Trypanocidal drugs for chronic asymptomatic Trypanosoma cruzi infection.
Prevention of chronic chagasic cardiomyopathy (CCC) by treating infected populations with trypanocidal therapy (TT) remains a challenge. Despite a renewed enthusiasm for TT, uncertainty regarding its efficacy, concerns about its safety and limited availability remain barriers for a wider use of conventional drugs. We have updated a previous version of this review. To systematically search, appraise, identify and extract data from eligible studies comparing the outcome of cohorts of seropositive individuals to Trypanosoma cruzi exposed to TT versus placebo or no treatment. We sought eligible studies in electronic databases (Cochrane Central Register of Controlled Trials (CENTRAL), Issue 1, 2014); MEDLINE (Ovid, 1946 to January week 5 2014); EMBASE (Ovid, 1980 to 2014 week 6) and LILACS (up to 6 May 2010)) by combining terms related with the disease and the treatment. The search also included a Google search, handsearch for references in review or selected articles, and search of expert files. We applied no language restrictions. Review authors screened the retrieved references for eligibility (those dealing with human participants treated with TT) and then assessed the pre-selected studies in full for inclusion. We included randomised controlled trials (RCTs) and observational studies that provided data on either mortality or clinical progression of CCC after at least four years of follow-up. Teams of two review authors independently carried out the study selection, data extraction and risk of bias assessment, with a referee resolving disagreement within the pairs. Data collection included study design, characteristics of the population and interventions or exposures and outcome measures. We defined categories of outcome data as parasite-related (positive serology, xenodiagnosis or polymerase chain reaction (PCR) after TT) and participant-related (including efficacy outcomes such as progression towards CCC, all-cause mortality and side effects of TT). We reported pooled outcome data as Mantel-Haenszel odds ratios (OR) or standardised mean differences (SMD) along with 95% confidence intervals (CI), using a random-effects model. I(2) statistics provided an estimate of heterogeneity across studies. We conducted an exploratory meta-regression analysis of the relationship between positive-serology and progression of CCC or mortality. We included 13 studies involving 4229 participants (six RCTs, n = 1096, five RCTs of intermediate risk of bias, one RCT of high risk of bias; four non-randomised experiments, n = 1639 and three observational studies, n = 1494). Ten studies tested nitroderivative drugs nifurtimox or benznidazole (three exposed participants to allopurinol, one to itraconazole). Five studies were conducted in Brazil, five in Argentina, one in Bolivia, one in Chile and one in Venezuela.TT was associated with substantial, but heterogeneous reductions on parasite-related outcomes such as positive serology (9 studies, OR 0.21, 95% CI 0.10 to 0.44, I(2) = 76%), positive PCR (2 studies, OR 0.50, 95% CI 0.27 to 0.92, I(2) = 0%), positive xenodiagnosis after treatment (6 studies, OR 0.35, 95% CI 0.14 to 0.86, I(2) = 79%), or reduction on antibody titres (3 studies, SMD -0.56, 95% CI -0.89 to -0.23, I(2) = 28%). Efficacy data on patient-related outcomes was largely from non-RCTs. TT with nitroderivatives was associated with potentially important, but imprecise and inconsistent reductions in progression of CCC (4 studies, 106 events, OR 0.74, 95% CI 0.32 to 1.73, I(2) = 66%) and mortality after TT (6 studies, 99 events, OR 0.55, 95% CI 0.26 to 1.14, I(2) = 48%). The overall median incidence of any severe side effects among 1475 individuals from five studies exposed to TT was 2.7%, and the overall discontinuation of this two-month therapy in RCTs (5 studies, 134 events) was 20.5% (versus 4.3% among controls) and 10.4% in other five studies (125 events). Despite the evidence that TT reduced parasite-related outcomes, the low quality and inconsistency of the data for patient-important outcomes must be treated with caution. More geographically diverse RCTs testing newer forms of TT are warranted in order to 1. estimate efficacy more precisely, 2. explore factors potentially responsible for the heterogeneity of results and 3. increase knowledge on the efficacy/tolerance balance of conventional TT.


Management of Chronic Pelvic Pain.
The management of chronic pelvic pain poses a significant challenge to both physicians and patients. Patients should be evaluated for both gynecologic and nongynecologic conditions, and >1 source may be identified. Treatment involves medical as well as surgical options, and it is important to set realistic goals with patients. Treatment may not be curative, but should improve the patient's quality of life.


Control of a virtual vehicle influences postural activity and motion sickness.
Everyday experience suggests that drivers are less susceptible to motion sickness than passengers. In the context of inertial motion (i.e., physical displacement), this effect has been confirmed in laboratory research using whole body motion devices. We asked whether a similar effect would occur in the context of simulated vehicles in a visual virtual environment. We used a yoked control design in which one member of each pair of participants played a driving video game (i.e., drove a virtual automobile). A recording of that performance was viewed (in a separate session) by the other member of the pair. Thus, the two members of each pair were exposed to identical visual motion stimuli, but the risk of behavioral contagion was minimized. Participants who drove the virtual vehicle (drivers) were less likely to report motion sickness than participants who viewed game recordings (passengers). Data on head and torso movement revealed that drivers tended to move more than passengers, and that the movements of drivers were more predictable than the movements of passengers. Before the onset of subjective symptoms of motion sickness movement differed between participants who (later) reported motion sickness and those who did not, consistent with a prediction of the postural instability theory of motion sickness. The results confirm that control is an important factor in the etiology of motion sickness and extend this finding to the control of noninertial virtual vehicles.


[Apoptosis and micro- and macroelement composition of lymphocytes in patients with pulmonary tuberculosis].
The paper describes the results of comparatively analyzing the parameters of apoptosis, micro- and macroelement spectrum of peripheral blood lymphocytes in healthy donors and in patients with chronic obstructive pulmonary disease (COPD) and pulmonary tuberculosis. In drug-responsive and drug-resistant pulmonary tuberculosis, unidirectional pretreatment changes were generally recorded in the activity of apoptosis and the spectrum of chemical elements of peripheral blood lymphocytes, which were most pronounced after completion of a phase of intensive antituberculosis chemotherapy. After termination of a complete course of the therapy, apoptotic activity lowered with the cationic composition of cells being normalized. The parameters differentiating pulmonary tuberculosis from COPD were ascertained, these included increases in the count of apoptotic cells and the cell concentrations of Ca2+, Zn2+, and Mg2+.


Role of Cytochrome P450 3A4 and 1A2 Phenotyping in Patients with Advanced Non-small-Cell Lung Cancer Receiving Erlotinib Treatment.
Erlotinib is metabolized by cytochrome p450 (CYP) 3A and CYP1A. This study assessed CYP3A4 (midazolam) and CYP1A2 (caffeine) phenotyping in plasma and dried blood spots (DBS) for predicting the pharmacokinetics and toxicity of erlotinib in 36 patients with advanced NSCLC. On day 1, erlotinib 150 mg OD was initiated, and the two oral probe drugs midazolam (2 mg) and caffeine (100 mg) were added on day 1. Plasma and DBS were collected for erlotinib, OSI-420 and probe drugs for up to 6 hr on day 1 and 2-weekly up to week 10. Probe drugs, erlotinib and OSI-420 were analysed using LC-MS-MS, and PK data were processed using population modelling. A high correlation was found between plasma and DBS concentrations for erlotinib (R2 = 0.960, p < 0.0001), OSI-420 (R2 = 0.971, p < 0.0001), midazolam (R2 = 0.995, p < 0.0001) and caffeine (R2 = 0.968, p < 0.0001). Apparent oral caffeine clearance was significantly correlated with erlotinib clearance (R2 = 0.33, p = 0.048), while midazolam clearance was not (R2 = -0.09, p = 0.596). Erlotinib clearance was lower in patients experiencing grade 2 or 3 rash as compared to patients experiencing grade 0 or 1 rash (3.15 versus 3.93 L/hr, p = 0.086 for Student's t-test). The results suggest that probe drug phenotyping is unlikely to substitute therapeutic drug monitoring of erlotinib in patients with advanced NSCLC, but erlotinib PK sampling from DBS may replace more invasive venous sampling and facilitate TDM in patients with cancer.


The influence of level of spinal cord injury on adipose tissue and its relationship to inflammatory adipokines and cardiometabolic profiles.
Level of injury (LOI) and the role of adipose tissue and its proinflammatory adipokines in cardiometabolic dysfunction following spinal cord injury (SCI) remains poorly understood. We aim to examine the influence of LOI on adipose tissue and its relationship to proinflammatory adipokines and cardiometabolic profiles following SCI. Cross sectional and correlational study. Clinical hospital and academic setting. Forty-seven individuals with chronic motor complete SCI (age 43.8±11.5 y, BMI: 27.3±5.3) were classified as having tetraplegia (TSCI; n=12) or paraplegia (PSCI; n=35). Non applicable. Visceral (VAT) and subcutaneous (SAT) adipose tissue volumes were measured using magnetic resonance imaging. Proinflammatory adipokines (tumor neurosis factor-α, interleukin-6 (IL-6), plasminogen activatable inhibitor-1, thrombin-activatable fibrinolysis inhibitor, and high-sensitivity c-reactive protein) and cardiovascular, carbohydrate, and lipid profiles were assessed according to standard techniques. VAT volume was greater in TSCI versus PSCI (p=0.042); however, after covarying for age this significance was lost (p>0.05). IL-6 was significantly elevated in TSCI (p<0.05), while other markers of inflammation generally were elevated, but did not reach statistical significance (p>0.05). Systolic blood pressure and total cholesterol were significantly lower in TSCI (p<0.05), while fasting glucose was significantly lower in PSCI (p<0.05). A number of proinflammatory adipokines and cardiometabolic markers significantly correlated with adipose tissue depots by LOI (p<0.05). The results show that LOI does not influence the distribution of adipose tissue, but does influence proinflammatory adipokines and cardiometabolic profiles following SCI. Further research is needed to evaluate impact of lean body mass on these findings.


Structure of an inactive RNA polymerase II dimer.
Eukaryotic gene transcription is carried out by three RNA polymerases: Pol I, Pol II and Pol III. Although it has long been known that Pol I can form homodimers, it is unclear whether and how the two other RNA polymerases dimerize. Here we present the cryo-electron microscopy (cryo-EM) structure of a mammalian Pol II dimer at 3.5 Å resolution. The structure differs from the Pol I dimer and reveals that one Pol II copy uses its RPB4-RPB7 stalk to penetrate the active centre cleft of the other copy, and vice versa, giving rise to a molecular handshake. The polymerase clamp domain is displaced and mobile, and the RPB7 oligonucleotide-binding fold mimics the DNA-RNA hybrid that occupies the cleft during active transcription. The Pol II dimer is incompatible with nucleic acid binding as required for transcription and may represent an inactive storage form of the polymerase.


Sandwich bone graft for vertical augmentation of the posterior maxillary region: a case report with 9-year follow-up.
The loss of teeth followed by bone resorption often lead to defects in the alveolar ridge, making installation of dental implants difficult. Correction of such bone defects, especially lack of height of the ridge, is a difficult problem for all dental surgeons. This report describes the outcome of treatment after alveolar ridge augmentation in the atrophic posterior maxillary region via segmental sandwich osteotomy combined with placement of an interpositional autograft prior to placement of endosseous implants. The technique was successfully used to treat a deficiency in the vertical dimension of the posterior maxillary region. Six months after graft surgery, two implants were successfully placed in accordance with the original treatment protocol, and they survived for 9 years of follow-up.


In vitro susceptibility testing of nonsporing anaerobes to ten antimicrobial agents.
Antibiotic Susceptibility was performed on sixty clinical isolates of nonsporing anaerobes against ten antimicrobial agents. The test was performed on Muller Hinton Agar and Wilkins Chalgren blood agar by preparing suspension of freshly isolated colonies in BHI broth. Apart from Metronidazole and Chloramphenicol newer antibiotics like Minocycline, Secnidazole, Tinidazole, Clarithromycin, Roxithromycin were also tried. Antimicrobial agents like metronidazole, Secnidazole, Tinidazole and Minocycline were 100% sensitive, followed by Chloramphenicol, Clarithromycin and Roxithromycin. These newer agents can be good alternatives for the treatment of non sporing anaerobes.


Some historical highlights and portents for the future of biomedical research on radium and the actinides.
Radiobiological research on the actinide elements has been a continuum since the first cryptic report by Hamilton at Berkeley, California, in February 1944. Yet certain landmarks in the work, certain people and certain organizations were responsible for the equivalent of quantum jumps in our concepts and understanding. This paper will review very briefly a few of these. Among them will be the realization of the biochemical and consequent biological differences between plutonium and radium, the first demonstration of carcinogenicity of the actinides, their behavior in bone, their relative toxicity, carcinogenesis after inhalation, the genesis of the "king-size" experiments to investigate their long-term effects, "hot particles" in lung, highlights of research with the transplutonics, and several others. To the extent possible, the review will consider not only the research findings, but their bearing on standard setting and the general operations in place at the time. Some of the past and current polemics will be touched upon.


Genetics of coronary artery disease: focus on genome-wide association studies.
With the advent of the genome-wide association (GWA) study, a promising new avenue for identifying genetic markers for complex diseases like coronary artery disease (CAD) has been opened. This avenue, however, is not without challenges and limitations, including the need for carefully designed and executed studies and the risk of false positive associations. Nonetheless, new markers have been identified through such studies that could potentially revolutionize the ways that individuals with CAD are identified and managed.


Outbreaks of severe myositis in cultured white sturgeon (Acipenser transmontanus L.) associated with Streptococcus iniae.
Outbreaks of an infectious disease affecting cultured white sturgeon (Acipenser transmontanus) were investigated. Clinical signs included erratic swimming, arching of the back and mortality. Necropsy findings included poorly demarcated yellow to dark-red and friable lesions in the epaxial muscle, ulcerative skin lesions and haemorrhages in the swim bladder and coelomic wall. Histological evaluation revealed areas of necrotizing and heterophilic myositis with aggregates of bacterial cocci. The lumen of blood vessels in the dermis, under ulcerated areas, and in the posterior kidney, was occluded by fibrin thrombi. Aggregates of Gram-positive cocci were observed in the muscle lesions and within the fibrin thrombi in the dermis and kidney. Genetically homogeneous Streptococcus iniae strains were recovered from affected fish from different outbreaks. The isolates shared high degree of similarity at gene locus (gyrB) with previously characterized S. iniae from cultured fish in California, confirming the emergence of this particular strain of S. iniae in US aquaculture.


Oestrus cycle of the Desert hamster (Phodopus roborovskii, Satunin, 1903).
The Desert hamster, Phodopus roborovskii, is one of the lesser-known laboratory animal models and therefore knowledge of its reproductive system and physiology is limited. This study investigated the time course of vaginal and behavioural oestrus cycles by means of vaginal smear cytology, serum luteinizing hormone (LH) levels, wheel-running activity patterns, and pairing tests. The oestrus cycle lasts between four and six days and follows a pattern rather similar to that described for other rodent species. An important finding of this study is the existence of a fifth cycle stage between pre-oestrus and oestrus, the so-called early oestrus. Early oestrus differs from pre-oestrus by a complete lack of leucocytes in the vaginal cytology and a dramatic increase of serum LH levels just before activity onset. The early oestrus stage lasts 4-6 h, but was not observed in every female. When present it affects the length of the whole oestrus cycle. With early oestrus the pre-oestrus stage lasts only 14-18 h and the total length of the oestrus cycle length is four days. Without early oestrus, the pre-oestrus is prolonged to 18-36 h and the oestrus cycle length varies between four and six days. Desert hamsters showed only subtle oestrus-correlated changes in wheel-running activity, i.e. they failed to show the characteristic scalloping of activity onset, but showed prolonged activity during early oestrus. Pairing tests revealed characteristic changes in the relative frequencies of socio-positive, neutral, aggressive and sexual behaviour during the course of the oestrus cycle, with an elevated level of sexual behaviour during oestrus.


Lipids enhance apolipoprotein C-II-derived amyloidogenic peptide oligomerization but inhibit fibril formation.
We investigated the effect of submicellar lipids on amyloid fibril formation. Thioflavin T fluorescence studies showed that submicellar levels of the short-chain phospholipids, dipentanoylphosphatidylcholine and dihexanoylphosphatidylcholine, strongly inhibited amyloid fibril formation by an 11-residue peptide derived from human apolipoprotein C-II (apoC-II(60-70)). In contrast, sedimentation equilibrium analysis of these peptide-lipid mixtures indicated the presence of soluble oligomeric complexes. To acquire insight into the atomic level influences of these lipids on the initial stages of aggregation of the peptide, we performed molecular dynamics (MD) simulations coupled with umbrella sampling to determine dimerization free energies of a number of beta-stranded and random coil dimer complexes, both in the presence and absence of lipids. The simulations indicate that, in contrast to their inhibitory effects on fibril formation, short-chain phospholipids promote the formation and stabilization of dimers by enhancing intersubunit hydrophobic interactions. On the basis of these experimental and computational results, we propose that peptide-bound lipids can inhibit amyloid fibril formation by trapping of dimers and other oligomeric species in diverse nonfibril forming conformations, reducing their likelihood of acquiring subunit conformations prone to fibril nucleation and growth. In light of the demonstrated cytotoxicity of amyloid peptide oligomers, our results suggest that, by enhancing the stability of oligomeric peptide species, the presence of solvated lipids may contribute to the cytotoxicity of fibrillogenic proteins and peptides.


Improving priors for human monoclonal antibody linear pharmacokinetic parameters by using half-lives from non-human primates.
Obtaining a good prior for the linear pharmacokinetics of new monoclonal antibodies (mAbs) would be an advantage not only for designing first-in-human (FIH) studies but also for stabilizing fitting of data with non-linear target-mediated disposition models. We estimated the pharmacokinetics from FIH studies for five mAbs using a two-compartment model, both separately and together, using a simple pool, a third hierarchical level of random effects for between mAb differences and non-human-primate half-lives as a predictor covariate for said differences. There was good agreement between compounds for the rapidly accessible central volume of 2.9 L (70 kg human), but clearances and peripheral volumes differed with terminal half-lives ranging from 15 to 28 days. The simple pool of human studies gave inter-individual variability estimates of 32% coefficient of variation (CV) for clearance and 33% CV for peripheral volume, larger than for separate fits (13-26% CV and 15-35% CV for clearance and volume respectively). Using third level hierarchical random effects gave inter-individual variability estimates close to those of separate fits (24% and 16% CV respectively). The between-mAb differences became predictable if non-human primate body weight scaled terminal half-life estimates were included as covariates on clearance and peripheral volume. In conclusion, ignoring inter-mAb variation leads to inflated estimates of inter-individual variability and unrealistic simulations for FIH studies. However, by using 70 kg body weight scaled terminal half-life estimates from non-human primates one can account for between-mAb differences and provide non-inflated priors for the linear pharmacokinetic parameters of new mAbs.


Effects of the Disease Characteristics and the Treatment on Psychological Status in Patients with Rheumatoid Arthritis and Ankylosing Spondylitis.
Various psychiatric disorders, especially depression and anxiety, are seen in 2/3 of the chronic rheumatic diseases with chronic pain. In this study, we aimed to define anxiety and depression rates in Rheumatoid Arthritis (RA) and Ankylosing Spondylitis (AS) patients (under treatment) with similar age and gender; to compare the obtained data with each other and healthy control group; and also we aimed to investigate the relationship between human leukocyte antigen B27(HLA-B27) in AS, Rheumatoid Factor (RF) and anti-cyclic citrullinated peptide antibodies (anti-CCP) in RA with anxiety and depression. 46 patients with RA, 43 patients with AS and 29 healthy volunteers were evaluated with Beck Depression Inventory (BAI) and Beck Anxiety Inventory (BAI). Participants were also noted for their educational status, occupation status, family history of illness, duration of the disease and their current treatments. Then we compared the obtained data with the healthy control group. SPSS (IBM Corp. Released 2012. IBM SPSS Statistics for Windows, Version 21.p=0. Armonk, NY: IBM Corp.) was used for performing statistical analysis. There was no difference between the groups according to age, sex, duration of illness (p=0.104, p=0.767, p=0.377). A significant difference between groups in terms of BAI values were determined (p=0.018). In subgroup analyzes, the median BAI value of AS group was found to be higher than the control group (p=0.020). There were no differences in BAI values between AS and RA groups or between RA and the control groups (p>0.05, p>0.05 respectively). Also, there were no differences between the groups in terms of BDI values (p=0.055). Especially, chronic pain-related diseases are often associated with mental disorders, especially depression and anxiety. As a result, a multidisciplinary approach including psychiatric support should be used when planning treatment for these patients.


Unusual behaviour of phototrophic picoplankton in turbid waters.
Autotrophic picoplankton (APP) abundance and contribution to phytoplankton biomass was studied in Hungarian shallow lakes to test the effect of inorganic turbidity determining the size distribution of the phytoplankton. The studied lakes displayed wide turbidity (TSS: 4-2250 mg l-1) and phytoplankton biomass (chlorophyll a: 1-460 μg l-1) range, as well as APP abundance (0 and 100 million cells ml-1) and contribution (0-100%) to total phytoplankton biomass. Inorganic turbidity had a significant effect on the abundance and contribution of APP, resulting in higher values compared to other freshwater lakes with the same phytoplankton biomass. Our analysis has provided empirical evidence for a switching point (50 mg l-1 inorganic turbidity), above which turbidity is the key factor causing APP predominance regardless of phytoplankton biomass in shallow turbid lakes. Our results have shown that turbid shallow lakes are unique waters, where the formerly and widely accepted model (decreasing APP contribution with increasing phytoplankton biomass) is not applicable. We hypothesize that this unusual behaviour of APP in turbid waters is a result of either diminished underwater light intensity or a reduced grazing pressure due to high inorganic turbidity.


Acetogenins from Annona muricata as potential inhibitors of antiapoptotic proteins: a molecular modeling study.
Apoptosis is a highly regulated process crucial for maintaining cellular homeostasis and development. The B-cell lymphoma 2 (Bcl-2) family of proteins play a crucial role in regulating apoptosis. Overexpressed Bcl-2 proteins are associated with the development and progression of several human cancers. Annona muricata is a tropical plant that belongs to the Annonaceae family and is well known for its anticancer properties. In this study, molecular docking and simulations were performed to investigate the inhibitory potential of phytochemicals present in A. muricata against antiapoptotic proteins of the Bcl-2 family including Bcl-2, B-cell lymphoma extra-large (Bcl-Xl), and Mcl-1. Docking results revealed that the acetogenins, such as annomuricin A, annohexocin, muricatocin A, annomuricin-D-one, and muricatetrocin A/B, exhibited strong binding interactions with Bcl-Xl when compared to Bcl-2 and Mcl-1. Binding score and interactions of these acetogenins were notably better than those of currently available synthetic and natural inhibitors. Molecular dynamics simulations of the top-scoring lead molecules established that these molecules could bind strongly and consistently in the active site of Bcl-Xl. These results suggest that acetogenins could be explored as selective natural inhibitors of Bcl-Xl that could assist in promoting the intrinsic pathway of apoptosis.


Spermine synthesis in the uterus of the ovariectomized rat in response to oestradiol-17 .
We reported that spermidine and spermine pools in the uterus both doubled within 24h after oestradiol administration to castrated rats (Russell & Taylor, 1971). Now we have studied the enzymic synthesis of spermine (by spermidine-dependent S-adenosyl-l-methionine decarboxylase) and find that the activity of the enzyme(s) involved is elevated soon after hormone administration. Enzyme activity is increased within 4h and is five times that of controls within 24h. Cycloheximide or actinomycin D administered at the time of oestradiol injection completely blocked the increase in enzyme activity. The enzyme involved in spermine synthesis, S-adenosyl-l-methionine decarboxylase, with S-adenosyl-l-methionine and spermidine as required substrates, was partially purified on Sephadex and DEAE-cellulose columns. The decarboxylation of S-adenosyl-l-methionine could not be separated from the transfer of a propylamine moiety from the decarboxylated S-adenosyl-l-methionine to spermidine to form spermine. We were unable also to separate this system from the enzyme that formed spermidine when S-adenosyl-l-methionine and putrescine are used as substrates. Spermidine-stimulated S-adenosyl-l-methionine decarboxylase has an apparent half-life of 60min, identical with the half-life reported for putrescine-stimulated S-adenosyl-l-methionine decarboxylase. These results strongly suggest that the same enzyme(s) operate in the synthesis of both spermidine and spermine.


Interaction of hemolytic anemia and genotype on hemolysis-induced gallstone formation in mice.
We previously reported that nb/nb mice with hereditary hemolytic anemia spontaneously developed calcium bilirubinate pigment gallstones. To assess the extent to which gallstone formation and bile composition is gene dependent, we transferred the hemolytic process by transplanting bone marrow from nb/nb mice into a nonhemolytic, but histocompatible genotype, W/Wv mice. Hematologic parameters of transplanted W/Wv mice were nearly identical to those of nb/nb mice. Like nb/nb mice, the percentage of transplanted mice with gallstones increased with the duration of the hemolysis and occurred twice as often in female mice as in male mice (37% vs. 19%; p less than 0.05). However, the rate of gallstone formation in transplanted mice was one-third less than that in nb/nb mice (3.6% per month vs. 5.5%; p less than 0.05). Analysis of hepatic bile revealed that (a) marrow-transplanted mice had higher concentrations of unconjugated bilirubin due to hemolysis (p less than 0.05) and of total bile acids determined by the W/Wv genotype (p less than 0.001) than their respective nb/nb counterparts and (b) transplanted mice with stones had a significantly lower proportion of cholic acid (p less than 0.005) and higher proportion of keto-bile acids (p less than 0.005) than transplanted mice without stones, suggesting that the cholic acid concentration may retard stone formation. These data indicate that the hemolytic process is the primary determinant of pigment gallstone formation in these mice and is influenced by the following factors: (a) duration of the hemolytic process, (b) gender, and (c) the genotype that regulates the composition of biliary components like bile acids.


Urine Eicosanoids in the Metabolic Abnormalities, Telmisartan, and HIV Infection (MATH) Trial.
Arachidonic acid metabolites (eicosanoids) reflect oxidative stress and vascular health and have been associated with anthropometric measures and sex differences in cross-sectional analyses of HIV-infected (HIV+) persons. Telmisartan is an angiotensin receptor blocker and PPAR-γ agonist with potential anti-inflammatory and metabolic benefits. We assessed telmisartan's effects on urine eicosanoids among HIV+ adults with central adiposity on suppressive antiretroviral therapy enrolled in a prospective clinical trial. Thirty-five HIV+ adults (15 women; 20 men) completed 24 weeks of open-label oral telmisartan 40mg daily. Lumbar computed tomography quantified visceral (VAT) and subcutaneous (SAT) abdominal adipose tissue. Urine F2-isoprostane (F2-IsoP), prostaglandin E2 (PGE-M), prostacyclin (PGI-M), and thromboxane B2 (TxB-M) were quantified at baseline and 24 weeks using gas/liquid chromatography-mass spectroscopy. Mann-Whitney-U tests compared sub-group differences; Spearman's rho assessed correlations between clinical factors and eicosanoid levels. Median PGE-M increased on telmisartan (p<0.01), with greater changes in men (+4.1 [p = 0.03] vs. +1.0 ng/mg cr in women; between-group p = 0.25) and participants losing >5% VAT (+3.7 ng/mg cr, p<0.01) and gaining >5% SAT (+1.7 ng/mg cr, p = 0.04). Median baseline F2-IsoP and TxB-M were slightly higher in women (both between-group p = 0.08) and did not change on telmisartan. Urine PGE-M increased with 24 weeks of telmisartan in virally suppressed, HIV+ adults with central adiposity. Associations with favorable fat redistribution suggest increased PGE-M may reflect a beneficial response.


SNPs detection in DHPS-WDR83 overlapping genes mapping on porcine chromosome 2 in a QTL region for meat pH.
The pH is an important parameter influencing technological quality of pig meat, a trait affected by environmental and genetic factors. Several quantitative trait loci associated to meat pH are described on PigQTL database but only two genes influencing this parameter have been so far detected: Ryanodine receptor 1 and Protein kinase, AMP-activated, gamma 3 non-catalytic subunit. To search for genes influencing meat pH we analyzed genomic regions with quantitative effect on this trait in order to detect SNPs to use for an association study. The expressed sequences mapping on porcine chromosomes 1, 2, 3 in regions associated to pork pH were searched in silico to find SNPs. 356 out of 617 detected SNPs were used to genotype Italian Large White pigs and to perform an association analysis with meat pH values recorded in semimembranosus muscle at about 1 hour (pH1) and 24 hours (pHu) post mortem.The results of the analysis showed that 5 markers mapping on chromosomes 1 or 3 were associated with pH1 and 10 markers mapping on chromosomes 1 or 2 were associated with pHu. After False Discovery Rate correction only one SNP mapping on chromosome 2 was confirmed to be associated to pHu. This polymorphism was located in the 3'UTR of two partly overlapping genes, Deoxyhypusine synthase (DHPS) and WD repeat domain 83 (WDR83). The overlapping of the 3'UTRs allows the co-regulation of mRNAs stability by a cis-natural antisense transcript method of regulation. DHPS catalyzes the first step in hypusine formation, a unique amino acid formed by the posttranslational modification of the protein eukaryotic translation initiation factor 5A in a specific lysine residue. WDR83 has an important role in the modulation of a cascade of genes involved in cellular hypoxia defense by intensifying the glycolytic pathway and, theoretically, the meat pH value. The involvement of the SNP detected in the DHPS/WDR83 genes on meat pH phenotypic variability and their functional role are suggestive of molecular and biological processes related to glycolysis increase during post-mortem phase. This finding, after validation, can be applied to identify new biomarkers to be used to improve pig meat quality.


Shifting hospital-hospice boundaries: historical perspectives on the institutional care of the dying.
Social forces have continually framed how hospitals perceive their role in care of the dying. Hospitals were originally conceived as places of hospitality and spiritual care, but by the 18th century illness was an opponent, conquered through science. Medicalization transformed hospitals to places of physical cure and scientific prowess. Death was an institutional liability. Equipped with new technologies, increased public demand, and the establishment of Medicare in 1965, modern hospitals became the most likely place for Americans to die--increasing after the 1940s and spiking in the 1990s. Medicare's 1983 hospice benefit began to reverse this trend. Palliative care has more recently proliferated, suggesting an institutional shift of alignment with traditional functions of care toward those facing death.


Factors for early tumor recurrence of single small hepatocellular carcinoma after percutaneous radiofrequency ablation therapy.
To evaluate the factors affecting the early tumor recurrence within one year in cirrhotic patients having a single small hepatocellular carcinoma (HCC) after complete tumor necrosis by radiofrequency ablation (RFA) therapy. Thirty patients with a single small HCC received RFA therapy by a RFA 2000 generator with LeVeen needle. Tri-phase computerized tomogram was followed every 2 to 3 mo after RFA. The clinical effects and tumor recurrence were recorded. The initial complete tumor necrosis rate was 86.7%. Twenty-two patients were followed for more than one year. The local and overall recurrence rates were 13.6% and 36.4%, 33.3% and 56.2%, 46.6% and 56.2% at 12, 24 and 30 mo, respectively. No major complication or procedure-related mortality was found. The risk factors for early local tumor recurrence within one year were larger tumor size, poor pathologic differentiation of tumor cells and advanced tumor staging. The age of patients with new tumor formation within one year was relatively younger (55.1+/-8.3 vs 66.7+/-10.8, P = 0.029). Large tumor size, poor pathologic differentiation of tumor cells and advanced tumor staging are the risk factors for early local tumor recurrence within one year, and young age is the positive predictor for new tumor formation within one year.


Systematic analysis of Prx genes in the Brachypodium genus and their expression pattern under abiotic constraints.
Peroxiredoxins (Prx) are ubiquitous peroxidases required for the removal of excess free radicals produced under stress conditions. Peroxiredoxin genes (Prx) in the Brachypodium genus were identified using bioinformatics tools and their expression profiles were determined under abiotic stress using RT-qPCR. The promoter regions of Prx genes contain several cis-acting elements related to stress response. In silico expression analysis showed that B. distachyon Prx genes (BdPrx) are tissue specific. RT-qPCR analysis revealed their differential expression when exposed to salt or PEG-induced dehydration stress. In addition, the upregulation of BdPrx genes was accompanied by accumulation of H2 O2 . Exogenous application of H2 O2 induced expression of almost all BdPrx genes. The identified molecular interaction network indicated that Prx proteins may contribute to abiotic stress tolerance by regulating key enzymes involved in lignin biosynthesis. Overall, our findings suggest the potential role of Prx genes in abiotic stress tolerance and lay the foundation for future functional analyses aiming to engineer genetically improved cereal lines.


[Gentamicin administration in newborns: once daily].
To determine the serum levels of gentamicin in newborn on one or two daily doses. Retrospective and subsequently prospective, descriptive. Department of Pediatrics of the Deventer Hospital, the Netherlands. Gentamicin trough and peak plasma levels were analysed retrospectively in 30 neonates to whom gentamicin 3-4 mg/kg/day in two doses had been administered in 1995. In a subsequent prospective study in 1996, 52 neonates received gentamicin 4 mg/kg/day in one dose. Optimal levels were defined as a trough of < 2 mg/l and a peak of 6-12 mg/l. Levels were determined using a immunoassay. Both groups were similar in gestational age, weight and age at the start of treatment. Both trough and peak plasma levels were not known in all patients. Adequate gentamicin trough levels were seen more often in the 'once daily' group than in the 'twice daily' group, in both the premature (12/14 = 86% versus 3/7 = 43%; p = 0.04) and non-premature (36/37 = 97% versus 18/23 = 78%; p = 0.017) neonates. Peak levels were higher in the 'once daily' group than in the 'twice daily' group, in both the prematures (11/13 = 85% versus 1/7 = 14%; p = 0.002) and non-prematures (25/28 = 89% versus 2/22 = 9%; p < 0.000001). Optimal trough and peak levels were found in 9/13 (69%) of the premature and 24/27 (89%) of the non-premature neonates treated according to the 'once daily' schedule, compared with 0 and 1/22 (5%) respectively in the neonates treated according to the 'twice daily' regimen (p = 0.003 and p < 0.0001, respectively). In view of the reported levels and the literature, an initial dose of gentamicin of 4.0 mg/kg/day once a day is advised for neonates.


Fluorophore-encapsulated solid-supported bilayer vesicles: a method for studying membrane permeation processes.
This letter describes a new method for studying the interaction of the membrane-lysing enzyme phospholipase A(2) (PLA(2)) with phospholipid bilayers by simultaneous measurements of enzyme binding and vesicle lysis using surface plasmon resonance (SPR) and permeabilization using surface plasmon field-enhanced fluorescence spectroscopy (SPFS). The PLA(2) inhibitor dimethyl-eicosadienoic acid was incorporated into the surface-bound vesicles and support bilayer in order to study its role in preventing PLA(2)-mediated vesicle lysis. This methodology has a generic applicability for the study of a range of membrane-disrupting agents.


Antitumour metallocenes: structure-activity studies and interactions with biomolecules.
The metallocene dihalides are a relatively new class of small, hydrophobic organometallic anticancer agents that exhibit antitumour properties against numerous cell lines including leukemias P388 and L1210, colon 38 and Lewis lung carcinomas, B16 melanoma, solid and fluid Ehrlich ascites tumours and several human colon and lung carcinomas transplanted into athymic mice. Titanocene dichloride 1 has been the most widely studied metallocene and the drug is currently in phase II clinical trials. Formation of metallocene-DNA complexes has been implicated in the mechanism of antitumour properties of the metallocenes, as both titanocene dichloride 1 and vanadocene dichloride 2 inhibit DNA and RNA synthesis, and titanium and vanadium accumulate in nucleic acid-rich regions of tumour cells. However, in contrast to the well characterized platinum-based anticancer drugs, the active species responsible for antitumour activity in vivo has not been identified and the mechanism whereby irreparable DNA damage and/or structural modification of DNA or other cellular targets occurs is poorly understood. This review will focus on recent studies that have been carried out in order to identify the biologically active species and more fully understand the molecular level mechanism of action of the metallocene dihalides. Studies with nucleotides, oligonucleotides, DNA and proteins including topoisomerases, protein kinase C and transferrin have provided important insight into potential cellular transport mechanisms and the interaction of metallocenes with biomolecular targets. New structure activity studies including the design of hydrolytically stable metallocenes and the preparation of highly water soluble amino acid analogues have not led to improved anticancer activity of titanocene dichloride 1. The vastly different chemical and hydrolytic stability of each of the metallocenes points to a unique mechanism of action of each metallocene in vivo.


Combined Internal and External Fixation for Diabetic Charcot Reconstruction: A Retrospective Case Series.
Diabetic Charcot neuroarthropathy is a complex, limb-threatening disease process with major lifestyle-altering repercussions for patients. When Charcot neuroarthropathy leads to unstable deformity, ulceration, and potential infection despite conservative therapies, foot and ankle surgeons often consider reconstructive limb salvage procedures to restore function. The purpose of the present study was to evaluate the clinical and radiographic outcomes of diabetic Charcot reconstruction using combined internal and external fixation. A total of 22 patients were reviewed; 16 (72.73%) midfoot and 6 (27.27%) tibiotalocalcaneal arthrodesis procedures were consecutively performed from March 2009 to May 2013. All surgical procedures were performed in nonacute phases of the Charcot process in patients with diagnosed diabetes mellitus and documented peripheral neuropathy. Patients were excluded from the study if they were not diabetic despite having undergone Charcot reconstruction, regardless of the fixation method, or if they did not complete radiographic imaging. During a mean follow-up period of 58.60 ± 42.37 (range 16 to 164) weeks, limb salvage was achieved in 20 patients (90.91%), and 2 (9.09%) required below-the-knee amputation at a mean of 42 ± 14.14 weeks. Wound dehiscence occurred in 8 (36.36%), pin tract infection in 10 (45.45%), and superficial wound infection in 9 (40.91%) and peaked in bimodal fashion at 4 and 8 weeks postoperatively. Radiographic analysis of the pre- versus postoperative alignment showed statistically significant changes in the lateral talo-first metatarsal angle (p = .02) and lateral talar declination angle (p = .01). The limb salvage rates with diabetic Charcot reconstruction are improving in part because of the continued development of increasingly superior modalities for both internal and external fixation.


Outcomes of Allogeneic Hematopoietic Cell Transplantation in T Cell Prolymphocytic Leukemia: A Contemporary Analysis from the Center for International Blood and Marrow Transplant Research.
T cell prolymphocytic leukemia (T-PLL) is a rare, aggressive malignancy with limited treatment options and poor long-term survival. Previous studies of allogeneic hematopoietic cell transplantation (alloHCT) for T-PLL are limited by small numbers, and descriptions of patient and transplantation characteristics and outcomes after alloHCT are sparse. In this study, we evaluated outcomes of alloHCT in patients with T-PLL and attempted to identify predictors of post-transplantation relapse and survival. We conducted an analysis of data using the Center for International Blood and Marrow Transplant Research database on 266 patients with T-PLL who underwent alloHCT between 2008 and 2018. The 4-year rates of overall survival (OS), disease-free survival (DFS), relapse, and treatment-related mortality (TRM) were 30.0% (95% confidence interval [CI], 23.8% to 36.5%), 25.7% (95% CI, 20% to 32%), 41.9% (95% CI, 35.5% to 48.4%), and 32.4% (95% CI, 26.4% to 38.6%), respectively. In multivariable analyses, 3 variables were associated with inferior OS: receipt of a myeloablative conditioning (MAC) regimen (hazard ratio [HR], 2.18; P < .0001), age >60 years (HR, 1.61; P = .0053), and suboptimal performance status, defined by Karnofsky Performance Status (KPS) <90 (HR, 1.53; P = .0073). Receipt of an MAC regimen also was associated with increased TRM (HR, 3.31; P < .0001), an elevated cumulative incidence of grade II-IV acute graft-versus-host disease (HR, 2.94; P = .0011), and inferior DFS (HR, 1.86; P = .0004). Conditioning intensity was not associated with relapse; however, stable disease/progression was correlated with increased risk of relapse (HR, 2.13; P = .0072). Both in vivo T cell depletion (TCD) as part of conditioning and KPS <90 were associated with worse TRM and inferior DFS. Receipt of total body irradiation had no significant effect on OS, DFS, or TRM. Our data show that reduced-intensity conditioning without in vivo TCD (ie, without antithymocyte globulin or alemtuzumab) before alloHCT was associated with long-term DFS in patients with T-PLL who were age ≤60 years or who had a KPS >90 or chemosensitive disease.


Accident investigation practices in Europe--main responses from a recent study of accidents in industry and transport.
Europe has during recent years been shocked by disasters from natural events and technical breakdowns. The consequences have been comprehensive, measured by lost lives, injuries, and material and environmental damage. ESReDA wanted in 2000--by setting up a special expert group on accident investigation--to clarify the state of art of accident investigation practices and to map the use of thoroughly accident investigation in order to learn lessons from past disasters and prevent new ones. The scope was to cover three sectors in the society: transport, production processes and storage of hazardous materials, and energy production. The main method used was a questionnaire, which was sent in 2001 to about 150 organisations. About 50 replies were analysed. The replies showed great variations but also similarities, among others in definition of accident and incident, the objectives of the investigation team, criteria used to start an investigation, the status of the investigation organisation, the flow of information, the composition of the investigation team, and the use of internal or international procedures or rules. Several methods (in total 14 different methods were mentioned) were used for carrying out accident /incident investigations. Most of the respondents were willing to co-operate in one or another way with ESReDA. Although there are important biases in the material, the results from questionnaire are important inputs to the future work of ESReDA Expert group in this field. 3 safety approaches have been identified.


Partialing alters interpersonal correlates of negative affective symptoms and traits: A circumplex illustration.
Negative affective symptoms (e.g., anxiety, depression, and anger) are correlated and have parallel associations with outcomes, as do related personality traits (i.e., facets of neuroticism), often prompting statistical control (i.e., partialing) to determine independent effects. However, such adjustments among predictor variables can alter their construct validity. In three studies, the interpersonal circumplex (IPC) and a related analytic approach (i.e., Structural Summary Method) were used to evaluate changes in interpersonal correlates of negative affective characteristics resulting from partialing. Samples of undergraduates (Sample 1 n = 3283; Sample 2 = 688) and married couples (n = 300 couples) completed self-report (three samples) and partner rating (sample 3) measures of anxiety, depression and anger, and IPC measures of interpersonal style. Anxiety, depression, and anger had expected interpersonal correlates across samples. Partialing depression eliminated interpersonal correlates of anxiety. When anxiety was controlled, depression measures were more strongly associated with submissiveness and less closely associated with low warmth. Adjustments involving anger magnified differences in dominance versus submissiveness associated with the negative affects. Removal of overlap among negative affective measures via partialing alters their interpersonal correlates, potentially complicating interpretation of adjusted associations.


Evolutionary ecology of resprouting and seeding in fire-prone ecosystems.
There are two broad mechanisms by which plant populations persist under recurrent disturbances: resprouting from surviving tissues, and seedling recruitment. Species can have one of these mechanisms or both. However, a coherent framework explaining the differential evolutionary pressures driving these regeneration mechanisms is lacking. We propose a bottom-up approach in addressing this question that considers the relative survivorship of adults and juveniles in an evolutionary context, based on two assumptions. First, resprouting and seeding can be interpreted by analogy with annual versus perennial life histories; that is, if we consider disturbance cycles to be analogous to annual cycles, then resprouting species are analogous to the perennial life history with iteroparous reproduction, and obligate seeding species that survive disturbances solely through seed banks are analogous to the annual life history with semelparous reproduction. Secondly, changes in the selective regimes differentially modify the survival rates of adults and juveniles and thus the relative costs and benefits of resprouting versus seeding. Our approach provides a framework for understanding temporal and spatial variation in resprouting and seeding under crown-fire regimes. It accounts for patterns of coexistence and environmental changes that contribute to the evolution of seeding from resprouting ancestors.


Protective LRRK2 R1398H Variant Enhances GTPase and Wnt Signaling Activity.
Mutations in LRRK2 are a common cause of familial and idiopathic Parkinson's disease (PD). Recently, the LRRK2 GTPase domain R1398H variant was suggested in genetic studies to confer protection against PD but mechanistic data supporting this is lacking. Here, we present evidence that R1398H affects GTPase function, axon outgrowth, and Wnt signaling in a manner opposite to pathogenic LRRK2 mutations. LRRK2 R1398H GTPase domain dimerization and GTP hydrolysis were increased whereas GTP binding was reduced, leading to a decrease in active GTP-bound LRRK2. This protective variant also increased axon length of primary cortical neurones in comparison to wild-type LRRK2, whereas the R1441G LRRK2 pathogenic mutant decreased axon outgrowth. Importantly, R1398H enhanced the stimulatory effect of LRRK2 on canonical Wnt signaling whereas the G2385R risk variant, in accordance with all previously tested pathogenic LRRK2 mutants, had the opposite effect. Molecular modeling placed R1398H in close proximity to PD-causing mutations suggesting that this protective LRRK2 variant, like familial mutations, affects intramolecular RocCOR domain interactions. Thus, our data suggest that R1398H LRRK2 is a bona fide protective variant. The opposite effects of protective versus PD associated LRRK2 variants on GTPase function and canonical Wnt signaling activity also suggests that regulation of these two basic signaling mechanisms is important for neuronal function. We conclude that LRRK2 mediated Wnt signaling and GTPase function are fundamental in conferring disease susceptibility and have clear implications for therapeutic target identification.


Changes in endoneurial fluid pressure, permeability, and peripheral nerve ultrastructure in experimental lead neuropathy.
The dynamics of endoneurial edema were studied by quantifying endoneurial fluid pressure (EFP) during the development of lead neuropathy and correlating these data with changes in blood-nerve barrier permeability and with morphological alterations in nerves, capillaries, and Schwann cells. EFP measured from the sciatic nerve in control Long-Evans rats was 2.1 +/- 1.0 cm H2O. EFP was significantly elevated 7 weeks after animals were started on a diet containing 6% lead carbonate, and it increased progressively until a plateau in pressure was reached between weeks 9 and 11. Thereafter, EFP gradually returned to normal values. The progressive increase in EFP was highly correlated with the extravasation of osmotically active macromolecules, traced by fluorescein isothiocyanate-dextran compounds of graded molecular weight and by horseradish peroxidase (HRP). Electron microscopy revealed extravasation of HRP between endothelial cells, intranuclear inclusions characteristic of lead poisoning in Schwann cell nuclei, demyelination, and remyelination. The observation of intranuclear inclusions consistent with lead deposition in Schwann cells strengthens the hypothesis that extravasated lead in the interstitial fluid causes direct injury to Schwann cells, giving rise to demyelination. Nerve compliance was determined.


Adoptive transfer of allergen-expressing B cells prevents IgE-mediated allergy.
Prophylactic strategies to prevent the development of allergies by establishing tolerance remain an unmet medical need. We previously reported that the transfer of autologous hematopoietic stem cells (HSC) expressing the major timothy grass pollen allergen, Phl p 5, on their cell surface induced allergen-specific tolerance in mice. In this study, we investigated the ability of allergen-expressing immune cells (dendritic cells, CD4+ T cells, CD8+ T cells, and CD19+ B cells) to induce allergen-specific tolerance in naive mice and identified CD19+ B cells as promising candidates for allergen-specific cell therapy. For this purpose, CD19+ B cells were isolated from Phl p 5-transgenic BALB/c mice and transferred to naive BALB/c mice, pre-treated with a short course of rapamycin and an anti-CD40L antibody. Subsequently, the mice were subcutaneously sensitized three times at 4-week intervals to Phl p 5 and Bet v 1 as an unrelated control allergen. Allergen-expressing cells were followed in the blood to monitor molecular chimerism, and sera were analyzed for Phl p 5- and Bet v 1-specific IgE and IgG1 levels by RBL assay and ELISA, respectively. In vivo allergen-induced lung inflammation was measured by whole-body plethysmography, and mast cell degranulation was determined by skin testing. The transfer of purified Phl p 5-expressing CD19+ B cells to naive BALB/c mice induced B cell chimerism for up to three months and prevented the development of Phl p 5-specific IgE and IgG1 antibody responses for a follow-up period of 26 weeks. Since Bet v 1 but not Phl p 5-specific antibodies were detected, the induction of tolerance was specific for Phl p 5. Whole-body plethysmography revealed preserved lung function in CD19+ B cell-treated mice in contrast to sensitized mice, and there was no Phl p 5-induced mast cell degranulation in treated mice. Thus, we demonstrated that the transfer of Phl p 5-expressing CD19+ B cells induces allergen-specific tolerance in a mouse model of grass pollen allergy. This approach could be further translated into a prophylactic regimen for the prevention of IgE-mediated allergy in humans.


Estimating glomerular filtration rate (GFR) in children. The average between a cystatin C- and a creatinine-based equation improves estimation of GFR in both children and adults and enables diagnosing Shrunken Pore Syndrome.
Estimating glomerular filtration rate (GFR) in adults by using the average of values obtained by a cystatin C- (eGFRcystatin C) and a creatinine-based (eGFRcreatinine) equation shows at least the same diagnostic performance as GFR estimates obtained by equations using only one of these analytes or by complex equations using both analytes. Comparison of eGFRcystatin C and eGFRcreatinine plays a pivotal role in the diagnosis of Shrunken Pore Syndrome, where low eGFRcystatin C compared to eGFRcreatinine has been associated with higher mortality in adults. The present study was undertaken to elucidate if this concept can also be applied in children. Using iohexol and inulin clearance as gold standard in 702 children, we studied the diagnostic performance of 10 creatinine-based, 5 cystatin C-based and 3 combined cystatin C-creatinine eGFR equations and compared them to the result of the average of 9 pairs of a eGFRcystatin C and a eGFRcreatinine estimate. While creatinine-based GFR estimations are unsuitable in children unless calibrated in a pediatric or mixed pediatric-adult population, cystatin C-based estimations in general performed well in children. The average of a suitable creatinine-based and a cystatin C-based equation generally displayed a better diagnostic performance than estimates obtained by equations using only one of these analytes or by complex equations using both analytes. Comparing eGFRcystatin and eGFRcreatinine may help identify pediatric patients with Shrunken Pore Syndrome.


No correlation between aggression and platelet (3)H-paroxetine binding in obsessive-compulsive disorder patients.
Different findings suggest that the serotonin (5-HT) system may be involved in both the regulation of aggression and the pathophysiology of obsessive-compulsive disorder (OCD). Our study aimed to evaluate the aggressive features of a group of OCD patients and to explore possible correlations with a serotonergic marker, namely platelet 5-HT transporter. Psychopathological and biological patterns were compared with those of a group of healthy controls and those of patients with major depression. Twenty-one patients affected by OCD, 21 by depression and 21 healthy controls were included in the study. Aggressive features were measured by means of the Buss and Durkee Hostility Inventory (BDHI). The platelet 5-HT transporter was evaluated by means of the (3)H-paroxetine binding parameters (maximum binding capacity, B(max) and dissociation constant, K(d)). The OCD patients showed a total score on the BDHI not significantly different from that of healthy controls and lower than that of depressed patients. The factor profile was similar in the 3 groups, but higher in the depressed patients. The irritability, resentment, guilt, negativism and suspiciousness factors were significantly more pronounced in depressed patients. Some sex-related difference in single factors were also observed. The B(max) of (3)H-paroxetine binding was lower in OCD patients than in depressives or healthy controls. OCD patients were more similar to healthy controls than to depressed patients with regard to aggressive features measured by means of the BDHI. This suggests that aggression in OCD is a complex phenomenon that probably requires specific instruments of evaluation.


Effect of fat intake on energy balance.
Most epidemiological studies indicate that obesity is more prevalent in populations consuming high fat diets. Furthermore, changes from a traditional to a westernized life style, characterized by a high-fat diet and decreased physical activity, result in dramatic increases in the prevalence and incidence of obesity in Native Americans, Pacific Islanders, and African populations. A possible explanation for the epidemic of obesity in response to high-fat intake can be found in the "oxidative hierarchy" that regulates macronutrient balance in the human body. Although carbohydrate and protein balances seem promptly regulated, fat balance is not. Short and midterm studies show that, unlike carbohydrate and protein intake, fat intake does not promote fat oxidation. Thus, "excess" fat intake results in fat deposition. As fat mass increases, so does fat oxidation, and a new equilibrium is reached when fat oxidation matches fat intake. However, there are large interindividual differences in this compensatory response to increased fat intake. Substrate oxidation is a familial trait, and individuals with a low fat-to-carbohydrate oxidation ratio are more prone to develop obesity than those with a high fat-to-carbohydrate oxidation ratio. Genetics may influence nutrient partitioning by influencing the activity of key enzymes of intermediate metabolism, such as lipoprotein lipase, beta-hydroxyl acyl CoA dehydrogenase, and acetyl CoA carboxylase.


Effect on the output of a luminescent solar concentrator on application of organic wavelength-selective mirrors.
To reduce surface loss in luminescent solar concentrators (LSCs), we systematically apply organic wavelength-selective mirrors, chiral nematic (cholesteric) liquid crystals, onto the LSCs with an air gap and determine their effect on waveguide output. The highest output is achieved using a scattering background and cholesteric mirror with a reflection band significantly redshifted (approximately 150 nm) from the emission peak of the fluorescent dye. The use of an air gap results in light bending away from the waveguide surface normal and, consequently, a redshift of the cholesteric mirrors is required. Up to 35% more dye-emitted light energy exits the waveguide edge after application of the cholesteric, and an increase in absolute edge power of 12% was found for a waveguide using a separate scatterer.


Decoding individual finger movements from one hand using human EEG signals.
Brain computer interface (BCI) is an assistive technology, which decodes neurophysiological signals generated by the human brain and translates them into control signals to control external devices, e.g., wheelchairs. One problem challenging noninvasive BCI technologies is the limited control dimensions from decoding movements of, mainly, large body parts, e.g., upper and lower limbs. It has been reported that complicated dexterous functions, i.e., finger movements, can be decoded in electrocorticography (ECoG) signals, while it remains unclear whether noninvasive electroencephalography (EEG) signals also have sufficient information to decode the same type of movements. Phenomena of broadband power increase and low-frequency-band power decrease were observed in EEG in the present study, when EEG power spectra were decomposed by a principal component analysis (PCA). These movement-related spectral structures and their changes caused by finger movements in EEG are consistent with observations in previous ECoG study, as well as the results from ECoG data in the present study. The average decoding accuracy of 77.11% over all subjects was obtained in classifying each pair of fingers from one hand using movement-related spectral changes as features to be decoded using a support vector machine (SVM) classifier. The average decoding accuracy in three epilepsy patients using ECoG data was 91.28% with the similarly obtained features and same classifier. Both decoding accuracies of EEG and ECoG are significantly higher than the empirical guessing level (51.26%) in all subjects (p<0.05). The present study suggests the similar movement-related spectral changes in EEG as in ECoG, and demonstrates the feasibility of discriminating finger movements from one hand using EEG. These findings are promising to facilitate the development of BCIs with rich control signals using noninvasive technologies.


Gene expression changes in the medial prefrontal cortex and nucleus accumbens following abstinence from cocaine self-administration.
Many studies of cocaine-responsive gene expression have focused on changes occurring during cocaine exposure, but few studies have examined the persistence of these changes with cocaine abstinence. Persistent changes in gene expression, as well as alterations induced during abstinence may underlie long-lasting drug craving and relapse liability. Whole-genome expression analysis was conducted on a rat cocaine binge-abstinence model that has previously been demonstrated to engender increased drug seeking and taking with abstinence. Gene expression changes in two mesolimbic terminal fields (mPFC and NAc) were identified in a comparison of cocaine-naïve rats with rats after 10 days of cocaine self-administration followed by 1, 10, or 100 days of enforced abstinence (n = 6-11 per group). A total of 1,461 genes in the mPFC and 414 genes in the NAc were altered between at least two time points (ANOVA, p < 0.05; +/- 1.4 fold-change). These genes can be subdivided into: 1) changes with cocaine self-administration that do not persist into periods of abstinence, 2) changes with cocaine self-administration that persist with abstinence, 3) and those not changed with cocaine self-administration, but changed during enforced abstinence. qPCR analysis was conducted to confirm gene expression changes observed in the microarray analysis. Together, these changes help to illuminate processes and networks involved in abstinence-induced behaviors, including synaptic plasticity, MAPK signaling, and TNF signaling.


Analysis of auditory phenotype and karyotype in 200 females with Turner syndrome.
Turner syndrome is the most common sex chromosome disorder in females, and is caused by a total or partial deletion of one X chromosome. The purpose of this study was to describe the auditory phenotype in a large group of individuals with Turner Syndrome, with analysis focusing on hearing loss and age, as well as the phenotypic relationship to karyotype variation. Our analysis of auditory function was part of a large-scale, natural history study in which clinical and genetic factors related to Turner syndrome were examined. This ascertainment avoids the bias inherent in studies of patients referred to audiology or otolaryngology specialty clinics. Analysis included data from 200 females with Turner syndrome ranging in age from 7 to 61 yr (mean=27.9 yr). We observed hearing loss in approximately one-half of females with Turner syndrome, and report on a common, previously unlabeled audiometric configuration found in 24% of ears tested. Our cross-sectional design revealed an observable deterioration in hearing loss above the averaged rate of age-related hearing loss seen in an otologically screened, standardized population. Karyotype analysis revealed air conduction thresholds that were significantly poorer in the 46, XdelXp and 46, XiXq groups than in the 46, XdelXq group. This natural history study provides a more representative description of the auditory phenotype associated with Turner syndrome than previous studies that may have been biased by the method of ascertainment. Correlative analysis of Turner syndrome-specific hearing loss features with karyotype revealed that air conduction threshold elevations are associated with loss of the p arm of chromosome X. Our cross-sectional data indicate a loss of hearing sensitivity at an accelerated rate beyond a normal age-related decline, which warrants continued audiologic monitoring in all females with Turner syndrome regardless of a history of normal hearing.


Risk Factors for 3-Year-Mortality and a Tool to Screen Patient in Dialysis Population.
Clinical parameters especially co-morbidities among end stage renal disease (ESRD) patients are associated with mortality. This study aims to determine the risk factors that are associated with mortality within three years among prevalent patients with ESRD. This is a cohort study where prevalent ESRD patients' details were recorded between May 2012 and October 2012. Their records were matched with national death record at the end of year 2015 to identify the deceased patients within three years. Four models were formulated with two models were based on logistic regression models but with different number of predictors and two models were developed based on risk scoring technique. The preferred models were validated by using sensitivity and specificity analysis. A total of 1332 patients were included in the study. Majority succumbed due to cardiovascular disease (48.3%) and sepsis (41.3%). The identified risk factors were mode of dialysis (P < 0.001), diabetes mellitus (P < 0.001), chronic heart disease (P < 0.001) and leg amputation (P = 0.016). The accuracy of four models was almost similar with AUC between 0.680 and 0.711. The predictive models from logistic regression model and risk scoring model were selected as the preferred models based on both accuracy and simplicity. Besides the mode of dialysis, diabetes mellitus and its complications are the important predictors for early mortality among prevalent ESRD patients. The models either based on logistic regression or risk scoring model can be used to screen high risk prevalent ESRD patients.


Longitudinal changes in serum cholesterol in man: an epidemiologic search for an etiology.
Serum cholesterol levels were determined in 1011 male participants of the Baltimore Longitudinal Study of Aging. This study presents the longitudinal changes in serum cholesterol from 1 July 1963 to 30 June 1977. Serum cholesterol values dropped 6% between 1970 and 1972. The span of this study was divided into two eras, one preceding and one following the drop. The effects of obesity, selected dietary constituents and physical activity were examined in an attempt to explain the secular change in serum cholesterol. Serum cholesterol levels were not significantly correlated to levels of weight or body mass index. Changes in weight were significantly positively correlated with changes in serum cholesterol. Overall, however, the study population did not experience a significant drop in weight and therefore, this relationship could not explain the observed drop in serum cholesterol. There were virtually no significant correlations between the absolute value of any of the dietary variables examined and the absolute level of serum cholesterol. There were significant but small changes in most dietary constituents; however, only changes in caloric intake were significantly positively correlated with changes in serum cholesterol. Because the overall change in caloric intake was small, it could explain less than 1 mg/dl of the 11 mg/dl drop. There was no overall change in physical activity. No significant correlations were found between either the level or change in physical activity and the level or change in serum cholesterol. It is concluded that neither weight nor physical activity could account for the observed changes in serum cholesterol. Changes in dietary constituents were significant and in a direction which would predict a lower serum cholesterol. However, for the group, dietary changes could not fully explain the drop in serum cholesterol. For individuals, the changes in diet poorly predicted changes in serum cholesterol. It is suggested that the observed secular drop in serum cholesterol may be due to factor(s) other than those studied.


TEL-AML1 fusion identifies a subset of children with standard risk acute lymphoblastic leukemia who have an excellent prognosis when treated with therapy that includes a single delayed intensification.
The Children's Cancer Group (CCG) found that children with moderate risk acute lymphoblastic leukemia (ALL) had an improved 5-year event-free survival (EFS) rate when treated with therapy that included a doubled delayed intensification (DDI) vs a single DI (SDI) phase. Because of increased toxicity with DDI, it is important to determine whether subgroups of children with ALL can be identified who have excellent outcomes with SDI therapy. TEL-AML1 fusion and hyperdiploid DNA content are present in the leukemic blasts of significant proportions of children with ALL and have been associated with an excellent prognosis. In this study, we retrospectively examined the impact of TEL-AML1 status and ploidy on treatment outcome in a cohort of 75 children with standard risk ALL treated at our institution between 1983 and 1993 with SDI therapy. TEL-AML1 fusion was present in 19/43 (44%) evaluable cases. Fifteen of 56 (27%) evaluable cases were classified as hyperdiploid based on a modal chromosome number of >/=51 and/or a DNA index of >/=1.16. The 7-year EFS was 81% for the 19 TEL-AML1-positive patients vs 54% for the 24 TEL-AML1-negative patients (P = 0.0264). In multivariate analyses, TEL-AML1-positive status was associated with a superior EFS (P = 0.02) even when the intial white blood count was included in the model. Overall survival (OS) at 7 years for TEL-AML1-positive patients was 100% vs 83% for TEL-AML1-negative patients (P = 0.0677). There were no differences in 7-year EFS or OS based on ploidy comparisons. These results underscore the need to examine closely the effects of treatment intensification on specific biologically defined subgroups of children with ALL.


[Ameliorating effects of dan-shen and its major ingredient calcium/magnesium lithospermate B on cognitive deficiencies in senescence-accelerated mouse].
Effect of the long-term treatment with a Dan-Shen (Salviae miltiorrhizae radix) methanol extract (DME) or its major ingredient lithospermate B (LSB) on memory and learning in scenescence-accelerated mouse (SAM) was investigated by means of Morris's water maze task. DME or LSB treatment significantly decreased the escape latency in the P8 strain of SAM (SAMP8), which strain spontaneously develops learning deficits. These results suggest that DME and LSB treatment improved spacial learning. Neurochemical investigations indicated that both drugs did not affect the cholinergic system, but enhanced functions of the glutamate-PKC system in hippocampus, since the increases in [3H]MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo[a,b]-cyclohepten-5,10-imine maleate) binding in cortex and [3H]PDBu (phorbol 12,13-dibutyrate) binding in hippocampus were observed in DME and LSB treatments. Our previous studies indicate the decrease in PDBu binding and NMDA receptor-mediated functions in SAMP8 brain. Thus, it is suggested that 1) Methanol extract of Dan-Shen is effective for prevention of spacial learning deficit caused with aging, 2) lithospermate B is one of the active ingredients, 3) SAMP8 is useful model animal to investigate drugs for anti-aging or anti-dementia.


Value of examining buffy coats for intragranulocytic micro-organisms in patients with fever.
To determine the significance of the presence of intragranulocytic micro-organisms in the blood buffy coat in patients with suspected infection, buffy coat examination and blood cultures were simultaneously performed in 455 consecutive patients with fever. There was no general correlation between the finding of intragranulocytic micro-organisms in the buffy coat and positive blood cultures. Patients with persistent bacteraemia and sterile blood cultures were, however, shown to have persistently positive buffy coat findings on repeated examination. These patients, who had culture-negative endocarditis or catheter-associated infections, had sterile blood cultures because of antibiotic treatment. Repeated positive findings in the buffy coat may therefore be valuable in detecting patients with persistent bacteraemia, but sporadic findings of micro-organisms in the buffy coats of acutely ill patients seem to have little diagnostic value.


[Comparative efficacy of drug combinations for anesthesia of short-term traumatological operations in children].
A prospective randomized study was conducted to evaluate the efficiency of two intravenous anesthesia modes in children during traumatological operations. Anesthesia induction and maintenance were carried out via intravenous injection of ketamine (2 mg/kg/hr) and propofol (4 mg/kg/hr) in Group 1 children and via that of propofol (4 mg/kg/ hr) and fentanyl (3 microg/kg/hr) in Group 2. The mean duration of operations was 43.6 +/- 27.8 and 29.6 +/- 17.8 min in Groups 1 and 2, respectively. No complications were observed in Group 1; short-term apnea was seen in 2 (7.6%) children during initial anesthesia in Group 2. The children of this group were also found to have lower respiration rate. Both drug combinations were ascertained to provide a sufficient anesthesia depth in non-intubated, spontaneously breathing children, but the use of a combination of propofol + ketamine (Group 1) produced no negative impact on hemodynamics and external respiration parameters, which allowed this combination to be recommended for short-term surgical interventions.


Oviposition preferences of dengue vectors; Aedes aegypti and Aedes albopictus in Sri Lanka under laboratory settings.
Investigations on oviposition behaviour of dengue vectors are critical for effective controlling of vector breeding. Therefore, the aim of the present study was to determine the oviposition behaviour of dengue vectors, Aedes aegypti and Aedes albopictus in Sri Lanka. Batches of 1000 adult mosquitoes (1 : 1, male: female ratio) housed in rearing cages were used for each experimental setup from Ae. aegypti and Ae. albopictus. Oviposition responses with respect to the size of the ovitrap, colours of the ovitrap, water source, sodium chloride (NaCl) concentration and presence/absence of larvae were evaluated by enumerating the number of eggs laid in the ovitraps. The analysis of variance and cluster analysis were used to investigate the significance in the variations among oviposition. The number of eggs laid by both species were improved with the increasing size of ovitraps. Ae. albopictus indicated the highest mean number of eggs in 0.2% of NaCl than in the ovitraps filled with distilled water. However, the egg laying preference was reduced with increasing salinity in both species. Drain water with low dissolved oxygen (DO) level (0.43 ± 0.12 mg l-1) was the preferred water source for both species, while a significantly high oviposition rate was observed in ovitraps with larvae. Black colour ovitraps attracted the majority of gravid females, while white was least preferred. There were no significant variations among oviposition behaviours of Ae. albopictus and Ae. aegypti. The ability of these vectors to breed in waste water with low DO levels may lead them to attain wide dissemination in the natural environment, enhancing their potential threat to human life.


Energy recovery from saline water by means of electrochemical cells.
An electrochemical concentration cell is proposed as a means of extracting the energy released from the mixing of freshwater with seawater. In order to obtain the maximum power from such a cell, a small amount of seawater must be added to the freshwater prior to its introduction into the cell in order to lower the internal resistance of the cell. The work available from the electrochemical concentration cell is of the same order of magnitude as the work derived from the use of an osmotic pump to extract energy from seawater. Both of these saline water techniques should be considered when unconventional, long-range power sources are evaluated.


Epidermal growth factor receptor (EGFR) signaling requires a specific endoplasmic reticulum thioredoxin for the post-translational control of receptor presentation to the cell surface.
The epidermal growth factor receptor (EGFR) is a well characterized receptor-tyrosine kinase that functions in development and serves a vital role in many human cancers. Understanding EGFR regulatory mechanisms, and hence approaches for clinical intervention, has focused on ligand-receptor interactions and tyrosine kinase activity. Here, we show using the NCI-H460 lung and A431 epidermoid human cancer cell lines that EGFR binding to anterior gradient homolog 2 (AGR2) in the endoplasmic reticulum is required for receptor delivery to the plasma membrane and thus EGFR signaling. Reduced AGR2 protein levels or mutation of an essential cysteine in the active site result in decreased cell surface EGFR and a concomitant decrease in signaling as reflected by AREG, EGR1, and FOS expression. Similar to previously described EGFR nulls, an AGR2 null also resulted in embryonic lethality. Consistent with its role in regulating EGFR-mediated signaling, AGR2 expression is also enhanced in many human cancers and promotes the transformed phenotype. Furthermore, EGFR-mediated signaling in NCI-H460 cells, which are resistant to the tyrosine kinase inhibitor AG1478, is also disrupted with reduced AGR2 expression. The results provide insights into why cancer prognosis or response to therapy often does not correlate with EGFR protein or RNA levels because they do not reflect delivery to the cell surface where signaling is initiated. AGR2, therefore, represents a novel post-translational regulator of EGFR-mediated signaling and a promising target for treating human cancers.


Single-fulcrum laparoscopic cholecystectomy: a single-incision and multi-port technique.
Single-incision laparoscopic cholecystectomy (LC) is still technically demanding and usually requires specially designed instruments. This article describes our own technique, a single-fulcrum LC using only standard ports and instruments. Between March 2009 and December 2010, 130 consecutive patients, all scheduled to undergo elective LC, underwent this single-fulcrum LC for benign gallbladder disease. Perioperative surgical outcomes were retrospectively evaluated. One hundred and ten patients (84.6%) underwent successful single-fulcrum LC, and 20 patients (15.4%) were converted to conventional surgery (n= 18) or required additional trocars (n= 2) during the procedure because of umbilical hernia (n= 3), severe inflammation or adhesion (n= 9), impacted cystic duct stone (n= 3), anatomical anomaly (n= 3) and iatrogenic injury (n= 2). Two intraoperative complications (iatrogenic injury) were securely managed using additional trocars and there was no post-operative morbidity or mortality. This single-fulcrum LC could be performed with comparable cost to conventional LC, and the sequential operative time showed reasonable learning curve. Single-fulcrum LC is feasible, safe and quite reproducible. The surgical wound can be dramatically reduced at a similar cost to conventional LC. It may be an alternative procedure for most uncomplicated benign gallbladder disease.


OSTEOSYNTHESIS OF PROXIMAL HUMERAL END FRACTURES WITH FIXED-ANGLE PLATE AND LOCKING SCREWS: TECHNIQUE AND RESULTS.
Describe the results of proximal humeral fractures surgically treated with the Philos locking plate system. Between March 2003 and October 2004 we prospectively reviewed 24 of 26 patients with proximal humerus fractures treated with a Philos plate. The mean follow-up time was 12 months and the mean age of patients was 57 years. Six patients had four-part proximal humerus fractures, 11 patients had three-part proximal humerus fractures, and nine patients had two-part proximal humerus fractures. Clinical evaluation was performed using the University of California at Los Angeles (UCLA) criteria. The mean UCLA score was 30 points (17-34). All fractures showed union. Three patients showed fracture union at varus position. The mean UCLA score for these patients was 27 points. Osteosynthesis with Philos plate provides a stable fixation method with good functional outcome.


Overdentures for acquired and congenital anomalies: 2. Partial overdentures.
The use of complete overdentures for the restoration of acquired and congenital anomalies has been advocated for many years. This therapeutic approach can provide an esthetic and functional restoration for missing, malformed, or discolored dentition. For some patients, tissue coverage similar to a complete denture is disconcerting, especially when the majority of the teeth are present. The removable partial overdenture provides a functional, esthetic, and economical alternative. A technique is described for the fabrication of the partial overdenture for acquired and congenital anomalies.


Rapid stabilisation of atherosclerotic plaque with 5-aminolevulinic acid-mediated sonodynamic therapy.
5-Aminolevulinic acid-mediated sonodynamic therapy (ALA-SDT) effectively induces the apoptosis of atherogenic macrophages, but whether it can stabilise atherosclerotic plaque in vivo is unclear. Here, we used an animal model to evaluate the effects of ALA-SDT on plaque stabilisation. Sixty rabbits were induced atherosclerotic plaques in the femoral artery with a combination of silastic tube placement with atherogenic diet, and randomly assigned into control (n = 12) and SDT (n = 48) groups. In the SDT group, after intravenous injected with ALA (60 mg/kg) animals underwent the treatment of ultrasound with intensities of 0.75, 1.00, 1.50 and 2.00 W/cm(²) (n = 12 for each intensity). Seven days after the treatment, the plaque disruption assay was performed to test plaque stability. We found that ALA-SDT with ultrasound intensity of 1.5 W/cm(²) showed the strongest efficacy to stabilise plaques. Under this condition, the frequency of plaque disruption decreased by 88% (p<0.01), positive area of macrophages reduced by 94% (p<0.001) and percentage content of lipids dropped by 60% (p < 0.001), while percentage content of collagens increased by 127% (p<0.001). We also found that the plaque stabilisation by ALA-SDT was associated with increased macrophage apoptosis and apoptotic cell clearance. Moreover, ALA-SDT decreased the contents and activities of matrix metalloproteinase-2,9 and increased the levels of tissue inhibitors of matrix metalloproteinase-1,2 in plaques. Our studies demonstrate that ALA-SDT promotes plaque stabilisation by inducing macrophage elimination and inhibiting matrix degradation. This method might be a promising regimen for atherosclerosis therapy.


Ocular involvement in Behçet's disease.
Behçet's disease is a chronic systemic disorder characterized by recurrent uveitis, aphthous lesions of the mouth, and ulcerations of the genitalia. Vision loss from ocular involvement is frequently the presenting symptom and optometrists should be aware of the various ocular signs of Behçet's disease. Management of the Behçet's patient involves systemic therapy and therefore requires comanagement with an internist and/or ophthalmologist. A case report of this infrequent type of uveitis is described along with a discussion of the care and visual prognosis of the Behçet's patient.


Logical Connectives Modulate Attention to Simulations Evoked by the Constituents They Link Together.
In previous studies investigating logical-connectives simulations, participants focused their attention on verifying truth-condition satisfaction for connective expressions describing visual stimuli (e.g., Dumitru, 2014; Dumitru and Joergensen, 2016). Here, we sought to replicate and extend the findings that conjunction and disjunction simulations are structured as one and two Gestalts, respectively, by using language - picture matching tasks where participants focused their attention exclusively on stimuli visuospatial properties. Three studies evaluated perceptual compatibility effects between visual displays varying stimuli direction, size, and orientation, and basic sentences featuring the logical connectives AND, OR, BUT, IF, ALTHOUGH, BECAUSE, and THEREFORE (e.g., "There is blue AND there is red"). Response times highlight correlations between the Gestalt arity of connective simulations and visual attention patterns, such that words referring to constituents in the same Gestalt were matched faster to visual stimuli displayed sequentially rather than alternatively, having the same size rather than different sizes, and being oriented along axes other than horizontal. The results also highlight attentional patterns orthogonal to Gestalt arity: visual stimuli corresponding to simulation constituents were processed faster when they appeared onscreen from left to right than from right to left, when they were emphasized or de-emphasized together (i.e., faster processing of all-small or all-large stimuli pairs), and when they formed a downward-oriented diagonal, which signals a simulation boundary. More generally, our findings suggest that logical connectives rapidly evoke simulations that trigger top-down attention patterns over the grouping and properties of visual stimuli corresponding to the constituents they link together.


Early proteomic analysis may allow noninvasive identification of hepatitis C response to treatment with pegylated interferon α-2b and ribavirin.
Chronic hepatitis C virus (HCV) infection represents a significant disease burden worldwide. Approximately 170 million people are chronically infected. HCV can lead to liver fibrosis, cirrhosis and hepatocellular carcinoma. Current standard treatment with pegylated interferon and ribavirin is suboptimal and up to 60% of patients fail to respond. Week 4 and 12 HCV RNA is used as a marker of response with nonresponders at 12 weeks discontinuing treatment. Earlier identification of nonresponders using novel biomarkers would be beneficial in preventing unnecessary toxicities and cost. This study profiled the proteomic response to treatment in HCV patients within the first 24 h using surface-enhanced laser desorption-ionization time-of-flight mass spectrometry (SELDI-TOF MS). Serum from 25 HCV infected individuals during the initial 24 h of treatment was profiled using SELDI-TOF MS. Arrays were analyzed on the ProteinChip Reader and time-of-flight spectra were generated. Peak detection was performed by Biomarker Wizard software and analyzed using BioConductor packages. Significant differences were seen between the proteomic profiles of responders and nonresponders to treatment. Overall 70 peaks differentiated responders from nonresponders. A random forest classifier identified a panel of 20 peaks, which differentiated responders from nonresponders with 87.4% accuracy. The CM10 chip revealed 16 peaks identifying genotype 1 responders from nonresponders. This study identifies early proteomic spectra as potential predictors of HCV treatment response using SELDI-TOF MS. This illustrates the importance of early biomarkers in the prediction of response within the first 24 h, which may aid in tailoring HCV treatment regimens.


Hydrogen sulfide-negative variant of Citrobacter.
The characteristics of 25 hydrogen sulfide-negative strains of Citrobacter were studied. The majority of isolates were from the respiratory tract and usually were of indeterminate clinical significance. All strains were highly susceptible to polymyxin B, gentamicin, kanamycin, nalidixic acid, and nitrofurantoin.


Electrophysiological and morphological maturation of murine fetal cardiomyocytes during electrical stimulation in vitro.
The aim of this study was to investigate whether continuous electrical stimulation affects electrophysiological properties and cell morphology of fetal cardiomyocytes (FCMs) in culture. Fetal cardiomyocytes at day 14.5 post coitum were harvested from murine hearts and electrically stimulated for 6 days in culture using a custom-made stimulation chamber. Subsequently, action potentials of FCM were recorded with glass microelectrodes. Immunostainings of α-Actinin, connexin 43, and vinculin were performed. Expression of ion channel subunits Kcnd2, Slc8a1, Cacna1, Kcnh2, and Kcnb1 was analyzed by quantitative reverse-transcriptase polymerase chain reaction. Action potential duration to 50% and 90% repolarization (APD50 and APD90) of electrically stimulated FCMs were significantly decreased when compared to nonstimulated control FCM. Alignment of cells was significantly higher in stimulated FCM when compared to control FCM. The expression of connexin 43 was significantly increased in stimulated FCM when compared to control FCM. The ratio between cell length and cell width of the stimulated FCM was significantly higher than in control FCM. Kcnh2 and Kcnd2 were upregulated in stimulated FCM when compared to control FCM. Expression of Slc8a1, Cacna1c, and Kcnb1 was not different in stimulated and control FCMs. The decrease in APD50 observed after electrical stimulation of FCM in vitro corresponds to the electrophysiological maturation of FCM in vivo. Expression levels of ion channels suggest that some important but not all aspects of the complex process of electrophysiological maturation are promoted by electrical stimulation. Parallel alignment, increased connexin 43 expression, and elongation of FCM are signs of a morphological maturation induced by electrical stimulation.


Interaction of selection and biased gene conversion in a multigene family.
A model of the evolutionary dynamics of a multigene family in a finite population under the joint effects of selection and (possibly biased) gene conversion is analyzed. It is assumed that the loss or fixation of a polymorphism at any particular locus in the gene family occurs on a much faster time scale than the introduction of new alleles to a monomorphic locus by gene conversion. A general formula for the fixation of a new allele throughout a multigene family for a wide class of selection functions with biased gene conversion is given for this assumption. Analysis for the case of additive selection shows that (i) unless selection is extremely weak or bias is exceptionally strong, selection usually dominates the fixation dynamics, (ii) if selection is very weak, then even a slight conversion bias can greatly alter the fixation probabilities, and (iii) if both selection and conversion bias are sufficiently small, the substitution rate of new alleles throughout a multigene family is approximately the single locus mutation rate, the same result as for neutral alleles at a single-copy gene. Finally, I analyze a fairly general class of underdominant speciation models involving multigene families, concluding for these models under weak conversion that although the probability of fixation may be relatively high, the expected time to fixation is extremely long, so that speciation by "molecular drive" is unlikely. Furthermore, speciation occurs faster by fixing underdominant alleles of the same effect at single-copy genes than by fixing the same number of loci in a single multigene family under the joint effects of selection, conversion, and drift.


Closure of abdominal wounds with polydioxanone. A prospective study.
Polydioxanone, an absorbable synthetic monofilament suture, was used to close abdominal wounds in 200 consecutive operative procedures. All patients were followed up for one year. Despite a high incidence of risk factors for impaired wound healing, the incidence of dehiscence and evisceration was zero; incisional hernia occurred in 2.9% of vertical midline wounds and in 3.6% of transverse incisions. This new suture material is safe and effective for closure of abdominal wounds.


Efficient degradation of 2,4,6-Trichlorophenol requires a set of catabolic genes related to tcp genes from Ralstonia eutropha JMP134(pJP4).
2,4,6-Trichlorophenol (2,4,6-TCP) is a hazardous pollutant. Several aerobic bacteria are known to degrade this compound. One of these, Ralstonia eutropha JMP134(pJP4), a well-known, versatile chloroaromatic compound degrader, is able to grow in 2,4,6-TCP by converting it to 2,6-dichlorohydroquinone, 6-chlorohydroxyquinol, 2-chloromaleylacetate, maleylacetate, and beta-ketoadipate. Three enzyme activities encoded by tcp genes, 2,4,6-TCP monooxygenase (tcpA), 6-chlorohydroxyquinol 1,2-dioxygenase (tcpC), and maleylacetate reductase (tcpD), are involved in this catabolic pathway. Here we provide evidence that all these tcp genes are clustered in the R. eutropha JMP134(pJP4) chromosome, forming the putative catabolic operon tcpRXABCYD. We studied the presence of tcp-like gene sequences in several other 2,4,6-TCP-degrading bacterial strains and found two types of strains. One type includes strains belonging to the Ralstonia genus and possessing a set of tcp-like genes, which efficiently degrade 2,4,6-TCP and therefore grow in liquid cultures containing this chlorophenol as a sole carbon source. The other type includes strains belonging to the genera Pseudomonas, Sphingomonas, or Sphingopixis, which do not have tcp-like gene sequences and degrade this pollutant less efficiently and which therefore grow only as small colonies on plates with 2,4,6-TCP. Other than strain JMP134, none of the bacterial strains whose genomes have been sequenced possesses a full set of tcp-like gene sequences.


Design and Implementation of a Portable Impedance Cardiography System for Noninvasive Stroke Volume Monitoring.
Measurement of the stroke volume (SV) and its changes over time can be very helpful for diagnosis of dysfunctions in the blood circulatory system and monitoring their treatments. Impedance cardiography (ICG) is a simple method of measuring the SV based on changes in the instantaneous mean impedance of the thorax. This method has received much attention in the last two decades because it is noninvasive, easy to be used, and applicable for continuous monitoring of SV as well as other hemodynamic parameters. The aim of this study was to develop a low-cost portable ICG system with high accuracy for monitoring SV. The proposed wireless system uses a tetrapolar configuration to measure the impedance of the thorax at 50 kHz. The system consists of carefully designed precise voltage-controlled current source, biopotential recorder, and demodulator. The measured impedance was analyzed on a computer to determine SV. After evaluating the system's electronic performance, its accuracy was assessed by comparing its measurements with the values obtained from Doppler echocardiography (DE) on 5 participants. The implemented ICG system can noninvasively provide a continuous measure of SV. The signal to noise ratio of the system was measured above 50 dB. The experiments revealed that a strong correlation (r = 0.89) exists between the measurements by the developed system and DE (P < 0.05). ICG as the sixth vital sign can be measured simply and reliably by the developed system, but more detailed validation studies should be conducted to evaluate the system performance. There is a good promise to upgrade the system to a commercial version domestically for clinical use in the future.