Treatment of periodontitis for glycaemic control in people with diabetes mellitus.
Glycaemic control is a key component in diabetes mellitus (diabetes) management. Periodontitis is the inflammation and destruction of the underlying supporting tissues of the teeth. Some studies have suggested a bidirectional relationship between glycaemic control and periodontitis. Treatment for periodontitis involves subgingival instrumentation, which is the professional removal of plaque, calculus, and debris from below the gumline using hand or ultrasonic instruments. This is known variously as scaling and root planing, mechanical debridement, or non-surgical periodontal treatment. Subgingival instrumentation is sometimes accompanied by local or systemic antimicrobials, and occasionally by surgical intervention to cut away gum tissue when periodontitis is severe. This review is part one of an update of a review published in 2010 and first updated in 2015, and evaluates periodontal treatment versus no intervention or usual care. OBJECTIVES: To investigate the effects of periodontal treatment on glycaemic control in people with diabetes mellitus and periodontitis. An information specialist searched six bibliographic databases up to 7 September 2021 and additional search methods were used to identify published, unpublished, and ongoing studies. SELECTION CRITERIA: We searched for randomised controlled trials (RCTs) of people with type 1 or type 2 diabetes mellitus and a diagnosis of periodontitis that compared subgingival instrumentation (sometimes with surgical treatment or adjunctive antimicrobial therapy or both) to no active intervention or 'usual care' (oral hygiene instruction, education or support interventions, and/or supragingival scaling (also known as PMPR, professional mechanical plaque removal)). To be included, the RCTs had to have lasted at least 3 months and have measured HbA1c (glycated haemoglobin). At least two review authors independently examined the titles and abstracts retrieved by the search, selected the included trials, extracted data from included trials, and assessed included trials for risk of bias. Where necessary and possible, we attempted to contact study authors. Our primary outcome was blood glucose levels measured as glycated (glycosylated) haemoglobin assay (HbA1c), which can be reported as a percentage of total haemoglobin or as millimoles per mole (mmol/mol). Our secondary outcomes included adverse effects, periodontal indices (bleeding on probing, clinical attachment level, gingival index, plaque index, and probing pocket depth), quality of life, cost implications, and diabetic complications. We included 35 studies, which randomised 3249 participants to periodontal treatment or control. All studies used a parallel-RCT design and followed up participants for between 3 and 12 months. The studies focused on people with type 2 diabetes, other than one study that included participants with type 1 or type 2 diabetes. Most studies were mixed in terms of whether metabolic control of participants at baseline was good, fair, or poor. Most studies were carried out in secondary care. We assessed two studies as being at low risk of bias, 14 studies at high risk of bias, and the risk of bias in 19 studies was unclear. We undertook a sensitivity analysis for our primary outcome based on studies at low risk of bias and this supported the main findings. Moderate-certainty evidence from 30 studies (2443 analysed participants) showed an absolute reduction in HbA1c of 0.43% (4.7 mmol/mol) 3 to 4 months after treatment of periodontitis (95% confidence interval (CI) -0.59% to -0.28%; -6.4 mmol/mol to -3.0 mmol/mol). Similarly, after 6 months, we found an absolute reduction in HbA1c of 0.30% (3.3 mmol/mol) (95% CI -0.52% to -0.08%; -5.7 mmol/mol to -0.9 mmol/mol; 12 studies, 1457 participants), and after 12 months, an absolute reduction of 0.50% (5.4 mmol/mol) (95% CI -0.55% to -0.45%; -6.0 mmol/mol to -4.9 mmol/mol; 1 study, 264 participants). Studies that measured adverse effects generally reported that no or only mild harms occurred, and any serious adverse events were similar in intervention and control arms. However, adverse effects of periodontal treatments were not evaluated in most studies. Our 2022 update of this review has doubled the number of included studies and participants, which has led to a change in our conclusions about the primary outcome of glycaemic control and in our level of certainty in this conclusion. We now have moderate-certainty evidence that periodontal treatment using subgingival instrumentation improves glycaemic control in people with both periodontitis and diabetes by a clinically significant amount when compared to no treatment or usual care. Further trials evaluating periodontal treatment versus no treatment/usual care are unlikely to change the overall conclusion reached in this review.


Scalable efficient expansion of mesenchymal stem cells in xeno free media using commercially available reagents.
The rapid clinical translation of mesenchymal stem cells (MSC) has resulted in the development of cell-based strategies for multiple indications. Unfortunately one major barrier to widespread implementation of MSC-based therapies is the limited supply of fetal calf serum (FCS) used to expand cells to therapeutic numbers. Additionally, the xenogeneic element of fetal calf serum has been previously demonstrated to stimulate antibody mediated reactions and in some cases sensitization leading to anaphylaxis. XcytePLUS™ media, a human platelet lysate based product, was used to supplement the culture medium at 5, 7.5 and 10% and compared to fetal calf serum at 10%, for human umbilical cord MSC expansion. Properties of the expanded cells were investigated. This study demonstrated equivalent or superior effects of human platelet lysate compared to standard FCS supplemented media, based on doubling rate, without loss of identity or function, as demonstrated with flow cytometry characterization. Differentiation into osteocytes, adipocytes and chondrocytes was comparable from cells expanded in either media supplement. These data support the implementation of human platelet lysate supplemented media as an alternative to xenogeneic containing preparations which may lead to safer MSC products with therapeutic uses.


Fatigue, quality of life and metabolic changes in men treated with first-line enzalutamide versus abiraterone plus prednisolone for metastatic castration-resistant prostate cancer (HEAT): a randomised trial protocol.
Enzalutamide and abiraterone acetate plus prednisolone (AAP) are used in combination with androgen-deprivation therapy to further suppress the androgen stimulation of metastatic castration-resistant prostate cancer (mCRPC). First-line mCRPC treatment with enzalutamide and AAP yields similar overall survival and radiographic progression-free survival in phase III trials. Thus, treatment selection relies on patient choice, cost and side effects. The aim of this randomised trial is to investigate differences in fatigue, health-related quality of life (HRQoL) and metabolic side effects in men with mCRPC treated with first-line enzalutamide versus AAP. In this ongoing open-label randomised (1:1) clinical trial, enzalutamide is compared with AAP as first-line treatment for men with mCRPC. The primary endpoint is fatigue assessed with the questionnaire Functional Assessment of Chronic Illness Therapy-Fatigue version 4. Secondary endpoints are changes in body composition (ie, fat mass, visceral adipose tissue, subcutaneous adipose tissue and lean body mass assessed with dual energy X-ray absorptiometry), glucose metabolism assessed with a 2-hour oral glucose tolerance test, serum lipids, blood pressure and HRQoL assessed with the questionnaire Functional Assessment of Cancer Therapy-Prostate (FACT-P). All study endpoints are assessed at baseline and 12-week postintervention. Blood and urine samples are collected at baseline and at time of progression on allocated treatment for future investigation of predictive and prognostic biomarkers in prostate cancer treatment. The planned sample size is 170 participants. All participants are recruited from Herlev and Gentofte Hospital, Denmark. Estimated last patient's last visit is February 2020. The study received project approval from the National Committee on Health Research Ethics and Danish Data Protection Agency and Danish Medicines Agency (EudraCT no.: 2017-000027-99). The results of the study will be published in peer-reviewed international journals and will be presented at national and international conferences and symposiums. Clinicaltrialsregister.eu (2017-000099-27).


Inhibition of biofouling by modification of forward osmosis membrane using quaternary ammonium cation.
In the operation of the forward osmosis (FO) process, biofouling of the membrane is a potentially serious problem. Development of an FO membrane with antibacterial properties could contribute to a reduction in biofouling. In this study, quaternary ammonium cation (QAC), a widely used biocidal material, was conjugated with a silane coupling agent (3-(trimethoxysilyl)-propyldimethyloctadecyl ammonium chloride) and used to modify an FO membrane to confer antibacterial properties. Fourier transform infrared spectroscopy (FT-IR) demonstrated that the conjugated QAC was successfully immobilized on the FO membrane via covalent bonding. Bacterial viability on the QAC-modified membrane was confirmed via colony count method and visualized via bacterial viability assay. The QAC membrane decreased the viability of Escherichia coli to 62% and Staphylococcus aureus to 77% versus the control membrane. Inhibition of biofilm formation on the QAC modified membrane was confirmed via anti-biofilm tests using the drip-flow reactor and FO unit, resulting in 64% and 68% inhibition in the QAC-modified membrane against the control membrane, respectively. The results demonstrate the effectiveness of the modified membrane in reducing bacterial viability and inhibiting biofilm formation, indicating the potential of QAC-modified membranes to decrease operation costs incurred by biofouling.


Idiopathic lymphoplasmacytic rhinitis in dogs: 37 cases (1997-2002).
To determine clinical signs and rhinoscopic, computed tomographic, and histologic abnormalities in dogs with idiopathic lymphoplasmacytic rhinitis. Retrospective case series. 37 dogs. Clinical information was obtained from medical records. Nasal computed tomographic images and histologic slides of biopsy specimens were reviewed. Dogs ranged from 1.5 to 14 years old (mean, 8 years); most (28) were large-breed dogs. Nasal discharge was unilateral in 11 of 26 (42%) dogs and bilateral in 15 of 26 (58%) dogs. In dogs with unilateral disease, duration of clinical signs ranged from 1.5 to 36 months (mean, 8.25 months; median, 2 months), and in dogs with bilateral disease, duration of signs ranged from 1.25 to 30 months (mean, 6.5 months; median, 4 months). Computed tomography (n = 33) most often revealed fluid accumulation (27/33 [82%]), turbinate destruction (23/33 [70%]), and frontal sinus opacification (14/33 [42%]). Rhinoscopy (n = 37) commonly demonstrated increased mucus and epithelial inflammation; turbinate destruction was detected in 8 of 37 (22%) dogs. Bilateral biopsy specimens from all 37 dogs were examined. Four dogs had only unilateral inflammatory changes. The remaining 33 dogs had bilateral lesions; in 20, lesions were more severe on 1 side than the other. Findings suggest that idiopathic lymphoplasmacytic rhinitis is a key contributor to chronic nasal disease in dogs and may be more common than previously believed. In addition, findings suggest that idiopathic lymphoplasmacytic rhinitis is most often a bilateral disease, even among dogs with unilateral nasal discharge.


Identification of DXCF cyanobacteriochrome lineages with predictable photocycles.
Diverse organisms use phytochrome photoreceptors to measure the ratio of red to far-red light in their respective environments. In addition to red/far-red phytochromes, many cyanobacteria contain distantly related cyanobacteriochrome (CBCR) photosensors that also use photoisomerization of a covalently bound linear tetrapyrrole (bilin) chromophore to measure multiple colors of light. CBCRs exhibit a remarkable variety of photocycles spanning the near ultraviolet and the entire visible spectrum. One group of CBCRs, distinguished by the presence of a conserved Asp-Xaa-Cys-Phe (DXCF) motif or variations thereon, includes members with violet/green, blue/teal, blue/green, blue/yellow, blue/orange, green/blue and green/teal photocycles. To date, it has not proven possible to predict such photocycles from primary amino acid sequence. We here use site-directed mutagenesis, phylogenetic analysis, and characterization of six new CBCRs to probe structure/function relationships in DXCF CBCRs. This approach has defined two groups of DXCF CBCRs with specialized green/blue and blue/orange photocycles that are robustly predictable from primary sequence data. Such knowledge facilitates the use of CBCRs for synthetic photobiological applications and informs approaches to understand the roles of CBCRs in cyanobacterial photobiology.


Predictors of metabolic monitoring among schizophrenia patients with a new episode of second-generation antipsychotic use in the Veterans Health Administration.
To examine the baseline metabolic monitoring (MetMon) for second generation antipsychotics (SGA) among patients with schizophrenia in the Veterans Integrated Service Network (VISN) 16 of the Veterans Health Administration (VHA). VISN16 electronic medical records for 10/2002-08/2005 were used to identify patients with schizophrenia who received a new episode of SGA treatment after 10/2003, in which the VISN 16 baseline MetMon program was implemented. Patients who underwent MetMon (MetMon+: either blood glucose or lipid testing records) were compared with patients who did not (MetMon-), on patient characteristics and resource utilization in the year prior to index treatment episode. A parsimonious logistic regression was used to identify predictors for MetMon+ with adjusted odds ratios (OR) and 95% confidence intervals (CI). Out of 4,709 patients, 3,568 (75.8%) underwent the baseline MetMon. Compared with the MetMon- group, the MetMon+ patients were found more likely to have baseline diagnoses or mediations for diabetes (OR [CI]: 2.336 [1.846-2.955]), dyslipidemia (2.439 [2.029-2.932]), and hypertension (1.497 [1.287-1.743]), substance use disorders (1.460 [1.257-1.696]), or to be recorded as obesity (2.052 [1.724-2.443]). Increased likelihood for monitoring were positively associated with number of antipsychotics during the previous year (FGA: 1.434 [1.129-1.821]; SGA: 1.503 [1.290-1.751]). Other significant predictors for monitoring were more augmentation episodes (1.580 [1.145-2.179]), more outpatient visits (1.007 [1.002-1.013])), hospitalization days (1.011 [1.007-1.015]), and longer duration of antipsychotic use (1.001 [1.001-1.001]). Among the MetMon+ group, approximately 38.9% patient had metabolic syndrome. This wide time window of 180 days, although congruent with the VHA guidelines for the baseline MetMon process, needs to be re-evaluated and narrowed down, so that optimally the monitoring event occurs at the time of receiving a new episode of SGA treatment. Future research will examine whether or not patients prescribed an SGA are assessed for metabolic syndrome following the index episode of antipsychotic therapy, and whether or not such baseline and follow-up monitoring programs in routine care are cost-effective. The baseline MetMon has been performed for a majority of the VISN 16 patients with schizophrenia prior to index SGA over the study period. Compared with MetMon- group, MetMon+ patients were more likely to be obese and manifest a more severe illness profile.


Visuomotor transformations underlying arm movements toward visual targets: a neural network model of cerebral cortical operations.
We propose a biologically realistic neural network that computes coordinate transformations for the command of arm reaching movements in 3-D space. This model is consistent with anatomical and physiological data on the cortical areas involved in the command of these movements. Studies of the neuronal activity in the motor (Georgopoulos et al., 1986; Schwartz et al., 1988; Caminiti et al., 1990a) and premotor (Caminiti et al., 1990b, 1991) cortices of behaving monkeys have shown that the activity of individual arm-related neurons is broadly tuned around a preferred direction of movements in 3-D space. Recent data demonstrate that in both frontal areas (Caminiti et al., 1990a,b, 1991) these cell preferred directions rotate with the initial position of the arm. Furthermore, the rotation of the population of preferred directions precisely corresponds to the rotation of the arm in space. The neural network model computes the motor command by combining the visual information about movement trajectory with the kinesthetic information concerning the orientation of the arm in space. The appropriate combination, learned by the network from spontaneous movement, can be approximated by a bilinear operation that can be interpreted as a projection of the visual information on a reference frame that rotates with the arm. This bilinear combination implies that neural circuits converging on a single neuron in the motor and premotor cortices can learn and generalize the appropriate command in a 2-D subspace but not in the whole 3-D space. However, the uniform distribution of cell preferred directions in these frontal areas can explain the computation of the correct solution by a population of cortical neurons. The model is consistent with the existing neurophysiological data and predicts how visual and somatic information can be combined in the different processing steps of the visuomotor transformation subserving visual reaching.


Effects of microcurrent and cryotherapy on C-reactive protein levels and muscle tone of patients with rotator cuff reconstruction.
[Purpose] The purpose of the present study was to apply early intervention via microcurrent and cryotherapy in patients who underwent rotator cuff reconstruction surgery, and to investigate the effects of such interventions on pain and inflammation levels based on the analysis of C-reactive protein (CRP) levels, and on changes in muscle tone. [Subjects and Methods] The study population consisted of 30 patients who had undergone rotator cuff reconstruction surgery, with 10 patients each assigned to the control, experimental I (E-1), and experimental II (E-II) groups. On the day after surgery, muscle tone, blood CRP level, and pain were measured. For the following two weeks, continues passive motion (CPM), icing, cryotherapy, and microcurrent were applied to the each group. After the respective interventions, CRP levels, pain, and muscle tone near the shoulder area were measured again. [Results] In the post-hoc test of between-group comparison, a statistically significant difference in CRP level was found in the cryotherapy group. A difference in shoulder muscle tone appeared only in the supraspinatus muscle, with post-hoc test results showing that the biggest change occurred in the cryotherapy group. [Conclusion] Cryotherapy may be able to help stabilize inflammation as well as reduce pain and muscle tension when applied in patients following rotator cuff reconstruction.


Cetuximab-induced anaphylaxis and IgE specific for galactose-alpha-1,3-galactose.
Cetuximab, a chimeric mouse-human IgG1 monoclonal antibody against the epidermal growth factor receptor, is approved for use in colorectal cancer and squamous-cell carcinoma of the head and neck. A high prevalence of hypersensitivity reactions to cetuximab has been reported in some areas of the United States. We analyzed serum samples from four groups of subjects for IgE antibodies against cetuximab: pretreatment samples from 76 case subjects who had been treated with cetuximab at multiple centers, predominantly in Tennessee, Arkansas, and North Carolina; samples from 72 control subjects in Tennessee; samples from 49 control subjects with cancer in northern California; and samples from 341 female control subjects in Boston. Among 76 cetuximab-treated subjects, 25 had a hypersensitivity reaction to the drug. IgE antibodies against cetuximab were found in pretreatment samples from 17 of these subjects; only 1 of 51 subjects who did not have a hypersensitivity reaction had such antibodies (P<0.001). IgE antibodies against cetuximab were found in 15 of 72 samples (20.8%) from control subjects in Tennessee, in 3 of 49 samples (6.1%) from northern California, and in 2 of 341 samples (0.6%) from Boston. The IgE antibodies were shown to be specific for an oligosaccharide, galactose-alpha-1,3-galactose, which is present on the Fab portion of the cetuximab heavy chain. In most subjects who had a hypersensitivity reaction to cetuximab, IgE antibodies against cetuximab were present in serum before therapy. The antibodies were specific for galactose-alpha-1,3-galactose.


High-dose vs low-dose proton pump inhibitors for upper gastrointestinal bleeding: a meta-analysis.
To evaluate the efficacy of high-dose proton pump inhibitors (PPIs) vs low-dose PPIs for patients with upper gastrointestinal bleeding. PubMed, Embase, the Cochrane Library, and Web of Science were searched to identify relevant randomized controlled trials (RCTs). Eligible trials were RCTs that compared high-dose PPI with low-dose PPI following endoscopic hemostasis. The primary endpoint was rebleeding; secondary endpoints were patient numbers that needed surgery, and mortality. The meta-analysis was performed with a fixed effects model or random effects model. Nine eligible RCTs including 1342 patients were retrieved. The results showed that high-dose intravenous PPI was not superior to low-dose intravenous PPI in reducing rebleeding [odds ratio (OR) = 1.091, 95% confidential interval (CI): 0.777-1.532], need for surgery (OR = 1.522, 95% CI: 0.643-3.605) and mortality (OR = 1.022, 95% CI: 0.476-2.196). Subgroup analysis according to different region revealed no difference in rebleeding rate between Asian patients (OR = 0.831, 95% CI, 0.467-1.480) and European patients (OR = 1.263, 95% CI: 0.827-1.929). Low-dose intravenous PPI can achieve the same efficacy as high-dose PPI following endoscopic hemostasis.


Development of an ALK2-biased BMP type I receptor kinase inhibitor.
The bone morphogenetic protein (BMP) signaling pathway has essential functions in development, homeostasis, and the normal and pathophysiologic remodeling of tissues. Small molecule inhibitors of the BMP receptor kinase family have been useful for probing physiologic functions of BMP signaling in vitro and in vivo and may have roles in the treatment of BMP-mediated diseases. Here we describe the development of a selective and potent inhibitor of the BMP type I receptor kinases, LDN-212854, which in contrast to previously described BMP receptor kinase inhibitors exhibits nearly 4 orders of selectivity for BMP versus the closely related TGF-β and Activin type I receptors. In vitro, LDN-212854 exhibits some selectivity for ALK2 in preference to other BMP type I receptors, ALK1 and ALK3, which may permit the interrogation of ALK2-mediated signaling, transcriptional activity, and function. LDN-212854 potently inhibits heterotopic ossification in an inducible transgenic mutant ALK2 mouse model of fibrodysplasia ossificans progressiva. These findings represent a significant step toward developing selective inhibitors targeting individual members of the highly homologous BMP type I receptor family. Such inhibitors would provide greater resolution as probes of physiologic function and improved selectivity against therapeutic targets.


Modelling contrast discrimination data suggest both the pedestal effect and stochastic resonance to be caused by the same mechanism.
Computational models of spatial vision typically make use of a (rectified) linear filter, a nonlinearity and dominant late noise to account for human contrast discrimination data. Linear-nonlinear cascade models predict an improvement in observers' contrast detection performance when low, subthreshold levels of external noise are added (i.e., stochastic resonance). Here, we address the issue whether a single contrast gain-control model of early spatial vision can account for both the pedestal effect, i.e., the improved detectability of a grating in the presence of a low-contrast masking grating, and stochastic resonance. We measured contrast discrimination performance without noise and in both weak and moderate levels of noise. Making use of a full quantitative description of our data with few parameters combined with comprehensive model selection assessments, we show the pedestal effect to be more reduced in the presence of weak noise than in moderate noise. This reduction rules out independent, additive sources of performance improvement and, together with a simulation study, supports the parsimonious explanation that a single mechanism underlies the pedestal effect and stochastic resonance in contrast perception.


Dissecting the Roles of the Calcineurin Pathway in Unisexual Reproduction, Stress Responses, and Virulence in Cryptococcus deneoformans.
The Ca2+/calmodulin-dependent protein phosphatase calcineurin orchestrates sexual reproduction, stress responses, and virulence via branched downstream pathways in the opportunistic human fungal pathogen Cryptococcus neoformans The calcineurin-binding protein Cbp1, the calcineurin temperature suppressor Cts1, the calcineurin-responsive zinc finger transcription factor Crz1, and the calcineurin targets Pbp1, Tif3, and Puf4, all function downstream of calcineurin to orchestrate distinct cellular processes. To elucidate how the calcineurin pathway regulatory network governs unisexual reproduction, stress responses, and virulence, we have analyzed the self-filamentous C. deneoformans strain, XL280α, and generated double mutants of these calcineurin downstream genes. We demonstrated that calcineurin governs unisexual reproduction at different sexual developmental stages, in which the initiation of the yeast-hyphal morphological transition is independent of Crz1, whereas the sporulation process is dependent on Crz1. Calcineurin-dependent unisexual reproduction is independent of the pheromone response pathway. Crz1 synergistically interacts with different calcineurin downstream targets in responding to ER, high-calcium, and cell wall stresses. We observed a widespread synergy suggesting that these proteins function in complex branched pathways downstream of calcineurin with some functional redundancy, which may allow efficient signaling network rewiring within the pathway for prompt adaptation to changing environments. Finally, we showed that deletion of PBP1 or TIF3 in the cna1∆ mutant background conferred a modest level of growth tolerance at 37°, but that the cna1∆ pbp1∆ and cna1∆ tif3∆ double mutants were both avirulent, suggesting that calcineurin may control virulence via mechanisms beyond thermotolerance.


Using plant breeding and genetics to overcome the incidence of grass tetany.
Plant breeders developing cultivars to minimize the hazards of grass tetany are concentrating largely on increasing herbage Mg concentrations in cool-season (C3) grasses. Significant genetic variation has been found for Mg, Ca and K concentrations within C3 grass species studied to date. For most C3 forage grass species, heritability estimates are highest for Mg, slightly lower for Ca and lowest for K concentrations. The largest genotype x environmental interactions are found for K values, whereas small environmental effects have been observed for Mg and Ca values. No C3 forage grass cultivar has been developed to date that would eliminate hypomagnesemia. Grass breeders need to develop more experimental C3 plant populations that have high Mg and Ca concentrations. These experimental synthetics with genetically altered mineral concentrations need to be fed to ruminants susceptible to grass tetany to determine whether grass tetany can be eliminated or reduced. Limited feeding trials using ruminants show that improved animal performance can be expected when feeding forage grasses bred for higher Mg concentrations.


Quantitative characterization of functional anatomical contributions to cognitive control under uncertainty.
Although much evidence indicates that RT increases as a function of computational load in many cognitive tasks, quantification of changes in neural activity related to increasing demand of cognitive control has rarely been attempted. In this fMRI study, we used a majority function task to quantify the effect of computational load on brain activation, reflecting the mental processes instantiated by cognitive control under conditions of uncertainty. We found that the activation of the frontoparieto-cingulate system as well as the deactivation of the anticorrelated default mode network varied parametrically as a function of information uncertainty, estimated as entropy with an information theoretic model. The current findings suggest that activity changes in the dynamic networks of the brain (especially the frontoparieto-cingulate system) track with information uncertainty, rather than only conflict or other commonly proposed targets of cognitive control.


Alkene cyclopropanation catalyzed by Halterman iron porphyrin: participation of organic bases as axial ligands.
With the iron(III) complex of the Halterman iron porphyrin [P*Fe(Cl)] and ethyl diazoacetate (EDA) as catalyst and carbene source, respectively, styrene-type substrates were converted to cyclopropyl esters with high trans/cis ratio (not less than 12) and high enantioselectivity for the trans-isomers (74-86% ee). The isomeric distribution of the cyclopropyl esters so obtained is akin to that obtained from the previously reported Ru(II) counterpart [P*Ru(CO)]. A linear Hammett correlation log(k(X)/k(H)) = sigma(+)rho was observed with rho = -0.57 suggesting the involvement of an electrophilic cyclopropanating species derived from the iron(II) center as the reactive intermediate in the catalytic cycle. This is further supported by a dramatic decrease in the enantioselectivity and trans/cis ratio observed in an experiment of styrene cyclopropanation when the reaction mixture was deliberately exposed to air. Axial ligand effects on the selectivities was also investigated. Substantial improvement in trans/cis ratios could be achieved by addition of organic bases such as pyridine (py) and 1-methylimidazole (MeIm) to the catalytic reaction. The existence of axially ligated iron carbene moieties, [P*Fe(CHCO(2)Et)(py)] and [P*Fe(CHCO(2)Et)(MeIm)], was established by electrospray mass spectrometry. Study of secondary kinetic isotope effect indicated that a more product-like transition state was generated by addition of MeIm.


Abnormal inhibition of return: A review and new data on patients with parietal lobe damage.
The study of the performance of patients with neurological disorders has been fruitful in revealing the nature and neural basis of inhibition of return (IOR). Thus, in recent years, studies have reported abnormal IOR in patients with Alzheimer's disease, patients diagnosed with schizophrenia, and brain-damaged patients. In the present study, we investigated the hypothesis that a spatial "disengagement deficit" (DD; Posner, Walker, Friedrich, & Rafal, 1984) contributed to the pattern of impaired IOR in the ipsilesional field of parietal patients, found in a previous work (Vivas, Humphreys, & Fuentes, 2003). In a first experiment, we replicated the attenuation of IOR for ipsilesional targets on those trials with a lateralized IOR procedure. With stimuli vertically aligned about fixation, we found intact IOR for both up and down targets. Most important, when we ameliorated the potential impact of a spatial DD by presenting both cues and target in the same hemifield, still we found impaired IOR in the ipsilesional field. We interpret these findings in terms of unilateral parietal damage leading to an imbalance of the relative salience of signals represented in a spatial map for directing attention.


Integrative network analysis highlights biological processes underlying GLP-1 stimulated insulin secretion: A DIRECT study.
Glucagon-like peptide 1 (GLP-1) stimulated insulin secretion has a considerable heritable component as estimated from twin studies, yet few genetic variants influencing this phenotype have been identified. We performed the first genome-wide association study (GWAS) of GLP-1 stimulated insulin secretion in non-diabetic individuals from the Netherlands Twin register (n = 126). This GWAS was enhanced using a tissue-specific protein-protein interaction network approach. We identified a beta-cell protein-protein interaction module that was significantly enriched for low gene scores based on the GWAS P-values and found support at the network level in an independent cohort from Tübingen, Germany (n = 100). Additionally, a polygenic risk score based on SNPs prioritized from the network was associated (P < 0.05) with glucose-stimulated insulin secretion phenotypes in up to 5,318 individuals in MAGIC cohorts. The network contains both known and novel genes in the context of insulin secretion and is enriched for members of the focal adhesion, extracellular-matrix receptor interaction, actin cytoskeleton regulation, Rap1 and PI3K-Akt signaling pathways. Adipose tissue is, like the beta-cell, one of the target tissues of GLP-1 and we thus hypothesized that similar networks might be functional in both tissues. In order to verify peripheral effects of GLP-1 stimulation, we compared the transcriptome profiling of ob/ob mice treated with liraglutide, a clinically used GLP-1 receptor agonist, versus baseline controls. Some of the upstream regulators of differentially expressed genes in the white adipose tissue of ob/ob mice were also detected in the human beta-cell network of genes associated with GLP-1 stimulated insulin secretion. The findings provide biological insight into the mechanisms through which the effects of GLP-1 may be modulated and highlight a potential role of the beta-cell expressed genes RYR2, GDI2, KIAA0232, COL4A1 and COL4A2 in GLP-1 stimulated insulin secretion.


Evidence for a developmental shift in the motivation underlying helping in early childhood.
We investigated children's positive emotions as an indicator of their underlying prosocial motivation. In Study 1, 2-, and 5-year-old children (N = 64) could either help an individual or watch as another person provided help. Following the helping event and using depth sensor imaging, we measured children's positive emotions through changes in postural elevation. For 2-year-olds, helping the individual and watching another person help was equally rewarding; 5-year-olds showed greater postural elevation after actively helping. In Study 2, 5-year-olds' (N = 59) positive emotions following helping were greater when an audience was watching. Together, these results suggest that 2-year-old children have an intrinsic concern that individuals be helped whereas 5-year-old children have an additional, strategic motivation to improve their reputation by helping.


Effects of kappa opioid receptors on conditioned place aversion and social interaction in males and females.
The effects of kappa opioid receptors (KOR) on motivated behavior are well established based on studies in male rodents, but relatively little is known about the effects of KOR in females. We examined the effects of KOR activation on conditioned place aversion and social interaction in the California mouse (Peromyscus californicus). Important differences were observed in long-term (place aversion) and short-term (social interaction) effects. Females but not males treated with a 2.5 mg/kg dose of U50,488 formed a place aversion, whereas males but not females formed a place aversion at the 10 mg/kg dose. In contrast the short term effects of different doses of U50,488 on social interaction behavior were similar in males and females. Acute injection with 10 mg/kg of U50,488 (but not lower doses) reduced social interaction behavior in both males and females. The effects of U50,488 on phosphorylated extracellular signal regulated kinase (pERK) and p38 MAP kinase were cell type and region specific. Higher doses of U50,488 increased the number of pERK neurons in the ventrolateral bed nucleus of the stria terminals in males but not females, a nucleus implicated in male aggressive behavior. In contrast, both males and females treated with U50,488 had more activated p38 cells in the nucleus accumbens shell. Unexpectedly, cells expressing activated p38 co-expressed Iba-1, a widely used microglia marker. In summary we found strong sex differences in the effects of U50,488 on place aversion whereas the acute effects on U50,488 induced similar behavioral effects in males and females.


In Vivo Optical Performance of a New Class of Near-Infrared-Emitting Conjugated Polymers: Borylated PF8-BT.
Borylated poly(fluorene-benzothiadiazoles) (PF8-BT) are π-conjugated polymers (CPs) with deep-red/near-infrared (NIR) absorption and emission profiles suitable for in vivo optical imaging. A fully borylated PF8-BT derivative (P4) was encapsulated in pegylated poly(lactic-co-glycolic acid) (PEG-PLGA) nanoparticles and compared with a reference NIR-emitting CP (PCPDTBT) or indocyanine green (ICG). All formulations satisfied quality requirements for parenterally administered diagnostics. P4 nanoparticles had higher quantum yield (2.3%) than PCPCDTBT (0.01%) or ICG nanoparticles (1.1%). The signal/background ratios (SBRs) of CP systems P4 and PCPDTBT in a phantom mouse (λem = 820 nm) increased linearly with fluorophore mass (12.5-100 μg/mL), while the SBRs of ICG decreased above 25 μg/mL. P4 nanoparticles experienced <10% photobleaching over 10 irradiations (PCPDTBT: ∼25% and ICG: >44%). In a mouse tumor xenograft model, P4 nanoparticles showed a 5-fold higher SBR than PCPDTBT particles with fluorophore accumulation in the liver > spleen > tumor. Blood chemistry and tissue histology showed no abnormalities compared to untreated animals after a single administration.


A real-time research platform to study vestibular implants with gyroscopic inputs in vestibular deficient subjects.
Researchers have succeeded in partly restoring damaged vestibular functionality in several animal models. Recently, acute interventions have also been demonstrated in human patients. Our previous work on a vestibular implant for humans used predefined stimulation patterns; here we present a research tool that facilitates motion-modulated stimulation. This requires a system that can process gyroscope measurements and send stimulation parameters to a hybrid vestibular-cochlear implant in real-time. To match natural vestibular latencies, the time from sensor input to stimulation output should not exceed 6.5 ms. We describe a system based on National Instrument's CompactRIO platform that can meet this requirement and also offers floating point precision for advanced transfer functions. It is designed for acute clinical interventions, and is sufficiently powerful and flexible to serve as a development platform for evaluating prosthetic control strategies. Amplitude and pulse frequency modulation to predetermined functions or sensor inputs have been validated. The system has been connected to human patients, who each have received a modified MED-EL cochlear implant for vestibular stimulation, and patient tests are ongoing.


Effect of in utero exposure to endocrine disruptors on fetal steroidogenesis governed by the pituitary-gonad axis: a study in rats using different ways of administration.
The effects of endocrine disruptors on testicular steroidogenesis in fetal rats were investigated in a study involving in utero exposure. In the major part of this study, pregnant rats at gestational day (GD)15 were given a single oral administration of the test substance, and then the expression of the following mRNAs in GD20 fetuses was determined: testicular steroidogenic acute-regulatory protein (StAR), a cholesterol transporter mediating the rate-limiting step of steroidogenesis, a ß-subunit of pituitary luteinizing hormone (LH), and a regulator of gonadal steroidogenesis. Among the substances tested, only di(2-ethylhexyl)phthalate (DEHP) reduced the expression of fetal testicular StAR. The others listed below exhibited little effect on fetal StAR: 2,2',4,4'-tetrabromodiphenylether, tributyltin chloride, atrazine, permethrin, cadmium chloride (Cd), lead acetate (Pb) and methylmercury (CH3HgOH). None of them, including DEHP, lacked the ability to reduce the expression of pituitary LHß mRNA. The present study also examined the potential of metals as modifiers of fetal steroidogenesis by giving them to pregnant dams in drinking water during GD1 and GD20. Under these conditions, Cd and Pb at a low concentration (0.01 ppm) significantly attenuated the fetal testicular expression of StAR mRNA without a concomitant reduction in LHß. No such effect was detected with CH3HgOH even at 1 ppm. These results suggest that: 1) DEHP, Cd and Pb attenuate the fetal production of sex steroids by directly acting on the testis, and 2) chronic treatment during the entire gestational period is more useful than a single administration for determining the hazardous effect of a suspected endocrine disruptor on fetal steroidogenesis.


Aneuploidy and telomere attrition are independent determinants of crisis in SV40-transformed epithelial cells.
Replicative immortality is achieved in vitro by overcoming two mortality checkpoints, M1 (senescence) and M2 (crisis). Cancer cells are thought to overcome M2 by activating telomerase, an enzyme believed to confer genomic stability in addition to maintaining telomeric sequences above a critical length. Here we show that a subset of cultured ovarian cystadenoma cells expressing SV40 large T-antigen, which allows bypassing of M1, develop a specific type of genomic instability, characterized by numerical (as opposed to structural) chromosomal alterations, that leads to non-telomere-based premature growth arrest/crisis. Cells recover from this type of growth arrest and stabilize their ploidy status without telomerase expression. In these cases, telomeres continue to shorten until a second, telomere-based growth arrest/crisis event is reached. Transfection of the catalytic subunit of telomerase does not immortalize cells harboring severe abnormalities in their DNA ploidy but results in immortalization of diploid cells. We conclude that changes in DNA ploidy constitute an important determinant of growth arrest that is independent of telomere attrition in a subset of SV40 large T-antigen-expressing cystadenoma cells. Reestablishment or emergence of ploidy stability, which is not always dependent on telomerase activation, is necessary for acquisition of the potential to achieve replicative immortality.


Translating secondary electrospray ionization-high-resolution mass spectrometry to the clinical environment.
While there has been progress in making use of breath tests to guide clinical decision making, the full potential of exhaled breath analysis still remains to be exploited. Here we summarize some of the reasons why this is the case, what we have done so far to overcome some of the existing obstacles, and our vision of how we think breath analysis will play a more prominent role in the coming years. In particular, we envision that real-time high-resolution mass spectrometry will provide valuable information in biomarker discovery studies. However, this can only be achieved by a coordinated effort, using standardized equipment and methods in multi-center studies to eventually deliver tangible advances in the field of breath analysis in a clinical setting. Concrete aspects such as sample integrity, compound identification, quantification and standardization are discussed. Novel secondary electrospray ionization developments with the aim of facilitating inter-groups comparisons and biomarker validation studies are also presented.


Clinical assessment of stereoscopic optic disc photographs for glaucoma: the European Optic Disc Assessment Trial.
To determine the diagnostic accuracy of judging optic disc photographs for glaucoma by ophthalmologists. Evaluation of diagnostic test and technology. A total of 243 of 875 invited ophthalmologists in 11 European countries. We determined how well each participant classified 40 healthy eyes and 48 glaucomatous eyes with varying severity of the disease on stereoscopic slides. Duplicate slides were provided for determining intraobserver agreement. All eyes were also imaged with the GDx with variable corneal compensation (GDx-VCC) (Carl Zeiss Meditec AG, Jena, Germany) and the Heidelberg Retina Tomograph (HRT) I (Heidelberg Engineering GmbH, Heidelberg, Germany). Diagnostic accuracies of clinicians were compared with those of the best machine classifiers. Accuracy of classification, expressed as sensitivity, specificity, and overall accuracy. Intraobserver agreement (kappa). The overall diagnostic accuracy of ophthalmologists was 80.5% (standard deviation [SD], 6.8; range, 61.4%-94.3%). The machine classifiers outperformed most observers in diagnostic accuracy; the GDx-VCC nerve fiber indicator and the HRT's best classifier correctly classified 93.2% and 89.8% of eyes, respectively. The intraobserver agreement (kappa) varied between -0.13 and 1.0 and was on average good (0.7). In general, ophthalmologists classify optic disc photographs moderately well for detecting glaucoma. There is, however, large variability in diagnostic accuracy among and agreement within clinicians. Common imaging devices outperform most clinicians in classifying optic discs. Proprietary or commercial disclosure may be found after the references.


Antiplasmodial dihetarylthioethers target the coenzyme A synthesis pathway in Plasmodium falciparum erythrocytic stages.
Malaria is a widespread infectious disease that threatens a large proportion of the population in tropical and subtropical areas. Given the emerging resistance against the current standard anti-malaria chemotherapeutics, the development of alternative drugs is urgently needed. New anti-malarials representing chemotypes unrelated to currently used drugs have an increased potential for displaying novel mechanisms of action and thus exhibit low risk of cross-resistance against established drugs. Phenotypic screening of a small library (32 kinase-inhibitor analogs) against Plasmodium falciparum NF54-luc asexual erythrocytic stage parasites identified a diarylthioether structurally unrelated to registered drugs. Hit expansion led to a series in which the most potent congener displayed nanomolar antiparasitic activity (IC50 = 39 nM, 3D7 strain). Structure-activity relationship analysis revealed a thieno[2,3-d]pyrimidine on one side of the thioether linkage as a prerequisite for antiplasmodial activity. Within the series, the oxazole derivative KuWei173 showed high potency (IC50 = 75 nM; 3D7 strain), good solubility in aqueous solvents (1.33 mM), and >100-fold selectivity toward human cell lines. Rescue experiments identified inhibition of the plasmodial coenzyme A synthesis as a possible mode of action for this compound class. The class of antiplasmodial bishetarylthioethers reported here has been shown to interfere with plasmodial coenzyme A synthesis, a mechanism of action not yet exploited for registered anti-malarial drugs. The oxazole congener KuWei173 displays double-digit nanomolar antiplasmodial activity, selectivity against human cell lines, high drug likeness, and thus represents a promising chemical starting point for further drug development.


The role of BK-type Ca2+-dependent K+ channels in spike broadening during repetitive firing in rat hippocampal pyramidal cells.
1. The role of large-conductance Ca2+-dependent K+ channels (BK-channels; also known as maxi-K- or slo-channels) in spike broadening during repetitive firing was studied in CA1 pyramidal cells, using sharp electrode intracellular recordings in rat hippocampal slices, and computer modelling. 2. Trains of action potentials elicited by depolarizing current pulses showed a progressive, frequency-dependent spike broadening, reflecting a reduced rate of repolarization. During a 50 ms long 5 spike train, the spike duration increased by 63.6 +/- 3.4 % from the 1st to the 3rd spike. The amplitude of the fast after-hyperpolarization (fAHP) also rapidly declined during each train. 3. Suppression of BK-channel activity with (a) the selective BK-channel blocker iberiotoxin (IbTX, 60 nM), (b) the non-peptidergic BK-channel blocker paxilline (2-10 microM), or (c) calcium-free medium, broadened the 1st spike to a similar degree ( approximately 60 %). BK-channel suppression also caused a similar change in spike waveform as observed during repetitive firing, and eliminated (occluded) most of the spike broadening during repetitive firing. 4. Computer simulations using a reduced compartmental model with transient BK-channel current and 10 other active ionic currents, produced an activity-dependent spike broadening that was strongly reduced when the BK-channel inactivation mechanism was removed. 5. These results, which are supported by recent voltage-clamp data, strongly suggest that in CA1 pyramidal cells, fast inactivation of a transient BK-channel current (ICT), substantially contributes to frequency-dependent spike broadening during repetitive firing.


Danio annulosus, a new species of chain Danio from the Shuvolong Falls in Bangladesh (Teleostei: Cyprinidae: Danioninae).
Danio annulosus, new species, is described from a small pool below the Shuvolong Falls in the Kaptai Lake system in Bangladesh. It shares with chain danios (D. assamila, D. dangila, D. catenatus, D. concatenatus, and D. sysphigmatus) a colour pattern consisting of series of dark rings with light interspaces along the side, complete lateral line, 14 circumpeduncular scales, a produced first ray in the pectoral fin, and a black humeral spot. It differs from other chain danios in possessing much shorter pectoral and pelvic fins, and a humeral spot that is slightly wider than deep instead of round or deeper than wide. The mitochondrial cytochrome c oxidase subunit I (COI) sequence separates D. annulosus from the most similar species, D. catenatus by a p-distance of 3.4%. Although recorded from only a single locality, Danio annulosus is expected to have a wider distribution in the Karnafuli River drainage.


Stepwise development of committed progenitors in the bone marrow that generate functional T cells in the absence of the thymus.
We identified committed T cell progenitors (CTPs) in the mouse bone marrow that have not rearranged the TCRbeta gene; express a variety of genes associated with commitment to the T cell lineage, including GATA-3, T cell-specific factor-1, Cbeta, and Id2; and show a surface marker pattern (CD44+ CD25- CD24+ CD5-) that is similar to the earliest T cell progenitors in the thymus. More mature committed intermediate progenitors in the marrow have rearranged the TCR gene loci, express Valpha and Vbeta genes as well as CD3epsilon, but do not express surface TCR or CD3 receptors. CTPs, but not progenitors from the thymus, reconstituted the alphabeta T cells in the lymphoid tissues of athymic nu/nu mice. These reconstituted T cells vigorously secreted IFN-gamma after stimulation in vitro, and protected the mice against lethal infection with murine CMV. In conclusion, CTPs in wild-type bone marrow can generate functional T cells via an extrathymic pathway in athymic nu/nu mice.


Posterior calibration of posterior predictive p values.
In order to accurately control the Type I error rate (typically .05), a p value should be uniformly distributed under the null model. The posterior predictive p value (ppp), which is commonly used in Bayesian data analysis, generally does not satisfy this property. For example there have been reports where the sampling distribution of the ppp under the null model was highly concentrated around .50. In this case, a ppp of .20 would indicate model misfit, but when comparing it with a significance level of .05, which is standard statistical practice, the null model would not be rejected. Therefore, the ppp has very little power to detect model misfit. A solution has been proposed in the literature, which involves calibrating the ppp using the prior distribution of the parameters under the null model. A disadvantage of this "prior-cppp" is that it is very sensitive to the prior of the model parameters. In this article, an alternative solution is proposed where the ppp is calibrated using the posterior under the null model. This "posterior-cppp" (a) can be used when prior information is absent, (b) allows one to test any type of misfit by choosing an appropriate discrepancy measure, and (c) has a uniform distribution under the null model. The methodology is applied in various testing problems: testing independence of dichotomous variables, checking misfit of linear regression models in the presence of outliers, and assessing misfit in latent class analysis. (PsycINFO Database Record


Enhancement of Neisseria meningitidis infection in mice by addition of iron bound to transferrin.
Small quantities of iron bound specifically to human transferrin were found to stimulate infection with Neisseria meningitidis strain M1011 in mice. An intraperitoneal injection of 17.5 mg of transferrin carrying 22.7 micrograms of Fe resulted in 100% mortality from infection, as compared with no mortality for the controls which had received saline. Five milligrams of ferri-transferrin (FeTf), carrying 6.5 micrograms of Fe, stimulated and prolonged bacteremia in the mice. Thus, FeTf maintained infection, whereas infection was controlled due to iron limitation in control mice. Comparative studies with apotransferrin (iron-free) revealed that the enhancement of infection was due to the supply of iron. FeTf was also found to relieve an iron limitation of growth achieved by ethylenediaminedihydroxyphenylacetic acid (EDDA) in vitro. FeTf abolished the lag phase for growth of N. meningitidis in a defined medium. The results of this study suggest that human FeTf is an immediate source of iron to N. meningitidis both in vitro and in vivo. These findings support the hypothesis that the levels of iron in the circulating transferrin pool of mice determine the course of experimental N. meningitidis infection.


What do changes in prematch vs. postmatch, 1, 2, and 3 days postmatch body weight tell us about fluid status in English Premiership rugby union players?
This study investigated changes in body weight pre and postmatch and 1, 2, and 3 days postmatch. Thirty-six players contracted to an English Premiership rugby union club had their pre and postmatch body weight and 1, 2, and 3 day postmatch body weight recorded across 14 matches played (10 at home and 4 away) during the official 2003-2004 professional rugby union season, representing a total of 262 player appearances. Body weight was recorded using a set of calibrated Seca digital scales with players wearing underwear only and toweled dry of all sweat (postmatch). Players were allowed to ingest fluid ad libitum throughout each match. A number of players recorded pre to postmatch reductions of body weight of >2% with some as high as 4.9%. Significant position-specific mean reductions in prematch to postmatch body weight (±SD) were found for both forwards (1.94 ± 0.14 kg) and backs (1.04 ± 0.17 kg). The mean gain in postmatch to 1-day postmatch body weight was significant for forwards (1.40 ± 0.27 kg) but not for backs (0.76 ± 0.30 kg). There were no significant mean differences between prematch and 2 or 3 days postmatch body weight for either forwards or backs. Forwards on average lost a significantly greater proportion of their weight pre to postmatch than backs (p = 0.005). Forwards were on average 99.5% of the prematch weight at 1 day postmatch, whereas backs were 99.7% (p = 0.598). Forwards were 99.6% of their prematch weight at 3 days postmatch, whereas backs were 100.4% (p = 0.035). Changes in fluid status can be effectively monitored by recording changes in body weight and is useful where players are undertaking training sessions within 1, 2, or 3 days after their last match as a measure of rehydration status.


Topical Treatment of Cutaneous Leishmaniasis in Israel, Part 1.
Cutaneous leishmaniasis is the most common form of leishmaniasis with global incidence of about 1.5 million cases annually. The disease is endemic in Israel and caused by two types, Leishmania major and Leishmania tropica. The two types of cutaneous leishmaniasis in Israel are not life threatening, but the multiple skin lesions developed from the contaminated sandfly bites cause significant damage to the quality of life for a few months in patients with Leishmania major and sometimes for more than a year in patients with Leishmania tropica. The disease ends spontaneously, often with disfiguring scars. The aim of the treatment is to significantly shorten the wound-healing process, hopefully with minimal scars and with parasite eradication. Topical treatment for this localized skin disease is very attractive, although only one medication is registered in Israel (15% paromomycin +12% methylbenzethonium chloride ointment), which is for the topical treatment of "Leishmania major." Relatively low efficacy and significant irritation and pain are two significant disadvantages that characterize this topical medication and could result in failure of the registered treatment. This article, which is presented in 3 parts, discusses three options in the treatment of cutaneous leishmaniasis, 1) amphotericin B liposomal gel and 2) paromomycin sulfate liposomal gel (free of the sensitizing methylbenzethonium chloride), both of which the author considers as efficacious in the treatment of cutaneous leishmaniasis, although to confirm these claims, randomized controlled trials must be conducted, and 3) photodynamic therapy. Most of the reports claim that the photodynamic therapy can achieve results above 90% healing of wounds in a relatively short period of time and with relatively minimal scars. However, a caveat must be held since some of these studies indicate that not all healed wounds become free of the parasite. The daylight option of photodynamic therapy is an interesting modality which abolishes the need for an expensive artificial light source and expensive hospitalization time and enables ambulatory treatment to be efficacious against both types of Leishmania in Israel. Formulations are provided for the three modalities, with the third option being based on 5-aminolevulinic acid hydrochloride as the photosensitizer for this therapy.


Immunomodulatory effects of a standardized Lycium barbarum fruit juice in Chinese older healthy human subjects.
Lycium barbarum has been traditionally used in combination with several herbs for medicinal properties, but systematic modern clinical evaluation as a single herb has not been reported. To examine the systematic effects of L. barbarum on immune function, general well-being, and safety, we tested the effects of a standardized L. barbarum fruit juice (GoChi, FreeLife International, Phoenix, AZ, USA) at 120 mL/day, equivalent to at least 150 g of fresh fruit, the amount traditionally used, or placebo for 30 days in a randomized, double-blind, placebo-controlled clinical study in 60 older healthy adults (55-72 years old). The GoChi group showed a statistically significant increase in the number of lymphocytes and levels of interleukin-2 and immunoglobulin G compared to pre-intervention and the placebo group, whereas the number of CD4, CD8, and natural killer cells or levels of interleukin-4 and immunoglobulin A were not significantly altered. The placebo group showed no significant changes in any immune measures. Whereas the GoChi group showed a significant increase in general feelings of well-being, such as fatigue and sleep, and showed a tendency for increased short-term memory and focus between pre- and post-intervention, the placebo group showed no significant positive changes in these measures. No adverse reactions, abnormal symptoms, or changes in body weight, blood pressure, pulse, visual acuity, urine, stool, or blood biochemistry were seen in either group. In conclusion, daily consumption of GoChi significantly increased several immunological responses and subjective feelings of general well-being without any adverse reactions.


Diagnostic Value of Histological Analysis of Punch Biopsies in Suspected Cutaneous Buruli Ulcer: A Study on 32 Cases of Confirmed Buruli Ulcer in Cameroon.
Buruli ulcer (BU) is a cutaneous infectious disease caused by Mycobacterium ulcerans. In this prospective study, we aim to clarify the main histopathological features of cutaneous BU based on 4-mm skin punch biopsies and to evaluate the diagnostic value of this method. Between 2011 and 2013, a prospective study was conducted in Cameroon. Dry swabs from ulcerative lesions and fine-needle aspirates of nonulcerative lesions were examined for Ziehl-Neelsen (ZN) staining, followed by PCR targeting IS2404 and culture. Two 4-mm punch biopsies were performed in the center and in the periphery of each lesion. The 364 patients included in the study had 422 lesions (381 were ulcerative and 357 lesions were biopsied). Among the 99 ulcerated lesions with a final diagnosis of BU, histological features for BU were fulfilled in 32 lesions. 32/32 showed subcutaneous necrosis with a neutrophilic inflammatory infiltrate. 26/32 presented alcohol-resistant bacilli confirmed by ZN stain on histology. Punch biopsies help in establishing the correct diagnosis of BU and also in the differential diagnosis of chronic ulcers. The main histological feature for BU is diffuse coagulative necrosis of subcutaneous tissue, with acid-fast bacilli detected by ZN stain.


Significant association and synergistic adverse prognostic effect of podocalyxin-like protein and epidermal growth factor receptor expression in colorectal cancer.
Podocalyxin-like 1 (PODXL) is an anti-adhesive transmembrane protein that has been demonstrated to be an independent factor of poor prognosis in colorectal cancer (CRC). The gene encoding PODXL is located to chromosome 7, which also harbours the gene for the epidermal growth factor receptor (EGFR). The aim of this study was to examine the associations between PODXL and EGFR expression in CRC in vitro and in vivo. EGFR expression was analysed in tumours from three independent patient cohorts; cohort 1 (n = 533), cohort 2 (n = 259) and cohort 3 (n = 310), previously analysed for immunohistochemical PODXL expression and KRAS and BRAF mutations (cohort 1 and 3). Levels of EGFR and PODXL were determined by western blot in six different CRC cell lines. High expression of PODXL was significantly associated with high EGFR expression (p < 0.001) in all three cohorts, and with BRAF mutation (p < 0.001) in cohort 1 and 3. High EGFR expression correlated with BRAF mutation (p < 0.001) in cohort 1. High EGFR expression was associated with adverse clinicopathological factors and independently predicted a reduced 5-year overall survival (OS) in cohort 1 (HR 1.77; 95 % CI 1.27-2.46), cohort 2 (HR 1.58; 95 % CI 1.05-2.38) and cohort 3 (HR 1.83; 95 % CI 1.19-2.81). The highest risk of death within 5 years was observed in patients with tumours displaying high expression of both EGFR and PODXL in cohort 1 and 3 (HR 1.97; 95 % CI 1.18-3.28 and HR 3.56; 95 % CI 1.75-7.22, respectively). Western blot analysis showed a uniform expression of PODXL and EGFR in all six examined CRC cell lines. The results from this study demonstrate that high expression of EGFR is an independent factor of poor prognosis in CRC. Moreover, strong links have been uncovered between expression of the recently proposed biomarker candidate PODXL with EGFR expression in CRC in vivo and in vitro, and with BRAF mutation in vivo. High expression of both PODXL and EGFR may also have a synergistic adverse effect on survival. These findings suggest a potential functional link in CRC between PODXL, EGFR and BRAF, all originating from chromosome 7, which may be highly relevant in the clinical setting and therefore merit future in-depth study.


Redefinition of working aqueous two-phase systems: a generic description for prediction of the effective phase chemical composition for process control and biorecovery.
Aqueous two-phase systems (ATPS) have been widely adopted for the combined purpose of solid liquid separation, and recovery and purification of bioproducts such as proteins, viruses and organelles from biological feedstocks and fermentation broth. However, in spite of potential advantages over other techniques applied to concentrated biological feedstocks, ATPS have been applied at process scale only by a few industries and research establishments. ATPS are sensitive to loading with modest to extreme quantities of biological feedstock due to the contribution of that material to phase formation in combination with the conventional phase-forming chemicals. This causes problem associated with the definition and manipulation of loaded working systems, which may be addresses as in the present study with the aid of distribution analysis of radiolabel led analytes (DARA) in representative process samples. The present study focussed on establishing a generic description for characterising ATPS loaded with biological feedstocks and the redefinition of the biological feedstock loaded system composition in terms of phase forming chemical equivalents. This evaluation will be useful to achieve ATPS process implementation where phase recycle/reuse is adopted without compromise to process operations and consistent protein recovery performance.


Symptoms and immunologic markers among vulcanization workers in rubber industries in southern Sweden.
The aim of this study was to estimate the risk of symptoms and the possible derangement of levels of immunologic markers for contemporary Swedish rubber workers. Furthermore, the relation between exposure and these biomarkers of response was examined using urinary levels of 2-thiothiazolidine-4-carboxylic acid (TTCA), which reflect the exposure. Included in the study were 166 exposed workers and 117 controls. Medical and occupational histories were obtained in structured interviews. Symptoms were recorded, and immunologic markers were analyzed in blood. Urinary levels of TTCA were determined by liquid chromatography tandem mass spectrometry. Compared with the controls, the exposed workers had increased risks of eye symptoms [odds ratio (OR) 3.0], nose bleeds (OR 4.0), burning and dry throat (OR 3.0), hoarseness (OR 2.4), severe dry cough (OR 3.8), nausea (OR 4.3), and headache (OR 2.5). When the exposed workers were divided into three groups according to the TTCA levels, the highest risks were observed among the exposed workers with intermediate TTCA levels. Furthermore, the exposed workers in all of the TTCA subgroups had elevated concentrations of total immunoglobulin G when compared with the controls. Elevated concentrations of leukocytes, neutrophils, and eosinophils were observed in the group with high TTCA levels. This work shows an increased risk of several symptoms and elevated levels of some immunologic markers among exposed workers in Swedish rubber industries. In addition, relationships between urinary levels of TTCA and some biomarkers of response were reported.


Low grade MALT lymphoma of the urinary bladder.
Primary lymphoma of the bladder is rare. Of the very few cases reported, most appear to be of low grade with a generally good prognosis. Since the concept of low grade lymphoma of mucosa associated lymphoid tissue (also known as marginal zone lymphoma in the REAL classification) was introduced, only six examples of this entity have been recorded at this site. We present a further case and describe its phenotypic characterization.


A progressive stage IIIB melanoma treated with oncolytic ECHO-7 virus: A case report.
Melanoma is an aggressive skin cancer form with a grave prognosis. Current results suggest that oncolytic virus treatment of melanoma has a high therapeutic potential. ECHO-7 (Rigvir) is the first oncolytic virus registered in Latvia. A female patient was diagnosed with stage IIIB melanoma in December 2012, over 9.4 years ago. After the first excision and re-excision, the patient had several recurrences and disease progressions. After the patient had received surgical treatment in 2014, ECHO-7 virus oncolytic virotherapy was started. Since then, the patient has experienced only one more disease progression episode in May 2015 and has been stable for over 60 months. The patient has not received any other treatment than surgery and oncolytic virotherapy. No severe adverse events have been reported during virotherapy. The present case suggests that ECHO-7 virotherapy is an effective treatment of skin melanoma.


Reliminary survey of ticks (Acari: Ixodidae) on cattle in Central Equatoria State, Southern Sudan.
In a preliminary survey conducted in 2005, the species composition and seasonality of ticks infesting cattle in Central Equatoria State, Southern Sudan was determined. Three locations were selected (Gumbo, Khor Rumla and Nyaing) and surveyed every 3 months. Two cattle herds in each of the three locations were visited four times during the study period. Total body collections of ticks were made from each of five cattle (Nilotic Zebu breed) kept in six different herds. Four tick genera and ten species were identified. The tick species identified were Amblyomma lepidum, Amblyomma variegatum, Boophilus annulatus, Boophilus decoloratus, Hyalomma marginatum rufipes, Hyalomma truncatum, Rhipicephalus appendiculatus, Rhipicephalus evertsi evertsi, Rhipicephalus praetextatus and Rhipicephalus sanguineus group. The highest number of ticks was collected in October during the rainy season. A finding of great significance was that R. appendiculatus, vector of East Coast fever, has now firmly established itself throughout the year with possible implications for cattle production in Central Equatoria State.


Seasonal Vitamin D Status in Polish Elite Athletes in Relation to Sun Exposure and Oral Supplementation.
Vitamin D does not only influence the musculoskeletal health and mineral homeostasis but it also affects cardiovascular, endocrine, nervous, immune and mental functions, thus it is of considerable importance for both physically active people and elite athletes. However, vitamin D deficiency is common worldwide and results from inadequate endogenous skin synthesis (insufficient ultraviolet B exposure) and diet. To improve the vitamin D status elite athletes often travel to lower latitude during winter. The aim of the study was to evaluate the seasonal vitamin D status in Polish elite athletes according to the sun exposure and oral supplementation. Serum concentration of 25-hydroxyvitamin D (25(OH)D) was measured in the years 2010-2014 in 409 elite athletes, who were divided into the following groups: OUTD-outdoor sports, represented by track and field athletes, who trained in Poland; IND-weightlifters, handball and volleyball players who trained indoors in Poland; SUN-track and field athletes who trained during Polish winter in lower latitude with high sunshine exposure; SUPL-track and field athletes who trained in Poland, had an inadequate vitamin D status (25(OH)D < 30 ng/ml) and were supplemented orally. Inadequate Vitamin D status was observed in 80% of OUTD and 84% of IND athletes in winter, whereas in summer the values amounted to 42% and 83%, respectively. The athletes exposed to sun in winter had significantly higher vitamin D concentration than OUTD group. Oral supplementation improved vitamin D concentration by 45%, whereas winter sun exposure caused its increase by 85%. Except for a few summer months an inadequate status of vitamin D was found in the majority of Polish elite athletes, with the deficiency level being similar to the one observed in non-athletic population. The most serious deficiency was observed in indoor disciplines. Adequate vitamin D status can be achieved by both increased sun exposure, especially in winter, and oral supplementation. Athletes should therefore routinely assess their vitamin D status and be educated how to approach their sunlight exposure, diet and supplementation.


Rapid Identification of Therapeutic Targets in Hematologic Malignancies via Functional Genomics.
The clinical application of gene-targeted drugs has transformed cancer therapy. The hallmark example of this strategy is use of the ABL kinase inhibitor imatinib for treatment of patients with chronic myeloid leukemia (CML). This remarkable clinical success has also stimulated an expansive search for personalized gene targets in all patients to facilitate broad application of targeted therapy for cancer. However, achievement of this objective will require simultaneous work towards several complementary goals. The first step towards broad application of gene-targeted therapy must entail a rapid means to identify target oncogenes in individual patients. Next, we must identify well-tolerated, gene-specific drugs that are collectively effective against a wide diversity of gene targets. Finally, we must develop protocols by which individual patients are matched with appropriate, gene-targeted drugs in a clinically relevant time frame. While these may seem like difficult tasks, we are fortunate to have a wide variety of new and rapidly evolving research tools at our disposal. These include next-generation sequencing of the genome and transcriptome, single nucleotide polymorphism (SNP)/copy number variations (CNV) and gene expression microarrays, and RNAi libraries for the application of functional screens. In this review we discuss the advantages and disadvantages of each of these techniques with the goal of demonstrating that no single technique will be sufficient as a standalone technology, but rather it will be the integration of all techniques that will enable broad application of gene-targeted cancer therapies.


Systemic administration of cellular IL-10 induces an effective, specific, and long-lived immune response against established tumors in mice.
Cellular IL-10 (cIL-10), the collective term for human and murine IL-10, has both stimulatory and inhibitory effects on diverse cell types, including costimulation of T cell proliferation, chemoattraction of CD8+ T cells, and stimulation of lymphokine-activated killer cell activity. Human IL-10 (hIL-10) differs from its EBV homolog viral IL-10 (vIL-10) by only 16% at the amino acid level; however, vIL-10 shares with cIL-10 predominantly inhibitory effects, such as macrophage deactivation. We administered cIL-10 systemically to mice bearing established (day 7) sarcomas, melanomas, or colorectal carcinomas. At high doses (20 to 60 micrograms/day x 7 days), cIL-10 induced rejection of tumors, delaying tumor outgrowth or resulting in complete cure. Sublethal irradiation (500 rad) of mice prior to tumor inoculation abrogated the IL-10 effect. Cured mice were immune to subsequent rechallenge with 10-fold higher inoculation with the same, but not a different, tumor. IL-12 also has potent antitumor activity and interacts with IL-10 in both complementary and antagonistic ways; co-administration of both cytokines resulted in additive antitumor activity. To compare cIL-10 vs vIL-10 effects in vivo, we engineered CL8-1 melanoma transfectants bearing the vIL-10 or the murine IL-10 (mIL-10) gene. Local secretion of mIL-10 induced rejection of tumors, while vIL-10 resulted in accelerated outgrowth. Subsequent systemic administration of cIL-10 to mice bearing vIL-10-transduced tumors completely reversed the local suppressive effects, leading to rejection, suggesting distinct pathways for cIL-10 and vIL-10 effects. That cIL-10 can stimulate the acquisition of an effective, specific, and long-lived antitumor immune response in murine models and can reverse the local immunosuppressive effects of vIL-10 indicates a potential role for cIL-10 administration in the biologic therapy of cancer and suggests a broader interpretation of IL-10 biology.


Craniofacial morphology in myostatin-deficient mice.
GDF-8 (myostatin) is a negative growth regulator of skeletal muscle, and myostatin-deficient mice are hypermuscular. Muscle size and force production are thought to influence growth of the craniofacial skeleton. To test this relationship, we compared masticatory muscle size and craniofacial dimensions in myostatin-deficient and wild-type CD-1 control mice. Myostatin-deficient mice had significantly (p < 0.01) greater body (by 18%) and masseter muscle weight (by 83%), compared with wild-type controls. Significant differences (p < 0.05) were noted for cranial vault length, maxillary length, mandibular body length, and mandibular shape index. Significant correlations were noted between masseter muscle weight and mandibular body length (r = 0.68; p < 0.01), cranial vault length (r = -0.57; p < 0.05), and the mandibular shape index (r = -0.56; p < 0.05). Masticatory hypermuscularity resulted in significantly altered craniofacial morphology, probably through altered biomechanical stress. These findings emphasize the important role that masticatory muscle function plays in the ontogeny of the cranial vault, the maxilla, and, most notably, the mandible.


Phase 3 clinical trial of steroids/mycophenolate mofetil vs steroids/placebo as therapy for acute GVHD: BMT CTN 0802.
Corticosteroids are the accepted primary therapy for acute graft-versus-host disease (GVHD), but durable responses are seen in only about half of the patients. Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0802, a phase 3 multicenter randomized double-blinded trial, was designed to test whether mycophenolate mofetil (MMF) plus corticosteroids was superior to corticosteroids alone as initial therapy for acute GVHD. Patients with newly diagnosed acute GVHD were eligible if they required systemic therapy. Patients were randomized to receive prednisone with either MMF or placebo. The primary end point was acute or chronic GVHD-free survival at day 56 after initiation of therapy. A futility rule for GVHD-free survival at day 56 was met at a planned interim analysis after 235 patients (of 372) were enrolled: 116 MMF, 119 placebo. Baseline characteristics were well balanced between treatment groups including grade and organ distribution of GVHD. GVHD-free survival at day 56, cumulative incidence of chronic GVHD at 12 months, overall survival, Epstein-Barr virus reactivation, severe, life-threatening infections, relapse at 12 months, and quality of life were similar. The addition of MMF to corticosteroids as initial therapy for acute GVHD does not improve GVHD-free survival compared with corticosteroids alone. This trial was registered at www.clinicaltrials.gov as #NCT01002742.


The Italian hemodilution trial in acute stroke. Italian Acute Stroke Study Group.
The Italian Acute Stroke Study is a prospective, multicenter, randomized, clinical trial to evaluate hemodilution in acute stroke. Thirty-one centers will recruit 1,200 patients with a recent (less than 12 hours) hemispheric acute stroke. Randomization is performed centrally, and patients are stratified by center and severity of neurologic deficit. Hemodilution is achieved by venesection and infusion of the same amount of dextran 40. Otherwise, both treated and control groups receive the standard treatment provided by each center within agreed guidelines. At 6 months after stroke, one member of the Clinical Coordinating Center, blind as to treatment allocation, collects data on mortality and disability by telephone. We expect to terminate the randomization on December 31, 1986, and the follow-up evaluation on June 30, 1987. The aim of the study is to evaluate whether mortality and disability are significantly reduced in the group treated with hemodilution compared with the control group.


Topical and Ingested Cooling Methodologies for Endurance Exercise Performance in the Heat.
This systematic review and meta-analysis aimed to assess studies which have investigated cooling methodologies, their timing and effects, on endurance exercise performance in trained athletes (Category 3; VO2max ≥ 55 mL·kg·min-1) in hot environmental conditions (≥28 °C). Meta-analyses were performed to quantify the effects of timings and methods of application, with a narrative review of the evidence also provided. A computer-assisted database search was performed for articles investigating the effects of cooling on endurance performance and accompanying physiological and perceptual responses. A total of 4129 results were screened by title, abstract, and full text, resulting in 10 articles being included for subsequent analyses. A total of 101 participants and 310 observations from 10 studies measuring the effects of differing cooling strategies on endurance exercise performance and accompanying physiological and perceptual responses were included. With respect to time trial performance, cooling was shown to result in small beneficial effects when applied before and throughout the exercise bout (Effect Size: -0.44; -0.69 to -0.18), especially when ingested (-0.39; -0.60 to -0.18). Current evidence suggests that whilst other strategies ameliorate physiological or perceptual responses throughout endurance exercise in hot conditions, ingesting cooling aids before and during exercise provides a small benefit, which is of practical significance to athletes' time trial performance.


Bronchioloalveolar differentiation in lung adenocarcinomas.
The goals of the study were to determine what percentage of neoplasms with a bronchioloalveolar (BAC) component were considered pure BAC by current World Health Organization (WHO) criteria. Next, we wanted to determine the number of mucinous BACs using histochemical staining with Alcian Blue PAS. Finally, we aimed to elucidate by immunohistochemistry the thyroid transcription factor-1 (TTF-1) frequency and cytokeratin 7 (CK7) expression, particularly in regard to the mucinous and non-mucinous subtypes of BAC tumors. We made a retrospective review of Hematoxylin and Eosin stained slides and classification of histologic grade, tumor subtype, and percentage of pure BAC pattern, with further characterization by histochemical staining for Alcian Blue PAS and Immunohistochemical staining for thyroid TTF-1 and CK7. Only 10 of 30 tumors examined could be classified as BAC by current strict WHO criteria. Nine cases were classified into non-mucinous and only one case was recognized as mucinous BAC, which showed positive staining for Alcian Blue PAS. TTF-1 positivity was in 100% of the non-mucinous BACs and complete absence of staining was in one case of mucinous BACs. CK7 expression in bronchioloalveolar carcinoma has demonstrated CK7 marked staining in 90% of non-mucinous BACs, also one case of mucinous BACs showed marked staining for TTF-1. BACs of mucinous morphology were notable for their conspicuous absence of TTF-1 immunoreactivity.


Mito-targeted antioxidant prevents cardiovascular remodelling in spontaneously hypertensive rat by modulation of energy metabolism.
Hypertension induced left ventricular hypertrophy (LVH) augments the risk of cardiovascular anomalies. Mitochondrial alterations result in oxidative stress, accompanied by decrease in fatty acid oxidation, leading to the activation of the hypertrophic program. Targeted antioxidants are expected to reduce mitochondrial reactive oxygen species more effectively than general antioxidants. This study was designed to assess whether the mito-targeted antioxidant, Mito-Tempol (Mito-TEMP) is more effective than the general oxidant, Tempol (TEMP) in reduction of hypertension and hypertrophy and prevention of shift in cardiac energy metabolism. Spontaneously hypertensive rats were administered either TEMP (20 mg/kg/day) or Mito-TEMP (2 mg/kg/day) intraperitoneally for 30 days. Post treatment, animals were subjected to 2D-echocardiography. Myocardial lysates were subjected to RPLC - LTQ-Orbitrap-MS analysis. Mid-ventricular sections were probed for markers of energy metabolism and fibrosis. The beneficial effect on cardiovascular structure and function was significantly higher for Mito-TEMP. Increase in mitochondrial antioxidants and stimulation of fatty acid metabolism; with significant improvement in cardiovascular function was apparent in spontaneously hypertensive rats (SHR) treated with Mito-TEMP. The study indicates that Mito-TEMP is superior to its non- targeted isoform in preventing hypertension induced LVH, and the beneficial effects on heart are possibly mediated by reversal of metabolic remodelling.


Phenylalanine and Phenylglycine Analogues as Arginine Mimetics in Dengue Protease Inhibitors.
Dengue virus is an increasingly global pathogen. One of the promising targets for antiviral drug discovery against dengue and related flaviviruses such as West Nile virus is the viral serine protease NS2B-NS3. We here report the synthesis and in vitro characterization of potent peptidic inhibitors of dengue virus protease that incorporate phenylalanine and phenylglycine derivatives as arginine-mimicking groups with modulated basicity. The most promising compounds were (4-amidino)-L-phenylalanine-containing inhibitors, which reached nanomolar affinities against dengue virus protease. The type and position of the substituents on the phenylglycine and phenylalanine side chains has a significant effect on the inhibitory activity against dengue virus protease and selectivity against other proteases. In addition, the non-natural, basic amino acids described here may have relevance for the development of other peptidic and peptidomimetic drugs such as inhibitors of the blood clotting cascade.


Neural Stem Cell-Based Anticancer Gene Therapy: A First-in-Human Study in Recurrent High-Grade Glioma Patients.
Purpose: Human neural stem cells (NSC) are inherently tumor tropic, making them attractive drug delivery vehicles. Toward this goal, we retrovirally transduced an immortalized, clonal NSC line to stably express cytosine deaminase (HB1.F3.CD.C21; CD-NSCs), which converts the prodrug 5-fluorocytosine (5-FC) to 5-fluorouracil (5-FU).Experimental Design: Recurrent high-grade glioma patients underwent intracranial administration of CD-NSCs during tumor resection or biopsy. Four days later, patients began taking oral 5-FC every 6 hours for 7 days. Study treatment was given only once. A standard 3 + 3 dose escalation schema was used to increase doses of CD-NSCs from 1 × 107 to 5 × 107 and 5-FC from 75 to 150 mg/kg/day. Intracerebral microdialysis was performed to measure brain levels of 5-FC and 5-FU. Serial blood samples were obtained to assess systemic drug concentrations as well as to perform immunologic correlative studies.Results: Fifteen patients underwent study treatment. We saw no dose-limiting toxicity (DLT) due to the CD-NSCs. There was 1 DLT (grade 3 transaminitis) possibly related to 5-FC. We did not see development of anti-CD-NSC antibodies and did not detect CD-NSCs or replication-competent retrovirus in the systemic circulation. Intracerebral microdialysis revealed that CD-NSCs produced 5-FU locally in the brain in a 5-FC dose-dependent manner. Autopsy data indicate that CD-NSCs migrated to distant tumor sites and were nontumorigenic.Conclusions: Collectively, our results from this first-in-human study demonstrate initial safety and proof of concept regarding the ability of NSCs to target brain tumors and locally produce chemotherapy. Clin Cancer Res; 23(12); 2951-60. ©2016 AACR.


Familial absence of the pectoralis major, serratus anterior, and latissimus dorsi muscles.
Congenital absence of shoulder girdle muscles is described in three generations of a family. The proband, a 3 year old boy, had absence of the sternocostal head of the right pectoralis major. His father had absence of the left serratus anterior and part of the left latissimus dorsi and his paternal grandfather had absence of the lower two-thirds of the left pectoralis major, with absence of the left serratus anterior and latissimus dorsi muscles. The condition is probably the result of a dominant gene. These observations show that absence of the pectoralis major is part of a wider spectrum of shoulder girdle defects. Where genetic advice is sought by persons with apparently sporadic absence of the pectoralis major, examination of the relatives is necessary.


Evaluation of Pain and Specimen Quality by Use of a Novel 25-Gauge Blood Collection Set With Ultra-Thin Wall Cannula and 5-Bevel Tip Design.
Phlebotomy has significant impact on overall patient satisfaction. Smaller gauge needles, such as a 25 gauge, may lessen patient discomfort but increase hemolysis and tube-filling times. Our studies evaluated the effect of a 5-bevel, 25-gauge blood collection set (BCS) with ultra-thin wall cannula [BD Vacutainer® UltraTouch™ Push Button BCS (UltraTouch)] on patient pain and anxiety compared with two 3-bevel, thin-wall, 23-gauge BCSs [BD Vacutainer® Safety-Lok™ (Safety-Lok) and Greiner Bio-One Vacuette® (Vacuette)]. Our studies also evaluated the 25-gauge UltraTouch for sample quality and tube filling compared with the 3-bevel, thin-wall, 23-gauge BD Vacutainer Push Button BCS. We conducted 2 studies with 214 subjects to compare pain and anxiety regarding future phlebotomy with the 3 aforementioned devices. Another study with 52 subjects assessed hemolysis in specimens collected with the UltraTouch and Push Button BCS; bench testing evaluated tube-filling times with these devices. A questionnaire captured pain upon needle insertion, overall pain, and anxiety regarding future phlebotomy. Hemolysis was evaluated visually, by Hemolysis Index and hemolysis-sensitive indicators potassium (K) and lactate dehydrogenase (LDH). A statistically significant decrease was noted for overall pain with UltraTouch compared with Vacuette and with insertion pain compared with Safety-Lok. There was no significant difference in anxiety regarding future phlebotomy. No increase was observed in Hemolysis Index, K or LDH. Tube-filling times were comparable for each device. The 25-gauge UltraTouch provided less overall pain compared with the 23-gauge Vacuette, less pain upon needle insertion than the 23-gauge Safety-Lok, and no compromise in specimen quality or flow rate.


Simpson's Paradox and the Impact of Different DNMT3A Mutations on Outcome in Younger Adults With Acute Myeloid Leukemia.
To evaluate the impact of DNMT3A mutations on outcome in younger patients with cytogenetic intermediate-risk acute myeloid leukemia. Diagnostic samples from 914 patients (97% < 60 years old) were screened for mutations in DNMT3A exons 13 to 23. Clinical outcome was evaluated according to presence or absence of a mutation and stratified according to type of mutation (R882, non-R882 missense, or truncation). DNMT3A mutations (DNMT3A(MUT)) were identified in 272 patients (30%) and associated with a poorer prognosis than wild-type DNMT3A, but the difference was only seen when the results were stratified according to NPM1 genotype. This example of Simpson's paradox results from the high coincidence of DNMT3A and NPM1 mutations (80% of patients with DNMT3A(MUT) had NPM1 mutations), where the two mutations have opposing prognostic impact. In the stratified analyses, relapse in patients with DNMT3A(MUT) was higher (hazard ratio, 1.35; 95% CI, 1.07 to 1.72; P = .01), and overall survival was lower (hazard ratio, 1.37; 95% CI, 1.12 to 1.87; P = .002). The impact of DNMT3A(MUT) did not differ according to NPM1 genotype (test for heterogeneity: relapse, P = .4; overall survival, P = .9). Further analysis according to the type of DNMT3A mutation indicated that outcome was comparable in patients with R882 and non-R882 missense mutants, whereas in those with truncation mutants, it was comparable to wild-type DNMT3A. These data confirm that presence of a DNMT3A mutation should be considered as a poor-risk prognostic factor, irrespective of the NPM1 genotype, and suggest that further consideration should be given to the type of DNMT3A mutation.


Clinical trials of new drugs for Alzheimer disease.
Alzheimer disease (AD) accounts for 60-70% of dementia cases. Given the seriousness of the disease and continual increase in patient numbers, developing effective therapies to treat AD has become urgent. Presently, the drugs available for AD treatment, including cholinesterase inhibitors and an antagonist of the N-methyl-D-aspartate receptor, can only inhibit dementia symptoms for a limited period of time but cannot stop or reverse disease progression. On the basis of the amyloid hypothesis, many global drug companies have conducted many clinical trials on amyloid clearing therapy but without success. Thus, the amyloid hypothesis may not be completely feasible. The number of anti-amyloid trials decreased in 2019, which might be a turning point. An in-depth and comprehensive understanding of the contribution of amyloid beta and other factors of AD is crucial for developing novel pharmacotherapies.In ongoing clinical trials, researchers have developed and are testing several possible interventions aimed at various targets, including anti-amyloid and anti-tau interventions, neurotransmitter modification, anti-neuroinflammation and neuroprotection interventions, and cognitive enhancement, and interventions to relieve behavioral psychological symptoms. In this article, we present the current state of clinical trials for AD at clinicaltrials.gov. We reviewed the underlying mechanisms of these trials, tried to understand the reason why prior clinical trials failed, and analyzed the future trend of AD clinical trials.


Genetic variation of Vibrio cholerae during outbreaks, Bangladesh, 2010-2011.
Cholera remains a major public health problem. To compare the relative contribution of strains from the environment with strains isolated from patients during outbreaks, we performed multilocus variable tandem repeat analyses on samples collected during the 2010 and 2011 outbreak seasons in 2 geographically distinct areas of Bangladesh. A total of 222 environmental and clinical isolates of V. cholerae O1 were systematically collected from Chhatak and Mathbaria. In Chhatak, 75 of 79 isolates were from the same clonal complex, in which extensive differentiation was found in a temporally consistent pattern of successive mutations at single loci. A total of 59 isolates were collected from 6 persons; most isolates from 1 person differed by sequential single-locus mutations. In Mathbaria, 60 of 84 isolates represented 2 separate clonal complexes. The small number of genetic lineages in isolates from patients, compared with those from the environment, is consistent with accelerated transmission of some strains among humans during an outbreak.


Global DNA methylation profiling technologies and the ovarian cancer methylome.
Cytosine methylation in DNA constitutes an important epigenetic layer of transcriptional and regulatory control in many eukaryotes. Profiling DNA methylation across the genome is critical to understanding the influence of epigenetics in normal biology and disease, such as cancer. Genome-wide analyses such as arrays and next-generation sequencing (NGS) technologies have been used to assess large fractions of the methylome at a single-base-pair resolution. However, the range of DNA methylation profiling techniques can make selecting the appropriate protocol a challenge. This chapter discusses the advantages and disadvantages of various methylome detection approaches to assess which is appropriate for the question at hand. Here, we focus on four prominent genome-wide approaches: whole-genome bisulfite sequencing (WGBS); methyl-binding domain capture sequencing (MBDCap-Seq); reduced-representation-bisulfite-sequencing (RRBS); and Infinium Methylation450 BeadChips (450 K, Illumina). We discuss some of the requirements, merits, and challenges that should be considered when choosing a methylome technology to ensure that it will be informative. In addition, we show how genome-wide methylation detection arrays and high-throughput sequencing have provided immense insight into ovarian cancer-specific methylation signatures that may serve as diagnostic biomarkers or predict patient response to epigenetic therapy.


Plasma endothelin levels and vascular effects of intravenous L-arginine infusion in subjects with uncomplicated insulin-dependent diabetes mellitus.
1. Uncomplicated insulin-dependent diabetes mellitus is associated with generalized vasodilatation. This vasodilatation is believed to contribute to the development of microvascular complications. The endothelium plays an important role in the regulation of vascular tone. 2. To investigate the role of endothelial mediators, we measured plasma endothelin levels and studied the vascular effects of intravenous L-arginine (the precursor of NO) in 10 male type 1 diabetic patients and 10 non-diabetic subjects. 3. The baseline plasma endothelin level was significantly lower in the diabetic patients [mean 1.7 (SD 0.5) versus 2.1 (0.4) pmol/l; P < 0.05] than in the control subjects. 4. During L-arginine infusion, plasma cyclic GMP (the second messenger for NO) increased in the control subjects [from 5.1 (2.9) to 6.9 (2.9) nmol/l; P < 0.05 versus saline] and in the diabetic patients [from 4.6 (1.8) to 5.7 (2.2) nmol/l; P = 0.09]. L-Citrulline (a by-product of NO synthesis from L-arginine) increased in both groups. The responses to L-arginine were not significantly different between the control subjects and the diabetic patients. The plasma atrial natriuretic peptide level did not change in either group during infusion of L-arginine or of an equal volume of isotonic saline. 5. Blood pressure decreased slightly during L-arginine administration in both groups. In control subjects, the extracellular fluid volume in the lower leg increased during L-arginine infusion as compared with saline; in the diabetic patients both L-arginine and saline increased the extracellular fluid volume.(ABSTRACT TRUNCATED AT 250 WORDS)