surgery and cancer: the present state, problems and future vision.
In the 1990s, laparoscopic surgery entirely changed the traditional style of surgical operations. Laparoscopic cholecystectomy has spread rapidly and is now established as the standard treatment. However, besides cholecystectomy, endoscopic procedures are still not applied so widely to a variety of surgical operations. This is because laparoscopic techniques, such as suturing or ligation, make it difficult for surgeons to perform other kinds of operations and thus greatly increase their mental and physical stress. It is necessary to introduce various advanced technologies such as: surgical robots, three dimensional (3D) images, computer graphics (CG), computer simulation technology and others. Surgical robots, including the AESOP, da Vinci and ZEUS systems, provide surgeons with technologically advanced vision and hand skills. As a result, such systems are expected to revolutionize the field of surgery. However, there have so far been few studies which discuss the indications of robotic surgery for tumors/cancer. Therefore, herein we review various studies published in English to focus on the application of robotic surgery to tumors/cancer. We point out that there are several problems to be solved for robot surgery: i) price of surgical robots, ii) training systems for surgeon, iii) coverage by medical insurance, iv) downsizing and v) navigation system. In conclusion, we believe that, in the near future as robotic technology continues to develop, almost all kinds of endoscopic surgery will be performed by this technology. It will replace traditional surgery not only in the treatment of benign diseases but also in malignant illnesses.


Genome Sequencing of Streptomyces atratus SCSIOZH16 and Activation Production of Nocardamine via Metabolic Engineering.
The Actinomycetes are metabolically flexible microorganisms capable of producing a wide range of interesting compounds, including but by no means limited to, siderophores which have high affinity for ferric iron. In this study, we report the complete genome sequence of marine-derived Streptomyces atratus ZH16 and the activation of an embedded siderophore gene cluster via the application of metabolic engineering methods. The S. atratus ZH16 genome reveals that this strain has the potential to produce 26 categories of natural products (NPs) barring the ilamycins. Our activation studies revealed S. atratus SCSIO ZH16 to be a promising source of the production of nocardamine-type (desferrioxamine) compounds which are important in treating acute iron intoxication and performing ecological remediation. We conclude that metabolic engineering provides a highly effective strategy by which to discover drug-like compounds and new NPs in the genomic era.


Botanical extracts as anti-aging preparations for the skin: a systematic review.
Although topical creams and other anti-aging products purport to reduce the appearance of aging and skin wrinkling, there has been no critical analysis in the scientific literature of their effectiveness. This systematic review critically evaluates the evidence for the effectiveness or efficacy of botanical treatments in reducing skin aging and wrinkling. MEDLINE, Embase, CINAHL®, CENTRAL and AMED databases were searched from their inception until October 2009. Reference lists of retrieved articles were hand-searched. Manufacturers and professional associations were contacted in order to identify further non-published studies. No language restrictions were applied. Only randomized clinical trials or controlled clinical trials assessing the effectiveness of botanical extracts in reducing wrinkling and aging of the skin were included. Data were extracted by two independent reviewers and methodological quality was assessed using the Jadad score and key aspects of the Cochrane risk of bias tool. Of 36 potentially relevant studies, 11 trials of botanical extracts for reducing skin wrinkling and the appearance of aging met all the inclusion criteria. No trials were identified following contact with anti-aging and cosmetic organizations, companies and professional bodies. A significant reduction in skin wrinkling was noted for date kernel extract, cork extract, soy extract, Rosaceae and peony extract. No significant reduction was noted for green tea, Vitaphenol® (a combination of green and white teas, mangosteen and pomegranate extract) or maca root. All trials were of poor methodological quality. Adverse effects were frequently not reported. In summary, there is some weak evidence to suggest that several botanical extracts may be effective in reducing the appearance of skin aging but no evidence that this effect is enduring. Independent replications with larger, more diverse samples, longer treatment durations and more rigorous study designs are required to validate these preliminary findings.


[Effect of Vitex negundo var. heterophylla seeds ethanol extract (VSE) on mice model of immunological hepatitis and acute inflammation].
To study the effects of Vitex negundo var. heterophylla seeds ethanol extract(VSE) on immunological hepatitis and acute inflammation mice model. Hepatic function in the immunological liver injury model was evaluated by assessing the levels of ALT in plasma, and the content of MDA, ORAC, NO and iNOS mRNA in liver tissues. VSE effect on the acute inflammation caused by croton oil and carrageenan was observed. Compared to the model group, 125 and 500 mg x kg(-1) VSE could inhibit the activities of ALT in mice plasma, and enhanced levels of ORAC and decreased levels of MDA and modulated levels of NO in liver tissues. Meanwhile, VSE could ameliorate the ear swelling induced by croton oil and reduced the thickness of mice hind paw induced by carrageenan as well. The results indicated that VSE exerted potential effects on immunological hepatitis and the mechanisms might be partly related to free radical scavenging activity and inhibit release of iNOS. VSE also showed partial effects on acute inflammation.


Proximal femoral focal deficiency. Evidence for a defect in proliferation and maturation of chondrocytes.
Proximal femoral focal deficiency is a rare congenital malformation, characterized by a failure of normal development of the proximal part of the femur. To our knowledge, there have been no reports on the histology of fetal growth plates that are affected by this disorder. To characterize this focal developmental anomaly further, we studied the histopathology of the growth plates and epiphyses from a twenty-one-week fetus with unilateral proximal femoral focal deficiency. Although the shape of the cartilaginous anlage of the fetus appeared normal, the growth plate of the proximal part of the involved femur was markedly abnormal. The major findings were: (1) striking failure of the proximal growth plate to migrate proximally, away from the central part of the diaphysis, and failure of formation of a normal growth plate; (2) failure of organization of proliferative and hypertrophic chondrocytes into longitudinal columns; (3) truncation of an immature hypertrophic zone that had abnormal septal architecture; and (4) disorganized vascular invasion with a honeycomb rather than a columnar pattern of primary trabeculae. In contrast, the histological characteristics of the growth plates from the distal part of the femur and from all other long bones were normal.


Dok-7 activates the muscle receptor kinase MuSK and shapes synapse formation.
The formation of the neuromuscular junction (NMJ) is orchestrated by the muscle-specific receptor tyrosine kinase MuSK and by neural agrin, an extracellular activator of MuSK. We previously showed that the MuSK-interacting protein Dok-7 is essential for neuromuscular synaptogenesis, although the mechanisms by which Dok-7 regulates MuSK activity and promotes synapse formation have been unclear. Here, we show that Dok-7 directly interacts with the cytoplasmic portion of MuSK and activates the receptor tyrosine kinase, and that neural agrin requires Dok-7 to activate MuSK. In vivo overexpression of Dok-7 increased MuSK activation and promoted NMJ formation. Furthermore, Dok-7 was required for the localization of MuSK in the central region of muscle, which is essential for the correct formation of NMJs in this region. These observations indicate that Dok-7 positively regulates neuromuscular synaptogenesis by controlling MuSK activity, its distribution, and its responsiveness to neural agrin.


High Basolateral Glucose Increases Sodium-Glucose Cotransporter 2 and Reduces Sirtuin-1 in Renal Tubules through Glucose Transporter-2 Detection.
Under diabetic conditions, sodium-glucose cotransporter 2 (SGLT2) for glucose uptake in proximal tubules (PTs) increases, whereas NAD+-dependent protein deacetylase silent mating type information regulation 2 homolog 1 (Sirtuin-1; SIRT1) for PT survival decreases. Therefore, we hypothesized that increased glucose influx by SGLT2 reduces SIRT1 expression. To test this hypothesis, db/db mice with diabetes and high-glucose (HG)-cultured porcine PT LLC-PK1 cells in a two-chamber system were treated with the SGLT2 inhibitor canagliflozin. We also examined SIRT1 and SGLT2 expression in human kidney biopsies. In db/db mice, SGLT2 expression increased with concomitant decreases in SIRT1, but was inhibited by canagliflozin. For determination of the polarity of SGLT2 and SIRT1 expression, LLC-PK1 cells were seeded into Transwell chambers (pore size, 0.4 µm; Becton Dickinson, Oxford, UK). HG medium was added to either or to both of the upper and lower chambers, which corresponded to the apical and basolateral sides of the cells, respectively. In this system, the lower chamber with HG showed increased SGLT2 and decreased SIRT1 expression. Canagliflozin reversed HG-induced SIRT1 downregulation. Gene silencing and inhibitors for glucose transporter 2 (GLUT2) blocked HG-induced SGLT2 expression upregulation. Gene silencing for the hepatic nuclear factor-1α (HNF-1α), whose nuclear translocation was enhanced by HG, blocked HG-induced SGLT2 expression upregulation. Similarly, gene silencing for importin-α1, a chaperone protein bound to GLUT2, blocked HG-induced HNF-1α nuclear translocation and SGLT2 expression upregulation. In human kidney, SIRT1 immunostaining was negatively correlated with SGLT2 immunostaining. Thus, under diabetic conditions, SIRT1 expression in PTs was downregulated by an increase in SGLT2 expression, which was stimulated by basolateral HG through activation of the GLUT2/importin-α1/HNF-1α pathway.


Role for fimbriae and lysine-specific cysteine proteinase gingipain K in expression of interleukin-8 and monocyte chemoattractant protein in Porphyromonas gingivalis-infected endothelial cells.
Recent cross-sectional and prospective epidemiological studies have demonstrated an association between periodontal disease and atherosclerosis and human coronary heart disease. Previously, we have established that the periodontal pathogen Porphyromonas gingivalis is capable of invading aortic, heart, and human umbilical vein endothelial cells (HUVEC). Since atherosclerosis is a chronic inflammatory response initiated at the vascular wall, interactions of P. gingivalis with endothelial cells and the subsequent host cell response to infection may be important in the pathogenesis of atherosclerosis. In this study we examined the consequences of P. gingivalis infection of HUVEC on the expression of the chemokines interleukin-8 (IL-8) and monocyte chemotactic protein 1 (MCP-1). HUVEC were found to constitutively produce low levels of IL-8 and MCP-1. The addition of P. gingivalis fimbrillin-specific peptides, lipopolysaccharides (LPS), or heat-killed whole cell preparations to HUVEC stimulated modest IL-8 and MCP-1 responses. In contrast, coculture of HUVEC with live P. gingivalis strain A7436, 33277, or 381 abolished the IL-8 and MCP-1 responses. Inhibition of IL-8 and MCP-1 production was not dependent on bacterial adherence since similar results were obtained with the nonadherent P. gingivalis fimA mutant DPG3 or when P. gingivalis was preincubated with fimbrillin peptide antisera prior to the addition to HUVEC. Furthermore, treatment of P. gingivalis-infected HUVEC with cytochalsin D, which prevented P. gingivalis invasion, also abolished the constitutive IL-8 and MCP-1 responses. Treatment of HUVEC with E. coli LPS stimulated robust IL-8 and MCP-1 responses that were abolished when stimulated cells were cocultured with live P. gingivalis. Analysis of P. gingivalis-infected HUVEC cultures by an RNase protection assay revealed an increase in the IL-8 transcript relative to uninfected HUVEC. Pretreatment of P. gingivalis with protease inhibitors prior to the addition to HUVEC prevented the inhibition of IL-8 and MCP-1 production in P. gingivalis-infected HUVEC, indicating that the inhibition was proteolytically mediated. Coculture of HUVEC with a P. gingivalis mutant deficient in lysine-specific cysteine proteinase (gingipain K [Kgp]) resulted in an increase in both IL-8 transcription and protein expression relative to that observed in HUVEC cocultured with the P. gingivalis wild-type strain. These results indicate that P. gingivalis can temporally modulate the chemokine response in endothelial cells through both fimbriae and gingipain-mediated mechanisms.


Identification and characterization of genomic regions on chromosomes 4 and 8 that control the rate of photosynthesis in rice leaves.
DNA marker-assisted selection appears to be a promising strategy for improving rates of leaf photosynthesis in rice. The rate of leaf photosynthesis was significantly higher in a high-yielding indica variety, Habataki, than in the most popular Japanese variety, Koshihikari, at the full heading stage as a result of the higher level of leaf nitrogen at the same rate of application of nitrogen and the higher stomatal conductance even when the respective levels of leaf nitrogen were the same. The higher leaf nitrogen content of Habataki was caused by the greater accumulation of nitrogen by plants. The higher stomatal conductance of Habataki was caused by the higher hydraulic conductance. Using progeny populations and selected lines derived from a cross between Koshihikari and Habataki, it was possible to identify the genomic regions responsible for the rate of photosynthesis within a 2.1 Mb region between RM17459 and RM17552 and within a 1.2 Mb region between RM6999 and RM22529 on the long arm of chromosome 4 and on the short arm of chromosome 8, respectively. The designated region on chromosome 4 of Habataki was responsible for both the increase in the nitrogen content of leaves and hydraulic conductance in the plant by increasing the root surface area. The designated region on chromosome 8 of Habataki was responsible for the increase in hydraulic conductance by increasing the root hydraulic conductivity. The results suggest that it may be possible to improve photosynthesis in rice leaves by marker-assisted selection that focuses on these regions of chromosomes 4 and 8.


Acquisition of Pseudomonas aeruginosa and its resistance phenotypes in critically ill medical patients: role of colonization pressure and antibiotic exposure.
The objective of this work was to investigate the risk factors for the acquisition of Pseudomonas aeruginosa and its resistance phenotypes in critically ill patients, taking into account colonization pressure. We conducted a prospective cohort study in an 8-bed medical intensive care unit during a 35-month period. Nasopharyngeal and rectal swabs and respiratory secretions were obtained within 48 hours of admission and thrice weekly thereafter. During the study, a policy of consecutive mixing and cycling periods of three classes of antipseudomonal antibiotics was followed in the unit. Of 850 patients admitted for ≥ 3 days, 751 (88.3%) received an antibiotic, 562 of which (66.1%) were antipseudomonal antibiotics. A total of 68 patients (8%) carried P. aeruginosa upon admission, and among the remaining 782, 104 (13%) acquired at least one strain of P. aeruginosa during their stay. Multivariate analysis selected shock (odds ratio (OR) = 2.1; 95% confidence interval (CI), 1.2 to 3.7), intubation (OR = 3.6; 95% CI, 1.7 to 7.5), enteral nutrition (OR = 3.6; 95% CI, 1.8 to 7.6), parenteral nutrition (OR = 3.9; 95% CI, 1.6 to 9.6), tracheostomy (OR = 4.4; 95% CI, 2.3 to 8.3) and colonization pressure >0.43 (OR = 4; 95% CI, 1.2 to 5) as independently associated with the acquisition of P. aeruginosa, whereas exposure to fluoroquinolones for >3 days (OR = 0.4; 95% CI, 0.2 to 0.8) was protective. In the whole series, prior exposure to carbapenems was independently associated with carbapenem resistance, and prior amikacin use predicted piperacillin-tazobactam, fluoroquinolone and multiple-drug resistance. In critical care settings with a high rate of antibiotic use, colonization pressure and non-antibiotic exposures may be the crucial factors for P. aeruginosa acquisition, whereas fluoroquinolones may actually decrease its likelihood. For the acquisition of strains resistant to piperacillin-tazobactam, fluoroquinolones and multiple drugs, exposure to amikacin may be more relevant than previously recognized.


Transient Receptor Potential Vanilloid 1 Expression Mediates Capsaicin-Induced Cell Death.
The transient receptor potential (TRP) ion channel family consists of a broad variety of non-selective cation channels that integrate environmental physicochemical signals for dynamic homeostatic control. Involved in a variety of cellular physiological processes, TRP channels are fundamental to the control of the cell life cycle. TRP channels from the vanilloid (TRPV) family have been directly implicated in cell death. TRPV1 is activated by pain-inducing stimuli, including inflammatory endovanilloids and pungent exovanilloids, such as capsaicin (CAP). TRPV1 activation by high doses of CAP (>10 μM) leads to necrosis, but also exhibits apoptotic characteristics. However, CAP dose-response studies are lacking in order to determine whether CAP-induced cell death occurs preferentially via necrosis or apoptosis. In addition, it is not known whether cytosolic Ca2+ and mitochondrial dysfunction participates in CAP-induced TRPV1-mediated cell death. By using TRPV1-transfected HeLa cells, we investigated the underlying mechanisms involved in CAP-induced TRPV1-mediated cell death, the dependence of CAP dose, and the participation of mitochondrial dysfunction and cytosolic Ca2+ increase. Together, our results contribute to elucidate the pathophysiological steps that follow after TRPV1 stimulation with CAP. Low concentrations of CAP (1 μM) induce cell death by a mechanism involving a TRPV1-mediated rapid and transient intracellular Ca2+ increase that stimulates plasma membrane depolarization, thereby compromising plasma membrane integrity and ultimately leading to cell death. Meanwhile, higher doses of CAP induce cell death via a TRPV1-independent mechanism, involving a slow and persistent intracellular Ca2+ increase that induces mitochondrial dysfunction, plasma membrane depolarization, plasma membrane loss of integrity, and ultimately, cell death.


Standardizing the complication rate after breast reduction using the Clavien-Dindo classification.
Published complication rates for breast reduction surgery, also known as reduction mammaplasty, vary between 4% and 54%. This wide range of complication rates could be attributable to the lack of a standardized classification of complications in plastic surgery. The aim of this study was to analyze our single-center complication rates after reduction mammaplasty using the Clavien-Dindo classification. We performed a retrospective chart review studying 804 patients between the ages of 18 and 81 years old who underwent breast reduction between 2005 and 2015 at our institution. Patients with a history of breast cancer, a previous breast operation, who did not undergo bilateral reduction mammaplasty, or who required systemic immunodeficiency/immunosuppressive drugs were excluded from our analysis. Complications were classified according to the Clavien-Dindo classification from Grades I to V. A total of 486 patients met the inclusion criteria for the analysis. Patients had an age (mean ± standard deviation) of 39 ± 13 years and a body mass index of 26 ± 4 kg/m2. Median follow-up was 274 days (interquartile range: 90.5-378). The overall rate of complications of reduction mammaplasty was 63%, with the majority of those being Grades I (48%) and II (9%), comprising 92% of all the complications. Operative revisions were required in 6% (1% Grade IIIA and 5% Grade IIIB). There were no complications graded in categories IV and V. Although complications occurred in more than half of the cases, the majority did not require operative reintervention. The Clavien-Dindo classification can classify the severity of complications and serve as a benchmark to compare complication rates between different practices. We believe that grading of complications should distinguish between those that do and do not require operative reinterventions.


Natural killing in immunodeficient patients.
Natural killing (NK) capacity was evaluated in peripheral blood mononuclear cells from 14 patients with well defined primary immunodeficiency disorders and compared with the activity of those cells in antibody-dependent cell-mediated cytotoxicity (ADCC) assays against antibody-coated erythrocyte (killed primarily by monocytes) and lymphoid or tumor targets (killed exclusively by lymphoid cells). A selective inability to lyse antibody-coated lymphocyte targets was observed with cells from patients with x-linked agammaglobulinemia, suggesting the involvement of either a different lymphocyte subpopulation or membrane receptor for NK and ADCC, or that a different functional susceptibility exists for the two types of killing. The only immunodeficiency state in which lymphocyte NK activity was found to be lacking was severe combined immunodediciency disease.


Y chromosome STR allelic and haplotype diversity in a Rwanda population from East Central Africa.
We have analyzed 17 Y-chromosomal STR loci in a population sample of 69 unrelated male individuals of the Rwanda-Hutu population from East Central Africa using an AmpFlSTR® Yfiler™ PCR amplification kit. A total of 62 unique haplotypes were identified among the 69 individuals studied. The haplotype diversity was found to be 0.9970 for this population. The gene diversity ranged from 0.1130 (DYS392) to 0.7722 (DYS385). Comparison of populations in this study with twenty-five other national and global populations using Principal Co-ordinate Analysis (PCA) and phylogenetic molecular analysis using a genetic distance matrix indicates a delineation of all the African populations from other unrelated populations. The results of population pair-wise Fst p values indicate statistically significant differentiation of the Rwandan population when compared with 25 other global populations including four African populations (p=0.0000). Analysis of Molecular Variance (AMOVA) of the Rwanda population with four other African populations indicated a 93% variance within populations and 7% variance among the five populations. A data base search of the 62 haplotypes yielded only one non-African haplotype match, suggesting these haplotypes are unique to the African continent.


Physiotherapist-led treatment for young to middle-aged active adults with hip-related pain: consensus recommendations from the International Hip-related Pain Research Network, Zurich 2018.
The 1st International Hip-related Pain Research Network meeting discussed four prioritised themes concerning hip-related pain in young to middle-aged adults: (1) diagnosis and classification of hip-related pain; (2) patient-reported outcome measures for hip-related pain; (3) measurement of physical capacity for hip-related pain; (4) physiotherapist-led treatment for hip-related pain. Thirty-eight expert researchers and clinicians working in the field of hip-related pain attended the meeting. This manuscript relates to the theme of physiotherapist-led treatments for hip-related pain. A systematic review on the efficacy of physiotherapist-led interventions for hip-related pain (published separately) was conducted and found that strong evidence for physiotherapist-led treatments was lacking. Prior to the meeting, draft consensus recommendations for consideration in the meeting were also developed based on the systematic review. The draft consensus recommendations were presented to all of the meeting participants via email, at least 1 week prior to the meeting. At the meeting, these recommendations were discussed, revised and voted on. Six recommendations for clinical practice and five recommendations for research were included and all gained consensus. Recommendations for clinical practice were that (i) Exercise-based treatments are recommended for people with hip-related pain. (ii) Exercise-based treatment should be at least 3 months duration. (iii) Physiotherapist-led rehabilitation after hip surgery should be undertaken. (iv) Patient-reported outcome measures, measures of physical impairment and measures of psychosocial factors should be used to monitor response to treatment. (v) Physical activity (that may include sport) is recommended for people with hip-related pain. (vi) Clinicians should discuss patient expectations, use shared-decision making and provide education. Recommendations for research were (i) Reporting of exercise programmes: Exercise descriptors such as load magnitude, number of repetitions and sets, duration of whole programme, duration of contractile element of exercise, duration of one repetition, time under tension, rest between repetitions, range of motion through which the exercise is performed, and rest between exercise sessions should be reported. (ii) Research should investigate the optimal frequency, intensity, time, type, volume and progression of exercise therapy. (iii) Research should examine the effect of patient education in people with hip-related pain. (iv) Research should investigate the effect of other treatments used in people with hip-related pain (for example: manual therapy, medications, injections). (v) Research should examine the impact of comorbidities and social determinants on treatment effectiveness in people with hip-related pain. Clinicians and researchers working with young to middle-aged active adults with hip-related pain may use these consensus recommendations to guide, develop, test and implement individualised, evidence-based physiotherapist-led rehabilitation programmes.


Evolution of the syphilis epidemic among men who have sex with men.
Syphilis has existed for millenni, but its epidemiology was only recently linked to men who have sex with men (MSM) after the introduction of penicillin in the 1940s; the syphilis epidemic became concentrated within the MSM community in subsequent decades. The HIV/AIDS epidemic in the 1980s led to a surge of new syphilis cases and revealed the potentiation between HIV and syphilis, as evidenced by a shift in the natural history of neurosyphilis. In response, MSM revolutionised their sexual behaviour by implementing community-driven seroadaptive strategies to stem HIV transmission. The Centers for Disease Control in the US called for the elimination of syphilis in the late 1990s since the rates had fallen sharply but this effort was overtaken by a resurgence of global outbreaks among MSM in the 2000s, many of which were linked to methamphetamine use and sexual networking websites. Syphilis remains highly prevalent today, especially among MSM and individuals infected with HIV, and it continues to present a significant public health conundrum. Innovative syphilis prevention strategies are warranted. MSM engaging in high-risk behaviour such as condomless anal receptive intercourse, sex with multiple partners or recreational drug use should be routinely screened for syphilis infection; they should also be counselled about the limits of seroadaptive behaviours and HIV pre-exposure prophylaxis as they relate to syphilis transmission.