Criteria for the selection of paediatric patients susceptible to reconciliation error.
Many medication errors occur during care transitions, which are critical points for patient safety. There is strong evidence in favour of medication reconciliation as a strategy to avoid errors in adults, though few studies have been made in the paediatric setting. Likewise, no recommendations have been established for the selection and/or prioritisation of paediatric patients amenable to reconciliation. A retrospective study was conducted involving patients subjected to reconciliation by a pharmacist on admission to hospital and who experienced at least one reconciliation error between January and November 2018. Univariable and multivariable analyses were performed to identify possible factors associated with reconciliation error, using a logistic regression model to determine the odds ratio (OR) with the corresponding 95% confidence interval (95% CI). The group of patients with at least one reconciliation error included 334 patients, compared with the group of patients without reconciliation errors, which included 1426 patients. It was determined that schoolchildren and adolescent patients had a risk of presenting a reconciliation error on hospital admission that was more than double for younger patients (OR 2.32, 95% CI 1.26 to 4.25, and OR 2.68, 95% CI 1.44 to 4.99, respectively). This risk was multiplied by five if we compared polymedicated patients versus non-polymedicated patients (OR 4.48, 95% CI 3.35 to 5.99). Patients with a neurological or onco-haematological underlying disease had a 12 and 10 times higher risk of presenting a reconciliation error compared with patients with other types of underlying diseases (OR 11.97, 95% CI 7.57 to 18.92, and OR 9.96, 95% CI 6.09 to 16.28, respectively). Finally, patients with narrow therapeutic index medicines in their usual treatment had an almost three times greater risk of presenting a reconciliation error when admitted to the hospital, although this last factor was not determined as an independent risk factor as for the others (OR 2.98, 95% CI 2.22 to 3.99). The paediatric population is characterised by a number of risk factors for reconciliation error. Knowledge of these factors can allow the prioritisation of medication reconciliation in a concrete group of patients. In order to generalise the results obtained in this study, they must be confirmed in other paediatric care settings involving larger samples and different types of patients.


Reducing cardiovascular disease risk using patient navigators, Denver, Colorado, 2007-2009.
Early identification of cardiovascular disease (CVD) risk is important to reach people in need of treatment. At-risk patients benefit from behavioral counseling in addition to medical therapy. The objective of this study was to determine whether enhanced counseling, using patient navigators trained to counsel patients on CVD risk-reduction strategies and facilitate patient access to community-based lifestyle-change services, reduced CVD risk among at-risk patients in a low-income population. We compared clinical characteristics at baseline and 12-month follow-up among 340 intervention and 340 comparison patients from community health centers in Denver, Colorado, between March 2007 and June 2009; all patients had a Framingham risk score (FRS) greater or equal to 10% at baseline. The intervention consisted of patient-centered counseling by bilingual patient navigators. At baseline and at 6-month and 12-month follow-up, we assessed health behaviors of intervention participants. We used an intent-to-treat approach for all analyses and measured significant differences by χ(2) and t tests. We found significant differences in several clinical outcomes. At follow-up, the mean FRS was lower for the intervention group (mean FRS, 15%) than for the comparison group (mean FRS, 16%); total cholesterol was lower for the intervention group (mean total cholesterol, 183 mg/dL) than for the comparison group (mean total cholesterol, 197 mg/dL). Intervention participants reported significant improvements in some health behaviors at 12-month follow-up, especially nutrition-related behaviors. Behaviors related to tobacco use and cessation attempts did not improve. Patient navigators may provide some benefit in reducing risk of CVD in a similar population.


Recognition and maturation of IL-18 by caspase-4 noncanonical inflammasome.
The canonical (caspase-1) and noncanonical (comprising caspases 4, 5 and 11; hereafter, caspase-4/5/11) inflammasomes both cleave gasdermin D (GSDMD) to induce pyroptosis1,2. Whereas caspase-1 processes IL-1β and IL-18 for maturation3-6, no cytokine target has been firmly established for lipopolysaccharide-activated caspase-4/5/117-9. Here we show that activated human caspase-4, but not mouse caspase-11, directly and efficiently processes IL-18 in vitro and during bacterial infections. Caspase-4 cleaves the same tetrapeptide site in pro-IL-18 as caspase-1. The crystal structure of the caspase-4-pro-IL-18 complex reveals a two-site (binary) substrate-recognition mechanism; the catalytic pocket engages the tetrapeptide, and a unique exosite that critically recognizes GSDMD10 similarly binds to a specific structure formed jointly by the propeptide and post-cleavage-site sequences in pro-IL-18. This binary recognition is also used by caspase-5 as well as caspase-1 to process pro-IL-18. In caspase-11, a structural deviation around the exosite underlies its inability to target pro-IL-18, which is restored by rationally designed mutations. The structure of pro-IL-18 features autoinhibitory interactions between the propeptide and the post-cleavage-site region, preventing recognition by the IL-18Rα receptor. Cleavage by caspase-1, -4 or -5 induces substantial conformational changes of IL-18 to generate two critical receptor-binding sites. Our study establishes IL-18 as a target of lipopolysaccharide-activated caspase-4/5. The finding is paradigm shifting in the understanding of noncanonical-inflammasome-mediated defences and also the function of IL-18 in immunity and disease.


A non-RD1 gene cluster is required for Snm secretion in Mycobacterium tuberculosis.
The Snm secretion system is a crucial virulence determinant of Mycobacterium tuberculosis. Genes encoding all known components of this alternative secretion pathway are clustered at the same genetic locus, known as RD1. Here, we show that a mutant M. tuberculosis strain containing a transposon insertion in the Rv3615c gene, which is situated outside the RD1 locus, results in loss of Snm secretion. Complementation analysis revealed that both Rv3615c and the downstream gene Rv3614c are required for Snm secretion. Thus, we have renamed the two genes snm9 and snm10 respectively. The snm9::Tn mutant phenocopies bona fide snm mutants, exhibiting attenuation in mice, macrophage growth defects and failure to suppress cytokine induction. Furthermore, yeast two-hybrid analysis revealed a physical interaction between Snm10 and Snm7 (Rv3882c), suggesting that Snm10 may function in complex with other Snm proteins during secretion. Thus, snm9 and snm10 are the first genes located outside the RD1 locus identified as critical components of Snm secretion. These data indicate that Snm secretion consists of an elaborate network of interactions that likely arose from multiple duplication events during the evolution of M. tuberculosis.


Right ventricular cardiomyocyte apoptosis in patients with acute myocardial infarction of the left ventricular wall.
Cardiac remodeling after acute myocardial infarction (AMI) is characterized by molecular and cellular mechanisms involving both the left (LV) and right ventricular (RV) walls. Cardiomyoycte apoptosis in the peri-infarct and remote LV myocardium has a central role in cardiac remodeling. Whether apoptosis also occurs in the right ventricle of patients with ischemic heart disease has not been investigated. The aim of the present study was to investigate the presence of cardiomyocyte apoptosis in the right ventricle in patients with AMI. We assessed the number of apoptotic cardiomyocytes using multiple samplings in the LV and RV walls of 12 patients selected at autopsy who died 4 to 42 days after AMI. Five patients without cardiac disease were also selected at autopsy as controls. Apoptotic rates were calculated from the number of cardiomyocytes showing double positive staining for in situ end-labeling of DNA fragmentation (TUNEL) and for activated caspase-3. Potentially false-positive results (DNA synthesis and RNA splicing) were excluded from cell counts. The apoptotic rate in the right ventricle in patients with AMI was significantly higher than in control hearts (median 0.8%, interquartile range 0.3 to 1.0 vs median 0.01%, interquartile range 0.01 to 0.03, p <0.001). RV apoptosis significantly correlated with such parameters of global adverse remodeling as cardiac diameter to LV free wall thickness (R = +0.57, p = 0.050). RV apoptosis was significantly higher in five cases (42%) with infarct involving the ventricular septum and an adjacent small area of the RV walls (median 1.0%, interquartile range 0.8 to 2.2 vs median 0.5%, interquartile range 0.2 to 1.0, p = 0.048, p <0.001 vs controls). The association between apoptotic rate in the right ventricle and cardiac remodeling was apparent even after exclusion of cases with RV AMI involvement (R = +0.82, p = 0.023 for diameter to LV wall thickness ratio and R = -0.91, p = 0.002 for RV free wall thickness). In conclusion, patients with cardiac remodeling after AMI had a significant increase in RV apoptosis even when ischemic involvement of the RV wall was not apparent.


Intra- and intermolecular triplex DNA formation in the murine c-myb proto-oncogene promoter are inhibited by mithramycin.
Mithramycin inhibits transcription by binding to G/C-rich sequences, thereby preventing regulatory protein binding. However, it is also possible that mithramycin inhibits gene expression by preventing intramolecular triplex DNA assembly. We tested this hypothesis using the DNA triplex adopted by the murine c-myb proto-oncogene. The 5'-regulatory region of c-myb contains two polypurine:polypyrimidine tracts with imperfect mirror symmetry, which are highly conserved in the murine and human c-myb sequences. The DNA binding drugs mithramycin and distamycin bind to one of these regions as determined by DNase I protection assay. Gel mobility shift assays, nuclease and chemical hypersensitivity and 2D-gel topological analyses as well as triplex-specific antibody binding studies confirmed the formation of purine*purine:pyrimidine inter- and pyrimidine*purine:pyrimidine intra-molecular triplex structures in this sequence. Mithramycin binding within the triplex target site displaces the major groove-bound oligonucleotide, and also abrogates the supercoil-dependent H-DNA formation, whereas distamycin binding had no such effects. Molecular modeling studies further support these observations. Triplex-specific antibody staining of cells pretreated with mithramycin demonstrates a reversal of chromosomal triplex structures compared to the non-treated and distamycin-treated cells. These observations suggest that DNA minor groove-binding drugs interfere with gene expression by precluding intramolecular triplex formation, as well as by physically preventing regulatory protein binding.


[Clinical analysis of a population with autosomal dominant polycystic kidney disease].
Autosomal dominant polycystic kidney disease is a multiorgan hereditary disorder. It is responsible for 7-10% of cases of end stage renal failure. It is caused by mutations in the genes PKD1 and PKD2. The diagnosis of this disease can be performed through ultrasounds, but the molecular diagnosis offers some advantages, such as the early detection of asymptomatic individuals who carry this genetic defect, in order to perform a preventive monitoring and genetic counselling. In this work, we present the results of the clinical analysis of 48 patients diagnosed with autosomal dominant polycystic kidney disease. The objectives of this work were to analyze the main clinical aspects of the disease. The average age of appearance of the first symptoms was 41.17 +/- 13.41 years in women and 49.91 +/- 12.52 years in men (p < 0.05). Arterial hypertension was the first sign of the disease (68.42%), with more cases in men than in women (p < 0.05), followed by chronic renal failure (68.29 %). The most common renal symptom during the evolution of the disease was chronic renal failure, which was present in all the patients of the study, followed by proteinuria (92.31%), end-stage renal failure (89.58%) and arterial hypertension (87.23%). In summary, our results reveal a high prevalence of patients with polycystic kidney disease who received a late diagnosis. This could possibly explain the high morbi-mortality associated to this condition. Given the high prevalence of chronic renal failure and endstage renal failure secondary to polycystic kidney disease in our study, the early diagnostic of the disease would carry better prognostic in relation with a more strict clinical followup. The arterial hypertension was the most frequent clinical manifestation of the disease in our study by what this entity should be included in all the hypertense patients of unknown etiology and on the other hand, the infectious complications should be a sign of alert in every patient with polycystic kidney disease.


Labeling internalizing anti-epidermal growth factor receptor variant III monoclonal antibody with (177)Lu: in vitro comparison of acyclic and macrocyclic ligands.
The monoclonal antibody (mAb) L8A4, reactive with the epidermal growth factor receptor variant III (EGFRvIII), internalizes rapidly in glioma cells after receptor binding. Combining this tumor-specific mAb with the low-energy beta-emitter (177)Lu would be an attractive approach for brain tumor radioimmunotherapy, provided that trapping of the radionuclide in tumor cells after mAb intracellular processing could be maximized. L8A4 mAb was labeled with (177)Lu using the acyclic ligands [(R)-2-amino-3-(4-isothiocyanatophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diamine-pentaacetic acid (CHX-A''-DTPA), 2-(4-isothiocyanatobenzyl)-diethylenetriaminepenta-acetic acid (pSCN-Bz-DTPA) and 2-(4-isothiocyanatobenzyl)-6-methyldiethylenetriaminepentaacetic acid (1B4M-DTPA), and the macrocyclic ligands S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane-tetraacetic acid (C-DOTA) and alpha-(5-isothiocyanato-2-methoxyphenyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (MeO-DOTA). Paired-label internalization and cellular processing assays were performed on EGFRvIII-expressing U87.DeltaEGFR glioma cells over 24 h to directly compare (177)Lu-labeled L8A4 to L8A4 labeled with (125)I using either iodogen or N-succinimidyl 4-guanidinomethyl-3-[(125)I]iodobenzoate ([(125)I]SGMIB). In order to facilitate comparison of labeling methods, the primary parameter evaluated was the ratio of (177)Lu to (125)I activity retained in U87.DeltaEGFR cells. All chelates demonstrated higher retention of internalized activity compared with mAb labeled using iodogen, with (177)Lu/(125)I ratios of >20 observed for the three DTPA chelates at 24 h. When compared to L8A4 labeled using SGMIB, except for MeO-DOTA, internalized activity for (125)I was higher than (177)Lu from 1-8 h with the opposite behavior observed thereafter. At 24 h, (177)Lu/(125)I ratios were between 1.5 and 3, with higher values observed for the three DTPA chelates. The nature of the chelate used to label this internalizing mAb with (177)Lu influenced intracellular retention in vitro, although at early time points, only MeO-DOTA provided more favorable results than radioiodination of the mAb via SGMIB.


[A newly-established method of isolated hypoxic hepatic perfusion].
To establish a simplified isolated hypoxic hepatic perfusion (IHHP) technique, and to provide basis for IHHP using balloon occlusion catheter technique. Twelve rabbits were randomly divided into two groups: IHHP group and transcatheter arterial infusion (TAI) group. Technique of IHHP: the aorta above celiac axis was clamped, the retrohepatic inferior vena cava (IVC) was clamped above and below the level of the hepatic veins and an outflow catheter was introduced into this isolated segment via a femoral vein. The inflow catheter was introduced into the gastroduodenal artery, and common hepatic artery was clamped. The perfusate which contained Mitomycin C (MMC, 0.5 mg/kg) were perfused into hepatic artery, the hepatic outflow was draw out, and then perfused through hepatic artery again, the perfusion continued for 15 minutes. At the end of the IHHP procedure a washout was performed with 50 mL hespander for 5 minutes. TAI group method: Transarterial infusion was performed via hepatic artery using the same dose of MMC. Blood (2 mL) was sampled from hepatic vein and peripheral vein at multiple time points from the start of perfusion. MMC was measured by reverse phase high pressure liquid chromatography (HPLC). All IHHP procedures were successfully completed, blood loss was all controlled in 8 mL, and total operation time lasted (2.78+/-0.65) hours. All animals could tolerate the IHHP procedure, and survived. The mean leakage into the systemic circulation during perfusion was 2.63%, and 7.75% during the total procedure. In IHHP group maximal plasma concentration (C(max)) of hepatic circulation was (5.108+/-1.592) mg/L, C(max) of systematic circulation was (0.110+/-0.057) mg/L. In TAI group, Cmax of hepatic vein was (0.730 +/-0.362) mg/L, C(max) of systematic circulation (2.690+/-0.762) mg/L (P<0.01). IHHP technique is feasible and leakage is relatively low, thus providing a reasonable basis for IHHP with balloon catheter technique.


Parametric Optimization of Lateral NIPIN Phototransistors for Flexible Image Sensors.
Curved image sensors, which are a key component in bio-inspired imaging systems, have been widely studied because they can improve an imaging system in various aspects such as low optical aberrations, small-form, and simple optics configuration. Many methods and materials to realize a curvilinear imager have been proposed to address the drawbacks of conventional imaging/optical systems. However, there have been few theoretical studies in terms of electronics on the use of a lateral photodetector as a flexible image sensor. In this paper, we demonstrate the applicability of a Si-based lateral phototransistor as the pixel of a high-efficiency curved photodetector by conducting various electrical simulations with technology computer aided design (TCAD). The single phototransistor is analyzed with different device parameters: the thickness of the active cell, doping concentration, and structure geometry. This work presents a method to improve the external quantum efficiency (EQE), linear dynamic range (LDR), and mechanical stability of the phototransistor. We also evaluated the dark current in a matrix form of phototransistors to estimate the feasibility of the device as a flexible image sensor. Moreover, we fabricated and demonstrated an array of phototransistors based on our study. The theoretical study and design guidelines of a lateral phototransistor create new opportunities in flexible image sensors.


Practical application of guinea pig telemetry system for QT evaluation.
The purpose of this study was to evaluate a telemetry system for examining QT evaluation in the conscious free-moving guinea pig using 10 reference compounds whose effects on human QT interval are well established: 8 positive references (bepridil, terfenadine, cisapride, haloperidol, pimozide, quinidine, E-4031 and thioridazine), and 2 negative references (propranolol and nifedipine). Pharmacokinetic experiments were also performed for the 8 positive references. Telemetry transmitters were implanted subcutaneously in male Hartley guinea pigs, and the RR and QT intervals were measured. All 8 positive references prolonged QTc (QTc = k x QT/RR(1/2)) 10% or more during the 60 min observation period. When the values of the QTc changes were plotted against the serum concentrations, the resulting curves exhibited an anticlockwise hysteresis loop for all 8 references. In guinea pigs treated with haloperidol, changes of the T-wave shape from positive to flat were observed. The 2 negative references did not prolong the QTc. These findings suggest that the present telemetry guinea pig model is useful for QT evaluation in the early stages of drug development, because of the small body size of guinea pigs and their action potential configuration, which is similar to that of humans.


Obesity, endogenous hormone metabolism, and prostate cancer risk: a conundrum of "highs" and "lows".
This perspective on the report by Neuhouser et al. (beginning on page 279 in this issue of the journal) examines the associations that have been observed between body mass index, serum insulin, preexisting diabetes, androgen metabolism, and prostate cancer risk. Based on data of the Prostate Cancer Prevention Trial, the observations by Neuhouser et al. plus findings from other studies suggest a complex mix of higher and lower risks for high- and low-grade cancer in association with obesity and endogenous hormone metabolism.


Hereditary colorectal cancer in the gastroenterology clinic: how common are at-risk patients and how do we find them?
Colorectal cancer is the second leading cause of cancer deaths in the United States in both men and women and is thus a major public health problem. The American Cancer Society estimated that in 2007, approximately 153,760 people in the United States were diagnosed with colorectal cancer and about 52,180 died of the disease. Colorectal cancer is largely preventable, however, and often curable when detected early. About 80% of people with colorectal cancer seem to have sporadic disease with no evidence of inheriting the disorder, and the remaining 20% have a familial or hereditary risk. Identifying those with heritable cancers is best accomplished through a detailed family history, easily obtained by a trained nurse. With a detailed family history, risk can be assessed and further screening via colonoscopy or genetic testing may be undertaken. Unfortunately, to date, there is no universally accepted method to collect family health histories to determine the risk of hereditary colorectal cancer. This study field tested two different intake tools that collect personal and family history information for (1) evaluating their effectiveness in identifying patients at risk for hereditary colorectal cancer in a gastroenterology center; (2) determining patient, nurse, and physician satisfaction with each tool; and (3) assessing the prevalence of patients at risk for hereditary colorectal cancer in a gastroenterology center. A purposive sample of six gastroenterology practices across the United States was utilized. Eligible subjects included all patients seen in those practices over a 2-month time frame. Each intake tool was administered over a 4-week time frame. Satisfaction questionnaires were given to a random selection of subjects, as well as involved nurses and providers at each site. Overall prevalence of those at risk for hereditary colorectal cancer was 26% for all sites, ranging from 11%-39% across sites and tools. This study is significant because it revealed a fairly high percentage of people at risk for hereditary colorectal cancer and showed how an initial risk assessment can be easily done by professional nurses and other healthcare providers who are in a unique position to help reduce the incidence and mortality from colorectal cancer.


[Primary health care essential attributes and the family health strategy].
The essential attributes of Primary Health Care are attention at first contact, longitudinality, completeness and coordination, and the derived attributes are family and community orientation and cultural competence. This paper discusses the presence of such attributes in Family Health Strategy, a political and governmental proposal to change the health care model in the context of the Unified Health System in Brazil.


Hyperglycemia: its imminent effects on mammalian nephrogenesis.
A sustained exposure of the mammalian embryo to very high glucose ambience is associated with a multitude of congenital birth defects, including those of the cardiovascular, CNS, skeletal and urogenital systems during the first 6-8 weeks of gestation in humans. These urogenital abnormalities may be associated with "caudal regression syndrome" or may occur alone in the form of partial or total renal agenesis. Similarly, an increase in the incidence of morphogenetic defects is observed in the offspring of streptozotocin-induced diabetic rats and mice, and also in non-obese diabetic mice. In certain cases, failure during the growth of the lower parts of embryos or newborn mice involving the genitourinary system has been observed in animals with severe diabetes. Investigators have utilized whole organ culture systems to delineate the mechanisms relevant to dysmorphogenesis of the embryonic metanephros. A marked dysmorphogenesis of the metanephros is observed upon treatment with a high concentration of D: -glucose. Associated with it are changes that include branching dysmorphogenesis of the ureteric bud iterations, reduced population of nascent nephrons, decreased expression of basement membrane proteoglycans, depletion of ATP stores, and fulminant apoptosis of the cells at the interface of mesenchyme and ureteric bud epithelium. The latter findings suggest that disruption of epithelial:mesenchymal interactions may be the major event responsible for the metanephric dysmorphogenesis induced by high glucose ambience.


Some Evidence That Truth-Tellers Are More Attractive Than Liars.
Despite the prevalence of deception, people rarely doubt others' sincerity. However, indirect evaluations of liars and truth-tellers may differ even in the absence of suspicion about veracity. Across three studies, we provide evidence for the truth attraction effect in two samples of target stimuli and three samples of participant judges. Target people are perceived as more attractive when telling the truth versus when they lie, an effect mediated by target warmth and openness. The truth attraction effect is stronger for female targets (vs. males); however, it is unaffected by the gender of the judge. Findings suggest people may be more likely to approach truth-tellers versus liars, even when not actively judging veracity. We discuss the challenges and benefits of treating both targets and participants as random factors in linear mixed-effect analyses and join the chorus of calls to increase the number of target stimuli in deception research.


Changes Of Intraocular Pressure In Vitrectomised Eyes After Removal Of Silicone Oil.
Patients with Rhegmatogenous retinal detachment develop raised intraocular pressure (IOP) when they undergo pars plana vitrectomy with silicone oil. The present study was done to document changes in IOP with silicone oil and after its removal. The interventional study was conducted at Eye department of Lady Reading Hospital Peshawar, from August 2012 to July 2014 on 30 patients with Rhegmatogenous retinal detachment in whom pars plana vitrectomy with silicone oil injection was indicated. IOP readings were obtained on 1st postoperative day, at one month and at 6 months; the silicone oil was removed after the third reading and the IOP readings obtained after 2 weeks. Of the 30 patients selected for the study, there were 25 (83.3%) males and 5 (16.7%) females with ages ranging from 12-80 years (mean age 41.83±21.43 years). The mean of three pre silicone oil removal IOP readings was 27.35±9.20 mmHgwhich was reduced to a mean of 16.10±6.14mmHg following the removal of silicone oil at 6 months (p<0.001). Postoperative raised IOP values were highly predictive of persistently elevated IOP readings in patients after six months. Vitrectomised eyes with silicone oil raised intraocular pressure which was reduced after silicone oil removal.


A computational and experimental mechanical study of nanocomposites for 3D printed scaffolds with a new geometry.
We present a combined study of the mechanical properties of 3D printed scaffolds made by nanocomposite materials based on polycaprolactone (PCL). The geometry and dimensions of the three different systems is the same. Τhe porosity is 50% for all systems. Distributions of von-Mises strains and stresses, and total deformations were obtained through Finite Element Analysis (FEA) for a maximum amount of force applied, in a compressive numerical experiment. Also compressive experiments were performed for both raw and 3D nanoconposite scaffolds.


Demographic disequilibrium in living nautiloids (Nautilus and Allonautilus): Canary in the coal mines?
Averaged demographic data from previously unfished populations of Nautilus and Allonautilus (Cephalopoda) provide a baseline to determine if a population is undisturbed and in "equilibrium" or is in "disequilibrium" as a result of fishery pressure. Data are available for previously undisturbed local nautiloid populations in Papua New Guinea, Australia, Indonesia, Fiji, Palau, American Samoa, New Caledonia and Vanuatu (total n = 2,669 live-caught, tagged and released animals). The data show that unfished populations average ~75% males and ~74% mature animals. By contrast, unpublished, anecdotal and historical records since 1900 from the heavily fished central Philippines have shown a persistent decline in trap yields and a change in demographics of N. pompilius. By 1979, a sample of fished live-caught animals (n = 353) comprised only ~28% males and ~27% mature animals. Continued uncontrolled trapping caused collapse of the fishery and the shell industry has moved elsewhere, including Indonesia. In addition, we show that estimated rates of population decline are offered by unpublished tag-release records in unfished Palau. These data show that patterns of trap yields and demographic differences between fished and unfished populations in relative age class and sex ratios can indicate disequilibria wrought by fisheries pressure that can render local populations inviable. Given adequate samples (n ≥100 live-caught animals), a threshold of <50% males and mature animals in fished populations should signal the need to initiate curative conservation initiatives. The current trajectory of uncontrolled nautiloid fisheries can only mean trouble and possibly extinction of local populations of this ancient, iconic molluscan lineage.


A 7-Gene Signature Depicts the Biochemical Profile of Early Prefibrotic Myelofibrosis.
Recent studies have shown that a large proportion of patients classified as essential thrombocythemia (ET) actually have early primary prefibrotic myelofibrosis (prePMF), which implies an inferior prognosis as compared to patients being diagnosed with so-called genuine or true ET. According to the World Health Organization (WHO) 2008 classification, bone marrow histology is a major component in the distinction between these disease entities. However, the differential diagnosis between them may be challenging and several studies have not been able to distinguish between them. Most lately, it has been argued that simple blood tests, including the leukocyte count and plasma lactate dehydrogenase (LDH) may be useful tools to separate genuine ET from prePMF, the latter disease entity more often being featured by anemia, leukocytosis and elevated LDH. Whole blood gene expression profiling was performed in 17 and 9 patients diagnosed with ET and PMF, respectively. Using elevated LDH obtained at the time of diagnosis as a marker of prePMF, a 7-gene signature was identified which correctly predicted the prePMF group with a sensitivity of 100% and a specificity of 89%. The 7 genes included MPO, CEACAM8, CRISP3, MS4A3, CEACAM6, HEMGN, and MMP8, which are genes known to be involved in inflammation, cell adhesion, differentiation and proliferation. Evaluation of bone marrow biopsies and the 7-gene signature showed a concordance rate of 71%, 79%, 62%, and 38%. Our 7-gene signature may be a useful tool to differentiate between genuine ET and prePMF but needs to be validated in a larger cohort of "ET" patients.


A mixed-methods study on perceptions towards use of Rapid Ethical Assessment to improve informed consent processes for health research in a low-income setting.
Rapid Ethical Assessment (REA) is a form of rapid ethnographic assessment conducted at the beginning of research project to guide the consent process with the objective of reconciling universal ethical guidance with specific research contexts. The current study is conducted to assess the perceived relevance of introducing REA as a mainstream tool in Ethiopia. Mixed methods research using a sequential explanatory approach was conducted from July to September 2012, including 241 cross-sectional, self-administered and 19 qualitative, in-depth interviews among health researchers and regulators including ethics committee members in Ethiopian health research institutions and universities. In their evaluation of the consent process, only 40.2% thought that the consent process and information given were adequately understood by study participants; 84.6% claimed they were not satisfied with the current consent process and 85.5% thought the best interests of study participants were not adequately considered. Commonly mentioned consent-related problems included lack of clarity (48.1%), inadequate information (34%), language barriers (28.2%), cultural differences (27.4%), undue expectations (26.6%) and power imbalances (20.7%). About 95.4% believed that consent should be contextualized to the study setting and 39.4% thought REA would be an appropriate approach to improve the perceived problems. Qualitative findings helped to further explore the gaps identified in the quantitative findings and to map-out concerns related to the current research consent process in Ethiopia. Suggestions included, conducting REA during the pre-test (pilot) phase of studies when applicable. The need for clear guidance for researchers on issues such as when and how to apply the REA tools was stressed. The study findings clearly indicated that there are perceived to be correctable gaps in the consent process of medical research in Ethiopia. REA is considered relevant by researchers and stakeholders to address these gaps. Exploring further the feasibility and applicability of REA is recommended.


Gene cluster responsible for secretion of and immunity to multiple bacteriocins, the NKR-5-3 enterocins.
Enterococcus faecium NKR-5-3, isolated from Thai fermented fish, is characterized by the unique ability to produce five bacteriocins, namely, enterocins NKR-5-3A, -B, -C, -D, and -Z (Ent53A, Ent53B, Ent53C, Ent53D, and Ent53Z). Genetic analysis with a genome library revealed that the bacteriocin structural genes (enkA [ent53A], enkC [ent53C], enkD [ent53D], and enkZ [ent53Z]) that encode these peptides (except for Ent53B) are located in close proximity to each other. This NKR-5-3ACDZ (Ent53ACDZ) enterocin gene cluster (approximately 13 kb long) includes certain bacteriocin biosynthetic genes such as an ABC transporter gene (enkT), two immunity genes (enkIaz and enkIc), a response regulator (enkR), and a histidine protein kinase (enkK). Heterologous-expression studies of enkT and ΔenkT mutant strains showed that enkT is responsible for the secretion of Ent53A, Ent53C, Ent53D, and Ent53Z, suggesting that EnkT is a wide-range ABC transporter that contributes to the effective production of these bacteriocins. In addition, EnkIaz and EnkIc were found to confer self-immunity to the respective bacteriocins. Furthermore, bacteriocin induction assays performed with the ΔenkRK mutant strain showed that EnkR and EnkK are regulatory proteins responsible for bacteriocin production and that, together with Ent53D, they constitute a three-component regulatory system. Thus, the Ent53ACDZ gene cluster is essential for the biosynthesis and regulation of NKR-5-3 enterocins, and this is, to our knowledge, the first report that demonstrates the secretion of multiple bacteriocins by an ABC transporter.


Low heritability of nest construction in a wild bird.
In birds and other taxa, nest construction varies considerably between and within populations. Such variation is hypothesized to have an adaptive (i.e. genetic) basis, but estimates of heritability in nest construction are largely lacking. Here, we demonstrate with data collected over 10 years from 1010 nests built by blue tits in nest-boxes that nest size (height of nest material) and nest composition (proportion of feathers in the nest) are repeatable but only weakly (12-13%) heritable female traits. These findings imply that nest construction may evolve but only if subjected to strong and consistent selection pressures.


Localization of putative carbonic anhydrases in two marine diatoms, Phaeodactylum tricornutum and Thalassiosira pseudonana.
It is believed that intracellular carbonic anhydrases (CAs) are essential components of carbon concentrating mechanisms in microalgae. In this study, putative CA-encoding genes were identified in the genome sequences of the marine diatoms Phaeodactylum tricornutum and Thalassiosira pseudonana. Subsequently, the subcellular localizations of the encoded proteins were determined. Nine and thirteen CA sequences were found in the genomes of P. tricornutum and T. pseudonana, respectively. Two of the β-CA genes in P. tricornutum corresponded to ptca1 and ptca2 identified previously. Immunostaining transmission electron microscopy of a PtCA1:YFP fusion expressed in the cells of P. tricornutum clearly showed the localization of PtCA1 within the central part of the pyrenoid structure in the chloroplast. Besides these two β-CA genes, P. tricornutum likely contains five α- and two γ-CA genes, whereas T. pseudonana has three α-, five γ-, four δ-, and one ζ-CA genes. Semi-quantitative reverse transcription PCR performed on mRNA from the two diatoms grown in changing light and CO(2) conditions revealed that levels of six putative α- and γ-CA mRNAs in P. tricornutum did not change between cells grown in air-level CO(2) and 5% CO(2). However, mRNA levels of one putative α-CA gene, CA-VII in P. tricornutum, were reduced in the dark compared to that in the light. In T. pseudonana, mRNA accumulation levels of putative α-CA (CA-1), ζ-CA (CA-3) and δ-CA (CA-7) were analyzed and all levels found to be significantly reduced when cells were grown in 0.16% CO(2). Intercellular localizations of eight putative CAs were analyzed by expressing GFP fusion in P. tricornutum and T. pseudonana. In P. tricornutum, CA-I and II localized in the periplastidial compartment, CA-III, VI, VII were found in the chloroplast endoplasmic reticulum, and CA-VIII was localized in the mitochondria. On the other hand, T. pseudonana CA-1 localized in the stroma and CA-3 was found in the periplasm. These results suggest that CAs are constitutively present in the four chloroplastic membrane systems in P. tricornutum and that CO(2) responsive CAs occur in the pyrenoid of P. tricornutum, and in the stroma and periplasm of T. pseudonana.


Pathophysiology of diurnal drooling in Parkinson's disease.
Drooling is an incapacitating feature of Parkinson's disease. Better pathophysiological insights are needed to improve treatment. In this study, we tested the hypothesis that the cause of drooling is multifactorial. We examined 15 patients with Parkinson's disease with distinct diurnal saliva loss ("droolers") and 15 patients with Parkinson's disease without drooling complaints ("nondroolers"). We evaluated all factors that could potentially contribute to drooling: swallowing capacity (maximum volume), functional swallowing (assessed with the dysphagia subscale of the Therapy Outcome Measures for rehabilitation specialists), unintentional mouth opening due to hypomimia (Unified Parkinson's Disease Rating Scale item), posture (quantified from sagittal photographs), and nose-breathing ability. We also quantified the frequency of spontaneous swallowing during 45 minutes of quiet sitting, using polygraphy. Droolers had more advanced Parkinson's disease than nondroolers (Unified Parkinson's Disease Rating Scale motor score 31 vs 22; P=.014). Droolers also scored significantly worse on all recorded variables except for nose breathing. Swallowing frequency tended to be higher, possibly to compensate for less efficient swallowing. Logistic regression with adjustment for age and disease severity showed that hypomimia correlated best with drooling. Linear regression with hypomimia as the dependent variable identified disease severity, dysphagia, and male sex as significant explanatory factors. Drooling in Parkinson's disease results from multiple risk factors, with hypomimia being the most prominent. When monitored, patients appear to compensate by increasing their swallowing frequency, much like the increased cadence that is used to compensate for stepping akinesia. These findings can provide a rationale for behavioral approaches to treat drooling.


Selective sensing of adenosine monophosphate (AMP) over adenosine diphosphate (ADP), adenosine triphosphate (ATP), and inorganic phosphates with zinc(II)-dipicolylamine-containing gold nanoparticles.
Mixed monolayer-protected gold nanoparticles containing surface-bound triethylene glycol and dipicolylamine groups aggregated in water/methanol, 1 : 2 (v/v) in the presence of nucleotides, if the solution also contained zinc(ii) nitrate to convert the dipicolylamine units into the corresponding zinc complexes. Nanoparticle aggregation could be followed with the naked eye by the colour change of the solution from red to purple followed by nanoparticle precipitation. The sensitivity was highest for adenosine triphosphate (ATP), which could be detected at concentrations >10 μM, and decreased over adenosine diphosphate (ADP) to adenosine monophosphate (AMP), consistent with the typically higher affinity of zinc(ii)-dipicolylamine-derived receptors for higher charged nucleotides. Inorganic sodium diphosphate and triphosphate interfered in the assay by also inducing nanoparticle aggregation. However, while the nucleotide-induced aggregates persisted even at higher analyte concentrations, the nanoparticles that were precipitated with inorganic salts redissolved again when the salt concentration was increased. The thus resulting solutions retained their ability to respond to nucleotides, but they now preferentially responded to AMP. Accordingly, AMP could be sensed selectively at concentrations ≥50 μM in an aqueous environment, even in the presence of other nucleotides and inorganic anions. This work thus introduces a novel approach for the sensing of a nucleotide that is often the most difficult analyte to detect with other assays.


Children's Peritraumatic Responses During Sexual Abuse Incidents: Exploring the Narratives of Children From Different Ethnoreligious Groups in Israel.
The peritraumatic response of children during incidents of child sexual abuse (CSA) is a neglected construct in the literature. Despite the widespread use of the fight-flight-freeze model, recent studies have shown that in the unique context of child abuse, additional peritraumatic responses could be relevant. The current mixed-methods study examined children's peritraumatic responses to CSA. The sample consisted of 249 forensic interviews with children aged from 4 to 13 years. An initial qualitative analysis resulted in identifying various ways in which the children responded to the abuse, the children's decision-making around these responses, as well their perceptions of their response. This analysis was followed by quantitative analyses, which explored the frequency of these peritraumatic responses and their correlation with the characteristics of the children and abuse. Six peritraumatic response categories were identified, the most common being fight, flight, and fear. Only ethnoreligious identity was significantly correlated with the fight-or-flight response, with a significantly lower frequency among Muslim and ultra-Orthodox Jewish children. Frequency of abuse and perpetrator familiarity were correlated with the frequency of the fight-or-flight response, indicating that the latter was less relevant in reoccurring incidents of abuse and with perpetrators who were family members. The findings promote the conceptualization of children's peritraumatic responses during incidents of abuse and the realization of the crucial role of children's ecological systems in their peritraumatic responses to incidents of abuse.


[Conductance of cytoplasmic membrane of photoreceptors by the method of intracellular dialysis].
To clear up the effect of agents proposed as a mediator in the phototransduction process on the rod outer segment cytoplasmic membrane a technique based on the intracellular dialysis method was developed. It was shown that in the presence of nucleoside-triphosphates 3',5'-cGMP increased cytoplasmic membrane sodium conductance of dialyzed rod outer segment by 1-4 nS. The dependence of the effect amplitude on the cyclic nucleotides concentrations was obtained. It is suggested that the conductance changes observed are due to the action of cyclic nucleotide dependent protein kinase on the rod outer segment plasma membrane.


Benthic microalgae community response to flooding in a tropical salt flat.
This research evaluated the effect of flooding on the microphytobenthos community structure in a microbial mat from a tropical salt flat. Field samples were collected during four consecutive days: on the first three days the salt flat was dry, on the fourth day it was flooded by rain. In order to evaluate the community maintained in flood conditions, samples from this area were collected and kept in the laboratory for 10 days with sea water. The results of total abundance of microphytobenthos varied from 4.2 × 108 to 2.9 × 109 organisms L-1, total density increased one order of magnitude under the effect of water for both situations of precipitation in the salt flat and in experimental conditions, an increase due to the high abundance of Microcoleus spp. Shannon index (H') was higher during the desiccation period. Our data suggest that changes in the abundance of organisms were due to the effect of water. The dominance of the most abundant taxa remained the same under conditions of desiccation and influence of water, and there is probably a consortium of microorganisms in the microbial mat that helps to maintain these dominances.


Biocompatible and biodegradable phosphorylcholine ionomers with reduced protein adsorption and cell adhesion.
In this paper a recently developed biodegradable phosphorylcholine ionomer (PC ionomer) was evaluated in different biological environments with a focus on the adsorption of proteins (fibrinogen) and the adhesion of cells. Our results have shown that the polar phosphoryl choline (PC) group may be enriched at the surface of cast films with an added hydrophilic environment. X-ray photoelectron spectroscopy confirmed the surface depletion of PC groups in dry conditions, as nitrogen and phosphorous atoms were found in the bulk of the material but not at the outermost surface layer. The surface enrichment leads to a strongly hydrophilic surface that prevents the adsorption of proteins and reduces the adhesion of cells. The non-functional and hydrophobic reference poly(trimethylene carbonate) (PTMC) adsorbs both proteins and cells, thus the wetting and low adhesion behavior of the PC ionomer can be attributed to the introduced PC functionality. Since the in vivo acceptance of biomaterials is determined by their ability to withstand protein adsorption the PC ionomer described in this paper is highly interesting for a number of in vivo applications in which the adsorption of proteins may be critical, for example, blood contact events.


Antiretroviral therapy exposure and insulin resistance in the Women's Interagency HIV study.
Evidence suggesting an increased risk of cardiovascular disease in HIV-infected individuals has heightened the need to understand the relation of HIV infection, antiretroviral therapy use, and non-HIV-related factors with insulin resistance (IR). Prospective study of 1614 HIV-infected and 604 HIV-uninfected participants from the Women's Interagency HIV Study between October 2000 and March 2007. Homeostasis model assessment (HOMA)-estimated IR at 11,019 semiannual visits. HIV-infected women reporting highly active antiretroviral therapy (HAART) had higher median HOMA than HIV-uninfected women {1.20 [95% confidence interval (CI): 1.11 to 1.30] times higher for those reporting protease inhibitor-containing HAART; 1.10 (95% CI: 1.01 to 1.20) times higher for those reporting non-protease inhibitor-containing HAART}. Among HIV-infected, cumulative exposure to nucleoside reverse transcriptase inhibitors (NRTIs) of > 3 years was associated with HOMA 1.13 (95% CI: 1.02 to 1.25) times higher than the HOMA without any cumulative NRTI exposure. Cumulative exposure to the NRTI stavudine of > 1 year was associated with HOMA 1.15 (95% CI: 1.05 to 1.27) times higher than the HOMA without any cumulative stavudine use. Family history of diabetes, hepatitis C virus seropositivity, higher body mass index, or reporting menopause was associated with higher HOMA. CINCLUSIONS: Longer cumulative exposure to NRTI; in particular, stavudine is associated with greater IR in HIV-infected women.


Evidence for physiological seed dormancy cycling in the woody shrub Asterolasia buxifolia and its ecological significance in fire-prone systems.
Dormancy cycling is a key mechanism that contributes to the maintenance of long-term persistent soil seed banks, but has not been recorded in long-lived woody shrub species from fire-prone environments. Such species rely on seed banks and dormancy break as important processes for post-fire recruitment and recovery. We used germination experiments with smoke treatments on fresh seeds and those buried for 1 year (retrieved in spring) and 1.5 years (retrieved the following late autumn) to investigate whether Asterolasia buxifolia, a shrub from fire-prone south-eastern Australia with physiologically dormant seeds, exhibited dormancy cycling. All seeds had an obligation for winter seasonal temperatures and smoke to promote germination, even after ageing in the soil. A high proportion of germination was recorded from fresh seeds. but germination after the first retrieval was significantly lower, despite high seed viability. After the second retrieval, germination returned to the initial level. This indicates a pattern of annual dormancy cycling; one of the few observations, to our knowledge, for a perennial species. Additionally, A. buxifolia's winter temperature and smoke requirements did not change over time, highlighting the potential for seeds to remain conditionally dormant (i.e. restricted to a narrow range of germination conditions) for long periods. For physiologically dormant species, such as A. buxifolia, we conclude that dormancy cycling is an important driver of successful regeneration, allowing seed bank persistence, sometimes for decades, during fire-free periods unsuitable for successful recruitment, while ensuring that a large proportion of seeds are available for recruitment when a fire occurs.


MSARI: multiple sequence alignments for statistical detection of RNA secondary structure.
We present a highly accurate method for identifying genes with conserved RNA secondary structure by searching multiple sequence alignments of a large set of candidate orthologs for correlated arrangements of reverse-complementary regions. This approach is growing increasingly feasible as the genomes of ever more organisms are sequenced. A program called msari implements this method and is significantly more accurate than existing methods in the context of automatically generated alignments, making it particularly applicable to high-throughput scans. In our tests, it discerned clustalw-generated multiple sequence alignments of signal recognition particle or RNaseP orthologs from controls with 89.1% sensitivity at 97.5% specificity and with 74.4% sensitivity with no false positives in 494 controls. We used msari to conduct a comprehensive scan for secondary structure in mRNAs of coding genes, and we found many genes with known mRNA secondary structure and compelling evidence for secondary structure in other genes. msari uses a method for coping with sequence redundancy that is likely to have applications in a large set of other comparison-based search methods. The program is available for download from http://theory.csail.mit.edu/MSARi.


The emergency department as a pathway to admission for poor and high-cost patients.
--To determine the importance of the emergency department as the means of access to the hospital for the poor and the fiscal implications of providing these services, we examined the relationship between patients' socioeconomic status and admission via the emergency department. We also determined the association between entering the hospital via the emergency department and hospital resource use. --We conducted a study of 20,089 patients admitted to five Massachusetts hospitals (three community, two tertiary care) during a 6-month period. We determined the proportions of patients within various socioeconomic and disease groupings who entered through the emergency department. We compared length of stay and charges for patients admitted through the emergency department with those for patients admitted through other routes. --Overall, 51% of patients entered via the emergency department. Elderly patients (age greater than 65 years; odds ratio, 1.87) and patients with lower socioeconomic status as measured by income, occupation, and education (odds ratios, 2.38, 1.47, and 1.69, respectively) were more likely to enter the hospital via the emergency department than other patients. After adjustment for diagnosis related group, severity as measured by DRGSCALE, and socioeconomic status as measured by income, and excluding outliers, patients admitted via the emergency department stayed 27% longer and incurred 13% higher charges than other patients (P less than .001). --Our data indicate that patients with lower socioeconomic status are more likely than other patients to use the emergency department as their means of access to the hospital and that patients admitted via the emergency department use far more resources than patients in the same diagnosis related group admitted by other means. Hospitals that make emergency department services more available may be more likely to hospitalize socioeconomically disadvantaged patients and may be at a substantial financial disadvantage under per-case reimbursement systems such as Medicare.


[Analysis of electrically evoked response (EER) in relation to the central visual pathway of the cat (1). Wave shape of the cat EER].
To analyze the Electrically evoked response (EER) in relation to the central visual pathway, the authors studied the properties of wave patterns and peak latencies of EER in 35 anesthetized adult cats. The cat EER showed two early positive waves on outward current (cornea cathode) stimulus and three or four early positive waves on inward current (cornea anode) stimulus. These waves were recorded within 50 ms after stimulus onset, and were the most consistent components in cat EER. The stimulus threshold for EER showed a less individual variation than amplitude. The difference of stimulus threshold between outward and inward current stimulus was also essentially negligible. The stimulus threshold was higher in early components than in late components. The peak latency of EER became shorter and the amplitude became higher, as the stimulus intensity was increased. However, this tendency was reversed and some wavelets started to appear when the stimulus was extremely strong. The recording using short stimulus duration and bipolar electrodes enabled us to reduce the electrical artifact of EER. These results obtained from cats were compared with those of humans and rabbits.


A role of CXC chemokine ligand 12/stromal cell-derived factor-1/pre-B cell growth stimulating factor and its receptor CXCR4 in fetal and adult T cell development in vivo.
The functions of a chemokine CXC chemokine ligand (CXCL) 12/stromal cell-derived factor-1/pre-B cell growth stimulating factor and its physiologic receptor CXCR4 in T cell development are controversial. In this study, we have genetically further characterized their roles in fetal and adult T cell development using mutant and chimeric mice. In CXCL12(-/-) or CXCR4(-/-) embryos on a C57BL/6 background, accumulation of T cell progenitors in the outer mesenchymal layer of the thymus anlage during initial colonization of the fetal thymus was comparable with that seen in wild-type embryos. However, the expansion of CD3(-)CD4(-)CD8(-) triple-negative T cell precursors at the CD44(-)CD25(+) and CD44(-)CD25(-) stages, and CD4(+)CD8(+) double-positive thymocytes was affected during embryogenesis in these mutants. In radiation chimeras competitively repopulated with CXCR4(-/-) fetal liver cells, the reduction in donor-derived thymocytes compared with wild-type chimeras was much more severe than the reduction in donor-derived myeloid lineage cells in bone marrow. Triple negative CD44(+)CD25(+) T cell precursors exhibited survival response to CXCL12 in the presence of stem cell factor as well as migratory response to CXCL12. Thus, it may be that CXCL12 and CXCR4 are involved in the expansion of T cell precursors in both fetal and adult thymus in vivo. Finally, enforced expression of bcl-2 did not rescue impaired T cell development in CXCR4(-/-) embryos or impaired reconstitution of CXCR4(-/-) thymocytes in competitively repopulated mice, suggesting that defects in T cell development caused by CXCR4 mutation are not caused by reduced expression of bcl-2.


An evidence-based systematic review on cognitive interventions for individuals with dementia.
To evaluate the current state of research evidence related to cognitive interventions for individuals with Alzheimer's disease or related dementias. A systematic search of the literature was conducted across 27 electronic databases based on a set of a priori questions, inclusion/exclusion criteria, and search parameters. Studies were appraised for methodological quality and categorized according to intervention technique and outcome (e.g., cognitive-communication impairment or activity limitation/participation restriction). Results were summarized and, when possible, analyzed quantitatively using indicators of treatment effect size. Forty-three studies met criteria for inclusion in the review. The most commonly used cognitive intervention techniques used were errorless learning, spaced-retrieval training, vanishing cues, or verbal instruction/cueing. Most treatment outcomes were measured at the cognitive-communication impairment level of functioning and were generally positive. However, results should be interpreted cautiously because of methodological limitations across studies. Research evidence to support the use of cognitive interventions for individuals with dementia is accumulating. Researchers are beginning to evaluate treatment efficacy, yet the focus tends to be on discovery, specifically, refining intervention variables that will facilitate optimal outcomes. Implications for clinical practice and avenues for future research are discussed.


Methoxy-Functionalized Glycerol-Based Aliphatic Polycarbonate: Organocatalytic Synthesis, Blood Compatibility, and Hydrolytic Property.
Polymers that are biocompatible and degradable are desired for tissue engineering approaches in the treatment of vascular diseases, especially for those involving small-diameter blood vessels. Herein, we report the compatibility of a newly developed glycerol-based aliphatic polycarbonate possessing simple methoxy side groups, named poly(5-methoxy-1,3-dioxan-2-one) (PMDO), with blood cells and plasma proteins as well as its susceptibility to hydrolysis. As a consequence of the organocatalytic ring-opening polymerization (ROP) of a methoxy-functionalized cyclic carbonate derived from glycerol, PMDO with a sufficiently high molecular weight (Mn 14 kg/mol) and a narrow distribution (D̵M 1.12) was obtained for evaluation as a bulk biomaterial. This study demonstrates for the first time the organocatalytic ROP of a glycerol-based cyclic carbonate in a controlled manner. Compared with the clinically applied aliphatic polycarbonate poly(trimethylene carbonate) (PTMC), PMDO inhibits platelet adhesion by 33% and denaturation of fibrinogen by 23%. Although the wettability of PMDO based on water contact angle was almost comparable to those of PTMC and poly(ethylene terephthalate), the reason for the inhibited platelet adhesion and protein denaturation appeared to be related to the presence of specific hydrated water formed in the hydrated polymer. The improved hydration of PMDO also enhanced the susceptibility to hydrolysis, with PMDO demonstrating a slightly higher hydrolytic property than PTMC. This simple glycerol-based aliphatic polycarbonate has the following benefits: bio-based characteristics of glycerol and improved blood compatibility and hydrolytic biodegradability stemming from moderate hydration of the methoxy side groups.


Embryo resorptions in mice induced by diterpene resin acids of Pinus ponderosa needles.
Ingestion of hexane extract of Pinus ponderosa needles causes reproductive failure in mice during the early stages of gestation. Virgin mice of the ICR strain were mated with males of proven fertility. The day the copulatory plug was observed was designated day 1 of gestation. Hexane extracts were administered daily via stomach tube at various concentrations and for various feeding periods. Implantation sites were stained by injections of pontamine sky blue dye on day 8 of gestation, fifteen minutes before sacrifice by cervical dislocation. Embryonic resorptions were observed in the uterus. The active components of the hexane extracts were isolated and identified as a mixture of diterpene resin acids. The diterpene resin acids are pimaric, isopimaric, sandaracopimaric, palustric/levopimaric, abietic, dehydroabietic and neoabietic acid.


Effects of inhaled brevetoxins in allergic airways: toxin-allergen interactions and pharmacologic intervention.
During a Florida red tide, brevetoxins produced by the dinoflagellate Karenia brevis become aerosolized and cause airway symptoms in humans, especially in those with pre-existing airway disease (e.g., asthma). To understand these toxin-induced airway effects, we used sheep with airway hypersensitivity to Ascaris suum antigen as a surrogate for asthmatic patients and studied changes in pulmonary airflow resistance (R(L) after inhalation challenge with lysed cultures of K. brevis (crude brevetoxins). Studies were done without and with clinically available drugs to determine which might prevent/reverse these effects. Crude brevetoxins (20 breaths at 100 pg/mL; n = 5) increased R(L) 128 +/- 6% (mean +/- SE) over baseline. This bronchoconstriction was significantly reduced (% inhibition) after pretreatment with the glucocorticosteroid budesonide (49%), the beta(2) adrenergic agent albuterol (71%), the anticholinergic agent atropine (58%), and the histamine H1-antagonist diphenhydramine (47%). The protection afforded by atropine and diphenhydramine suggests that both cholinergic (vagal) and H1-mediated pathways contribute to the bronchoconstriction. The response to cutaneous toxin injection was also histamine mediated. Thus, the airway and skin data support the hypothesis that toxin activates mast cells in vivo. Albuterol given immediately after toxin challenge rapidly reversed the bronchoconstriction. Toxin inhalation increased airway kinins, and the response to inhaled toxin was enhanced after allergen challenge. Both factors could contribute to the increased sensitivity of asthmatic patients to toxin exposure. We conclude that K. brevis aerosols are potent airway constrictors. Clinically available drugs may be used to prevent or provide therapeutic relief for affected individuals.


Plasma membrane compartmentalization in yeast by messenger RNA transport and a septin diffusion barrier.
Asymmetric localization of proteins plays a key role in many cellular processes, including cell polarity and cell fate determination. Using DNA microarray analysis, we identified a plasma membrane protein-encoding mRNA (IST2) that is transported to the bud tip by an actomyosin-based process. mRNA localization created a higher concentration of IST2 protein in the bud compared with that of the mother cell, and this asymmetry was maintained by a septin-mediated membrane diffusion barrier at the mother-bud neck. These results indicate that yeast creates distinct plasma membrane compartments, as has been described in neurons and epithelial cells.


Regulation of Egr-1, SRF, and Sp1 mRNA expression in contracting skeletal muscle cells.
The early cellular signals associated with contractile activity initiate the activation and induction of transcription factors that regulate changes in skeletal muscle phenotype. The transcription factors Egr-1, Sp1, and serum response factor (SRF) are potentially important mediators of mitochondrial biogenesis based on the prevalence of binding sites for them in the promoter regions of genes encoding mitochondrial proteins, including PGC-1 alpha, the important regulator of mitochondrial biogenesis. Thus, to further define a role for transcription factors at the onset of contractile activity, we examined the time-dependent alterations in Egr-1, Sp1, and SRF mRNA and the levels in electrically stimulated mouse C(2)C(12) skeletal muscle cells. Early transient increases in Egr-1 mRNA levels within 30 min (P < 0.05) of contractile activity led to threefold increases (P < 0.05) in Egr-1 protein by 60 min. The increase in Egr-1 mRNA was not because of increased stability, as Egr-1 mRNA half-life after 30 min of stimulation showed only a 58% decline. Stimulation of muscle cells had no effect on Sp1 mRNA but led to progressive increases (P < 0.05) in SRF mRNA by 30 and 60 min. This was not matched by increases in SRF protein but occurred coincident with increases (P < 0.05) in SRF-serum response element DNA binding at 30 and 60 min as a result of SRF phosphorylation on serine-103. To assess the importance of the recovery period, 12 h of continuous contractile activity was compared with four successive 3-h bouts, with an intervening 21-h recovery period after each bout. Continuous contractile activity led to a twofold increase (P < 0.05) in Egr-1 mRNA, no change in SRF mRNA, and a 43% decrease in Sp1 mRNA expression. The recovery period prevented the decline in Sp1 mRNA, produced a decrease in Egr-1 mRNA, and had no effect on SRF mRNA. Thus continuous and intermittent contractile activity evoked different specific transcription factor expression patterns, which may ultimately contribute to divergent qualitative, or temporal patterns of, phenotypic adaptation in muscle.


[A small water-borne tularemia outbreak].
The aim of this study was to investigate a small tularemia outbreak in a village of Karamürsel county of Kocaeli province (located in North-west part of Turkey), between 22 January - 8 March 2005 and to present the anti-epidemic measures implemented. Following diagnosis of oropharyngeal tularemia in two patients living in the same village, a field investigation was performed at this region. All patients have undergone physical examination. Blood samples and if possible throat swabs and lymph node aspirates were taken from the patients and water samples from the natural spring water suspected to be the source of the infection, were also taken. Cultures were performed from the clinical samples and filtrated water samples. Francisella tularensis antibodies were screened by microagglutination (MA) test in the serum samples of the patients. F. tularensis DNA was investigated in the filtrated water samples by real-time PCR assay. A total of 17 patients were diagnosed as tularemia with their clinical features and MA test results (> or = 1/80). All the patients had oropharyngeal tularemia except one who had ulceroglandular form. The age range of the patients was 27-80 years (mean age: 48 +/- 17 years), and 10 (59%) were female. Weakness (100%), swelling on the neck (94%) and sore throat (88%) were the most common symptoms, whereas cervical lymphadenopathy (94%) was the most frequently seen clinical finding. F. tularensis could not be grown in the cultures, however F. tularensis DNA was detected in the samples of the natural spring water by real time PCR. The patients were treated with streptomycin, ciprofloxacin, or doxycycline, and all the patients have recovered. The outbreak was taken under control after cleaning the spring water tank and chlorination of the water.


LONG-TERM SURVIVAL OF PSEUDOGYMNOASCUS DESTRUCTANS AT ELEVATED TEMPERATURES.
White-nose syndrome is an emerging fungal disease that has devastated hibernating bat populations across eastern North America. The causal pathogen, Pseudogymnoascus destructans (PD), is a psychrophilic fungus with a known maximal growth temperature of 20 C. Although it is widely speculated that PD is primarily spread between hibernacula by the movement of bats, experimental evidence is lacking to demonstrate that PD can endure temperatures experienced by active bats for periods of time that would facilitate dispersal of viable fungus. We used an in vitro culture-based approach to study the survival of PD conidia on three artificial growth media and bat fur. The fungus was incubated at three temperatures it might realistically be exposed to on nonhibernating bats or in the environment outside of caves and mines (24 C, 30 C, and 37 C). When incubated on artificial media, we found that PD conidia were able to survive for a maximum of 150 d when exposed to temperatures of 24 C, 60 d at 30 C, and 15 d at 37 C. At all temperatures, maximal survival duration was recorded when conidia were incubated on brain-heart infusion agar with 10% volume of sheep (Ovis aries) blood. When incubated on bat fur, viable PD was recovered at 180 d, 60 d, and 5 d when exposed to temperatures of 24 C, 30 C, and 37 C, respectively. Our results suggest that viable PD conidia may be able to survive on or within the bodies of bats, which may facilitate long-distance dispersal. The long-term viability of the fungus on various fomites may differ, and therefore must be assessed for each potential substrate.


Nile Red Quantifier: a novel and quantitative tool to study lipid accumulation in patient-derived circulating monocytes using confocal microscopy.
The inflammatory profile of circulating monocytes is an important biomarker for atherosclerotic plaque vulnerability. Recent research revealed that peripheral lipid uptake by monocytes alters their phenotype toward an inflammatory state and this coincides with an increased lipid droplet (LD) content. Determination of lipid content of circulating monocytes is, however, not very well established. Based on Nile Red (NR) neutral LD imaging, using confocal microscopy and computational analysis, we developed NR Quantifier (NRQ), a novel quantification method to assess LD content in monocytes. Circulating monocytes were isolated from blood and used for the NR staining procedure. In monocytes stained with NR, we clearly distinguished, based on 3D imaging, phospholipids and exclusively intracellular neutral lipids. Next, we developed and validated NRQ, a semi-automated quantification program that detects alterations in lipid accumulation. NRQ was able to detect LD alterations after ex vivo exposure of isolated monocytes to freshly isolated LDL in a time- and dose-dependent fashion. Finally, we validated NRQ in patients with familial hypercholesterolemia and obese subjects in pre- and postprandial state. In conclusion, NRQ is a suitable tool to detect even small differences in neutral LD content in circulating monocytes using NR staining.


FAK overexpression and p53 mutations are highly correlated in human breast cancer.
Focal adhesion kinase (FAK) is overexpressed in a number of tumors, including breast cancer. Another marker of breast cancer tumorigenesis is the tumor suppressor gene p53 that is frequently mutated in breast cancer. In the present study, our aim was to find a correlation between FAK overexpression, p53 expression and mutation status in a population-based series of invasive breast cancer tumors from the Carolina Breast Cancer Study. Immunohistochemical analyses of 622 breast cancer tumors revealed that expression of FAK and p53 were highly correlated (p = 0.0002) and FAK positive tumors were 1.8 times more likely to be p53 positive compared to FAK negative tumors [odds ratio (OR) = 1.8; 95% Confidence Interval (CI) 1.2-2.8, adjusted for age, race and stage at diagnosis]. Tumors positive for p53 expression showed higher intensity of FAK staining (p < 0.0001) and higher percent of FAK positive staining (p < 0.0005). From the same study, we evaluated 596 breast tumors for mutations in the p53 gene, using single strand conformational polymorphism and sequencing. Statistical analyses were performed to determine the correlation between p53 mutation status and FAK expression in these tumors. We found that FAK expression and p53 mutation were positively correlated (p < 0.0001) and FAK positive tumors were 2.5 times more likely to be p53 mutation positive compared to FAK negative tumors [adjusted OR = 2.5, 95% CI 1.6-3.9]. This is the first analysis demonstrating a high correlation between FAK expression and p53 mutations in a population-based series of breast tumors.


Unique genome organization of non-mammalian papillomaviruses provides insights into the evolution of viral early proteins.
The family Papillomaviridae contains more than 320 papillomavirus types, with most having been identified as infecting skin and mucosal epithelium in mammalian hosts. To date, only nine non-mammalian papillomaviruses have been described from birds (n = 5), a fish (n = 1), a snake (n = 1), and turtles (n = 2). The identification of papillomaviruses in sauropsids and a sparid fish suggests that early ancestors of papillomaviruses were already infecting the earliest Euteleostomi. The Euteleostomi clade includes more than 90 per cent of the living vertebrate species, and progeny virus could have been passed on to all members of this clade, inhabiting virtually every habitat on the planet. As part of this study, we isolated a novel papillomavirus from a 16-year-old female Adélie penguin (Pygoscelis adeliae) from Cape Crozier, Ross Island (Antarctica). The new papillomavirus shares ∼64 per cent genome-wide identity to a previously described Adélie penguin papillomavirus. Phylogenetic analyses show that the non-mammalian viruses (expect the python, Morelia spilota, associated papillomavirus) cluster near the base of the papillomavirus evolutionary tree. A papillomavirus isolated from an avian host (Northern fulmar; Fulmarus glacialis), like the two turtle papillomaviruses, lacks a putative E9 protein that is found in all other avian papillomaviruses. Furthermore, the Northern fulmar papillomavirus has an E7 more similar to the mammalian viruses than the other avian papillomaviruses. Typical E6 proteins of mammalian papillomaviruses have two Zinc finger motifs, whereas the sauropsid papillomaviruses only have one such motif. Furthermore, this motif is absent in the fish papillomavirus. Thus, it is highly likely that the most recent common ancestor of the mammalian and sauropsid papillomaviruses had a single motif E6. It appears that a motif duplication resulted in mammalian papillomaviruses having a double Zinc finger motif in E6. We estimated the divergence time between Northern fulmar-associated papillomavirus and the other Sauropsid papillomaviruses be to around 250 million years ago, during the Paleozoic-Mesozoic transition and our analysis dates the root of the papillomavirus tree between 400 and 600 million years ago. Our analysis shows evidence for niche adaptation and that these non-mammalian viruses have highly divergent E6 and E7 proteins, providing insights into the evolution of the early viral (onco-)proteins.


Load-separation curves for the contact of self-affine rough surfaces.
There are two main approximate theories in the contact of rough solids: Greenwood-Williamson asperity theories (GW) and Persson theories. Neither of them has been fully assessed so far with respect to load-separation curves. Focusing on the most important case of low fractal dimension (D f = 2.2) with extensive numerical studies we find that: (i) Persson's theory describes well the regime of intermediate pressures/contact area, but requires significant corrective factors: the latter depend also on upper wavevector cutoff of the roughness; hence, (ii) Persson's theory does not predict the correct functional dependence on magnification; (iii) asperity theories in the discrete version even neglecting interaction effects are more appropriate in the range of relatively large separations, also to take into consideration of the large scatter in actual realization of the surface.


Binding-site assessment by virtual fragment screening.
The accurate prediction of protein druggability (propensity to bind high-affinity drug-like small molecules) would greatly benefit the fields of chemical genomics and drug discovery. We have developed a novel approach to quantitatively assess protein druggability by computationally screening a fragment-like compound library. In analogy to NMR-based fragment screening, we dock approximately 11,000 fragments against a given binding site and compute a computational hit rate based on the fraction of molecules that exceed an empirically chosen score cutoff. We perform a large-scale evaluation of the approach on four datasets, totaling 152 binding sites. We demonstrate that computed hit rates correlate with hit rates measured experimentally in a previously published NMR-based screening method. Secondly, we show that the in silico fragment screening method can be used to distinguish known druggable and non-druggable targets, including both enzymes and protein-protein interaction sites. Finally, we explore the sensitivity of the results to different receptor conformations, including flexible protein-protein interaction sites. Besides its original aim to assess druggability of different protein targets, this method could be used to identifying druggable conformations of flexible binding site for lead discovery, and suggesting strategies for growing or joining initial fragment hits to obtain more potent inhibitors.


Regulatory Efficacy of Spirulina platensis Protease Hydrolyzate on Lipid Metabolism and Gut Microbiota in High-Fat Diet-Fed Rats.
Lipid metabolism disorder (LMD) is a public health issue. Spirulina platensis is a widely used natural weight-reducing agent and Spirulina platensis is a kind of protein source. In the present study, we aimed to evaluate the effect of Spirulina platensis protease hydrolyzate (SPPH) on the lipid metabolism and gut microbiota in high-fat diet (HFD)-fed rats. Our study showed that SPPH decreased the levels of triglyceride (TG), total cholesterol (TC), low-density-lipoprotein cholesterol (LDL-c), alanine transaminase (ALT), and aspartate transaminase (AST), but increased the level of high-density-lipoprotein cholesterol (HDL-c) in serum and liver. Moreover, SPPH had a hypolipidemic effect as indicated by the down-regulation of sterol regulatory element-binding transcription factor-1c (SREBP-1c), acetyl CoA carboxylase (ACC), SREBP-1c, and peroxisome proliferator-activated receptor-γ (PPARγ) and the up-regulation of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) and peroxisome proliferator-activated receptorα (PPARα) at the mRNA level in liver. SPPH treatment enriched the abundance of beneficial bacteria. In conclusion, our study showed that SPPH might be produce glucose metabolic benefits in rats with diet-induced LMD. The mechanisms underlying the beneficial effects of SPPH on the metabolism remain to be further investigated. Collectively, the above-mentioned findings illustrate that Spirulina platensis peptides have the potential to ameliorate lipid metabolic disorders, and our data provides evidence that SPPH might be used as an adjuvant therapy and functional food in obese and diabetic individuals.


Sclerosing cholangitis of the bifurcation of the common hepatic duct.
Primary sclerosing cholangitis localized in a segment of the extrahepatic biliary tree is extremely rare. This article describes the case of a 23-year old male who had obstructive jaundice and was found to have primary sclerosing cholangitis of the bifurcation of the common hepatic duct. The lesion was successfully resected.


Novel antifungal activity of purpurin against Candida species in vitro.
The antifungal activity of purpurin (1,2,4-trihydroxy-9,10-anthraquinone), a natural red anthraquinone pigment in madder root (Rubia tinctorum L.), was evaluated by a broth microdilution assay against a total of 24 Candida isolates representing six species. The minimum inhibitory concentration (MIC) range of purpurin was 1.28-5.12 μg/ml. Mechanistic studies using the rhodamine 6G extrusion assay indicated that purpurin inhibited the energy-dependent efflux pumps of the Candida isolates in a dose-dependent manner. Furthermore, purpurin demonstrated a dose-dependent depolarization of mitochondrial membrane potential, one of the biochemical checkpoints regulating cell death in eukaryotic cells, suggesting a possible linkage between purpurin antifungal mechanism and Candida apoptosis.


[Mechanisms of development of histological and cytochemical changes in mammals (rats) during orbital flights].
The review surveys the publications on morphological and cytological changes in different functional systems of mammals (rats) flown on board the biological satellites of the Cosmos series. The paper gives an evidence that major changes in rats during orbital flights are induced by motor deprivation resulting in distinct metabolic disorders which histologically are represented as osteoporosis of the spongy segments of the long tubular skeletal bones, their periosteocytic osteolysis and atrophic developments in skeletal muscles. The paper discusses neurotrophic nature of these changes and emphasizes the contribution of stress reactions at different flight stages, especially on return to 1 g.


Tissue distribution and quantitation of the mRNAs for three rat tachykinin receptors.
The family of mammalian tachykinin receptors consists of substance P receptor (SPR), neuromedin K receptor (NKR) and substance K receptor (SKR). In this investigation, tissue and regional distributions of the mRNAs for the three rat tachykinin receptors were investigated by blot-hybridization and RNase-protection analyses using the previously cloned receptor cDNAs. SPR mRNA is widely distributed in both the nervous system and peripheral tissues and is expressed abundantly in the hypothalamus and olfactory bulb, as well as in the urinary bladder, salivary glands and small and large intestines. In contrast, NKR mRNA is predominantly expressed in the nervous system, particularly in the cortex, hypothalamus and cerebellum, whereas SKR mRNA expression is restricted to the peripheral tissues, being abundant in the urinary bladder, large intestine, stomach and adrenal gland. Thus, the mRNAs for the three tachykinin receptors show distinct patterns of expression between the nervous system and peripheral tissues. Blot-hybridization analysis in combination with S1 nuclease protection and primer-extension analyses revealed that there are two large forms of SKR mRNA expressed commonly in the peripheral tissues, and two additional small forms of the mRNA expressed specifically in the adrenal gland and eye. These analyses also showed that the multiple forms of SKR mRNA differ in the lengths of the 5' mRNA portions, and that the two small forms of the mRNA, if translated, encode a truncated SKR polypeptide lacking the first two transmembrane domains. This investigation thus provides the comprehensive analysis of the distribution and mode of expression of the mRNAs for the multiple peptide receptors and offers a new basis on which to interpret the diverse functions of multiple tachykinin peptides in the CNS and peripheral tissues.


Diagnostic value of multiple tumor markers for patients with esophageal carcinoma.
Various studies assessing the diagnostic value of serum tumor markers in patients with esophageal cancer remain controversial. This study aims to comprehensively and quantitatively summarize the potential diagnostic value of 5 serum tumour markers in esophageal cancer. We systematically searched PubMed, Embase, Chinese National Knowledge Infrastructure (CNKI) and Chinese Biomedical Database (CBM), through February 28, 2013, without language restriction. Studies were assessed for quality using QUADAS (quality assessment of studies of diagnostic accuracy). The positive likelihood ratio (PLR) and negative likelihood ratio (NLR) were pooled separately and compared with overall accuracy measures using diagnostic odds ratios (DORs) and symmetric summary receiver operating characteristic (SROC) curves. Of 4391 studies initially identified, 44 eligible studies including five tumor markers met the inclusion criteria for the meta-analysis, while meta-analysis could not be conducted for 12 other tumor markers. Approximately 79.55% (35/44) of the included studies were of relatively high quality (QUADAS score≥7). The summary estimates of the positive likelihood ratio (PLR), negative likelihood ratio (NLR) and diagnostic odds ratio (DOR) for diagnosing EC were as follows: CEA, 5.94/0.76/9.26; Cyfra21-1, 12.110.59/22.27; p53 antibody, 6.71/0.75/9.60; SCC-Ag, 7.66/0.68/12.41; and VEGF-C, 0.74/0.37/8.12. The estimated summary receiver operating characteristic curves showed that the performance of all five tumor markers was reasonable. The current evidence suggests that CEA, Cyfra21-1, p53, SCC-Ag and VEGF-C have a potential diagnostic value for esophageal carcinoma.


[The selection of spongiosa donors for a bone bank].
A prospective trial was carried out in 156 unselected patients (41 men, mean age 67.5 years, 115 women, mean age 71.4 years) who had undergone total hip joint replacement because of degenerative or inflammatory arthritis or fracture of the neck of the femur. The excised femoral heads were subjected to three-stage bone bank screening so as to ascertain how many of them would pass the clinical, biochemical and microbiological exclusion criteria. Only 26 out of 156 femoral heads (17%) proved to be acceptable for the bone bank. Ninety patients (58%) were excluded on clinical grounds such as old age (over 80 years), malignant neoplasms, rheumatoid arthritis, previous intraarticular injections or long-term steroid medication. Positive hepatitis serology excluded 19%, and raised preoperative neopterin concentration excluded 25%, though three months postoperatively this was confirmed in only 2%. Routine neopterin assay seems to be a useful step towards improved bone bank screening, since neopterin concentration is clearly increased in recent virus infections such as HIV. Bacterial contamination was of no practical importance. Because of the low proportion of femoral heads passed as suitable for the bone bank, the existing exclusion criteria will have to be critically scrutinized, and alternative procedures for harvesting bone safe for transplantation (freeze drying, autoclaving, irradiation) will have to be employed.


Prevalence of anxiety and depressive symptoms among obese pregnant and postpartum women: an intervention study.
Although studies have shown an association between anxiety and depression and obesity, psychological health among obese women during and after pregnancy has not been carefully studied. The aim of this study was to investigate psychological well-being using symptoms of depression and/or anxiety among obese pregnant women attending a weight gain restriction program and to then compare this group with a control group receiving traditional antenatal care. 151 obese pregnant women in an intervention group and 188 obese pregnant women in a control group answered the Beck Anxiety Inventory (BAI) and the Edinburgh Postnatal Depression Scale (EPDS). Group differences between the two groups were estimated by using the χ2 - test on categorical variables. The Student's t-test on continuous, normally distributed variables measuring changes in mean score on BAI and EPDS over time was used. To make a more comprehensive assessment of group differences, between as well as within the two groups, logistic regressions were performed with the BAI and EPDS as dependent variables, measured at gestational weeks 15 and 35 and 11 weeks postnatal. The grouping variable has been adjusted for socio-demographic variables and complications. The prevalence of symptoms of anxiety during pregnancy varied between 24% and 25% in the intervention group and 22% and 23% in the control group. The prevalence of symptoms of anxiety postnatally was 9% in the intervention group and 11% in the control group. Five percent of the women in the intervention group and 4% of the women in the control group showed symptoms of anxiety during the course of pregnancy and at the postpartum assessment. The prevalence of symptoms of depression during pregnancy varied between 19% and 22% in the intervention group but was constant at 18% in the control group. Postnatal prevalence was 11% in both groups. Six percent of the women in the intervention group and 4% in the control group showed symptoms of depression during the course of pregnancy and at the postpartum assessment. We found no differences between the two groups as concerns demographic characteristics, weight gain in kg, or the distribution of scores on anxiety and depressive symptoms nor did we find differences in the fluctuation of anxiety and depressive symptoms over time between the women in the intervention group and in the control group. Obese pregnant women attending an intervention program seem to have the same risk of experiencing anxiety and/or depressive symptoms as do obese pregnant and postnatal women in general.


Pharmacotherapy Approaches in Nontuberculous Mycobacteria Infections.
Nontuberculous mycobacteria (NTM) comprise a heterogeneous group of organisms, with only a small subset known to cause disease in humans. Although NTM infection is not a reportable disease, both the increasing clinical recognition and recent advancements in laboratory diagnostic capabilities of NTM infections in immunocompromised and immunocompetent patients are rapidly evolving. We reviewed antimicrobial agents used to treat the most frequently encountered NTM infections and examined optimized drug dosing strategies, toxicity profiles, drug-drug interactions, and the role of therapeutic drug monitoring. Antimicrobial susceptibility testing and patient monitoring on therapy were also examined. We used PubMed to review the published literature on the management of select NTM pathogens, the common syndromes encountered since 2000, and select pharmacokinetic principles of select antimicrobial agents used since 1990. We included select clinical trials, systematic reviews, published guidelines, and observational studies when applicable. The prolonged duration and the necessity for combination therapy for most forms of NTM disease can be problematic for many patients. A multidisciplinary care team that includes pharmacy engagement may help increase rates of optimal patient tolerability and successful treatment completion.


Human psychopharmacology of ketocyclazocine as compared with cyclazocine, morphine and placebo.
The activity of ketocyclazocine, a putative kappa opioid receptor agonist, was studied and compared with that of morphine, a mu opioid receptor agonist, and cyclazocine, a putative kappa and sigma opioid receptor agonist, vs. placebo in 10 drug abusers. The measures included vital signs and pupil measurements, established and new observer- and subject-completed psychopharmacologic questionnaires and several methods of drug discrimination. The results indicate that ketocyclazocine is different from morphine-like agonists in that it produces only minimal miosis and lacks euphoriant action. It causes a dysphoric state and was clearly discriminated from morphine. The dysphoria and pattern of responses was similar to cyclazocine though ketocyclazocine was discriminated from cyclazocine. This is consistent with the concept that morphine and ketocyclazocine have separate modes of primary activity. The similarity between ketocyclazocine and cyclazocine obscures the assignment of particular drug effects to activity at the kappa receptor.


[The National Research Program 1A: a community-oriented intervention study. Methodological considerations on various types of studies].
Intervention tricals can principally be classified into community or clinically oriented designs. The clinical approach of the randomized controlled trial (RCT) implies the individual randomization of a volunteer population into a study and a control group. In community-oriented trials, however, the study and control group are not composed of individuals, but rather of total population groups (e.g. communities, factories). The paper gives first an overview over the historial development of epidemiological methods as the basis for both study types. Shortcomings and advantages both of RCT's and of community trials are discussed, using the examples of the "diet-heart" hypothesis and of the National Research Program 1A design, respectively. The two study types uses as primary endpoints for the analysis changes in risk factor distribution, morbidity and/or mortality. A recent alternative is presented, too: advances in angiography allow direct measurements of changes in vessels with atherosclerotic disease. The different study types available complement one another in trying to understand the mechanisms involved in disease of multifactorial origin.


Differential expression of the presynaptic cytomatrix protein bassoon among ribbon synapses in the mammalian retina.
Bassoon is a 420-kDa presynaptic protein which is highly concentrated at the active zones of nerve terminals of conventional synapses, both excitatory glutamatergic and inhibitory GABAergic, in rat brain. It is thought to be involved in the organization of the cytomatrix at the site of neurotransmitter release. In the retina, there are two structurally and functionally distinct types of synapses: ribbon and conventional synapses. Antibodies against bassoon were applied to sections of rat and rabbit retina. Strong punctate immunofluorescence was found in the outer and inner plexiform layers. Using pre- and post-embedding immunostaining and electron microscopy, bassoon was localized in the outer plexiform layer at ribbon synapses formed by rods and cones but was absent from basal synaptic contacts formed by cones. In the inner plexiform layer a different picture emerged. As in the brain, bassoon was found at conventional inhibitory GABAergic synapses, made by amacrine cells, but it was absent from the bipolar cell ribbon synapses. These data demonstrate differences in the molecular composition of the presynaptic apparatuses of outer and inner plexiform layer ribbon synapses. Thus, differential equipment with cytomatrix proteins may account for the functional differences observed between the two types of ribbon synapses in the retina.


Accurate Ab Initio Quantum Mechanics Simulations of Bi2Se3 and Bi2Te3 Topological Insulator Surfaces.
It has been established experimentally that Bi2Te3 and Bi2Se3 are topological insulators, with zero band gap surface states exhibiting linear dispersion at the Fermi energy. Standard density functional theory (DFT) methods such as PBE lead to large errors in the band gaps for such strongly correlated systems, while more accurate GW methods are too expensive computationally to apply to the thin films studied experimentally. We show here that the hybrid B3PW91 density functional yields GW-quality results for these systems at a computational cost comparable to PBE. The efficiency of our approach stems from the use of Gaussian basis functions instead of plane waves or augmented plane waves. This remarkable success without empirical corrections of any kind opens the door to computational studies of real chemistry involving the topological surface state, and our approach is expected to be applicable to other semiconductors with strong spin-orbit coupling.


Transforming growth factor-beta receptor III downregulation in prostate cancer: is inhibin B a tumor suppressor in prostate?
The transforming growth factor-beta (TGF-beta) pathway plays dual roles in cancer, inhibiting epithelial cell growth under normal physiologic conditions, but promoting invasion and metastasis once growth inhibitory responses are lost. Two recent papers show that TGF-beta receptor III is the most common TGF-beta pathway component downregulated in prostate cancer. Here, we discuss the implications of these findings and what it may mean about the biology of this disease.


Glycosaminoglycan and growth factor mediated murine calvarial cell proliferation.
Understanding the complex mechanisms underlying bone remodeling is crucial to the development of novel therapeutics. Glycosaminoglycans (GAGs) localised to the extracellular matrix (ECM) of bone are thought to play a key role in mediating aspects of bone development. The influence of isolated GAGs was studied by utilising in vitro murine calvarial monolayer and organ culture model systems. Addition of GAG preparations extracted from the cell surface of human osteoblasts at high concentrations (5 microg/ml) resulted in decreased proliferation of cells and decreased suture width and number of bone lining cells in calvarial sections. When we investigated potential interactions between the growth factors fibroblast growth factor-2 (FGF2), bone morphogenic protein-2 (BMP2) and transforming growth factor-beta1 (TGFbeta1) and the isolated cell surface GAGs, differences between the two model systems emerged. The cell culture system demonstrated a potentiating role for the isolated GAGs in the inhibition of FGF2 and TGFbeta1 actions. In contrast, the organ culture system demonstrated an enhanced stimulation of TFGbeta1 effects. These results emphasise the role of the ECM in mediating the interactions between GAGs and growth factors during bone development and suggest the GAG preparations contain potent inhibitory or stimulatory components able to mediate growth factor activity.