A Semi-Supervised Deep Rule-Based Approach for Complex Satellite Sensor Image Analysis.
Large-scale (large-area), fine spatial resolution satellite sensor images are valuable data sources for Earth observation while not yet fully exploited by research communities for practical applications. Often, such images exhibit highly complex geometrical structures and spatial patterns, and distinctive characteristics of multiple land-use categories may appear at the same region. Autonomous information extraction from these images is essential in the field of pattern recognition within remote sensing, but this task is extremely challenging due to the spectral and spatial complexity captured in satellite sensor imagery. In this research, a semi-supervised deep rule-based approach for satellite sensor image analysis (SeRBIA) is proposed, where large-scale satellite sensor images are analysed autonomously and classified into detailed land-use categories. Using an ensemble feature descriptor derived from pre-trained AlexNet and VGG-VD-16 models, SeRBIA is capable of learning continuously from both labelled and unlabelled images through self-adaptation without human involvement or intervention. Extensive numerical experiments were conducted on both benchmark datasets and real-world satellite sensor images to comprehensively test the validity and effectiveness of the proposed method. The novel information mining technique developed here can be applied to analyse large-scale satellite sensor images with high accuracy and interpretability, across a wide range of real-world applications.


Finding the team for Mars: a psychological and human factors analysis of a Mars Desert Research Station crew.
A two-week mission in March and April of 2011 sent six team members to the Mars Desert Research Station (MDRS). MDRS, a research facility in the high Utah desert, provides an analogue for the harsh and unusual working conditions that will be faced by men and women who one day explore Mars. During the mission a selection of quantitative and qualitative psychological tests were administered to the international, multidisciplinary team. A selection of the results are presented along with discussion.


Dementia: a global health priority - highlights from an ADI and World Health Organization report.
Alzheimer's Disease International is the worldwide federation of Alzheimer associations that represent people with dementia and their families. Alzheimer's Disease International has commissioned a number of World Alzheimer Reports since 2009 and was involved in the recently launched report Dementia: A Public Health Priority by the World Health Organization. From these reports, we can learn about the growing impact of Alzheimer's disease and other dementias on our societies and the need to take action. Developing national Alzheimer plans is a key tool for this action.


Azythromicin versus amoxicillin-clavulanate in the treatment of acute sinusitis in children.
In this prospective study we compared the efficiency of azithromycin and amoxicillin-clavulanate in treatment of acute sinusitis in children. Seventy patients were included in the age between 5 and 15 years. Beside ENT and pediatricians examination, nasal and throat smear on culture and antibiogram is taken from all the patients, as well as, X-ray of paranasal sinuses and laboratory findings, followed by check-up of nasal and throat smear and X-ray of paranasal sinuses. Azithromycin in single daily dose of 10 mg/kg during three days showed same efficiency as amoxicillin-clavulanate given three times per day in dose of 45 mg/kg during ten days.


Locally-delivered T-cell-derived cellular vehicles efficiently track and deliver adenovirus delta24-RGD to infiltrating glioma.
Oncolytic adenoviral vectors are a promising alternative for the treatment of glioblastoma. Recent publications have demonstrated the advantages of shielding viral particles within cellular vehicles (CVs), which can be targeted towards the tumor microenvironment. Here, we studied T-cells, often having a natural capacity to target tumors, for their feasibility as a CV to deliver the oncolytic adenovirus, Delta24-RGD, to glioblastoma. The Jurkat T-cell line was assessed in co-culture with the glioblastoma stem cell (GSC) line, MGG8, for the optimal transfer conditions of Delta24-RGD in vitro. The effect of intraparenchymal and tail vein injections on intratumoral virus distribution and overall survival was addressed in an orthotopic glioma stem cell (GSC)-based xenograft model. Jurkat T-cells were demonstrated to facilitate the amplification and transfer of Delta24-RGD onto GSCs. Delta24-RGD dosing and incubation time were found to influence the migratory ability of T-cells towards GSCs. Injection of Delta24-RGD-loaded T-cells into the brains of GSC-bearing mice led to migration towards the tumor and dispersion of the virus within the tumor core and infiltrative zones. This occurred after injection into the ipsilateral hemisphere, as well as into the non-tumor-bearing hemisphere. We found that T-cell-mediated delivery of Delta24-RGD led to the inhibition of tumor growth compared to non-treated controls, resulting in prolonged survival (p = 0.007). Systemic administration of virus-loaded T-cells resulted in intratumoral viral delivery, albeit at low levels. Based on these findings, we conclude that T-cell-based CVs are a feasible approach to local Delta24-RGD delivery in glioblastoma, although efficient systemic targeting requires further improvement.


Modelling the time evolution of active caspase-3 protein in the rat lens after in vivo exposure to ultraviolet radiation-B.
To introduce a model for the time evolution of active caspase-3 protein expression in albino rat lens up to 24 hours after in vivo exposure to low dose UVR in the 300 nm wavelength region (UVR-300 nm). Forty Sprague-Dawley rats were unilaterally exposed in vivo to 1 kJ/m2 UVR-300 nm for 15 minutes. At 0.5, 8, 16, and 24 hours after the UVR exposure, the exposed and contralateral not-exposed lenses were removed and processed for immunohistochemistry. The differences in the probability of active caspase-3 expression at four different time points after exposure were used to determine the time evolution of active caspase-3 expression. A logistic model was introduced for the expression of active caspase-3. The parameters for the exposed and the not exposed lenses were estimated for the observation time points. The exposure to UVR-300 nm impacted on the parameters of the logistic model. Further, the parameters of the model varied with time after exposure to UVR-300 nm. The logistic model predicts the impact of exposure to UVR-300 nm on the spatial distribution of probability of active caspase-3 protein expression, depending on time.


Enhanced excitability of thalamic sensory neurons and slow-wave EEG pattern after stimuli that induce spinal long-term potentiation.
Spinal nociceptive neurons are well known to undergo a process of long-term potentiation (LTP) following conditioning by high-frequency sciatic nerve stimulation (HFS) at intensities recruiting C-fibers. However, little if any information exists as to whether such HFS conditioning that produces spinal LTP affects sensory transmission at supraspinal levels. The present study explored this possibility. Conventional extracellular recording methods were used to examine the consequences of HFS versus sham HFS conditioning on individual wide-dynamic range thalamic neurons located in the ventro-postero-lateral (VPL) nucleus in isoflurane-anesthetized rats. Following HFS, the ongoing firing rate and stimulus-evoked (brush, pinch, sciatic nerve) responses were markedly enhanced as were responses to juxtacellular, microiontophoretic applications of glutamate. These HFS-induced enhancements lasted throughout the recording period. Sham stimuli had no effect on VPL neuron excitability. Cortical electroencephalographic (EEG) wave activities were also measured around HFS in conjunction with VPL neuron recordings. The cortical EEG pattern under baseline conditions consisted of recurring short duration bursts of high-amplitude slow waves followed by longer periods of flat EEG. Following HFS, the EEG shifted to a continuous large-amplitude, slow-wave pattern within the 0.5-8.0 Hz bandwidth lasting throughout the recording period. Sham HFS did not alter EEG activity. Sciatic nerve conditioning at A-δ fiber strength, known to reverse spinal LTP, did not alter enhanced neuronal excitability or the EEG slow-wave pattern induced by HFS. These data support the concept that HFS conditioning of the sciatic nerve, which leads to spinal LTP, is associated with distinct, long-lasting changes in the excitability of neurons comprising thalamocortical networks.


Cushing disease as possible cause of persistent growth failure despite growth hormone therapy in a small for gestational age male.
Growth hormone (GH) therapy in children with small for gestational age (SGA) has been shown to be of significant therapeutic benefit. We report the case of an 11-year-old Caucasian male who developed early adrenarche, hypertension and insulin resistance on GH therapy for SGA and profound short stature (ht -5 SD). This patient demonstrated a poor response to GH therapy and developed physical and biochemical findings of insulin resistance responsive to metformin therapy. He remained hypertensive, however, and continued to have elevated serum dehydroepiandrosterone sulfate levels. Urinary free cortisol excretion was subsequently found to be elevated. The diagnosis of Cushing's disease was confirmed with inferior petrosal sinus sampling and pituitary MRI. The patient underwent partial adenohypophysectomy with resulting normalization of plasma cortisol levels and associated symptoms. Our patient's diagnosis of Cushing's disease was complicated by his past history of poor growth since birth and history of SGA. The signs of Cushing's disease did not overtly appear until GH therapy was initiated to help treat severe short stature. It is possible that the metabolic effects of GH therapy unmasked the presence of underlying Cushing's disease.


Using anti-poly(ethylene glycol) bioparticles for the quantitation of PEGylated nanoparticles.
Attachment of polyethylene glycol (PEG) molecules to nanoparticles (PEGylation) is a widely-used method to improve the stability, biocompatibility and half-life of nanomedicines. However, the evaluation of the PEGylated nanomedicine pharmacokinetics (PK) requires the decomposition of particles and purification of lead compounds before analysis by high performance liquid chromatography (HPLC), mass spectrometry, etc. Therefore, a method to directly quantify un-decomposed PEGylated nanoparticles is needed. In this study, we developed anti-PEG bioparticles and combined them with anti-PEG antibodies to generate a quantitative enzyme-linked immunosorbent assay (ELISA) for direct measurement of PEGylated nanoparticles without compound purification. The anti-PEG bioparticles quantitative ELISA directly quantify PEG-quantum dots (PEG-QD), PEG-stabilizing super-paramagnetic iron oxide (PEG-SPIO), Lipo-Dox and PEGASYS and the detection limits were 0.01 nM, 0.1 nM, 15.63 ng/mL and 0.48 ng/mL, respectively. Furthermore, this anti-PEG bioparticle-based ELISA tolerated samples containing up to 10% mouse or human serum. There was no significant difference in pharmacokinetic studies of radiolabeled PEG-nanoparticles (Nano-X-111In) through anti-PEG bioparticle-based ELISA and a traditional gamma counter. These results suggest that the anti-PEG bioparticle-based ELISA may provide a direct and effective method for the quantitation of any whole PEGylated nanoparticles without sample preparation.


Mechanical, but not infective, pacemaker erosion may be successfully managed by re-implantation of pacemakers.
When a pacemaker box causes erosion it is usually removed and a new pacemaker implanted at a contralateral site. In this study when there was no evidence of systemic infection an attempt was made to clean and reimplant the same pacemaker in the same site. Over 10 years 62 patients had pacemaker reimplantation. In 18 patients the procedure was repeated a second time. Reimplantation was successful after at least six months follow up in 38 patients (61%): in nine two attempts had been made. Mean hospital stay for all patients was 21.3 days; for patients in whom the procedure was successful it was 12.5 days and for those in whom it was unsuccessful it was 35.4 days. 31 (82%) of the 38 patients in whom reimplantation was successful had no bacterial growth from wound swabs from 17/24 (71%) patients in whom reimplantation was unsuccessful (p < 0.001). Bacteria were grown from swabs from 7/8 patients with a protruding wire compared with 9/23 patients with a protruding pacemaker (p = 0.05). Thin patients and those who were older were more likely to have successful reimplantation: neither association reached statistical significance. A clinical impression of infection was not helpful. If re-implantation had been attempted only in the patients with negative wound swabs or intact skin the success rate would have been 74% at a cost of 5010 pounds per patient compared with a cost of 6509 pounds per patient for explantation and a reimplantation of a new contralateral pacemaker. These data support the hypothesis that pacemaker erosion is caused by primary infection or by a non-infective process (probably mechanical pressure). Pacemaker erosion that is not caused by infection can be successfully managed by ipsilateral reimplantation and this approach saves money.


Clonal population structure of encapsulated Haemophilus influenzae.
Chromosomal genotypes of 2,209 isolates of the six polysaccharide capsule types of Haemophilus influenzae recovered from human hosts worldwide were characterized by an analysis of electrophoretically demonstrable allelic profiles at 17 metabolic enzyme loci. For 222 representative isolates, restriction fragment length polymorphism patterns produced by digestion of cap region DNA were also determined. With few exceptions, isolates belonging to individual phylogenetic lines or groups of allied lineages identified by multilocus enzyme electrophoresis had characteristic cap region restriction fragment length polymorphism patterns and characteristic combinations of cap region patterns and outer membrane protein types. The occurrence of strong associations of characters and the recovery of isolates with identical genetic properties in widely separated geographic regions and over a 40-year period indicated that the population structure of encapsulated H. influenzae is clonal. Recombination of chromosomal genes, including those mediating capsule synthesis, apparently is not a major factor in the short-term evolution of these pathogenic organisms and, therefore, may be of minor clinical significance.


In vivo investigation of protein-protein interactions for helicases using tandem affinity purification.
A key component in determining the functional role of any protein is the elucidation of its binding partners using protein-protein interaction (PPI) data. Here we examine the use of tandem affinity purification (TAP) tagging to study RNA/DNA helicase PPIs in Escherichia coli. The tag, which consists of a calmodulin-binding region, a TEV protease recognition sequence, and an IgG-binding domain, is introduced into E. coli using a lambdared recombination system. This method prevents the overproduction of the target protein, which could generate false interactions. The interacting proteins are then affinity purified using double affinity purification steps and are separated by SDS-PAGE followed by mass spectrometry identification. Each protein identified would represent a physical interaction in the cell. These interactions may potentially be mediated by an RNA/DNA template, for which the helicase would likely be needed to disrupt the secondary structures.


Percolation Theory, Thermoelasticity, and Discrete Hydrothermal Venting in the Earth's Crust.
As hydrothermal fluid ascends through a network of cracks into cooler crust, heat is transferred from the fluid to the adjacent rock. The thermal stresses caused by this heating close cracks that are more or less vertical. This heating may affect network connections and destroy the permeable crack network. Thermoelastic stresses caused by a temperature difference of approximately 1000 degrees C can decrease the interconnectivity of a crack network to the percolation threshold. If the temperature is slightly less, thermoelastic stresses may focus the discharge in hydrothermal systems into discrete vents.


Development of auditory processing in 6- to 11-yr-old children.
The aim of this study is to provide developmental standards on a variety of temporal, spectral, and binaural psychoacoustic (auditory processing [AP]) tests in typically developing children, including immediate and delayed retest reliability, and comparisons between single listener performance on different tests. This study also informs choices on the selection of tests for clinical evaluation of hearing and listening (e.g., for auditory processing disorder). This is a laboratory-based study of AP threshold and variability of 75 children, aged 6 to 11 yrs, and 21 young adults with normal audiometry recruited from local schools and colleges. Data were gathered in clinic-like conditions, without training and across two sessions. Eleven individual (e.g., simultaneous masking and backward masking [BM], amplitude modulation [AM], and frequency modulation [FM] detection) and three derived (temporal integration, frequency resolution, masking level difference) measure tests were embedded within a suite of computer games, each employing a three-interval, three-alternative (odd-one-out) forced choice response paradigm and a staircase adaptive method. AP measures generally showed lower thresholds and reduced variance with increasing age. At 6 to 7 yrs, performance was markedly poorer than in the older groups; 35% of the children could not do the test of frequency discrimination (FD). However, on all the tasks, some children in the same group performed at near-adult levels. The distribution of performance between individuals varied widely across tasks, with clustered performance on tests of tone detection (with or without a simultaneous masker) and AM detection, and scattered performance on BM, FM detection, and FD. Threshold maturity was achieved at different rates across tests and by 10 to 11 yrs of age on all tests except FD. Masking level difference (MLD) performance did not change with age. Retest reliability was mostly high within test sessions but, again, was poorer for some of the younger children. Between test sessions separated by one to several weeks, reliability varied from poor (for FM detection) to high (for long tone detection in quiet, BM, and FD). Correlations between thresholds on different tests were generally low. Data suggest that the perception of different auditory stimuli occurs and develops using rather independent mechanisms, even for tasks that are closely related in procedure. While individual children can perform reliably on several distinct tasks, differences between individuals on the same tasks can be large. Because some of the youngest children perform reliably across time, at or near adult levels, immaturity between 6 and 11 yrs of age, as reflected in group statistics, reflects poor performance of some individual children rather than obligate, age-related deficits in AP. While several of the tests used were found to have potential clinical applicability, because of their reliability and ability to distinguish between individuals, it is currently unclear how performance on such tests relates to everyday listening skills.


Distinction of cervical cancer biopsies by use of infrared microspectroscopy and probabilistic neural networks.
Fourier-transform infrared spectroscopy has shown alterations of spectral characteristics of cells and tissues as a result of carcinogenesis. The research reported here focuses on the diagnosis of cancer in formalin-fixed biopsied tissue for which immunochemistry is not possible and when PAP-smear results are to be confirmed. The data from two groups of patients (a control group and a group of patients diagnosed with cervical cancer) were analyzed. It was found that the glucose/phosphate ratio decreases (by 23-49%) and the RNA/DNA ratio increases (by 38-150%) in carcinogenic compared with normal tissue. Fourier-transform microspectroscopy was used to examine these tissues. This type of study in larger populations may help to set standards or classes with which to use treated biopsied tissue to predict the possibility of cancer. Probabilistic neural networks and statistical tests as parts of these biopsies predict the possibility of cancer with a high degree of accuracy (> 95%).


A systematic review: Cost-effectiveness of continuous glucose monitoring compared to self-monitoring of blood glucose in type 1 diabetes.
Continuous glucose monitoring (CGM) is rapidly becoming a vital tool in the management of type 1 diabetes. Its use has been shown to improve glycaemic management and reduce the risk of hypoglycaemic events. The cost of CGM remains a barrier to its widespread application. We aimed to identify and synthesize evidence about the cost-effectiveness of utilizing CGM in patients with type 1 diabetes. Studies were identified from MEDLINE, Embase and Cochrane Library from January 2010 to February 2022. Those that assessed the cost-effectiveness of CGM compared to self-monitored blood glucose (SMBG) in patients with type 1 diabetes and reported lifetime incremental cost-effectiveness ratio (ICER) were included. Studies on critically ill or pregnant patients were excluded. Nineteen studies were identified. Most studies compared continuous subcutaneous insulin infusion and SMBG to a sensor-augmented pump (SAP). The estimated ICER range was [$18,734-$99,941] and the quality-adjusted life year (QALY) gain range was [0.76-2.99]. Use in patients with suboptimal management or greater hypoglycaemic risk revealed more homogenous results and lower ICERs. Limited studies assessed CGM in the context of multiple daily injections (MDI) (n = 4), MDI and SMBG versus SAP (n = 2) and three studies included hybrid closed-loop systems. Most studies (n = 17) concluded that CGM is a cost-effective tool. This systematic review suggests that CGM appears to be a cost-effective tool for individuals with type 1 diabetes. Cost-effectiveness is driven by reducing short- and long-term complications. Use in patients with suboptimal management or at risk of severe hypoglycaemia is most cost-effective.


Ultrasound-guided percutaneous transhepatic cholecystostomy for acute acalculous cholecystitis.
Ultrasound-guided percutaneous transhepatic cholecystostomy was performed in six critically ill patients who had acute acalculous cholecystitis. The clinical conditions of all six patients improved dramatically following transhepatic cholecystostomy. No complications of this bedside procedure occurred. Cholangiography via the inserted pigtail catheter was normal in four patients. Their catheters were removed after ten to 21 days. At follow-up examinations at four to 30 months they were free of signs of gallbladder disease. In one patient, ultrasonography showed desquamation of the mucosa in the gallbladder, which led to the decision to perform cholecystectomy two days after cholecystostomy. One patient, suffering from cholangiocarcinoma, died 120 days after cholecystostomy with the catheter in situ. In our experience, ultrasound-guided percutaneous transhepatic cholecystostomy is the treatment of choice to overcome a critical period in patients with acute acalculous cholecystitis. When post-drainage cholangiography is normal, cholecystectomy at a later stage is not indicated in the majority of these patients.


Amount of Time to Eat Lunch Is Associated with Children's Selection and Consumption of School Meal Entrée, Fruits, Vegetables, and Milk.
There are currently no national standards for school lunch period length and little is known about the association between the amount of time students have to eat and school food selection and consumption. Our aim was to examine plate-waste measurements from students in the control arm of the Modifying Eating and Lifestyles at School study (2011 to 2012 school year) to determine the association between amount of time to eat and school meal selection and consumption. We used a prospective study design using up to six repeated measures among students during the school year. One thousand and one students in grades 3 to 8 attending six participating elementary and middle schools in an urban, low-income school district where lunch period lengths varied from 20 to 30 minutes were included. School food selection and consumption were collected using plate-waste methodology. Logistic regression and mixed-model analysis of variance was used to examine food selection and consumption. Compared with meal-component selection when students had at least 25 minutes to eat, students were significantly less likely to select a fruit (44% vs 57%; P<0.0001) when they had <20 minutes to eat. There were no significant differences in entrée, milk, or vegetable selections. Among those who selected a meal component, students with <20 minutes to eat consumed 13% less of their entrée (P<0.0001), 10% less of their milk (P<0.0001), and 12% less of their vegetable (P<0.0001) compared with students who had at least 25 minutes to eat. During the school year, a substantial number of students had insufficient time to eat, which was associated with significantly decreased entrée, milk, and vegetable consumption compared with students who had more time to eat. School policies that encourage lunches with at least 25 minutes of seated time might reduce food waste and improve dietary intake.


Multiplex meta-analysis of RNA expression to identify genes with variants associated with immune dysfunction.
We demonstrate a genome-wide method for the integration of many studies of gene expression of phenotypically similar disease processes, a method of multiplex meta-analysis. We use immune dysfunction as an example disease process. We use a heterogeneous collection of datasets across human and mice samples from a range of tissues and different forms of immunodeficiency. We developed a method integrating Tibshirani's modified t-test (SAM) is used to interrogate differential expression within a study and Fisher's method for omnibus meta-analysis to identify differentially expressed genes across studies. The ability of this overall gene expression profile to prioritize disease associated genes is evaluated by comparing against the results of a recent genome wide association study for common variable immunodeficiency (CVID). Our approach is able to prioritize genes associated with immunodeficiency in general (area under the ROC curve = 0.713) and CVID in particular (area under the ROC curve = 0.643). This approach may be used to investigate a larger range of failures of the immune system. Our method may be extended to other disease processes, using RNA levels to prioritize genes likely to contain disease associated DNA variants.


Dynamic remodeling of microbial biofilms by functionally distinct exopolysaccharides.
Biofilms are densely populated communities of microbial cells protected and held together by a matrix of extracellular polymeric substances. The structure and rheological properties of the matrix at the microscale influence the retention and transport of molecules and cells in the biofilm, thereby dictating population and community behavior. Despite its importance, quantitative descriptions of the matrix microstructure and microrheology are limited. Here, particle-tracking microrheology in combination with genetic approaches was used to spatially and temporally study the rheological contributions of the major exopolysaccharides Pel and Psl in Pseudomonas aeruginosa biofilms. Psl increased the elasticity and effective cross-linking within the matrix, which strengthened its scaffold and appeared to facilitate the formation of microcolonies. Conversely, Pel reduced effective cross-linking within the matrix. Without Psl, the matrix becomes more viscous, which facilitates biofilm spreading. The wild-type biofilm decreased in effective cross-linking over time, which would be advantageous for the spreading and colonization of new surfaces. This suggests that there are regulatory mechanisms to control production of the exopolysaccharides that serve to remodel the matrix of developing biofilms. The exopolysaccharides were also found to have profound effects on the spatial organization and integration of P. aeruginosa in a mixed-species biofilm model of P. aeruginosa-Staphylococcus aureus. Pel was required for close association of the two species in mixed-species microcolonies. In contrast, Psl was important for P. aeruginosa to form single-species biofilms on top of S. aureus biofilms. Our results demonstrate that Pel and Psl have distinct physical properties and functional roles during biofilm formation. Importance: Most bacteria grow as biofilms in the environment or in association with eukaryotic hosts. Removal of biofilms that form on surfaces is a challenge in clinical and industrial settings. One of the defining features of a biofilm is its extracellular matrix. The matrix has a heterogeneous structure and is formed from a secretion of various biopolymers, including proteins, extracellular DNA, and polysaccharides. It is generally known to interact with biofilm cells, thus affecting cell physiology and cell-cell communication. Despite the fact that the matrix may comprise up to 90% of the biofilm dry weight, how the matrix properties affect biofilm structure, maturation, and interspecies interactions remain largely unexplored. This study reveals that bacteria can use specific extracellular polymers to modulate the physical properties of their microenvironment. This in turn impacts biofilm structure, differentiation, and interspecies interactions.


SKF 525-A inhibition, induction, and 452-nm complex formation.
After administration of SKF 525-A to rats a portion of the cytochrome P-450 in hepatic microsomes was found in the reduced form as a stable complex absorbing at 452 nm. As much as 40% of the total cytochrome P-450 was bound in the complexed form after a single administration of SKF 525-A. The addition of potassium ferricyanide (50 muM) to hepatic microsomes from SKF 525-A-treated rats destroyed the complex and made the total cytochrome P-450 available for carbon monoxide binding. At early times after administration of SKF 525-A, when the amount of complexed cytochrome P-450 was maximum, mixed-function oxidase activities (p-nitroanisole O-demethylase and norbenzphetamine 455-nm complex formation) were greatly inhibited. Later, as the amount of complexed cytochrome P-450 slowly decreased, these mixed-function oxidase activities gradually returned and reached control values in about 48 hr. Induction with daily doses of SKF 525-A for several days increased total cytochrome P-450 content up to 5-fold, which was more than induction with phenobarbital, but this was evident only after destruction of the complex with ferricyanide. The maximum increase in uncomplexed cytochrome P-450 was only 2-fold. Treatment of these microsomal suspensions with ferricyanide enhanced ethylmorphine N-demethylase, p-nitroanisole O-demethylase and norbenzphetamine 455-nm complex formation.


Gaussian modes in high loss laser resonators.
Matrix techniques are applied to the mode analysis of laser resonators having spherical mirrors and Gaussian profiles of the mirror reflectivity. These same analytical methods provide a useful approximation to the mode and loss characteristics of conventional resonators having an abrupt discontinuity of the reflectivity. Mode selection in apertured waveguides and resonators is also discussed.


Nonpenetrating filtration surgery for glaucoma: control by surgery only.
To report on intraocular pressure (IOP) control by nonpenetrating filtration surgery without medical treatment in eyes with primary open-angle glaucoma (POAG). Oxford Eye Center and St. John Eye Hospital, Johannesburg, South Africa. This retrospective study evaluated IOP control by nonpenetrating filtration surgery in 46 patients (86 eyes) with POAG who had surgery between February 1992 and February 1998 (mean follow-up 46 months); 48 eyes were previously treated, and 38 were newly diagnosed, untreated eyes. Under a trapezoidal scleral flap, a deep sclerectomy and a fenestration in Schlemm's canal were created without penetrating the anterior chamber. Postoperatively, when IOP rose above 20 mm Hg, instead of adding medical treatment, the filtration site was revised to re-establish filtration. The mean drop in IOP was 50%, from a mean of 30.4 mm Hg preoperatively to a mean of 15.35 mm Hg postoperatively. After a mean period of successful filtration of 29.9 months, the filtration site was revised in 48 eyes (56%) to maintain the IOP below 21 mm Hg without medication. The reoperation rate was 4.7 times higher in previously treated patients than in untreated patients. Nonpenetrating filtration surgery in eyes with POAG was more rewarding in untreated patients than in medically treated patients. To control IOP without medication, revision of the filtration site is feasible and needed in the medium and long term.


Fatty acid-binding protein 4, a point of convergence for angiogenic and metabolic signaling pathways in endothelial cells.
Fatty acid-binding protein 4 (FABP4) is an adipogenic protein and is implicated in atherosclerosis, insulin resistance, and cancer. In endothelial cells, FABP4 is induced by VEGFA, and inhibition of FABP4 blocks most of the VEGFA effects. We investigated the DLL4-NOTCH-dependent regulation of FABP4 in human umbilical vein endothelial cells by gene/protein expression and interaction analyses following inhibitor treatment and RNA interference. We found that FABP4 is directly induced by NOTCH. Stimulation of NOTCH signaling with human recombinant DLL4 led to FABP4 induction, independently of VEGFA. FABP4 induction by VEGFA was reduced by blockade of DLL4 binding to NOTCH or inhibition of NOTCH signal transduction. Chromatin immunoprecipitation of the NOTCH intracellular domain showed increased binding to two specific regions in the FABP4 promoter. The induction of FABP4 gene expression was dependent on the transcription factor FOXO1, which was essential for basal expression of FABP4, and FABP4 up-regulation following stimulation of the VEGFA and/or the NOTCH pathway. Thus, we show that the DLL4-NOTCH pathway mediates endothelial FABP4 expression. This indicates that induction of the angiogenesis-restricting DLL4-NOTCH can have pro-angiogenic effects via this pathway. It also provides a link between DLL4-NOTCH and FOXO1-mediated regulation of endothelial gene transcription, and it shows that DLL4-NOTCH is a nodal point in the integration of pro-angiogenic and metabolic signaling in endothelial cells. This may be crucial for angiogenesis in the tumor environment.


Clinical Indicators for Endotracheal Suctioning in Adult Patients Receiving Mechanical Ventilation.
Critically ill patients who need mechanical ventilation require endotracheal suctioning. Guidelines recommend coarse crackles over the trachea and/or the presence of a sawtooth pattern on the flow-volume loop of the ventilator waveform as the best indicators. To determine clinical cues for endotracheal suctioning in patients who require mechanical ventilation. A descriptive study of 42 adult patients receiving mechanical ventilation. After baseline endotracheal suctioning with a closed-system device, patients were assessed hourly up to 4 hours for guideline-based cues for endotracheal suctioning and lung sounds were auscultated. Endotracheal suctioning was done when cues were detected or 4 hours after baseline suctioning. Secretions were collected, measured, and weighed. Most patients were male (62%) and white (93%). Mean age was 51 years, and mean duration of mechanical ventilation was 7.5 days. The median time to endotracheal suctioning was 2 hours, and a mean of 4.4 mL of secretions was removed. Three patients had no cues identified but had 1.0 mL or more of secretions. The most frequent cues were crackles over the trachea (88%), sawtooth waveform (33%), coughing (29%), and visible secretions (5%). Cues resolved and physiological parameters improved after suctioning. Coarse lung sounds did not improve. Patients receiving mechanical ventilation should be routinely assessed for coarse crackles over the trachea, the most common indicator for endotracheal suctioning. Despite common practice, assessment of lung sounds to identify the need for suctioning is not supported.


Growth of the human ilium: the anomalous sacroiliac junction.
Despite the major anatomical importance of the human ilium in medicine and forensic investigations, little is understood about its pattern of growth. This study was conducted to investigate the changes in the surface area of the human ilium from birth through to adolescence in 80 human ilia. A photographic image of the pelvic surface of each bone was taken and examined using an image quantification package. The surface areas of four regions of interest were quantified: the auricular, post-auricular (PA), iliac fossa, and whole pelvic surface of the ilium. The results highlight a rapid increase in surface area for all regions in the first few years after birth which continues, albeit at a slower rate, until ∼4 years of age when the rate of growth is further reduced. Although the ilium and its various components continue to grow between 5 years and puberty, the rate of growth is markedly reduced until puberty when growth of the pelvis again increases. Interestingly, analysis of the differential growth of the auricular region compared with the PA region throughout development suggests that the PA region exhibits more advanced growth. This may indicate that its role in structural development for the purposes of preparation and maintenance of bipedal stance and locomotion may have been previously poorly understood.


Further Investigations on the Crosslinking of Tarsal Collagen as a Treatment for Eyelid Laxity: Optimizing the Procedure in Animal Tissue.
A follow-up experimental study on the exposure of animal tarsal plate to ultraviolet-A radiation aimed at establishing an optimum range for safe irradiation conditions. Sheep tarsus specimens were excised postmortem and then subjected to irradiation with ultraviolet-A rays (wavelength 365 nm) at higher irradiances than those reported in an initial study, using a laboratory radiation source. The mechanical properties (tensile strength and Young's modulus) of irradiated and nonirradiated samples were evaluated in a mechanical tester. The test and control specimens were examined histologically with an aim to assess the effects of radiation upon the meibomian glands and tarsal collagen networks, and to establish a safe range for the exposure irradiance level. As expected, irradiation induced both stiffening and strengthening of the tarsal plate specimens. At an irradiance of 50 mW/cm for 3-minute exposure, these effects were at their maximum level, after which a decline in mechanical characteristics were observed. No destruction of the tarsal connective tissue or the meibomian glands were noticed up to an irradiance of 125 mW/cm for 3-minute exposure, corresponding to a fluence of 22.5 J/cm. Histology revealed that the collagen network surrounding the glands were packed more compactly following irradiation. At a fluence of 45 J/cm, massive destruction of periglandular collagen-rich network and meibocytes were demonstrated histologically. The study indicates that irradiation of tarsal collagen leading to tissue stiffening shall be carried out at levels of fluence between 10 and 15 J/cm, a region that is deemed safe. The exposure time can be adjusted according to the surgeon's decision.Safe irradiation conditions are established for the exposure of ex vivo ovine tarsus to ultraviolet-A radiation as a potentially effective treatment for eyelid laxity in human patients.


A great option for elderly patients with locally invasive bladder cancer, BOAI-CDDP-radiation (OMC regimen).
We have developed a novel bladder preservation therapy, balloon-occluded arterial infusion (BOAI) of cisplatin/gemcitabine, concomitantly with hemodialysis, along with concurrent irradiation [the so-called 'OMC (Osaka Medical College) regimen']. The OMC regimen delivers an extremely high concentration of anticancer agent to the site of a tumor without systemic adverse effects, since more than 95% of free Pt was efficiently eliminated by hemodialysis, which enables short hospital stay. In this study, we investigated the efficiency of OMC regimen in patients aged over 70 years with muscle-invasive bladder cancer without metastasis. A total of 134 such patients were assigned to receive either the OMC regimen (n=89) or cystectomy (n=45). OMC regimen patients who failed to achieve CR underwent cystectomy, or secondary BOAI with gemcitabine (1,600 mg). The OMC regimen, which delivers an extremely high concentration of anticancer agent to the tumor site without systemic adverse effects, yielded CR in >91% (81/89) of patients. More than 96% (78/81) of the CR patients survived without recurrence with intact bladder after a mean follow-up of 164 (range 16-818) weeks. The 5- and 10-year bladder intact survival rates were 87.2 and 69.8%, and overall survival rates were 88.4 and 70.7% (vs. 59.9 and 33.3% for cystectomy, p=0.0002), respectively, although the median age in the OMC regimen group was significantly greater than in the cystectomy group (median, range = 77, 70-98 vs. 74, 70-89; p=0.0003). No patients suffered grade II or more severe toxicities; the oldest patient, aged 91 years, successfully completed this therapy. In conclusion, the OMC regimen is a useful bladder preservation strategy for elderly patients with locally invasive bladder cancer, not only in those for whom cystectomy is indicated, but also in patients whose condition is not amenable to curative treatment and for whom palliation would otherwise seem the only option.


The catalytic mechanism of carbonic anhydrase.
It is shown that an "inverse" relationship between the pH dependencies of the rates of hydration of CO(2) and dehydration of HCO(3) (-) by carbonic anhydrase (EC 188.8.131.52) is a direct consequence of the thermodynamic equilibrium between CO(2) and HCO(3) (-) and independent of any assumptions about the catalytic mechanism. It is further shown that proposed mechanisms for carbonic anhydrase involving HCO(3) (-) as the substrate in the dehydration reaction and a proton transfer reaction, EH(+) right harpoon over left harpoon E + H(+), as an obligatory step during catalysis obey the rule of microscopic reversibility. This includes mechanisms in which the proton dissociation is from a zinc-coordinated water molecule. Such mechanisms can be in accord with the observed rapid turnover rates of the enzyme, since rapid proton exchange can occur with the buffer components, EH(+) + B right harpoon over left harpoon E + BH(+). Mechanisms in which H(2)CO(3) is the substrate in dehydration avoid the proton-transfer step, but require that H(2)CO(3) combines with enzyme more rapidly than in a diffusion-controlled reaction. Physico-chemical evidence for and against a zinc-hydroxide mechanism is discussed.


Meta-Analysis of Large-Scale Randomized Trials to Determine the Effectiveness of Inhibition of the Renin-Angiotensin Aldosterone System in Heart Failure.
Renin-angiotensin-aldosterone system (RAAS) inhibition is 1 of the most effective strategies for the management of heart failure with reduced systolic function. However, trials that included patients with preserved systolic function have not shown a clear beneficial effect. Pooling evidence from several heart failure trials provides the opportunity to better assess the differential effects of RAAS inhibition across the continuum of systolic function. The authors searched MEDLINE for large-scale trials published from 1966 to March 2014 that compared RAAS inhibitors against placebos. Studies were eligible for inclusion if they were conducted in heart failure populations with either clinical signs of heart failure or reduced ejection fractions. Inverse variance-weighted fixed-effects meta-analysis was used to pool outcomes of interest, with metaregression used to test for trends. In 16 trials with 54,621 randomized heart failure participants, RAAS inhibition reduced the risks for hospitalization for heart failure by 20% (relative risk [RR] 0.80, 95% confidence interval [CI] 0.77 to 0.83), cardiovascular mortality by 14% (RR 0.86, 95% CI 0.83 to 0.90), and all-cause mortality by 11% (RR 0.89, 95% CI 0.85 to 0.92). However, proportional effects decreased with increasing mean left ventricular ejection fraction (LVEF) for all outcomes (p for trend <0.01). Although there was no significant proportional effect on cardiovascular and all-cause mortality in trials with a mean LVEF >50%, RAAS inhibition was still found to decrease the risk for heart failure hospitalization in patients with preserved LVEFs (RR 0.88, 95% CI 0.80 to 0.97). In conclusion, the relative beneficial effects of RAAS inhibition in heart failure decreases with increasing left ventricular systolic function. Nonetheless, RAAS inhibition significantly reduces the risks for all-cause mortality and cardiovascular mortality in patients with moderately reduced LVEFs and the incidence of hospitalization in patients with preserved left ventricular function.


Phase II trial of 5-fluorouracil and leucovorin in combination with interferon-alpha and interleukin-2 for advanced renal cell cancer.
Recent clinical trials have demonstrated activity of chemoimmunotherapy with interleukin-2 (IL-2), interferon-[alpha], and 5-fluorouracil (5-FU) in advanced renal cell cancer. A phase II study was performed to evaluate the affect of adding the potentiating agent leucovorin to this combination regimen. Treatment courses consisted of IL-2 5 MIU/m2 subcutaneously days 1, 3, and 5 of weeks 1 to 4, interferon-[alpha] 3 MIU/m2 subcutaneously on days 1, 3, and 5 of weeks 1 to 4, and leucovorin 50 mg/m2 IV followed by 5-FU 450 mg/m2 IV infusion weekly weeks 1 to 4. Patients were given no treatment on weeks 5 and 6 of the 6-week treatment cycle. Of the 20 patients enrolled in the study, 16 were evaluable for toxicity and 15 were evaluable for tumor response. The most severe toxicities included three reports of grade IV diarrhea; overall, nine incidents of grade III or IV toxicity were reported. No objective antitumor responses were observed, and the median time to progression was 2.8 months. We conclude that this combination chemoimmunotherapy regimen has substantial toxicity but no significant antitumor activity in patients with advanced stage renal cell carcinoma.


Proteomic Tissue-Based Classifier for Early Prediction of Prostate Cancer Progression.
Although ~40% of screen-detected prostate cancers (PCa) are indolent, advanced-stage PCa is a lethal disease with 5-year survival rates around 29%. Identification of biomarkers for early detection of aggressive disease is a key challenge. Starting with 52 candidate biomarkers, selected from existing PCa genomics datasets and known PCa driver genes, we used targeted mass spectrometry to quantify proteins that significantly differed in primary tumors from PCa patients treated with radical prostatectomy (RP) across three study outcomes: (i) metastasis ≥1-year post-RP, (ii) biochemical recurrence ≥1-year post-RP, and (iii) no progression after ≥10 years post-RP. Sixteen proteins that differed significantly in an initial set of 105 samples were evaluated in the entire cohort (n = 338). A five-protein classifier which combined FOLH1, KLK3, TGFB1, SPARC, and CAMKK2 with existing clinical and pathological standard of care variables demonstrated significant improvement in predicting distant metastasis, achieving an area under the receiver-operating characteristic curve of 0.92 (0.86, 0.99, p = 0.001) and a negative predictive value of 92% in the training/testing analysis. This classifier has the potential to stratify patients based on risk of aggressive, metastatic PCa that will require early intervention compared to low risk patients who could be managed through active surveillance.


Single-Locus versus Multilocus Patterns of Local Adaptation to Climate in Eastern White Pine (Pinus strobus, Pinaceae).
Natural plant populations are often adapted to their local climate and environmental conditions, and populations of forest trees offer some of the best examples of this pattern. However, little empirical work has focused on the relative contribution of single-locus versus multilocus effects to the genetic architecture of local adaptation in plants/forest trees. Here, we employ eastern white pine (Pinus strobus) to test the hypothesis that it is the inter-genic effects that primarily drive climate-induced local adaptation. The genetic structure of 29 range-wide natural populations of eastern white pine was determined in relation to local climatic factors using both a reference set of SSR markers, and SNPs located in candidate genes putatively involved in adaptive response to climate. Comparisons were made between marker sets using standard single-locus outlier analysis, single-locus and multilocus environment association analyses and a novel implementation of Population Graphs. Magnitudes of population structure were similar between the two marker sets. Outlier loci consistent with diversifying selection were rare for both SNPs and SSRs. However, genetic distances based on the multilocus among population covariances (cGD) were significantly more correlated to climate, even after correcting for spatial effects, for SNPs as compared to SSRs. Coalescent simulations confirmed that the differences in mutation rates between SSRs and SNPs did not affect the topologies of the Population Graphs, and hence values of cGD and their correlations with associated climate variables. We conclude that the multilocus covariances among populations primarily reflect adaptation to local climate and environment in eastern white pine. This result highlights the complexity of the genetic architecture of adaptive traits, as well as the need to consider multilocus effects in studies of local adaptation.


First case of atypical takotsubo cardiomyopathy in a bilateral lung-transplanted patient due to acute respiratory failure.
Takotsubo cardiomyopathy which is characterised by a transient left ventricular wall motion abnormality was first described in 1990. The disease is still not well known, and as such it is suggested that an emotional trigger is mandatory in this disease. We present the case of a 51-year old female patient seven years after bilateral lung transplantation, who developed acute respiratory distress syndrome and subsequently suffered from atypical takotsubo cardiomyopathy with transient severe reduction of ejection fraction and haemodynamic instability needing acute intensive care treatment. Acute respiratory failure has emerged as an important physical trigger factor in takotsubo cardiomyopathy. Little is known about the association of hypoxia and takotsubo cardiomyopathy which can elicit a life-threatening condition requiring acute intensive care. Therefore, experimental studies are needed to investigate the role of hypoxia in takotsubo cardiomyopathy.


Safe use of mobile phones in hospitals.
This research evaluated possibilities to use different types of mobile telephones in the hospital environment by testing the disturbances in medical equipment caused by radiofrequency fields emitted by the phones. The research was carried out by the Finnish Institute of Occupational Health (FIOH) in cooperation with the Technical Research Centre of Finland (VTT), and focused mainly on equipment situated within the Maria Hospital of the City of Helsinki. The Helsinki Hospital District and tile Medical Engineering Centre of the Helsinki University Central Hospital (HUCH) also participated in this project.


Self-supporting polymer pipes for low loss single-mode THz transmission.
In this paper, a self-supporting polymer pipe is proposed and investigated for THz wave transmission. Utilizing fiber drawing technique for polymer fiber, self-supporting pipes with wall thickness of several tens micrometers can be fabricated using polymethylmethacrylate (PMMA). The guiding mechanism and transmission characteristics of the self-supporting pipes are investigated theoretically, showing that it can support single-mode transmission at THz band. The self-supporting pipe samples with different structure parameters are fabricated and measured experimentally, showing that it can support single HE(11) mode transmission. Theoretical analysis and experimental results show that this self-supporting polymer pipe is a promising candidate for low loss THz fibers.


Development of antimicrobial synbiotics using potentially-probiotic faecal isolates of Lactobacillus fermentum and Bifidobacterium longum.
The aims of the present study were to investigate in vitro the antimicrobial activity of Lactobacillus fermentum and Bifidobacterium longum, isolated from faeces of healthy elderly individuals, against enterohaemorrhagic Escherichia coli (E. coli O157:H7) and enteropathogenic E. coli (E. coli O86), to determine the capability of the selected strains to tolerate acid and bile in vitro, to select suitable carbohydrates in order to enhance the growth and maximise antimicrobial activity of the putative probiotic organisms and examine the adhesion properties of the synbiotics. Antimicrobial activity of the putative probiotics and synbiotics was investigated by a microtitre method using cell-free culture supernatants (CFCS). Results of the antimicrobial assay showed that both putative probiotic strains produced compounds at pH 5 that lead to higher lag phases of both E. coli O157:H7 and E. coli O86. When half the quantity of cell-free culture supernatants of both probiotic strains was used at pH 5, B. longum maintained the same antimicrobial effect against both strains of E. coli, whereas L. fermentum lead to a higher lag phase of E. coli O86 only. Neutralization of the culture supernatants with alkali reduced the antimicrobial effect with only cell-free supernatant of L. fermentum causing lower maximum growth rates of E. coli O157:H7 and E. coli O86. L. fermentum appeared to be acid tolerant whereas B. longum was more susceptible to acid and both isolates were bile tolerant. A short chain fructooligosaccharide (scFOS) and an isomalto-oligosaccharide (IMO) proved to be the most effective substrates, enhancing antimicrobial activity for L. fermentum and B. longum respectively. The adhesion of the synbiotic combinations showed that L. fermentum, exhibited higher percentage of adhesion when grown on glucose and as a synbiotic combination with scFOS whereas B. longum exhibited lowest percentage of adhesion when grown on both glucose and IMO.


Ion irradiation of pure and amorphous CH4 ice relevant for astrophysical environments.
This work presents a physicochemical study of frozen amorphous methane (at 16 K) under bombardment by medium-mass ions (15.7 MeV 16O5+) with implications for icy bodies in the outer Solar System exposed to the action of cosmic rays and energetic particles. The experiment was performed at the Grand Accélérateur National d'Ions Lourds (GANIL) located in Caen, France. The results demonstrate that irradiation of CH4-containing ices by swift medium mass ions with delivered energy covering both stopping power regimes until its implantation on ice (i.e. electronic and nuclear) leads to the production of many hydrocarbons, such as C2H2, C2H4, C2H6, and C3H8 (the most abundant daughter species produced). Values for the effective dissociation cross section of CH4 and the average value for the effective formation cross-sections of its daughter species were about 10-14 cm2 and 10-15 cm2, respectively. The half-life of methane ice in the presence of swift medium mass ions extrapolated to some outer Solar System environments is estimated to be around 106 years. The measured sputtering yield of methane due to incoming swift ions was about 7.30 × 105 molecules per impact. Such parameters can be used as models to estimate the amount of CH4 and other molecular species desorbed from the icy surfaces that are constantly being incorporated to the gaseous atmosphere in the vicinity of these outer Solar System bodies due to the presence of energetic particles and cosmic rays.


Nanoemulsion enhances α-tocopherol succinate bioavailability in rats.
The vitamin E analogue, α-tocopherol succinate (α-TOS), has a broad anti-tumor effect. α-TOS can induce cancer cells apoptosis and suppress tumor growth by targeting mitochondria. Low bioavailability of α-TOS is the major problem encountered with formulation development. In our study, α-TOS nanoemulsion (α-TOS-NE) was demonstrated as a new drug delivery system of α-TOS to increase the bioavailability. MTT-based cytotoxicity assay and mitochondrial membrane potential (ΔY) were performed on human breast cancer cell lines MCF-7 and human oral epithelial cancer cell lines KB to evaluate in vitro anticancer efficacy of α-TOS-NE. In comparison with free α-TOS, α-TOS-NE exhibited a stronger cytotoxicity and decreased ΔΨ. Pharmacokinetic profiles of I.V. α-TOS-NE group, I.P. α-TOS-NE group, and I.P. free α-TOS group (7% DMSO/93% PEG) were drawn. First of all, nanoemultion (NE) enables the I.V. injection of α-TOS, make it possible to be an I.V. preparation. Second, compare to the I.P. free α-TOS group, I.P. α-TOS-NE group had a higher bioavailability. Thus, NE improved the strong anti-cancer efficacy of α-TOS while increasing its in vivo bioavailability in rats. In conclusion, our laboratory-made NE was a safe drug delivery system for clinical trials and could be a promising formulation for α-TOS by I.V administration.


Impact of a novel 14 bp MEN1 deletion in a patient with hyperparathyroidism and gastrinoma.
Multiple endocrine neoplasia type 1 (MEN-1) is a rare autosomal-dominant disease characterized by tumors in endocrine and/or non endocrine organs due to mutations in MEN1 encoding a nuclear scaffold protein'menin' involved in regulation of different cellular activities. We report a novel 14 bp MEN1 deletion mutation in a 35-year-old female with history of recurrent epigastric pain, vomiting, loose stools and weight loss. On evaluation she was diagnosed to have multifocal gastro-duodenal gastrinoma with paraduodenal lymph nodes and solitary liver metastasis. She was also found to have primary hyperparathyroidism with bilateral inferior parathyroid adenoma. Pancreatico-duodenectomy with truncalvagotomy was performed. Four months later, radiofrequency ablation (RFA) of segment 4 of the liver was done followed by three and a half parathyroidectomy. MEN1 screening was carried out for the patient and her family members. MEN-1 sequencing in the patient revealed a heterozygous 14 bp exon 8 deletion. Evaluation for pathogenicity and protein structure prediction showed that the mutation led to a frameshift thereby causing premature termination resulting in a truncated protein. To conclude, a novel pathogenic MEN1 deletion mutation affecting its function was identified in a patient with hyperparathyroidism and gastrinoma. The report highlights the clinical consequences of the novel mutation and its impact on the structure and function of the protein. It also provides evidence for co-existence of pancreatic and duodenal gastrinomas in MEN1 syndrome. MEN1 testing provides important clues regarding etiology and therefore should be essentially undertaken in asymptomatic first degree relatives who could be potential carriers of the disease. Identification of a novel pathogenic MEN1 deletion mutation.MEN1 mutation screening in patients with pituitary, parathyroid and pancreatic tumors, and their first degree relatives gives important clues about the etiology.Pancreatic and duodenal gastrinomas may co-exist simultaneously in MEN1 syndrome.


2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside-stimulated dental pulp stem cells-derived conditioned medium enhances cell activity and anti-inflammation.
Dental pulp stem cells (DPSCs) contribute to the regeneration of various tissues and have superior proliferation, immune privilege, and anti-inflammation properties to other mesenchymal stem cells. 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside (THSG) not only enhances the aforementioned properties of DPSCs but also promotes self-renewal and reprogramming-like ability. However, whether THSG enhances the aforementioned properties and abilities through direct or indirect interaction mechanisms remains unclear. To address this knowledge gap, we examined the effects of THSG-stimulated DPSC-derived conditioned medium (THSG-CM) on the activity and anti-inflammation properties of cells. DPSCs were treated with various concentrations of THSG to produce THSG-CM, which was then collected, analyzed, and lyophilized. A cytokine profiling antibody assay was used to compare protein components between THSG-treated and nontreated CM. Human skin fibroblasts (HSFs) and human gingival fibroblasts (HGFs) were used to investigate the effect of THSG-CM on cell proliferation, anti-inflammation, and wound healing abilities; for this investigation, MTS assay, quantitative real-time PCR analysis, and 2-well silicone inserts wound model were conducted. We observed that THSG enhanced the secretion of growth- and immune-associated proteins in THSG-CM and increased the proliferation of HSFs and HGFs. Furthermore, THSG-CM significantly attenuated lipopolysaccharide-stimulated mRNA levels of cytokines in both cells and improved wound healing abilities. We conclude that THSG-CM had more beneficial effects on cell activity and anti-inflammation in the HSFs and HGFs than DPSC-derived CM. DPSC-derived CM can be developed into a cell-free regenerative strategy in the future, and its therapeutic efficacy may be improved by THSG-CM.


Ecological effects of pharmaceuticals in aquatic systems--impacts through behavioural alterations.
The study of animal behaviour is important for both ecology and ecotoxicology, yet research in these two fields is currently developing independently. Here, we synthesize the available knowledge on drug-induced behavioural alterations in fish, discuss potential ecological consequences and report results from an experiment in which we quantify both uptake and behavioural impact of a psychiatric drug on a predatory fish (Perca fluviatilis) and its invertebrate prey (Coenagrion hastulatum). We show that perch became more active while damselfly behaviour was unaffected, illustrating that behavioural effects of pharmaceuticals can differ between species. Furthermore, we demonstrate that prey consumption can be an important exposure route as on average 46% of the pharmaceutical in ingested prey accumulated in the predator. This suggests that investigations of exposure through bioconcentration, where trophic interactions and subsequent bioaccumulation of exposed individuals are ignored, underestimate exposure. Wildlife may therefore be exposed to higher levels of behaviourally altering pharmaceuticals than predictions based on commonly used exposure assays and pharmaceutical concentrations found in environmental monitoring programmes.


Protein profiles of CCL5, HPGDS, and NPSR1 in plasma reveal association with childhood asthma.
Asthma is a common chronic childhood disease with many different phenotypes that need to be identified. We analyzed a broad range of plasma proteins in children with well-characterized asthma phenotypes to identify potential markers of childhood asthma. Using an affinity proteomics approach, plasma levels of 362 proteins covered by antibodies from the Human Protein Atlas were investigated in a total of 154 children with persistent or intermittent asthma and controls. After screening, chemokine ligand 5 (CCL5) hematopoietic prostaglandin D synthase (HPGDS) and neuropeptide S receptor 1 (NPSR1) were selected for further investigation. Significantly lower levels of both CCL5 and HPGDS were found in children with persistent asthma, while NPSR1 was found at higher levels in children with mild intermittent asthma compared to healthy controls. In addition, the protein levels were investigated in another respiratory disease, sarcoidosis, showing significantly higher NPSR1 levels in sera from sarcoidosis patients compared to healthy controls. Immunohistochemical staining of healthy tissues revealed high cytoplasmic expression of HPGDS in mast cells, present in stroma of both airway epithelia, lung as well as in other organs. High expression of NPSR1 was observed in neuroendocrine tissues, while no expression was observed in airway epithelia or lung. In conclusion, we have utilized a broad-scaled affinity proteomics approach to identify three proteins with altered plasma levels in asthmatic children, representing one of the first evaluations of HPGDS and NPSR1 protein levels in plasma.


A house dust mite allergen homologue from poultry red mite Dermanyssus gallinae (De Geer).
Tropomyosin is an allergenic, actin-binding protein and a proposed vaccine candidate from several species of parasite. Tropomyosin cDNA, obtained by polymerase chain reaction (PCR) amplification from Dermanyssus gallinae RNA, encoded a predicted protein with 89% and 88% identity to tropomyosins from the ticks Boophilus microplus and Haemaphysalis longicornis, respectively, and 85% identity to the house dust mite (HDM) tropomyosin Der p 10. Mouse antibodies raised against HDM tropomyosin reacted with a band of 38 kDa on Western blots of D. gallinae extract, consistent with the molecular masses of acarine tropomyosins and the putative product of the cDNA encoding D. gallinae tropomyosin. When the same preparation of D. gallinae proteins was used in Western blots with serum from infested hens, the IgY component of the serum bound to a number of mite proteins, but not to tropomyosin, indicating that hens are not directly exposed to this allergen during a natural infestation. Immunolocalization of tropomyosin in mites indicated a ubiquitous distribution of the molecule in mite tissues. Immunolocalization and Western blotting also indicated that poultry red mites ingest host IgY.


Chronic exposure to triclosan sustains microbial community shifts and alters antibiotic resistance gene levels in anaerobic digesters.
Triclosan, an antimicrobial chemical found in consumer personal care products, has been shown to stimulate antibiotic resistance in pathogenic bacteria. Although many studies focus on antibiotic resistance pertinent to medical scenarios, resistance developed in natural and engineered environments is less studied and has become an emerging concern for human health. In this study, the impacts of chronic triclosan (TCS) exposure on antibiotic resistance genes (ARGs) and microbial community structure were assessed in lab-scale anaerobic digesters. TCS concentrations from below detection to 2500 mg kg(-1) dry solids were amended into anaerobic digesters over 110 days and acclimated for >3 solid retention time values. Four steady state TCS concentrations were chosen (30-2500 mg kg(-1)). Relative abundance of mexB, a gene coding for a component of a multidrug efflux pump, was significantly higher in all TCS-amended digesters (30 mg kg(-1) or higher) relative to the control. TCS selected for bacteria carrying tet(L) and against those carrying erm(F) at concentrations which inhibited digester function; the pH decrease associated with digester failure was suspected to cause this selection. Little to no impact of TCS was observed on intI1 relative abundance. Microbial communities were also surveyed by high-throughput 16S rRNA gene sequencing. Compared to the control digesters, significant shifts in community structure towards clades containing commensal and pathogenic bacteria were observed in digesters containing TCS. Based on these results, TCS should be included in studies and risk assessments that attempt to elucidate relationships between chemical stressors (e.g. antibiotics), antibiotic resistance genes, and public health.


Gene expression-based classification of non-small cell lung carcinomas and survival prediction.
Current clinical therapy of non-small cell lung cancer depends on histo-pathological classification. This approach poorly predicts clinical outcome for individual patients. Gene expression profiling holds promise to improve clinical stratification, thus paving the way for individualized therapy. A genome-wide gene expression analysis was performed on a cohort of 91 patients. We used 91 tumor- and 65 adjacent normal lung tissue samples. We defined sets of predictor genes (probe sets) with the expression profiles. The power of predictor genes was evaluated using an independent cohort of 96 non-small cell lung cancer- and 6 normal lung samples. We identified a tumor signature of 5 genes that aggregates the 156 tumor and normal samples into the expected groups. We also identified a histology signature of 75 genes, which classifies the samples in the major histological subtypes of non-small cell lung cancer. Correlation analysis identified 17 genes which showed the best association with post-surgery survival time. This signature was used for stratification of all patients in two risk groups. Kaplan-Meier survival curves show that the two groups display a significant difference in post-surgery survival time (p = 5.6E-6). The performance of the signatures was validated using a patient cohort of similar size (Duke University, n = 96). Compared to previously published prognostic signatures for NSCLC, the 17 gene signature performed well on these two cohorts. The gene signatures identified are promising tools for histo-pathological classification of non-small cell lung cancer, and may improve the prediction of clinical outcome.


Everolimus versus azathioprine in maintenance lung transplant recipients: an international, randomized, double-blind clinical trial.
Everolimus is a proliferation signal inhibitor with immunosuppressive activity that may reduce the rate of progression of chronic rejection, bronchiolitis obliterans syndrome (BOS), after lung transplantation. In a randomized, double-blind clinical trial, 213 BOS-free maintenance patients received everolimus (3 mg/day) or azathioprine (AZA, 1-3 mg/kg/day) in combination with cyclosporine and corticosteroids. The prospectively defined primary endpoint was the incidence of efficacy failure (decline in FEV1 >15%[deltaFEV1 >15%], graft loss, death or loss to follow-up) at 12 months. Incidence of efficacy failure at 12 months was significantly lower in the everolimus group than AZA (21.8% vs. 33.9%; p = 0.046); at 24 months, rates of efficacy failure became similar between the groups. At 12 months, the everolimus group had significantly reduced incidences of deltaFEV1 >15%, deltaFEV1 >15% with BOS, and acute rejection. At 24 months, only incidence of acute rejection remained significantly less in the everolimus group. Treatment discontinuations (particularly due to adverse events), serious adverse events and high serum creatinine values were more common with everolimus. For the first time, a drug has demonstrated significant slowing of loss in lung function, suggesting that patients kept on prolonged maintenance treatment with everolimus may benefit from replacing AZA with everolimus 3 months after lung transplantation.


Endoscopic obstruction in rectal cancers: survival and recurrence patterns following curative surgery.
It is controversial whether preoperative obstruction in rectal cancers can affect prognosis or influence recurrence patterns. We investigated the association between endoscopic obstruction with survival and recurrence patterns in patients with locally advanced rectal cancers. An observational study and multivariate analysis were conducted to identify determinants of survival and to compare recurrence patterns between patients with obstructive or nonobstructive tumors after curative resection. Endoscopic obstruction was defined as a luminal obstruction of the rectum severe enough to prevent the colonoscope from passing beyond the tumor. Cancer was obstructive in 91 patients (16.8%) and nonobstructive in 452 (83.2%). Median follow-up was 50 (range, 3-161) months. Local recurrence occurred in 17 patients (14 nonobstructed [5.4%] and 3obstructed [5.5%]; P=1.0) and systemic recurrence in 83 (62 nonobstructed [23.8%] and 21 obstructed [38.2%]; P=.042]). Endoscopic obstruction was a significant prognostic factor in stage III rectal cancers (P=.001) but not in stage II tumors. The multivariate analysis showed that endoscopic obstruction was an independent prognostic factor for overall survival, but not for disease-free survival, in patients with stage III rectal cancers. Endoscopic obstruction was associated with multiple-site systemic recurrence that was unsalvageable (salvageable surgery, 24 nonobstructed [40%] and 2 obstructed [10%]; P=.014). Endoscopic obstruction in patients with stage III rectal cancer predicted worse overall survival and was associated with multiple-site systemic recurrence.


Cortical filamentous actin disassembly and scinderin redistribution during chromaffin cell stimulation precede exocytosis, a phenomenon not exhibited by gelsolin.
Immunofluorescence and cytochemical studies have demonstrated that filamentous actin is mainly localized in the cortical surface of the chromaffin cell. It has been suggested that these actin filament networks act as a barrier to the secretory granules, impeding their contact with the plasma membrane. Stimulation of chromaffin cells produces a disassembly of actin filament networks, implying the removal of the barrier. The presence of gelsolin and scinderin, two Ca(2+)-dependent actin filament severing proteins, in the cortical surface of the chromaffin cells, suggests the possibility that cell stimulation brings about activation of one or more actin filament severing proteins with the consequent disruption of actin networks. Therefore, biochemical studies and fluorescence microscopy experiments with scinderin and gelsolin antibodies and rhodamine-phalloidin, a probe for filamentous actin, were performed in cultured chromaffin cells to study the distribution of scinderin, gelsolin, and filamentous actin during cell stimulation and to correlate the possible changes with catecholamine secretion. Here we report that during nicotinic stimulation or K(+)-evoked depolarization, subcortical scinderin but not gelsolin is redistributed and that this redistribution precedes catecholamine secretion. The rearrangement of scinderin in patches is mediated by nicotinic receptors. Cell stimulation produces similar patterns of distribution of scinderin and filamentous actin. However, after the removal of the stimulus, the recovery of scinderin cortical pattern of distribution is faster than F-actin reassembly, suggesting that scinderin is bound in the cortical region of the cell to a component other than F-actin. We also demonstrate that peripheral actin filament disassembly and subplasmalemmal scinderin redistribution are calcium-dependent events. Moreover, experiments with an antibody against dopamine-beta-hydroxylase suggest that exocytosis sites are preferentially localized to areas of F-actin disassembly.


Rights of patients in developing countries: the case of Turkey.
Patient rights are universal values which we have to adopt. It is not so easy, however, to put such values and principles into effect. As approaches and attitudes differ from individual to individual, from society to society, and from country to country, a uniform application of these values is difficult. If we want to reach a general conclusion about the status of patient rights in the world as whole, we should examine the situation in individual countries. As far as Turkey is concerned, we can say that, although the idea of patient rights is accepted in principle, patient rights have yet to be adequately implemented.


Molecular and Coarse-Grained Modeling to Characterize and Optimize Dendrimer-Based Nanocarriers for Short Interfering RNA Delivery.
Dendrimer nanocarriers are unique hyper-branched polymers with biomolecule-like properties, representing a promising prospect as a nucleic acid delivery system. The design of effective dendrimer-based gene carriers requires considering several parameters, such as carrier morphology, size, molecular weight, surface chemistry, and flexibility/rigidity. In detail, the rational design of the dendrimer surface chemistry has been ascertained to play a crucial role on the efficiency of interaction with nucleic acids. Within this framework, advances in the field of organic chemistry have allowed us to design dendrimers with even small difference in the chemical structure of their surface terminals. In this study, we have selected two different cationic phosphorus dendrimers of generation 3 functionalized, respectively, with pyrrolidinium (DP) and morpholinium (DM) surface groups, which have demonstrated promising potential for short interfering RNA (siRNA) delivery. Despite DP and DM differing only for one atom in their chemical structure, in vitro and in vivo experiments have highlighted several differences between them in terms of siRNA complexation properties. In this context, we have employed coarse-grained molecular dynamics simulation techniques to shed light on the supramolecular characteristics of dendrimer-siRNA complexation, the so-called dendriplex formations. Our data provide important information on self-assembly dynamics driven by surface chemistry and competition mechanisms.


Reduced Frontal P3a Amplitude in Migraine Patients during the Pain-Free Period.
Neuropsychological and neuroimaging studies both suggest that frontal lobe dysfunction is present in migraineurs. Since P3a abnormalities manifest in other diseases associated with attention problems, such as attention deficit hyperactivity disorder, we hypothesized that migraine patients have P3a abnormalities, particularly in the frontal region. Event-related potentials were measured using a passive auditory oddball paradigm in 16 female migraineurs (aged 22.9±2.0 years, mean±SD) during the interictal period and in 16 age-matched healthy females (22.6±2.0 years). The amplitudes and latencies were analyzed independently using repeated-measures analysis of variance. Nonparametric statistical testing using a cluster-level randomization method was performed to localize the abnormalities. The mean P3a amplitude at frontal areas during the third trials was significantly lower in migraineurs (1.06 µV) than in controls (1.69 µV, p=0.026). P3a amplitudes were negatively correlated with the duration of the migraine history (r=-0.618, p=0.014). Cluster-based nonparametric statistical analysis showed that the amplitudes over left frontal areas were significantly lower in migraine patients than in controls. A reduced P3a amplitude of migraineurs reflects attentional deficits and frontal dysfunction. The negative correlation between P3a amplitude and the duration of the migraine history suggests that attentional deficits and frontal dysfunction are either the cause or the result of headache.


Ukrain therapy of stage T1N0M0 bladder cancer patients.
The aim of the present study was to evaluate the efficacy of Ukrain as a new treatment modality in 28 patients with stage T1N0M0 bladder cancer. The tumor dimensions varied from 0.5 x 0.5 cm to 3 x 4 cm. The first group (nine patients) was treated with a total dose of 100 mg Ukrain, the second group (10 patients) received 200 mg Ukrain, and the third group (nine patients) was treated with 300 mg Ukrain. In all patients Ukrain was administered i.v. at a dose of 10 mg per day. In the patients from the second and third group each course of treatment, consisting of 10 injections, was followed by 14 days of no treatment. Ukrain, at a total dose from 100-300 mg as neoadjuvant therapy in patients with T1N0M0 bladder cancer, resulted in either complete or partial regression of tumors in 60.7 +/- 9.2% of cases. The best treatment regime included three courses of Ukrain at 2-week intervals.


The in vitro effects of 2-methoxyestradiol-bis-sulphamate on cell numbers, membrane integrity and cell morphology, and the possible induction of apoptosis and autophagy in a non-tumorigenic breast epithelial cell line.
2-methoxyestradiol (2ME2) exerts estrogen receptor-independent anti-proliferative, anti-angiogenic and anti-tumor activity in vitro and in vivo. Due to its low bioavailability and rapid metabolic degradation, several analogues have been developed in recent years. 2-methoxyestradiol-bis-sulphamate (2-MeOE2bisMATE) is a bis-sulphamoylated derivative of 2ME2 with anti-proliferative activity. The aim of this study was to investigate cell signaling events induced by 2-MeOE2bisMATE in a non-tumorigenic cell line (MCF-12A) by analysing its influence on cell number, morphology and membrane integrity, and the possible induction of apoptosis and autophagy. Dose- and time-dependent studies revealed that 48 h exposure to 2-MeOE2bisMATE (0.4 μM) resulted in a decrease in cell numbers to 79%. A slight increase in the level of lactate dehydrogenase production was observed in the 2-MeOE2bisMATE-treated cells. Morphological studies revealed an increase in the number of cells in metaphase. Hallmarks of apoptosis were also found, namely nuclear fragmentation and apoptotic bodies. In addition, increased lysosomal staining was observed via fluorescent microscopy, suggesting the induction of another type of cell death, namely autophagy. Since 2-MeOE2bisMATE is regarded as a potential anti-cancer agent, it is also imperative to investigate the susceptibility of non-tumorigenic cells to its influence. The data generated from this study contributes to the understanding of the action that 2-MeOE2bisMATE exerts on the non-tumorigenic MCF-12A breast epithelial cell line.


Comparing reactive and memory-one strategies of direct reciprocity.
Direct reciprocity is a mechanism for the evolution of cooperation based on repeated interactions. When individuals meet repeatedly, they can use conditional strategies to enforce cooperative outcomes that would not be feasible in one-shot social dilemmas. Direct reciprocity requires that individuals keep track of their past interactions and find the right response. However, there are natural bounds on strategic complexity: Humans find it difficult to remember past interactions accurately, especially over long timespans. Given these limitations, it is natural to ask how complex strategies need to be for cooperation to evolve. Here, we study stochastic evolutionary game dynamics in finite populations to systematically compare the evolutionary performance of reactive strategies, which only respond to the co-player's previous move, and memory-one strategies, which take into account the own and the co-player's previous move. In both cases, we compare deterministic strategy and stochastic strategy spaces. For reactive strategies and small costs, we find that stochasticity benefits cooperation, because it allows for generous-tit-for-tat. For memory one strategies and small costs, we find that stochasticity does not increase the propensity for cooperation, because the deterministic rule of win-stay, lose-shift works best. For memory one strategies and large costs, however, stochasticity can augment cooperation.


Assessing the health effects of long-term exposure to insecticide-treated mosquito nets in the control of malaria in endemic regions.
Malaria is a protozoan disease caused in humans by the genus Plasmodium of which four species are known: P. falciparum, P. vivax, P. ovale, and P. malariae. It is transmitted through the bite of infected female mosquitoes of the genus Anopheles. Malaria is endemic in tropical and subtropical regions of the world. It is characterized by extreme exhaustion associated with paroxysms of high fever, sweating, shaking chills, and anemia. Approximately 40% of the world''s population, mostly those living in the poorest nations, are at risk. Much of the deaths due to malaria occur in Africa, mostly among children. The search for prevention and control interventions that are effective and sustainable remains an abiding challenge for national governments and international health agencies. To this end, the World Health Organization and several nongovernmental organizations are investing in the use of insecticide-treated mosquito nets (ITMNs) as a viable option. Trials of ITMNs in the 1980s and 1990s showed that they reduce deaths in young children by an average of 20% and multilateral agencies, spearheaded by Roll Back Malaria (RBM), seek to have 60% of the populations at risk sleeping under ITMNs by 2005. All pesticides are toxic by nature and present risks of adverse effects that depend on toxicity of the chemical and the degree of exposure. While there is agreement that ITMNs can be effective in reducing malaria morbidity and mortality under field trials, a number of factors relating to their sustainability and contribution to health improvement in less-developed countries have yet to be determined. In particular, the adverse effects associated with their long-term use and misuse has yet to be fully evaluated. Although this paper examines potential neurotoxic and neurobehavioral effects of long-term use of ITMNs and discusses priority public health actions for protecting the health of users, it forms the basis for further research.


New oral anticoagulants: which one should my patient use?
The new oral anticoagulants are rapidly replacing warfarin for several indications. In contrast to warfarin, which lowers the functional levels of all of the vitamin K-dependent clotting factors, the new agents target either factor Xa or thrombin. With targeted inhibition of coagulation, the new oral anticoagulants have pharmacologic and clinical features that distinguish them from warfarin. Focusing on these features, this paper (a) compares the pharmacology of the new oral anticoagulants with that of warfarin (b) identifies the class effects of these drugs and their differentiating features, (c) reviews their current indications, and (d) uses this information to help clinicians make informed decisions regarding the choice of the right anticoagulant for the right patient.


Genetic structure in the Sherpa and neighboring Nepalese populations.
We set out to describe the fine-scale population structure across the Eastern region of Nepal. To date there is relatively little known about the genetic structure of the Sherpa residing in Nepal and their genetic relationship with the Nepalese. We assembled dense genotype data from a total of 1245 individuals representing Nepal and a variety of different populations resident across the greater Himalayan region including Tibet, China, India, Pakistan, Kazakhstan, Uzbekistan, Tajikistan and Kirghizstan. We performed analysis of principal components, admixture and homozygosity. We identified clear substructure across populations resident in the Himalayan arc, with genetic structure broadly mirroring geographical features of the region. Ethnic subgroups within Nepal show distinct genetic structure, on both admixture and principal component analysis. We detected differential proportions of ancestry from northern Himalayan populations across Nepalese subgroups, with the Nepalese Rai, Magar and Tamang carrying the greatest proportions of Tibetan ancestry. We show that populations dwelling on the Himalayan plateau have had a clear impact on the Northern Indian gene pool. We illustrate how the Sherpa are a remarkably isolated population, with little gene flow from surrounding Nepalese populations.


The role of electronic coupling in linear porphyrin arrays probed by single-molecule fluorescence spectroscopy.
Single-molecule photophysical properties of two families of linear porphyrin arrays have been investigated by single-molecule fluorescence detection techniques. Butadiyne-linked arrays (Z(N)B) with extensive π-conjugation perform as photostable one-quantum systems. This demonstration has been suggested by the long-lasting initial emissive state and subsequent discrete one-step photobleaching in the fluorescence intensity trajectories (FITs). As in the behavior of a one-quantum system, Z(N)B shows anti-bunching data in the coincidence measurements. On the other hand, in directly-linked arrays (Z(N)) with strong dipole coupling, each porphyrin moiety keeps individual character in photobleaching dynamics. The stepwise photobleachings in the FITs account for this explanation. Most of the FITs of Z(N) do not carry momentary cessation of fluorescence emission, which has been explained by the strongly bound electron-hole pair of Frenkel exciton that suppresses charge transfer between the molecule and surrounding polymers. These results give insight into the influences of interchromophorinc interactions between porphyrin moieties in the multiporphyrin arrays on their fluorescence dynamics at the single-molecule level.


Infections caused by filamentous fungi in patients with hematologic malignancies. A report of 391 cases by GIMEMA Infection Program.
To evaluate the clinical characteristics of patients with hematologic malignancies developing a filamentous fungi infection (FFI) and to define the prognostic factors for their outcome. A retrospective study, conducted on patients admitted to 14 Hematology divisions of tertiary care or university hospitals, participating in the GIMEMA Infection Program, over a ten-year period (1988-1997). The study included patients with hematological malignancies and a histologically and/or microbiologically proven or probable FFI. We included 391 patients (male/female: 262/129, median age 49 years) with hematologic malignancies (225 acute myeloid leukemia, 67 acute lymphocytic leukemia, 30 chronic myeloid leukemia, 22 non-Hodgkin's lymphoma, 12 myelodysplastic syndrome, 10 aplastic anemia, 7 Hodgkin's disease, 8 chronic lymphocytic leukemia, 5 multiple myeloma, and 5 hairy cell leukemia) who developed a proven FFI. Eighty percent of the patients had been neutropenic for an average of 14 days before the infection, and 71% had an absolute neutrophil count lower than 0.5 x 10(9)/L at the time of FFI diagnosis. The primary sites of infection were: lungs (85%), nose and paranasal sinus (10%), and other sites (5%). The diagnosis was made while still alive in 310 patients (79%), and at autopsy in the remaining 81 patients (21%). Chest X-ray was diagnostic in 77% of patients with pulmonary FFI, while computed tomography (CT) scan of the thorax was positive in 95% of cases. A significant diagnostic advantage for CT scan was observed in 145 patients who had both a chest X-ray and CT scan. Aspergillus was identified as the cause of FFI in 296 patients, Mucorales in 45 patients, Fusarium in 6 patients and other filamentous fungi species in 4 patients, while in a further 40 patients no agent was identifiable. The overall mortality rate three months after the diagnosis of FFI was 74%, and fungal infection had been the cause of death in 51% of patients. Our retrospective study shows that FFI still remains a life-threatening complication in neutropenic patients. Despite appropriate treatment, half of the patients die due to this complication. The use of glucocorticoids and recovery from neutropenia are the most important prognostic factors. Mucorales infections are associated with a significantly poorer prognosis than those due to Aspergillus spp.


Pregnancy outcome in women with inflammatory bowel disease treated with anti-tumor necrosis factor and/or thiopurine therapy: a multicenter study from Japan.
Anti-tumor necrosis factor drugs (anti-TNF) and thiopurines are important treatment options in patients with inflammatory bowel disease (IBD), including during pregnancy. However, there are limited data on the benefit/risk profile of anti-TNF and thiopurines during pregnancy in Asia. The aim of this study was to analyze pregnancy outcomes of female Japanese IBD patients treated with anti-TNF and/or thiopurines. This cross-sectional study assessed pregnancy outcomes in 72 women with IBD. Pregnancy outcomes were compared among 31 pregnancies without exposure to infliximab (IFX), adalimumab (ADA), or thiopurines; 24 pregnancies with exposure to anti-TNF treatment (23 IFX, 1 ADA); 7 pregnancies with exposure to thiopurines alone; and 10 pregnancies with exposure to both IFX and thiopurines. Thirty-five of the 41 pregnancies (85.3%) that were exposed to anti-TNF treatment and/or thiopurines resulted in live births after a median gestational period of 38 weeks. Of the 35 live births, 3 involved premature deliveries; 7, low birth weight; and 1, a congenital abnormality. There were 6 spontaneous abortions in pregnancies that were exposed to anti-TNF treatment (17.7%). Pregnancy outcomes among the 4 groups were similar, except for the rate of spontaneous abortions (P =0.037). Exposure to anti-TNF treatment or thiopurines during pregnancy was not related to a higher incidence of adverse pregnancy outcomes in Japanese IBD patients except for spontaneous abortion.


Investigating low-valent compositions in the Na3V2O2x(PO4)2F3-2x family: structural transitions and their consequences.
A member of the family of compounds with the formula Na3V2O2x(PO4)2F3-2x is synthesized by carbothermal reduction and 2 consecutive hydrothermal processes. The initial structural and spectroscopic characterization indicates that there are two phases in the as-synthesized material, a mixed valent phase with an intermediate V oxidation state adopting a P42/mnm space group at about 66%, and another phase with a V oxidation state close to V3+ adopting an Amam space group at about 33%. The role of each species in the electrode function is interrogated using in situ synchrotron X-ray diffraction and these data indicate that soon after charge begins, the Amam phase transforms into the P42/mnm phase. Further structural evolution of the material shows a prevailing two-phase reaction at lower potentials and a significant solid solution region during the high potential feature in the electrochemical curve with a final two-phase region at the end of charge. The conversion of the Amam component into P42/mnm showed no reversibility upon discharge. This phase-mixed electrode appears to illustrate that the mixed valent P42/mnm phase dominates electrochemical behavior during cycling and this may prove vital when preparing members in the sodium vanadium fluorophosphate family, especially if there is an energetically preferred phase for cycling.


microRNA-132 regulates dendritic growth and arborization of newborn neurons in the adult hippocampus.
Newborn neurons in the dentate gyrus of the adult hippocampus rely upon cAMP response element binding protein (CREB) signaling for their differentiation into mature granule cells and their integration into the dentate network. Among its many targets, the transcription factor CREB activates expression of a gene locus that produces two microRNAs, miR-132 and miR-212. In cultured cortical and hippocampal neurons, miR-132 functions downstream from CREB to mediate activity-dependent dendritic growth and spine formation in response to a variety of signaling pathways. To investigate whether miR-132 and/or miR-212 contribute to the maturation of dendrites in newborn neurons in the adult hippocampus, we inserted LoxP sites surrounding the miR-212/132 locus and specifically targeted its deletion by stereotactically injecting a retrovirus expressing Cre recombinase. Deletion of the miR-212/132 locus caused a dramatic decrease in dendrite length, arborization, and spine density. The miR-212/132 locus may express up to four distinct microRNAs, miR-132 and -212 and their reverse strands miR-132* and -212*. Using ratiometric microRNA sensors, we determined that miR-132 is the predominantly active product in hippocampal neurons. We conclude that miR-132 is required for normal dendrite maturation in newborn neurons in the adult hippocampus and suggest that this microRNA also may participate in other examples of CREB-mediated signaling.


Individual risk alleles of susceptibility to schizophrenia are associated with poor clinical and social outcomes.
Many patients with schizophrenia have poor clinical and social outcomes. Some risk alleles closely related to the onset of schizophrenia have been reported to be associated with their clinical phenotypes, but the direct relationship between genetic vulnerability to schizophrenia and clinical/social outcomes of schizophrenia, as evaluated by both practical clinical scales and 'real-world' function, has not been investigated. We evaluated the clinical and social outcomes of 455 Japanese patients with schizophrenia by severity of illness according to the Clinical Global Impression-Severity Scale (CGI-S) and social outcomes by social adjustment/maladjustment at 5 years after the first visit. We examined whether 46 single nucleotide polymorphisms (SNPs) selected from a Japanese genome-wide association study of susceptibility to schizophrenia were associated with clinical and social outcomes. We also investigated the polygenic risk scores of 46 SNPs. Allele-wise association analysis detected three SNPs, including rs2623659 in the CUB and Sushi multiple domains-1 (CSMD1) gene, associated with severity of illness at end point. The severity of illness at end point was associated with treatment response, but not with the severity of illness at baseline. Three SNPs, including rs2294424 in the C6orf105 gene, were associated with social outcomes. Point estimates of odds ratios showed positive relationships between polygenic risk scores and clinical/social outcomes; however, the results were not statistically significant. Because these results are exploratory, we need to replicate them with a larger sample in a future study.