Candidemia in patients with diabetes mellitus: epidemiology and predictors of mortality.
Candidemia is the fourth most frequent nosocomial bloodstream infection in the US. The clinical characteristics and outcome of candidemia in adult patients with diabetes mellitus (DM) have not been reported in the literature. The objective of the study was to determine the epidemiology and determinants of mortality in diabetic patients with candidemia. A retrospective cohort study among diabetic patients with candidemia was carried out at 2 medical centers. The primary outcome was death from any cause after the onset of candidemia until discharge from the hospital. A stepwise logistic regression analysis was performed to determine the predictors of mortality. From June 1995 to June 2003, 87 patients with both DM and candidemia were studied. Candida albicans was the most common (48/87, 55%) and Candida glabrata the second most common isolate of candidemia (18/87, 21%). Overall hospital mortality was 39% (34/87). Logistic regression analysis identified 3 independent determinants of death; Apache II score > or =23 (OR 8.3, 95% CI{2.7, 25.4}, p =0.0002), nosocomial candidemia (OR 10.2, 95% CI{1.1, 97.9}, p = 0.04), and mechanical ventilation (OR 3.6, 95% CI{1.1, 11.2}, p = 0.03). The study demonstrates the emergence of non-albicans species of Candida as major causes of candidemia among diabetic patients. The severity of illness reflected by Apache II was the most significant predictor of mortality among diabetic patients with candidemia.


Performance of relaxed-clock methods in estimating evolutionary divergence times and their credibility intervals.
The rapid expansion of sequence data and the development of statistical approaches that embrace varying evolutionary rates among lineages have encouraged many more investigators to use DNA and protein data to time species divergences. Here, we report results from a systematic evaluation, by means of computer simulation, of the performance of two frequently used relaxed-clock methods for estimating these times and their credibility intervals (CrIs). These relaxed-clock methods allow rates to vary in a phylogeny randomly over lineages (e.g., BEAST software) and in autocorrelated fashion (e.g., MultiDivTime software). We applied these methods for analyzing sequence data sets simulated using naturally derived parameters (evolutionary rates, sequence lengths, and base substitution patterns) and assuming that clock calibrations are known without error. We find that the estimated times are, on average, close to the true times as long as the assumed model of lineage rate changes matches the actual model. The 95% CrIs also contain the true time for >or=95% of the simulated data sets. However, the use of incorrect lineage rate model reduces this frequency to 83%, indicating that the relaxed-clock methods are not robust to the violation of underlying lineage rate model. Because these rate models are rarely known a priori and are difficult to detect empirically, we suggest building composite CrIs using CrIs produced from MultiDivTime and BEAST analysis. These composite CrIs are found to contain the true time for >or=97% data sets. Our analyses also verify the usefulness of the common practice of interpreting the congruence of times inferred from different methods as a reflection of the accuracy of time estimates. Overall, our results show that simple strategies can be used to enhance our ability to estimate times and their CrIs when using the relaxed-clock methods.


Descriptive epidemiology and short-term outcomes of heart failure hospitalisation in rural Haiti.
There is increasing attention to cardiovascular diseases in low-income countries. However, little is known about heart failure (HF) in rural areas, where most of the populations in low-income countries live. We studied HF epidemiology, care delivery and outcomes in rural Haiti. Among adults admitted with HF to a rural Haitian tertiary care hospital during a 12-month period (2013-2014), we studied the clinical characteristics and short-term outcomes including length of stay, inhospital death and outpatient follow-up rates. HF accounted for 392/1049 (37%) admissions involving 311 individuals; over half (60%) were women. Mean age was 58.8 (SD 16.2) years for men and 48.3 (SD 18.8) years for women; 76 (41%) women were <40 years of age. Median length of stay was 10 days (first and second quartiles 7, 17), and inhospital mortality was 12% (n=37). Ninety nine (36%) of the 274 who survived their primary hospitalisation followed-up at the hospital's outpatient clinic, and 18 (6.6%) were readmitted to the same hospital within 30 days postdischarge. Decreased known follow-up (p<0.01) and readmissions (p=0.03) were associated with increased distance between patient residence and hospital. Among the one-quarter (81) patients with echocardiograms, causes of HF included: non-ischaemic cardiomyopathy (64%), right HF (12%), hypertensive heart disease (7%) and rheumatic heart disease (5%). One-half of the women with cardiomyopathy by echocardiogram had peripartum cardiomyopathy. HF is a common cause of hospitalisation in rural Haiti. Among diagnosed patients, HF is overwhelming due to non-atherosclerotic heart disease and particularly affects young adults. Implementing effective systems to improve HF diagnosis and linkage to essential outpatient care is needed to reduce long-term morbidity and mortality.


Clinical supervision: a review of underlying concepts and developments.
This review examines how psychiatric clinical supervision is represented in the psychiatric literature and its relevance for Australasian psychiatry. The literature was first identified then reviewed using Medline and Psychlit, manual searches of relevant journals and personal contact with some key workers in Australia and New Zealand. The predominantly American literature written two to three decades ago reflected the conditions in which psychiatry was practised at that time, largely based in asylums or private offices and informed by the dominant psychoanalytic discourse of that era. These articles, frequently anecdotal and with little empirical support, conceptualized supervision as a developmental process, a syndrome, or a process of identification. They focused substantially on the nature of the relationship between the trainee and supervisor. More recent writers have included trainees' perspectives. They have identified a number of problems with supervision, including role conflicts, uncertainty about boundaries, lack of supervisory training and lack of effective feedback, and have introduced the concepts of adult learning as highly relevant. These concerns, however, have led to little change to date. The implementation by the Royal Australian and New Zealand College of Psychiatrists (RANZCP) of new training by-laws provides an opportunity to define the meaning of supervision in the current clinical context, to undertake research to clarify the key elements in the process, and to evaluate different techniques of supervision.


Association of insulin-degrading enzyme with a 70 kDa cytosolic protein in hepatoma cells.
We have investigated the biosynthesis, subcellular location and expression of insulin-degrading enzyme (IDE). a type-I peroxisomal protease, in semi-permeabilized hepatoma cells using pulse-chase experiments, non-denaturing immunoprecipitation protocols and Northern-blot analyses. In HcpG2 cell lysates prepared from cells radiolabelled with Tran[35S]-label, immunoprecipitated IDE was observed immediately after a 5 min pulse and subsequently declined during chase with t1/2 of approx. 33 h. In addition to the 110 kDa IDE protein, a protein of 70 kDa (p70) was identified in radiolabelled immunoprecipitates when using a monoclonal anti-IDE antibody 9B12 under non-denaturing conditions. This same antibody did not recognize p70 on Western blots of whole-cell lysates nor in sequential immunoprecipitates of immunocomplex-bead eluates from anti-IDE immunoprecipitations. Likewise, cross-linking studies performed on intact HepG2 and H35 hepatoma cells in vivo revealed the existence of a hetero-oligomeric complex of 180 kDa in which IDE and p70 were physically associated. Digitonin-permeabilization studies in normal and 35S-labelled HepG2 cells have defined a predominant association of IDE and its associated protein p70 with cytosol (supernatant); only a minor amount of the protein IDE was detected in peroxisomes (cellular pellet). Immunoprecipitation of IDE from 35S-labelled cell lysates of normal and stably transfected Chinese hamster ovary cells overexpressing IDE failed to detect p70. Treatment of HepG2 cells with clofibrate, a peroxisome proliferator, resulted in a dose-dependent increase of the two human IDE transcripts of 3.6 and 3.2 kb. This effect was not accompanied by a similar change at the protein level, nor by a change in the subcellular location of the proteins IDE and p70. Based on these findings we propose that in hepatoma cells: (1) IDE mainly exists in a stable cytoplasmic pool that is unchanged in cells undergoing peroxisomal proliferation; and (2) p70 binding to IDE may serve to maintain the dual cytosolic and peroxisomal pools of IDE in a stable equilibrium.


Novel layered clustering-based approach for generating ensemble of classifiers.
This paper introduces a novel concept for creating an ensemble of classifiers. The concept is based on generating an ensemble of classifiers through clustering of data at multiple layers. The ensemble classifier model generates a set of alternative clustering of a dataset at different layers by randomly initializing the clustering parameters and trains a set of base classifiers on the patterns at different clusters in different layers. A test pattern is classified by first finding the appropriate cluster at each layer and then using the corresponding base classifier. The decisions obtained at different layers are fused into a final verdict using majority voting. As the base classifiers are trained on overlapping patterns at different layers, the proposed approach achieves diversity among the individual classifiers. Identification of difficult-to-classify patterns through clustering as well as achievement of diversity through layering leads to better classification results as evidenced from the experimental results.


Induction of human tumor-loaded dendritic cells.
A preferred anti-cancer vaccine would be tumor-specific, simple to rapidly construct and safe to administer. It would permit immunization against a spectrum of the tumor's distinctive antigens, without requiring their prior identification. Toward these goals, we describe a modification of standard extracorporeal photopheresis (ECP) which initiates, within a single day, both monocyte-to-dendritic cell (DC) differentiation and malignant cell apoptosis. The transition of monocytes to immature DCs was identified by the expression of cytoplasmic CD83 and membrane CD36 in the absence of membrane CD14 staining, as well as induction of membrane CD83 expression. Differentiating DCs were avidly phagocytic and engulfed apoptotic malignant T cells. Differentiating DCs were capable of stimulating significant proliferation of normal alloreactive lymphocyte responders, indicting increased expression of membrane MHC class II molecules. This approach provides a clinically practical means of developing tumor-loaded cells that have initiated the transition to DCs without the requirement of exogenous cytokines, excessive cellular manipulation or isolation. Construction of DC vaccines using this methodology can be generalized to other diseases and may offer a novel approach for improved cancer immunotherapy.


Solving crimes with hypnosis.
Following a brief review of the literature on hypnosis and memory, this paper overviews the procedures that are used in conducting forensic hypnosis interviews. Ten forensic hypnosis cases are then described. These real world cases are in stark contrast to research done in an artificial laboratory setting where the information to be recalled lacks personal relevance and was not associated with emotionally arousing situations. These cases illustrate how forensic hypnosis can result in obtaining important additional investigative leads which lead to the solving of crimes.


Phytochemical and Pharmacological Properties of Chaenomeles speciosa: An Edible Medicinal Chinese Mugua.
Chaenomeles plants are adapted to diverse ecological zones particularly the temperate areas of Korea, Japan, and China. In China, Chaenomeles speciosa is mainly planted in Chongqing, Anhui, and Hubei provinces. Most of the studies till date have been focused on the anti-inflammatory activities of C. speciosa fractions. The present study aimed to review the maximum literature reported for the presence of various phytochemicals in C. speciosa. In addition, the pharmacological properties of these chemical compounds of this plant shall also be discussed. The extracts of the various parts of the plant are rich in diversity of antioxidants, organic acids, phenolics, terpenoids, and many different phytochemicals that bear strong anticancer, antioxidant, antiviral, antibacterial properties, anti-inflammation, antihyperlipidemic, antihyperglycemic, and anti-Parkinson properties. C. speciosa fruits have broad scope in industry as well as in medicines. Not only the leaves and fruits of C. speciosa plant, but various other parts including roots, seeds, bark twigs, and flowers all have long history of clinical trials in curing many human ailments. However, the maximum accessible data concerning the chemical compositions and their broad pharmacological properties of C. speciosa plant parts is pretty restricted that make it more appealing for in-depth investigations.


Local adaptation and matching habitat choice in female barn owls with respect to melanic coloration.
Local adaptation is a major mechanism underlying the maintenance of phenotypic variation in spatially heterogeneous environments. In the barn owl (Tyto alba), dark and pale reddish-pheomelanic individuals are adapted to conditions prevailing in northern and southern Europe, respectively. Using a long-term dataset from Central Europe, we report results consistent with the hypothesis that the different pheomelanic phenotypes are adapted to specific local conditions in females, but not in males. Compared to whitish females, reddish females bred in sites surrounded by more arable fields and less forests. Colour-dependent habitat choice was apparently beneficial. First, whitish females produced more fledglings when breeding in wooded areas, whereas reddish females when breeding in sites with more arable fields. Second, cross-fostering experiments showed that female nestlings grew wings more rapidly when both their foster and biological mothers were of similar colour. The latter result suggests that mothers should particularly produce daughters in environments that best match their own coloration. Accordingly, whiter females produced fewer daughters in territories with more arable fields. In conclusion, females displaying alternative melanic phenotypes bred in habitats providing them with the highest fitness benefits. Although small in magnitude, matching habitat selection and local adaptation may help maintain variation in pheomelanin coloration in the barn owl.


Remarkable size-spectra stability in a marine system undergoing massive invasion.
The Mediterranean Sea is an invasion hotspot, with non-indigenous species suspected to be a major driver behind community changes. We used size spectra, a reliable index of food web structure, to examine how the influx of Red Sea fishes into the Mediterranean Sea has impacted the indigenous species community. This is the first attempt to use changes in the size spectra to reveal the effect of biological invasions. We used data from trawl catches along Israel's shoreline spanning 20 years to estimate changes in the community size spectra of both indigenous and non-indigenous species. We found that the relative biomass of non-indigenous species increased over the 20 years, especially for small and large species, leading to a convergence with the indigenous species size spectra. Hence, the biomass of indigenous and non-indigenous species has become identical for all size classes, suggesting similar energetic constraints and sensitivities to fishing. However, over this time period the size spectrum of indigenous species has remained remarkably constant. This suggests that the wide-scale invasion of non-indigenous species into the Mediterranean may have had little impact on the community structure of indigenous species.


MRI-based multiscale models for the hemodynamic and structural evaluation of surgically reconstructed aortic arches.
The surgical reconstruction of the aortic arch is necessary in pediatric patients suffering from different types of congenital heart malformations, in particular, coarctation of the aorta. Among the reconstruction techniques used in surgical practice end-to-end anastomosis (E/E), Gore-tex graft interposition (GGI) and Gore-tex patch graft aortoplasty (GPGA) are compared in this study with a control model, employing a computational fluid-structure-interaction scheme. This study analyzes the impact of introducing synthetic materials on aortic hemodynamics and wall mechanics. Three-dimensional (3D) geometries of a porcine aortic arch were derived from magnetic resonance imaging (MRI) images. Inlet conditions were derived from MRI velocimetry. A multiscale approach was used for the imposition of outlet conditions, wherein a lumped parameter net provided an active afterload. Evidence was found that ring-like repairs increased blood velocity, whereas GPGA limited it. Vortex presence was greater and longer lasting in GGI. The highest power losses corresponded to GPGA. GGI had an intermediate effect, while E/E dissipated only slightly more than the control case. Wall stresses peak in a longitudinal strip on the subject's left side of the vessel, particularly in the frontal area. There was a concentration of stress at the suture lines. All surgical techniques performed equally well in restoring physiological pressures.


How should alcohol dependence be treated? The public view.
The aim of this study was to assess public preferences on sources of help and treatment, and perception of prognosis for alcohol dependence. A household survey was administered in 2002 to a probabilistic sample of 500 individuals, all residents of the city of São Paulo, Brazil, with ages ranging from 18 to 65. A vignette in colloquial language describing an individual with alcohol dependence (according to DSM-IV and ICD-10 criteria) was presented together with a structured questionnaire with questions about the vignette. The public considered the help of lay people, self-help groups and psychologists the most useful. Medical professionals were viewed less favourably. The treatments and activities most recommended were psychotherapy and general activities, such as physical activities, keeping the mind busy and attending church services. Medical treatments were seen as more harmful than helpful. The more important determinants were identification of alcohol dependence as mental illness, religion and number of years of school completed. Prognosis with treatment was viewed as favourable. These results may indicate that the public needs to receive more information on the full range of treatments options, especially those related to professional or formal treatment.


Non-linear Physiology and Gene Expression Responses of Harmful Alga Heterosigma akashiwo to Rising CO2.
Heterosigma akashiwo is a raphidophyte known for forming ichthyotoxic blooms. In order to predict the potential impacts of rising CO2 on H. akashiwo it is necessary to understand the factors influencing growth rates over a range of CO2 concentrations. Here we examined the physiology and gene expression response of H. akashiwo to concentrations from 200 to 1000ppm CO2. Growth rate data were combined from this and previous studies and fit with a CO2 limitation-inhibition model that revealed an apparent growth optimum around 600-800ppm CO2. Physiological changes included a significant increase in C:N ratio at ∼800ppm CO2 and a significant decrease in hydrogen peroxide concentration at ∼1000ppm. Whole transcriptome sequencing of H. akashiwo revealed sharp distinctions in metabolic pathway gene expression between ∼600 and ∼800ppm CO2. Hierarchical clustering by co-expression identified groups of genes with significant correlations to CO2 and growth rate. Genes with significant differential expression with CO2 included carbon concentrating mechanism genes such as beta-carbonic anhydrases and a bicarbonate transporter, which may underpin shifts in physiology. Genes involved in cell motility were significantly changed by both elevated CO2 and growth rate, suggesting that future ocean conditions could modify swimming behavior in this species.


The 5'-nucleotidases as regulators of nucleotide and drug metabolism.
The 5'-nucleotidases are a family of enzymes that catalyze the dephosphorylation of nucleoside monophosphates and regulate cellular nucleotide and nucleoside levels. While the nucleoside kinases responsible for the initial phosphorylation of salvaged nucleosides have been well studied, many of the catabolic nucleotidases have only recently been cloned and characterized. Aside from maintaining balanced ribo- and deoxyribonucleotide pools, substrate cycles that are formed with kinase and nucleotidase activities are also likely to regulate the activation of nucleoside analogues, a class of anticancer and antiviral agents that rely on the nucleoside kinases for phosphorylation to their active forms. Both clinical and in vitro studies suggest that an increase in nucleotidase activity can inhibit nucleoside analogue activation and result in drug resistance. The physiological role of the 5'-nucleotidases will be covered in this review, as will the evidence that these enzymes can mediate resistance to nucleoside analogues.


Pharmacokinetics of [14C]-Benzo[a]pyrene (BaP) in humans: Impact of Co-Administration of smoked salmon and BaP dietary restriction.
Benzo[a]pyrene (BaP), a polycyclic aromatic hydrocarbon (PAH), is a known human carcinogen. In non-smoking adults greater than 95% of BaP exposure is through diet. The carcinogenicity of BaP is utilized by the U.S. EPA to assess relative potency of complex PAH mixtures. PAH relative potency factors (RPFs, BaP = 1) are determined from high dose animal data. We employed accelerator mass spectrometry (AMS) to determine pharmacokinetics of [14C]-BaP in humans following dosing with 46 ng (an order of magnitude lower than human dietary daily exposure and million-fold lower than animal cancer models). To assess the impact of co-administration of food with a complex PAH mixture, humans were dosed with 46 ng of [14C]-BaP with or without smoked salmon. Subjects were asked to avoid high BaP-containing diets and a 3-day dietary questionnaire given to assess dietary exposure prior to dosing and three days post-dosing with [14C]-BaP. Co-administration of smoked salmon, containing a complex mixture of PAHs with an RPF of 460 ng BaPeq, reduced and delayed absorption. Administration of canned commercial salmon, containing very low amounts of PAHs, showed the impacts on pharmacokinetics were not due to high amounts of PAHs but rather a food matrix effect.


The effects of metabolic syndrome, obesity, and the gut microbiome on load-induced osteoarthritis.
Metabolic syndrome is characterized by obesity, hyperglycemia, hypertension, insulin resistance, and dyslipidemia. Metabolic syndrome is associated with osteoarthritis (OA), but it is unclear if the association is attributable to increased mechanical loading on joints caused by obesity or other aspects of metabolic syndrome. Here we examined the effects of altered metabolism, obesity, and the gut microbiome on load-induced OA. Cartilage damage was induced through cyclic compressive loading in four groups of adult male mice: Toll-like receptor-5 deficient (TLR5KO) mice that develop metabolic syndrome due to alterations in the gut microbiome, TLR5KO mice submitted to chronic antibiotics to prevent metabolic syndrome (TLR5KOΔMicrobiota), C57BL/6J mice fed a high fat diet to cause obesity (HFD), and untreated C57BL/6J mice (WT). Loading was applied for 2 weeks (n = 10-11/group) or 6 weeks (n = 10-11/group). After 2 weeks of loading, cartilage damage (OARSI score) was not different among groups. After 6 weeks of loading, HFD mice had increased load-induced cartilage damage, while TLR5KO mice had cartilage damage comparable to WT mice. TLR5KOΔMicrobiota mice had less cartilage damage than other groups. HFD mice had elevated serum inflammatory markers. Each group had a distinct gut microbiome composition. Severe obesity increased load-induced cartilage damage, while milder changes in adiposity/metabolic syndrome seen in TLR5KO mice did not. Furthermore, the effects of systemic inflammation/obesity on cartilage damage depend on the duration of mechanical loading. Lastly, reduced cartilage damage in the TLR5KOΔMicrobiota mice suggests that the gut microbiome may influence cartilage pathology.


Qualitative research methods in palliative medicine and palliative oncology--an introduction.
Qualitative research methods can be used as a complement to quantitative methods in palliative research. Possible applications are 1) for the induction of hypotheses, 2) for the development of quality-of-life instruments, 3) for the exploration of complex phenomena and personal experiences, 4) for studying attitudes, 5) for the observation of interactions and 6) for validation of quantitative results. Depending on the context and the research question, different qualitative methods such as hermeneutics, phenomenology, grounded theory or phenomenography might be used. The assumptions, the main steps and the methods are briefly described, with some examples from palliative situations.


[Prevalence of hypertension among obese children and adolescents].
There has been an increase in chronic diseases affecting the population not only in the world but also in Brazil. Hypertension and obesity fit this context, including among early age individuals. This paper aims at investigating the prevalence of hypertension among obese children and adolescents, checking its manifestation in compliance with gender and age. The study involved 129 obese individuals, ages ranging from 7 to 14 years, both sexes. The evaluation consisted of anthropometric measures and blood pressure measurements. The data were then analysed statistically through BioEstat 3.0 program, which indicated the prevalence of hypertension in both sexes (male = 15.8% and female = 26.4%), with no significant differences between each other. The disease was also present in the different age groups, especially among those aged 13 to 14 (52.4%), who were statistically different from other age groups, which, in turn, were not different from each other. This led to the conclusion that hypertension was remarkably present in the investigated population, indicating that the obesity can interfere in the elevation of the children's blood pressure and adolescents.


Trinuclear complexes of palladium(ii) with chalcogenated N-heterocyclic carbenes: catalysis of selective nitrile-primary amide interconversion and Sonogashira coupling.
3-Methyl-1-(2-(phenylthio/seleno)ethyl)-1H-benzo[d]imidazol-3-ium iodide (L1/L2), a precursor of sulfated/selenated N-heterocyclic carbene, was synthesized by the reaction of benzimidazole with 1,2-dichloroethane followed by treatment with PhS/SeNa and MeI. The reaction of L1/L2 with Ag2O followed by treatment with [Pd(CH3CN)2Cl2] (metal to ligand ratio 3 : 2), i.e. transmetallation, resulted in trinuclear palladium(ii) complexes [Pd3(L1/L2-HI)2(CH3CN)Cl6] (1-2). The complexes were characterized with 1H, 13C{1H} and 77Se{1H} NMR (2 only), elemental analyses, HR-MS and single-crystal X-ray diffraction. The geometry of three Pd atoms in each complex is nearly square planar. The Pd-S/Se, Pd-C, Pd-N and Pd-Cl bond distances (Å) in 1/2 are 2.3179(19)/2.4312(10), 1.968(7)/1.952(4), 2.073(8)/2.079(4) and 2.2784(19)-2.298(2)/2.292(2)-2.3003(15), respectively. In both the complexes, all Cl are trans to each other. For the central Pd atom, two benzimidazole rings are also trans to each other. The C-HCl non-covalent interactions result in a three-dimensional network. The moisture and air insensitive trinuclear Pd(ii) complexes 1 and 2 are thermally stable and efficient as a catalyst for nitrile-amide interconversion and amine-free Sonogashira C-C coupling (in the presence of CuI). The optimum temperature is 80 °C for the interconversion and 110 °C for the coupling. The catalytic protocols are applicable to both aliphatic and aromatic amides/nitriles. The optimum catalyst loading is 1 mol% for the C-C coupling and 0.5 to 1 mol% for the interconversion. K2CO3 as a base gives the best result for Sonogashira C-C coupling. In the conversion of nitriles to amides, the formation of an acid was not detected. After using once, 1/2 can carry out the conversion of ten fresh lots of nitriles to amides with almost the same efficiency. The real catalytic species for the interconversion and coupling appear to be based on Pd(ii) and Pd(0), respectively.


Ultrasound-guided port-a-cath positioning with the new one-shoot technique: thoracic complications.
Port-a-cath catheterization is often required for those patients who need long-term therapies (malnutrition, neoplasm, renal failure, other severe diseases). The use of ports for a wide range of indications is not exempt from complications. Ultrasound-guided central venous catheterization (CVC) is a safe and fast technique for the introduction of the catheter inside a central vein. This retrospective study reports our experience with US-guided CVC in patient eligible for port-a-cath implantation. From January 2007 to March 2017, 108 CVC (out of 770 procedures), were positioned using an ultrasound guide, with the new "one-shoot technique" (group 1) and the classic Seldinger technique (group 2). One-shoot techniques showed a reduced operative time, in comparison to Seldinger technique, with a negligible minor complication rate. No major complication were evidenced. CVC is a safe procedure, although not free from complications. Ultrasonography enhances safety of the procedure by decreasing puncture attempts and complications; it is helpful in patients with vascular anatomical variations, with no visualized or palpable landmarks or for patients with coagulation disorders.


Effects of the Brazilian tax reform plans on the tobacco market.
There has been an intense debate in the Brazilian National Congress on how to reform the country's tax system on consumption. This paper investigates the effects of the tax reform under the Constitutional Amendment Bill 45/2019 on cigarette prices, consumption and tax collection. The reform will introduce a new goods and services tax (GST) and tobacco excise tax (TET). The micro data from the National Household Sample Survey (PNAD) of 2008 and the National Health Survey (PNS) of 2013 are inputs in the simulation in order to determine the smoking behaviour and consumer responses to price changes as accurately as possible across the different Brazilian states. We developed three scenarios for the tobacco tax reform and their effects on cigarette prices, smoking behaviour and tax collection. We also estimate the size of the illicit cigarette market by Brazilian state and simulate the impacts of a 10% reduction in its market share. Overall, we found that a GST of 27% and a TET of either 51%, 56% or specific 3.89 BRL per pack would lead to considerably higher cigarette prices, lower cigarette consumption and, above all, an increase of cigarette tax collection between 8% and 27% depending on the state. A discretionary 10% reduction in the illicit market would add about 8.5% of extra tax collection per year to the country. The simulated scenarios demonstrated that, to keep the cigarette prices at least at the same level as those in the current tax scheme, TET should be no less than 77.85% of the retail price. This means that any politically feasible tax reform should result in higher cigarette prices and a reduction in cigarette consumption. Considering the nationwide effect, in all scenarios, the total increase in tobacco tax revenue is around 8.5% or 1.5 billion BRL per year. This extra revenue is highly desirable in an environment of chronic fiscal imbalance and the COVID-19 pandemic crisis.


Linguistic description of relative positions in images.
Fuzzy set methods have been used to model and manage uncertainty in various aspects of image processing, pattern recognition, and computer vision. High-level computer vision applications hold a great potential for fuzzy set theory because of its links to natural language. Linguistic scene description, a language-based interpretation of regions and their relationships, is one such application that is starting to bear the fruits of fuzzy set theoretic involvement. In this paper, we are expanding on two earlier endeavors. We introduce new families of fuzzy directional relations that rely on the computation of histograms of forces. These families preserve important relative position properties. They provide inputs to a fuzzy rule base that produces logical linguistic descriptions along with assessments as to the validity of the descriptions. Each linguistic output uses hedges from a dictionary of about 30 adverbs and other terms that can be tailored to individual users. Excellent results from several synthetic and real image examples show the applicability of this approach.


Dissociation of avian salt gland: separation procedures and characterization of dissociated cells.
A procedure for dissociation of the nasal salt glands of the domestic duck, Anas platyrhynchos, into suspensions of individual cells has been developed. This technique employs enzymatic digestion with collagenase, hyaluronidase, and chymotrypsin; divalent cation chelation with EDTA; and gentle mechanical dispersion. Average cellular yields of 39 and 26% based on DNA recovered were obtained from the glands of freshwater- and saline-adapted ducks, respectively. Epithelial secretory cells comprised 60-80% of the cell suspensions with the remainder of the populations consisting of endothelial cells, fibroblasts, and blood cells. The dissociated cells were viable as judged by trypan blue exclusion (80-100%, maintenance of ultrastructural integrity, and retention of responsiveness to secretagogues and metabolic inhibitors. Methacholine chloride (0.5 mM) stimulated oxygen consumption by suspensions of both freshwater- and saline-adapted cells, whereas ouabain (0.05 mM) abolished the methacholine-stimulated respiratory response. These cell suspensions provide a promising system for the in vitro study of secretory mechanisms in the avian salt gland.


Infantile swallowing: surgical meaning.
The aim of this retrospective work on 30 patients affected by dento-skeletal III class and Infantile Swallowing (I.S.), treated between 2006 and 2014, is to analyze the causes of eventual surgical relapses and to underline the consequences of untreated Infantile Swallowing. Infantile Swallowing can be correlated with a relapse in the surgical treatment and therefore requires investigation and treatment beforehand any surgical approach. Between the 2006 and 2014 a number of 30 patients affected by III dento-skeletal class and I.S. were treated with a pre-surgery protocol, surgery and a post-surgery protocol. The surgical protocol consisted of: Le Fort I and Bilateral Sagittal Split Osteotomy (BSSO). Out of the 30 patients 3 received previous surgical treatment in another locality without going through pre- and post-surgery protocols for I.S., and they presented themselves about 14 months post-surgery to the first examination having a relapse of the dento-skeletal III class. No skeletal relapse has ever been recorded today in the 30 patients treated with pre and post-surgery protocols and Le Fort I and BSSO osteotomy. Relapses are commonly attributed to surgical errors or inappropriate surgical program only; in our analysis we observed that the 100% of relapses were due to an untreated or undiagnosed I.S. that caused derangement of bicortical screw and incorrect bony formation and consequently a sort of an improper "distraction osteogenesis".


Uranium stabilization of c28: a tetravalent fullerene.
Laser vaporization experiments with graphite in a supersonic cluster beam apparatus indicate that the smallest fullerene to form in substantial abundance is C(28). Although ab initio quantum chemical calculations predict that this cluster will favor a tetrahedral cage structure, it is electronically open shell. Further calculations reveal that C(28) in this structure should behave as a sort of hollow superatom with an effective valence of 4. This tetravalence should be exhibited toward chemical bonding both on the outside and on the inside of the cage. Thus, stable closed-shell derivatives of C(28) with large highest occupied molecular orbital-lowest unoccupied molecular orbital gaps should be attainable either by reacting at the four tetrahedral vertices on the outside of the C(28) cage to make, for example, C(28)H(4), or by trapping a tetravalent atom inside the cage to make endothedral fullerenes such as Ti@C(28). An example of this second, inside route to C(28) stabilization is reported here: the laser and carbon-arc production of U@C(28).


[The role of Vavilov-Cherenkov radiation in visual sensations induced by protons].
The sensitivity of human eyes to ionizing particles and the mechanism of their detection were studied. The experimental data obtained by protons with very different intensity of Cherenkov radiation in the vitreous humour (460 and 1850 MeV) showed that Cherenkov radiation plays an essential role in the visual sensation.


Behaviors of highly professional resident physicians.
Unprofessional behaviors in medical school predict high stakes consequences for practicing physicians, yet little is known about specific behaviors associated with professionalism during residency. To identify behaviors that distinguish highly professional residents from their peers. Comparative study of 148 first-year internal medicine residents at Mayo Clinic from July 1, 2004, through June 30, 2007. Professionalism as determined by multiple observation-based assessments by peers, senior residents, faculty, medical students, and nonphysician professionals over 1 year. Highly professional residents were defined as those who received a total professionalism score at the 80th percentile or higher of observation-based assessments on a 5-point scale (1, needs improvement; 5, exceptional). They were compared with residents who received professionalism scores below the 80th percentile according to In-Training Examination (ITE) scores, Mini-Clinical Evaluation Exercise (mini-CEX) scores, conscientious behaviors (percentage of completed evaluations and conference attendance), and receipt of a warning or probation from the residency program. The median total professionalism score among highly professional residents was 4.39 (interquartile range [IQR], 4.32-4.44) vs 4.07 (IQR, 3.91-4.17) among comparison residents. Highly professional residents achieved higher median scores on the ITE (65.5; IQR, 60.5-73.0 vs 63.0; IQR, 59.0-67.0; P = .03) and on the mini-CEX (3.95; IQR, 3.63-4.20 vs 3.69; IQR, 3.36-3.90; P = .002), and they completed a greater percentage of required evaluations (95.6%; IQR, 88.1%-99.0% vs 86.1%; IQR, 70.6%-95.0%; P < .001) compared with residents with lower professionalism scores. In multivariate analysis, a professionalism score in the top 20% of residents was independently associated with ITE scores (odds ratio [OR] per 1-point increase, 1.07; 95% confidence interval [CI], 1.01-1.14; P = .046), mini-CEX scores (OR, 4.64; 95% CI, 1.23-17.48; P = .02), and completion of evaluations (OR, 1.07; 95% CI, 1.01-1.13; P = .02). Six of the 8 residents who received a warning or probation had total professionalism scores in the bottom 20% of residents. Observation-based assessments of professionalism were associated with residents' knowledge, clinical skills, and conscientious behaviors.


Serotonergic Regulation of Prefrontal Cortical Circuitries Involved in Cognitive Processing: A Review of Individual 5-HT Receptor Mechanisms and Concerted Effects of 5-HT Receptors Exemplified by the Multimodal Antidepressant Vortioxetine.
It has been known for several decades that serotonergic neurotransmission is a key regulator of cognitive function, mood, and sleep. Yet with the relatively recent discoveries of novel serotonin (5-HT) receptor subtypes, as well as an expanding knowledge of their expression level in certain brain regions and localization on certain cell types, their involvement in cognitive processes is still emerging. Of particular interest are cognitive processes impacted in neuropsychiatric and neurodegenerative disorders. The prefrontal cortex (PFC) is critical to normal cognitive processes, including attention, impulsivity, planning, decision-making, working memory, and learning or recall of learned memories. Furthermore, serotonergic dysregulation within the PFC is implicated in many neuropsychiatric disorders associated with prominent symptoms of cognitive dysfunction. Thus, it is important to better understand the overall makeup of serotonergic receptors in the PFC and on which cell types these receptors mediate their actions. In this Review, we focus on 5-HT receptor expression patterns within the PFC and how they influence cognitive behavior and neurotransmission. We further discuss the net effects of vortioxetine, an antidepressant acting through multiple serotonergic targets given the recent findings that vortioxetine improves cognition by modulating multiple neurotransmitter systems.


Splenosis mimicking metastases from breast carcinoma.
The case history is presented of a patient with breast cancer who was extensively investigated for presumed hepatic metastases, which were finally diagnosed as splenosis, the heterotopic autotransplantation of splenic tissue after traumatic rupture of the spleen. This case history highlights the importance of obtaining a pathological diagnosis prior to labelling a patient as having metastatic disease. This is especially important for patients who have an unusual pattern or appearance of metastases or for whom the risk of metastatic disease is presumed to be minimal.


Risk of IDDM in children of diabetic mothers decreases with increasing maternal age at pregnancy.
Offspring of women with insulin-dependent diabetes mellitus (IDDM) have a significantly lower risk of IDDM than the offspring of men with IDDM. Furthermore, a negative association of the risk of IDDM in the offspring with maternal age at delivery has been reported. This study tested the association with maternal age in an independent set of families (n = 103) in which the mother had at least one pregnancy before and after the onset of IDDM. In the 304 offspring, the mean +/- SE risk of IDDM by age 20 was 6.0 +/- 2.4% for those born at maternal ages less than 25 yr, whereas, the risk was significantly lower (0.7 +/- 0.7%) for those born at older maternal ages (P = 0.03). These 304 offspring were combined with a sample of 1391 offspring previously reported for a multivariate analysis of other factors related to pregnancy. In the combined analysis, the risk of IDDM in offspring born at maternal ages greater than 25 yr was one-fifth that for offspring born to younger mothers. The risk of IDDM in the offspring was not significantly related to birth order, mother's age at first pregnancy, or the interval between pregnancies for subsequent ones. The risk for the children born before the mother's onset of diabetes was higher than that for those exposed in utero to her diabetes, but the difference did not reach statistical significance. In conclusion, although genetic factors are important determinants of susceptibility to IDDM, exposure to maternal diabetes protects offspring from IDDM during the first 2 decades of life.(ABSTRACT TRUNCATED AT 250 WORDS)


[Mechanical ventilation in neuromuscular diseases: do not start too early, but certainly not too late].
Three patients had chronic respiratory disorders: a 42-year-old man with glycogenosis type II was tired, had headaches, poor pulmonary function values and, according to the arterial blood gas values, hypercapnia; a man aged 24 with Duchenne's muscular dystrophy had variable moderate dyspnoea with hypoxia and hypercapnia, and a man aged 64 years with an mitochondrial myopathy complained of dyspnoea and headache but had good blood gas values. The symptoms and abnormalities of the first patient were suppressed by nocturnal ventilatory support through a nasal mask system, the second preferred to refrain from ventilatory support and died a few weeks later and the symptoms of the third patient decreased without ventilatory support. Assessing a ventilatory disorder in patients with a neuromuscular disease is not always simple. Symptoms suggestive of nocturnal hypoventilation may occur in patients without respiratory insufficiency. It is also possible for patients with chronic respiratory insufficiency to be free of symptoms. Determinations of the arterial blood gas values are the most reliable method. Since normal daytime values do not exclude a nocturnal respiratory insufficiency, it is advisable in case of suspicion of nocturnal hypoventilation to measure the arterial blood gas values at night, as well. Nocturnal pulse oximetry does not always adequately reflect the degree of hypoventilation. In view of the positive effects of assisted respiration, adequate diagnostic examinations and early referral to a centre for home mechanical ventilation are advisable.


Effects of central activation of serotonin 5-HT2A/2C or dopamine D 2/3 receptors on the acute and repeated effects of clozapine in the conditioned avoidance response test.
Acute administration of clozapine (a gold standard of atypical antipsychotics) disrupts avoidance response in rodents, while repeated administration often causes a tolerance effect. The present study investigated the neuroanatomical basis and receptor mechanisms of acute and repeated effects of clozapine treatment in the conditioned avoidance response test in male Sprague-Dawley rats. 2,5-dimethoxy-4-iodo-amphetamine (DOI, a preferential 5-HT2A/2C agonist) or quinpirole (a preferential dopamine D2/3 agonist) was microinjected into the medial prefrontal cortex (mPFC) or nucleus accumbens shell (NAs), and their effects on the acute and long-term avoidance disruptive effect of clozapine were tested. Intra-mPFC microinjection of quinpirole enhanced the acute avoidance disruptive effect of clozapine (10 mg/kg, sc), while DOI microinjections reduced it marginally. Repeated administration of clozapine (10 mg/kg, sc) daily for 5 days caused a progressive decrease in its inhibition of avoidance responding, indicating tolerance development. Intra-mPFC microinjection of DOI at 25.0 (but not 5.0) μg/side during this period completely abolished the expression of clozapine tolerance. This was indicated by the finding that clozapine-treated rats centrally infused with 25.0 μg/side DOI did not show higher levels of avoidance responses than the vehicle-treated rats in the clozapine challenge test. Microinjection of DOI into the mPFC immediately before the challenge test also decreased the expression of clozapine tolerance. Acute behavioral effect of clozapine can be enhanced by activation of the D2/3 receptors in the mPFC. Clozapine tolerance expression relies on the neuroplasticity initiated by its antagonist action against 5-HT2A/2C receptors in the mPFC.


The inflation response of the posterior bovine sclera.
An in vitro inflation test method was developed to characterize the mechanical behavior of the bovine posterior sclera. The method used digital image correlation to provide a spatially resolved, full-field deformation map of the surface of the posterior sclera in response to controlled pressurization. A series of experiments were performed in the range of 2-6 kPa (15-45 mmHg) to characterize the load-unload displacement response at various pressure rates and the time-dependent displacement response at different applied pressures. The magnitude of the displacement was largest in the peripapillary region, mainly between the apex and the optic nerve head. Further, the results showed that bovine scleral tissue exhibited nonlinear and viscoelastic behavior characterized by a rate-dependent displacement response, hysteresis during unloading and creep. The creep rate was insensitive to the applied pressure, suggesting that the tissue can be modeled as a quasilinear viscoelastic material in the physiological pressure range of 2-6 kPa.


An Ex Vivo Choroid Sprouting Assay of Ocular Microvascular Angiogenesis.
Pathological choroidal angiogenesis, a salient feature of age-related macular degeneration, leads to vision impairment and blindness. Endothelial cell (EC) proliferation assays using human retinal microvascular endothelial cells (HRMECs) or isolated primary retinal ECs are widely used in vitro models to study retinal angiogenesis. However, isolating pure murine retinal endothelial cells is technically challenging and retinal ECs may have different proliferation responses than choroidal endothelial cells and different cell/cell interactions. A highly reproducible ex vivo choroidal sprouting assay as a model of choroidal microvascular proliferation was developed. This model includes the interaction between choroid vasculature (EC, macrophages, pericytes) and retinal pigment epithelium (RPE). Mouse RPE/choroid/scleral explants are isolated and incubated in growth-factor-reduced basal membrane extract (BME) (day 0). Medium is changed every other day and choroid sprouting is quantified at day 6. The images of individual choroid explant are taken with an inverted phase microscope and the sprouting area is quantified using a semi-automated macro plug-in to the ImageJ software developed in this lab. This reproducible ex vivo choroidal sprouting assay can be used to assess compounds for potential treatment and for microvascular disease research to assess pathways involved in choroidal micro vessel proliferation using wild type and genetically modified mouse tissue.


Aetiological stratification as a conceptual framework for gene-by-environment interaction research in psychiatry.
It has been argued that gene-by-environment interactions (G × E) research is unlikely to progress knowledge about psychiatric disorders, in contrast to genome-wide association (GWA) studies. However, G × E approaches are not alternatives for gene-hunting but a way to identify genetic and biological mechanisms within subgroups of patients exposed to a similar aetiological (environmental) factor via a process of 'aetiological stratification'. This is important as diagnostic categories targeted by GWA studies are inherently heterogeneous and lack biological validity. Aetiological stratification builds on examining possible phenotypic and/or molecular specificity associated with exposure to the environmental factor across multiple potentially relevant disorders, combined with efforts to identify an underlying biological substrate. G × E hypotheses within this framework investigate (1) which genes influence the degree to which individuals develop identified biological alterations that link environmental exposure to specific phenotypic and/or molecular characteristics within or across psychiatric disorders and (2) which genes are implicated in determining the development of psychopathology once this biological alteration has been brought about. As gene-hunting is not a goal in itself, the examination of pathway and/or polygenic risk scores may be more informative than the examination of individual markers, at the same time reducing multiple testing and the associated risk of spurious findings.


An Intersensory Interaction Account of Priming Effects-and Their Absence.
Psychological researchers have found that exposures to stimuli (primes) can subsequently influence people's behavior by pathways that would seem to be quite remote. For example, people exposed to words associated with older adults may walk more slowly. Recently priming studies, particularly those showing dramatic effects on social behavior, have been under scrutiny because of the unreliability of empirical results. In this article, we shed light on the issue by describing a general model of intersensory interaction, in which two or more sources of information provide an estimate or "bid" on a property of the world, with the perceptual outcome being a weighted combination of the bids. When it is extended by adding bids that stem from memory or inference, the model identifies systematic factors that might undermine priming, including random variation in estimates, contextual influences on memory retrieval and inference, competition among information sources, and cognitive control. These factors are not only explanatory but are predictive of when priming effects can be expected. Our hope is that by promoting the understanding of underlying processes that may explain how primes can influence behavior, the bidding model and the general approach that it represents offer novel insights into the hotly debated area of priming research.


The osmotic properties of sulphoethyl-sephadex. A model for cartilage.
1. Observations are reported on the variation of the swelling of sulphoethyl-Sephadex C-50 and C-25, and of the partition of NaCl between solution and gel, with the concentration of NaCl. 2. The results were interpreted in terms of Manning's (1969) treatment of the interactions between polyionic polymers and simple electrolytes and of Flory's (1953) treatment of the swelling of gels. 3. The results indicate net inner osmotic pressures as high as 3.6x10(5)Pa (140 mosmolar=3.6x10(5)N/m(2)) in 0.15m-NaCl. 4. It is suggested that cartilage may have net inner osmotic pressure of the order of 10(5)Pa.


Persistent back pain due to malignant lymphadenopathy.
Back pain is a common problem in rheumatology clinics and has a wide differential diagnosis. Ten young patients are described with the syndrome of persistent back pain, severe enough to prevent sleep, and characteristically eased by sitting forwards, which accompanies malignant retroperitoneal lymphadenopathy. Spinal movements and x rays are typically normal. Repeated thorough examinations are required to detect superficial adenopathy or testicular swellings. Ultrasound scanning usually reveals the nodes, which can also be demonstrated by computed tomographic (CT) scanning. These young patients have a variety of cancers, many of which can be cured, so increased awareness of this syndrome could save lives.


Intelligent Protein Design and Molecular Characterization Techniques: A Comprehensive Review.
In recent years, the widespread application of artificial intelligence algorithms in protein structure, function prediction, and de novo protein design has significantly accelerated the process of intelligent protein design and led to many noteworthy achievements. This advancement in protein intelligent design holds great potential to accelerate the development of new drugs, enhance the efficiency of biocatalysts, and even create entirely new biomaterials. Protein characterization is the key to the performance of intelligent protein design. However, there is no consensus on the most suitable characterization method for intelligent protein design tasks. This review describes the methods, characteristics, and representative applications of traditional descriptors, sequence-based and structure-based protein characterization. It discusses their advantages, disadvantages, and scope of application. It is hoped that this could help researchers to better understand the limitations and application scenarios of these methods, and provide valuable references for choosing appropriate protein characterization techniques for related research in the field, so as to better carry out protein research.


Transdermal nitroglycerin as an adjuvant to patient-controlled morphine analgesia after total knee arthroplasty.
Nitroglycerin (NTG) has been shown to be a useful adjunct for pain treatment without increasing adverse side effects. The effects of NTG on postoperative morphine consumption after knee replacement were evaluated. After undergoing total knee replacement, patients receiving patient-controlled morphine analgesia were randomly assigned to receive either an NTG or a placebo patch. The blinded investigator assessed each patient using a visual analogue scale at rest and while moving, as well as the patient's morphine requirements, sedation score, sleep quality, nausea and vomiting, vital signs and postoperative bleeding. Two of the patients in the NTG group suffered postoperative myocardial infarctions after removal of the patch. Because of these two serious adverse effects, the study was stopped prematurely. In the subset of patients studied, NTG conferred no advantage over placebo in pain control (visual analogue scale at rest or during movement) and in satisfaction scores. The use of NTG patches conferred no advantage over the use of placebo in patients receiving patient-controlled morphine analgesia after total knee replacement. Two myocardial infarcts occurred in this group. Therefore, the safety of postoperative NTG patch use for pain control must be questioned.


Discriminative evaluative conditioning in the long-term after severe accidental injury.
Impairments in classical fear conditioning and deficits in discriminative learning are observed in posttraumatic stress disorder (PTSD). However, it is unknown whether similar impairments can be found with types of discriminative learning other than classical conditioning, such as evaluative conditioning (EC), in which the valence of a stimulus can be transferred to other stimuli. In this study, we investigated whether EC is also influenced by traumatic experiences independently of presence of PTSD. We tested 14 accident survivors with remitted PTSD, 14 survivors without PTSD, and 16 non-trauma controls. We used behavioral measures, psychophysiological indicators, and subjective ratings for tasks. General effects of learning were observed across groups and conditioning/extinction. Trauma controls had slower reaction times (RTs) to the aversive conditioned stimulus compared to appetitive conditioned and neutral stimuli, as well as slower RTs and increased accuracy during conditioning than during extinction. Remitted PTSD participants showed opposite results, demonstrating decreased accuracy and slower RTs during conditioning as compared to during extinction. No discriminative effect was found in the non-trauma controls and the remitted PTSD participants. These results suggest that a traumatic experience influences EC, and that this influence differs between individuals who have and have not developed PTSD after traumatic exposure.


Utilizing an iron(iii)-chelation masking strategy to prepare mono- and bis-functionalized aerobactin analogues for targeting pathogenic bacteria.
A direct and selective method for the functionalization of aerobactin has been described. Selectivity was achieved by masking the functioning carboxylate via iron-chelation, leaving the two remaining carboxylates for direct modification. Both mono- and bis-functionalized aerobactin effectively targeted pathogenic bacteria, showing a facile method with prospective applications.


[A case of thoracic actinomycosis].
A case of thoracic actinomycosis manifest as round shadow in the lung is described. Diagnosis was based on the presence of actinomycetes in a transthoracic lung biopsy sample. Treatment for 3 months resulted in recovery. No relapse was documented during 1 year follow-up period.


Species delimitation using dominant and codominant multilocus markers.
We propose a method for delimiting species based on dominant or codominant multilocus data using Gaussian clustering with a noise component for outliers. Case studies show that provisional species delimited using Gaussian clustering based on dominant multilocus data correspond well with provisional species delimited based on other data. However, the performance of Gaussian clustering in delimiting species based on few codominant markers was only moderate. Species represented by few individuals are usually included in the noise component because clusters are difficult to recognize with limited data. As alternative methods, we evaluated two model-based clustering methods originally proposed to infer population structure and assign individuals to populations based on the assumption of Hardy-Weinberg equilibrium within populations, namely STRUCTURE and STRUCTURAMA, as well as the "fields for recombination" approach. The latter resulted in lumping all individuals of each data set with codominant markers together, and whereas STRUCTURE often provides no decision about the number of clusters, STRUCTURAMA usually yields correct or almost correct numbers of clusters. The classification success of STRUCTURAMA analyses based on codominant markers was very good, but its performance with dominant markers was less consistent. Based on the classification success of the different methods for delimiting species with dominant and codominant multilocus markers in the case studies, we recommend using Gaussian clustering for data sets with dominant markers and STRUCTURAMA for data sets with codominant markers.


Hepatotoxic activity of Campylobacter jejuni.
Hepatotoxic factor(s) were isolated from whole-cell lysates of Campylobacter jejuni GIFU 8734 and purified by chromatography. A single intravenous injection of 10 micrograms of this factor reproducibly produced hepatitis in mice, as determined by histology and liver function tests. The hepatic lesions were very similar to those evoked by C. jejuni infection. Tissue-culture studies with mouse hepatocytes demonstrated that low concentrations of the factor caused release of hepatic enzymes into the medium without appreciable cytolysis. High concentrations of the factor induced cytolysis. These effects were neutralised by antiserum to the factor, but not by antisera to the lipopolysaccharide of C. jejuni or to the heat-labile enterotoxin of Escherichia coli. Among 20 clinical isolates of C. jejuni, only four evoked hepatitis in mice and produced the hepatotoxic factor.


Families and the natural history of blood pressure. A 27-year follow-up study.
Previous studies on familial aggregation of blood pressure (BP) have reported data on family history of hypertension. Data on actual parental BP levels and the subsequent natural history of BP in their offspring are scarce. In a population-based study with 596 children aged 5 to 19 years, cardiovascular risk factors were measured annually from 1975 through 2002. Parental data were obtained at baseline. Repeated BP measurements were studied as a function of tertiles of age-adjusted BP measured in their parents at baseline. Systolic BP during follow-up was higher in offspring whose parents were both in the highest tertile compared with children whose parents were not in the highest tertile (difference 2.7 mm Hg, 95% confidence interval 0.2 to 5.2). Having both parents in the highest tertile of diastolic BP resulted in a substantially higher diastolic BP ranging from 1.9 mm Hg at age 15 years to 8.5 mm Hg at age 45 years. These differences were adjusted for age, sex, body mass index, total serum cholesterol, smoking habits, and alcohol consumption. The results of this study indicate that actual parental BP is an important predictor of BP development from childhood into young adulthood. This is important when constituting cardiovascular risk profiles for children and young adults.


Photocrosslinking of DNA using 4-methylpyranocarbazole nucleoside with thymine base selectivity.
This report describes a novel photocrosslinker, 4-methylpyranocarbazole nucleoside (MEPK), that can be induced to crosslink using visible light. Previously, we reported a visible light-responsive artificial nucleic acid, pyranocarbazole nucleoside (PCX). MEPK can selectively photocrosslink to thymine bases in a complementary nucleic acid strand. It was synthesized by introducing a methyl group at the 4-position of PCX, and it can differentiate between thymine and cytosine. The previously reported visible light-responsive artificial nucleic acid PCX has a low synthetic yield. MEPK was synthesized by Pechmann condensation which suppressed by-product formation, making the synthesis more efficient, and resulting in a higher yield than that of PCX. MEPK is expected to have practical applications as a photocrosslinker that can be manipulated with visible light and that selectively targets thymine bases.


Pre-diagnostic serum levels of inflammation markers and risk of ovarian cancer in the prostate, lung, colorectal and ovarian cancer (PLCO) screening trial.
Pro-inflammatory mechanisms may explain the increased ovarian cancer risk linked to more lifetime ovulations, endometriosis, and exposure to talc and asbestos, as well as decreased risk with non-steroidal anti-inflammatory drugs. Limited data are available to estimate ovarian cancer risk associated with levels of circulating inflammatory markers. We conducted a nested case-control study within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Pre-diagnostic serum levels of 46 inflammation-related biomarkers (11 with a priori hypotheses; 35 agnostic) were measured in 149 incident ovarian cancer cases and 149 matched controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression and adjusted for identified covariates. Increased ovarian cancer risk was associated with elevated levels of C-reactive protein (CRP) [tertile (T)3 vs. T1: OR (95% CI) 2.04 (1.06-3.93), p-trend=0.03], interleukin (IL)-1α [detectable vs. undetectable: 2.23 (1.14-4.34)] and tumor necrosis factor alpha (TNF-α) [T3 vs. T1: 2.21 (1.06-4.63), p-trend=0.04]. Elevated IL-8 was non-significantly associated with risk [T3 vs. T1: 1.86 (0.96-3.61), p-trend=0.05]. In analyses restricted to serous ovarian cancer (n=83), the associations with CRP and IL-8 remained or strengthened [CRP T3 vs. T1: 3.96 (1.14-11.14), p-trend=0.008; IL-8 T3 vs. T1: 3.05 (1.09-8.51), p-trend=0.03]. Elevated levels of CRP and TNF-α remained positively associated with ovarian cancer risk in analysis restricted to specimens collected at least 5years before diagnosis (n=56). These results suggest that CRP, IL-1α, IL-8, and TNF-α are associated with increased risk of subsequently developing ovarian cancer.


Analysis of the social consequences and value implications of the Everyday Discrimination Scale (EDS): implications for measurement of discrimination in health research.
The Everyday Discrimination Scale (EDS) is one of the most widely used measures of discrimination in health research, and has been useful for capturing the impact of discrimination on health. However, psychometric analysis of this measure has been predominantly among Black Americans, with limited examination of its effectiveness in capturing discrimination against other social groups. This paper explores the theoretical and historical foundations of the EDS, and draws on the analytic framework of Messick's theory of unified validity to examine the effectiveness of the EDS in capturing diverse experiences of discrimination. Encompassing both social consequences and value implications, Messick's unified validity contends that psychometric evaluation alone is insufficient to justify instrument use or ensure social resonance of findings. We argue that despite the robust psychometric properties and utility in addressing anti-Black race-related discrimination, the theoretical foundations and research use of the EDS have yet to respond to current discrimination theory, particularly intersectionality. This paper concludes with guidance for researchers in using the EDS in health research across diverse populations, including in data collection, analysis, and presentation of findings.


Online availability of dextropropoxyphene over time, 2003-2005.
Online pharmacies are increasingly common, and some of them have been reported to inappropriately supply prescription-only medicines. Dextropropoxyphene-containing compounds are addictive and frequently implicated in fatalities occurring in the United Kingdom. We aimed here at assessing the online availability of dextropropoxyphene for purchase over a time-span of 2 years (September 2003-August 2005). A Google search was run in September 2003 using different sets of keywords and the first 100 links identified were thoroughly assessed. In March 2005, the same e-pharmacies websites identified at baseline were accessed again and a Google search using the same sets of keywords previously used was run as well. Furthermore, a specialized search with Froogle was run both in March and August 2005. Although an illegal practice in most countries, a number of websites willing to sell the compound internationally were identified at the time of the baseline search. In March 2005, the Google search for vending websites identified 361,000 links, compared with 40,000 18 months before. Only half of dextropropoxyphene vending e-pharmacies were still active by March 2005 but, at that point in time, access to Froogle apparently facilitated the task of online dextropropoxyphene purchase. By August 2005, however, the same Froogle search identified only one link aimed at online dextropropoxyphene shopping. In the United Kingdom, dextropropoxyphene-related products will be withdrawn later this year but this may have only limited impact on the availability of the compound. The emergence of Internet as an unregulated source of controlled substances is an important development that may have significant public health implications. This issue needs to be dealt with at both international and national level.


Efficacy of an electronic cognitive behavioural therapy program delivered via the Online Psychotherapy Tool for depression and anxiety related to the COVID-19 Pandemic: Pilot Study.
Lockdowns and social distancing resulting from the COVID-19 pandemic have worsened the population's mental health and made it more difficult for individuals to receive care. Electronic cognitive behavioural therapy (e-CBT) is a cost-effective and evidence-based treatment for anxiety and depression that can be accessed remotely. The objective of the study was to investigate the efficacy of online psychotherapy tailored to depression and anxiety symptoms during the pandemic. The pilot study used a pre-post design to evaluate the efficacy of a 9-week e-CBT program designed for individuals with depression and anxiety affected by the pandemic. Participants were adults (n = 59) diagnosed with major depressive disorder and/or generalized anxiety disorder, whose mental health symptoms initiated or worsened during the COVID-19 pandemic. The online psychotherapy program focused on teaching coping, mindfulness, and problem-solving skills. Symptoms of anxiety and depression, resilience, and quality of life were assessed. Participants demonstrated significant improvements in symptoms of anxiety (p = 0.023) and depression (p = 0.029) after the intervention. Similar trends were observed in the intent-to-treat analysis. No significant differences were observed in resilience and quality of life measures. The sample comprised mostly females, making it challenging to discern the benefits of the intervention in males. Although a pre-post design is less rigorous than a controlled trial, this design was selected to observe changes in scores during a critical period. e-CBT for COVID-19 is an effective and accessible treatment option. Improvements in clinical symptoms of anxiety and depression can be observed in individuals whose mental health is affected by COVID-19. ClinicalTrials.gov NCT04476667. RR2-10.2196/24913.


Effects of total fat intake on bodyweight in children.
As part of efforts to prevent childhood overweight and obesity, we need to understand the relationship between total fat intake and body fatness in generally healthy children. To assess the effects of total fat intake on measures of weight and body fatness in children and young people not aiming to lose weight. For this update we revised the previous search strategy and ran it over all years in the Cochrane Library, MEDLINE (Ovid), MEDLINE (PubMed), and Embase (Ovid) (current to 23 May 2017). No language and publication status limits were applied. We searched the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov for ongoing and unpublished studies (5 June 2017). We included randomised controlled trials (RCTs) in children aged 24 months to 18 years, with or without risk factors for cardiovascular disease, randomised to a lower fat (30% or less of total energy (TE)) versus usual or moderate-fat diet (greater than 30%TE), without the intention to reduce weight, and assessed a measure of weight or body fatness after at least six months. We included prospective analytical cohort studies in these children if they related baseline total fat intake to weight or body fatness at least 12 months later. We duplicated inclusion decisions and resolved disagreement by discussion with other authors. We extracted data on participants, interventions or exposures, controls and outcomes, and trial or cohort quality characteristics, as well as data on potential effect modifiers, and assessed risk of bias for all included studies. We extracted outcome data using the following time point ranges, when available: RCTs: baseline to six months, six to 12 months, one to two years, two to five years and more than five years; cohort studies: baseline to one year, one to two years, two to five years, five to 10 years and more than 10 years. We planned to perform random-effects meta-analyses with relevant subgrouping, and sensitivity and funnel plot analyses where data allowed. We included 24 studies comprising three parallel-group RCTs (n = 1054 randomised) and 21 prospective analytical cohort studies (about 25,059 children completed). Twenty-three were conducted in high-income countries. No meta-analyses were possible, since only one RCT reported the same outcome at each time point range for all outcomes, and cohort studies were too heterogeneous.For the RCTs, concerns about imprecision and poor reporting limited our confidence in our findings. In addition, the inclusion of hypercholesteraemic children in two trials raised concerns about applicability. Lower versus usual or modified total fat intake may have made little or no difference to weight over a six- to twelve month period (mean difference (MD) -0.50 kg, 95% confidence interval (CI) -1.78 to 0.78; 1 RCT; n = 620; low-quality evidence), nor a two- to five-year period (MD -0.60 kg, 95% CI -2.39 to 1.19; 1 RCT; n = 612; low-quality evidence). Compared to controls, lower total fat intake (30% or less TE) probably decreased BMI in children over a one- to two-year period (MD -1.5 kg/m2, 95% CI -2.45 to -0.55; 1 RCT; n = 191; moderate-quality evidence), with no other differences evident across the other time points (two to five years: MD 0.00 kg/m2, 95% CI -0.63 to 0.63; 1 RCT; n = 541; greater than five years; MD -0.10 kg/m2, 95% CI -0.75 to 0.55; 1 RCT; n = 576; low-quality evidence). Lower fat intake probably slightly reduced total cholesterol over six to 12 months compared to controls (MD -0.15 mmol/L, 95% CI -0.24 to -0.06; 1 RCT; n = 618; moderate-quality evidence), but may make little or no difference over longer time periods. Lower fat intake probably slightly decreased low-density lipoprotein (LDL) cholesterol over six to 12 months (MD -0.12 mmol/L, 95% CI -0.20 to -0.04; 1 RCT; n = 618, moderate-quality evidence) and over two to five years (MD -0.09, 95% CI -0.17 to -0.01; 1 RCT; n = 623; moderate-quality evidence), compared to controls. However, lower total fat intake probably made little or no difference to HDL-C over a six- to 12-month period (MD -0.03 mmol/L, 95% CI -0.08 to 0.02; 1 RCT; n = 618; moderate-quality evidence), nor a two- to five-year period (MD -0.01 mmol/L, 95% CI -0.06 to 0.04; 1 RCT; n = 522; moderate-quality evidence). Likewise, lower total fat intake probably made little or no difference to triglycerides in children over a six- to 12-month period (MD -0.01 mmol/L, 95% CI -0.08 to 0.06; 1 RCT; n = 618; moderate-quality evidence). Lower versus usual or modified fat intake may make little or no difference to height over more than five years (MD -0.60 cm, 95% CI -2.06 to 0.86; 1 RCT; n = 577; low-quality evidence).Over half the cohort analyses that reported on primary outcomes suggested that as total fat intake increases, body fatness measures may move in the same direction. However, heterogeneous methods and reporting across cohort studies, and predominantly very low-quality evidence, made it difficult to draw firm conclusions and true relationships may be substantially different. We were unable to reach firm conclusions. Limited evidence from three trials that randomised children to a lower total fat intake (30% or less TE) versus usual or modified fat intake, but with no intention to reduce weight, showed small reductions in body mass index, total- and LDL-cholesterol at some time points with lower fat intake compared to controls, and no consistent differences in effects on weight, high-density lipoprotein (HDL) cholesterol or height. Associations in cohort studies that related total fat intake to later measures of body fatness in children were inconsistent and the quality of this evidence was mostly very low. Twenty-three out of 24 included studies were conducted in high-income countries, and may not be applicable in low- and middle-income settings. High-quality, longer-term studies are needed, that include low- and middle-income settings and look at both possible benefits and risks.


Current pharmacological therapies for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis.
Nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) is considered to be a hepatic manifestation of metabolic syndrome, and its incidence is rapidly increasing worldwide. It is currently the most common chronic liver disease. NASH can progress to liver cirrhosis and hepatocellular carcinoma, and may result in liver-related death. Currently, the principal treatment for NAFLD/NASH is lifestyle modification by diet and exercise. However, pharmacological therapy is indispensable because obese patients with NAFLD often have difficulty maintaining improved lifestyles. The pathogenesis of NAFLD/NASH has not been completely elucidated. However, insulin resistance, inflammatory cytokines, and oxidative stress are thought to be important in the development and/or progression of the disease. Currently, insulin sensitizers (thiazolidinediones) and antioxidants (vitamin E) seem to be the most promising therapeutic agents for NAFLD/NASH, and lipid-lowering drugs, pentoxifylline, angiotensin receptor blockers, and n-3 polyunsaturated fatty acids also have promise. However, there is a lack of consensus regarding the most effective and appropriate pharmacotherapy for NAFLD/NASH. Animal experiments suggest that herbal medicines and natural products may be promising therapeutic agents for NAFLD/NASH, but their efficacy and safety are yet to be investigated in human studies. In this paper, we review the existing and potential pharmacological therapies for NAFLD/NASH.


Infectious diseases biobanking as a catalyst towards personalized medicine: Mycobacterium tuberculosis paradigm.
Research for biomarkers supporting personalized medicine in infectious diseases is needed, especially for tuberculosis in which the existing toolbox does not yet address the public health priorities. Biobanks are essential infrastructures in this effort by collecting, authenticating and preserving human and/or bacterial specimens. A broad range of specimens should be collected prior to, during and following treatment, with a comprehensive characterisation of the sample donors and the samples themselves to accommodate the most recent technological platforms in biomarker research. This review explains current state-of-the-field biobanking practices in tuberculosis and suggests technical and managerial improvements to ensure long-term preservation and optimal use of the specimens. Open-access and certified biobanks are an essential component of a strategy supporting the development of drugs and diagnostic tests for both public health and personalised medicine. Biobanks have a role to play in the interaction between these two - not always compatible - approaches.


Differential geographical risk of initial Pseudomonas aeruginosa acquisition in young US children with cystic fibrosis.
Pseudomonas aeruginosa is the sentinel respiratory pathogen in cystic fibrosis patients. We conducted a retrospective study to examine whether state of residence affected risk of P. aeruginosa acquisition among US children under 6 years of age with cystic fibrosis by using data from the Cystic Fibrosis Foundation National Patient Registry, 2003-2009. The outcome was time to first isolation of P. aeruginosa from a respiratory culture. We used a Bayesian hierarchical Weibull regression model with interval-censored outcomes. Spatial random effects, included at the state level and modeled using an intrinsic conditional autoregressive prior, allowed estimation of the residual spatial correlation. The regression portion of the model was adjusted for demographic and disease characteristics potentially affecting P. aeruginosa acquisition. A total of 3,608 children met the inclusion criteria and were followed for an average of 2.1 (standard deviation, 1.6) years. P. aeruginosa was cultured in 1,714 (48%) subjects. There was a moderately elevated spatial residual relative risk. An estimated 95% credible interval for the residual hazard ratio under 1 of the fitted models was 0.64-1.57; the strongest positive association was observed in the Southern states. The fact that risk for P. aeruginosa acquisition displayed spatial dependence suggests that regional factors, such as climate, may play an important role in P. aeruginosa acquisition.


Liver transplantation for acute Budd-Chiari syndrome in identical twin sisters with Factor V leiden mutation.
Budd-Chiari syndrome (BCS) is uncommon in the children. The cause of BCS comprises several diseases leading to thrombophilia. Activated protein C resistance as a result of a single gene mutation in factor V, the so called factor V Leiden (FVL), is the most common cause of thrombophilia. We report a simultaneous occurrence of BCS in identical twin sisters of 13 years of age with heterozygous FVL mutation. One sister presented with acute BCS leading to fulminant hepatic failure. She underwent liver transplantation with subsequent normalization of activated protein C resistance. The other twin sister, who was diagnosed with extensive thromboses of the inferior vena cava, portal vein, and hepatic veins, was successfully managed by aggressive chemical and mechanical thrombolysis followed by therapeutic anticoagulation. Genomic DNA studies confirmed heterozygosity of FVL mutation in the sisters' father and older brother. The exact cause of the BCS in children should be thoroughly and rapidly investigated, and, if necessary, immediate family members should also be tested for genetic defects in factor V or concomitant thrombophilia.


Dolastatin 15 induces apoptosis and BCL-2 phosphorylation in small cell lung cancer cell lines.
The dolastatins are natural peptides which inhibit microtubule assembly and induce apoptosis in a number of malignant cell types. In small cell lung cancer (SCLC), bcl-2 overexpression is very common and appears to be a mediator of cell growth and treatment-resistance, suggesting that bcl-2 is a rational target for novel anti-SCLC strategies. Since several other tubulin-binding agents have been reported to induce apoptosis in association with phosphorylation and inactivation of bcl-2, we evaluated the effects of dolastatin 10 and 15 in SCLC cells. The growth inhibitory activity of dolastatin 10 and 15 was evaluated in four SCLC cell lines with an MTT assay. Cell cycle and the induction of apoptosis were evaluated by flow cytometry and fluorescent microscopy. Immunoblot analysis was used to determine bcl-2 expression and phosphorylation. Dolastatin 15 displayed growth inhibitory activity against all four SCLC cell lines (NCI-H69, NCI-H82, NCI-H345, NCI-H446) with IC50 values ranging from 0.039-28.8 nM, which were 2.7-9.2-fold higher than the values for dolastatin 10. All four SCLC cell lines underwent G2/M arrest within 24 hours of exposure to dolastatin 15, and three had morphologic evidence of apoptosis after 48 hours. Immunoblot analysis of dolastatin 15-treated cells which overexpressed bcl-2 revealed a pattern consistent with bcl-2 phosphorylation. Dolastatin 15 has in vitro activity against SCLC cells, but is less potent than dolastatin 10. This activity is associated with the induction of apoptosis and bcl-2 phosphorylation. These findings suggest that further evaluation of the activity of the dolastatins in SCLC is reasonable and that the pharmacologic modulation of apoptotic pathways deserves further study as a potential anticancer strategy.


[Food protein-induced enterocolitis syndrome caused by fish ingestion. A case report].
Food protein-induced enterocolitis syndrome (FPIES) occurs in young infants who present with protracted vomiting and/or diarrhea which generally start 1-4 hours after certain food protein ingestion. Cow's milk and soy protein are most often responsible, but FPIES may be caused by solid foods such as egg white, wheat, rice, nuts, chicken and fish. We report the case of a 12 month-old girl who presented to the Emergency Department with profuse vomiting and diarrhoea having occurred 2 hours after fish ingestion. The patient was dehydrated. Antibiotics and intravenous fluids were administered. Her condition rapidly improved and she was discharged with the diagnosis of gastroenteritis.At the age of 15 months, she was re-admitted to the Emergency Department for the same symptoms, again some 2 hours after fish ingestion. She received the same treatment and rapidly recovered. With the probable diagnosis of fish allergy, the patient was advised to eliminate fish, until further evaluation. At the age of 31 months, a diagnostic oral food challenge was performed and was positive. Skin prick test and serum specific IgE were negative. The diagnosis of FPIES caused by fish protein was established and strict avoidance of fish was recommended.


Quality of Life and Functional Vision in Children with Glaucoma.
To evaluate the effect of glaucoma on functional vision and on vision-related (VR) and health-related (HR) quality of life (QoL) in children up to 16 years of age. Cross-sectional observational study. One hundred nineteen children 2 to 16 years of age (mean age, 9.4 years; standard deviation [SD], 4.56 years) with glaucoma and their parents. Completion of 3 validated instruments for children to assess (1) functional visual ability (FVA) with the Cardiff Visual Ability Questionnaire for Children (CVAQC), (2) VR QoL with the Impact of Vision Impairment for Children (IVI-C), and (3) HR QoL with the Pediatric Quality of Life Inventory (PedsQL) version 4.0. Cardiff Visual Ability Questionnaire for Children, IVI-C, and PedsQL scores. Scores for FVA, VR QoL, and HR QoL were reduced in children with glaucoma: median CVAQC score, -1.24 (interquartile range [IQR], -2.2 to -0.11; range, -3.00 higher visual ability to +2.80 lower visual ability); mean IVI-C score, 67.3 (SD, 14.4; normal VR QoL, 96); median PedsQL self-report, 78.8 (IQR, 67.4-90.2); parent report, 71.2 (IQR, 55.7-85.8); and family impact score, 74.3 (IQR, 56.9-88.5; normal HR QoL, 100). Psychosocial subscores were lower than physical subscores on the PedsQL. Older children reported less impairment on CVAQC, IVI-C, and PedsQL than younger children. Parents reported greater impact on their child's HR QoL than children reported themselves. Glaucoma and its management have a marked impact on a child's FVA and QoL. Children with glaucoma report HR QoL scores similar to those described by children with severe congenital cardiac defects, who have undergone liver transplants, or who have acute lymphoblastic leukemia.


The bound iron-sulfur clusters of type-I homodimeric reaction centers.
The hallmark of a Type-I photosynthetic reaction center (RC) is the presence of three [4Fe-4S](2+/1+) clusters, named F(X), F(A), and F(B) that act as terminal electron acceptors. Their function is to increase the distance, and hence the lifetime, of the initial charge-separated state so that diffusion-mediated processes, such as the reduction of ferredoxin, can occur. Type-I homodimeric RCs, such as those found in heliobacteria, green-sulfur bacteria, and Candidatus Chloracidobacterium thermophilum, are less well understood than Photosystem I, the prototypical Type-I heterodimeric RC found in cyanobacteria and plants. Here, we review recent progress that has been made in elucidating the spectroscopic and biochemical properties of the bound Fe/S clusters and their cognate proteins in homodimeric Type-I RCs. In Heliobacterium modesticaldum, the identification and characterization of two loosely bound polypeptides, PshBI and PshBII that harbor the F(A) and F(B) clusters threatens to break the long-accepted assumption that Type-I RCs harbor one tightly bound F(A)/F(B)-containing protein. Additionally, the detection of the F(X) cluster in S = 1/2 and S = 3/2 ground spin states has resolved the long-standing issue of its missing EPR spectrum. In Chlorobaculum tepidum, the focus is on the biochemical properties of the unusual extrinsic Fe/S protein, PscB, which is readily dissociable from the RC core. The C-terminal domain of PscB is constructed as a bacterial ferredoxin, harboring the F(A) and F(B) clusters, but the N-terminal domain contains a number of PxxP motifs and is rich in Lys, Pro, and Ala residues, features characteristic of proteins that interact with SH3 domains. Little is known about Candidatus Chloracidobacterium thermophilum except that the photosynthetic RC is predicted to be a Type-I homodimer with an F(X)-binding site. These findings are placed in a context that promises to unify the acceptor side of homodimeric Type-I RCs in prokaryotic phototrophs.


Quantification and spatial distribution of salicylic acid in film tablets using FT-Raman mapping with multivariate curve resolution.
In this study, we proposed a rapid and sensitive method for quantification and spatial distribution of salicylic acid in film tablets using FT-Raman spectroscopy with multivariate curve resolution (MCR). For this purpose, the constituents of film tablets were identified by using FT-Raman spectroscopy, and then eight different concentrations of salicylic acid tablets were visualized by Raman mapping. MCR was applied to mapping data to expose the active pharmaceutical ingredients in the presence of other excipients by monitoring distribution maps and combination of FT-Raman mapping with MCR enabled the determination of lower salicylic acid concentrations. In addition, the distribution of major excipient, lactose, was examined in the tablet form. A calibration curve was obtained by plotting the intensity of the Raman signal at 1635 cm-1 versus the concentration of salicylic acid and the correlation was found to be linear within the range of 0.5%-3.9% with a correlation coefficient of 0.99. The limit of detection for the technique was determined 0.35%. The ability of the technique to quantify salicylic acid in tablet test samples was also investigated.


Meta-analysis of chromovitrectomy with indocyanine green in macular hole surgery.
To report a meta-analysis of the literature comparing internal limiting membrane (ILM) peeling with and without indocyanine green (ICG) staining in macular hole (MH) treatment. A Pubmed search was conducted from January 1999 to June 2004. Manuscripts describing the anatomical and functional outcomes of vitrectomy plus ILM peeling with and without ICG application in MH surgery were reviewed. A statistical meta-analysis was performed including studies which defined anatomical outcomes as closure of the MH and disappearance of the fluid cuff and functional outcomes as improvement of 2 or more Snellen lines. A secondary outcome was to investigate the incidence of retinal pigment epithelium (RPE) alterations with and without ICG staining in MH surgery. Results including all types of MHs in 837 eyes indicated the same anatomical success but worse functional outcomes in the group with ICG application (p = 0.0008; odds ratio = 0.587, 95% confidence interval = 0.427-0.808). A higher incidence of RPE alterations in the ICG injection group was observed. The incidence of RPE alterations was found to be 1.98%, whereas RPE changes were noted in 13.83% of 201 patients with ICG application (odds ratio = 7.998). This meta-analysis of previous reports comparing ILM peeling with and without intravitreal ICG application in the treatment of MHs demonstrated statistically worse functional outcomes when ICG was applied (p = 0.0008). A higher number of RPE alterations were observed in the ICG-stained group.


Exploring a non-ATP pocket for potential allosteric modulation of PI3Kα.
Allosteric modulators offer a novel approach for kinase inhibition because they target less conserved binding sites compared to the active site; thus, higher selectivity may be obtained. PIK-108, a known pan phosphoinositide 3-kinase (PI3K) inhibitor, was recently detected to occupy a non-ATP binding site in the PI3Kα C-lobe. This newly identified pocket is located close to residue 1047, which is frequently mutated in human cancers (H1047R). In order to assess the interactions, stability, and any possible allosteric effects of this inhibitor on PI3Kα, extensive molecular dynamics (MD) simulations in aqueous solution were performed for the wild type (WT) human, WT murine, and H1047R human mutant PI3Kα proteins with PIK-108 placed in both catalytic and non-ATP sites. We verify the existence of the second binding site in the vicinity of the hotspot H1047R PI3Kα mutation through binding site identification and MD simulations. PIK-108 remains stable in both sites in all three variants throughout the course of the simulations. We demonstrate that the pose and interactions of PIK-108 in the catalytic site are similar in the murine WT and human mutant forms, while they are significantly different in the case of human WT PI3Kα protein. PIK-108 binding in the non-ATP pocket also differs significantly among the three variants. Finally, we examine whether the non-ATP binding site is implicated in PI3Kα allostery in terms of its communication with the active site using principal component analysis and perform in vitro experiments to verify our hypotheses.


Predictive implications of ventricular premature contractions associated with treadmill stress testing.
Follow-up data on future coronary events was collected on 6,500 patients who had undergone stress testing; 1,327 of these exhibited ventricular premature contractions (VPCs) associated with one or more phases of treadmill stress testing (TSTs). Eighty-three percent of all patients tested had known or suspected cardiovascular disease. The annual incidence of new coronary events (myocardial infarction, angina, cardiac death) during a five year follow-up was 1.7% among 1,067 patients without VPCs or ischemic ST changes, 6.4% in 758 patients with VPCs alone, 9.5% among 609 patients with ischemic ST changes alone and 11.4% in 569 patients with VPCs plus ischemic ST changes. The significance of VPCs associated with the TSTs rests largely upon the clinical status of the persons tested. VPCs observed among patients referred for TSTs for the evaluation of known or suspected cardiovascular disease, with or without ischemic ST abnormalities, represent a definite risk factor for future coronary events.


Phenytoin activates Smad3 phosphorylation and periostin expression in drug-induced gingival enlargement.
Drug-induced gingival enlargement (DIGE) is a fibrotic condition associated with systemic administration of the anti-epileptic drug, phenytoin. We have previously demonstrated that periostin, which is transforming growth factor-beta (TGF-β) inducible gene, is upregulated in various fibrotic conditions including gingival enlargement associated with nifedipine. The objective of this study was to assess periostin expression in phenytoin-induced gingival enlargement (PIGE) tissues and to investigate the mechanisms underlying periostin expression. Human PIGE tissues were assessed using Masson's trichrome, with cell infiltration and changes in extracellular matrix composition characterized through labeling with antibodies to periostin, phospho-SMAD 3, TGF-β, as well as the macrophage markers CD68 and RM3/1. Using human gingival fibroblasts (HGFs) in vitro we examined the pathways through which phenytoin acts on fibroblasts. In PIGE tissues, which demonstrate altered collagen organization and increased inflammatory cell infiltration, periostin protein was increased compared with healthy tissues. p-SMAD2/3, the transcription factor associated with canonical TGF-β signaling, is localized to the nuclei in both gingival fibroblasts and oral epithelial cells in PIGE tissues, but not in healthy tissue. In vitro culture of HGFs with 15 and 30 μg/ml of phenytoin increased periostin protein levels, which correlated with p-SMAD3 phosphorylation. Inhibition of canonical TGF-β signaling with SB431542 significantly reduced phenytoin induction of SMAD3 phosphorylation and periostin expression in HGFs. Analysis of PIGE tissues showed a subset of CD68 stained macrophages were TGF-β positive and that RM1/3 regenerative macrophages were present in the tissues. Our results demonstrate that phenytoin up-regulates periostin in HGFs in a TGF-β-dependent manner.