Predictors of loss of atrioventricular synchrony in single lead VDD pacing.
To evaluate maintenance of proper VDD function, defined as persistence of sinus rhythm with atrial synchronous ventricular pacing, and to define factors predicting failure of the VDD mode in patients with atrioventricular (AV) block and normal sinus function. Observational study in 86 consecutive patients (mean (SD) age 74 (12) years; 38 women, 48 men) with single lead VDD pacing systems (Intermedics Unity, n = 66, Medtronic Thera VDD, n = 20), implanted for high degree AV block with documented normal sinus node. Pacemaker function was assessed by event counters, telemetric measurements, and Holter recordings. Demographic, radiological, and pacing variables were correlated with loss of proper VDD function. During a mean (SD) follow up of 10 (10) months (range 1-37), sinus rhythm and atrial triggered ventricular pacing were maintained in 70 of 86 patients (81%). Atrial undersensing was observed in nine patients, lead migration in two, atrial fibrillation in three, and symptomatic sinus bradycardia in two. Univariate predictors of loss of proper VDD function were: low position of the atrial dipole relative to the carina (> or = 6 cm; p < 0.01) during fluoroscopy; and maximum programmable atrial sensitivity of the pacemaker (p = 0.03). In a multivariate analysis, only dipole position remained predictive of outcome (p < 0.02). Not predictive were sex, age, symptoms before pacemaker implantation, cardiothoracic ratio or dilatation of individual heart chambers on chest x ray, side of device implant, and P wave amplitude at implant. To maintain proper VDD function in the long term, a low anatomical dipole position relative to the carina should be avoided. Electrical guidance of dipole positioning does not seem to influence long term outcome.


Standardized beam bouquets for lung IMRT planning.
The selection of the incident angles of the treatment beams is a critical component of intensity modulated radiation therapy (IMRT) planning for lung cancer due to significant variations in tumor location, tumor size and patient anatomy. We investigate the feasibility of establishing a small set of standardized beam bouquets for planning. The set of beam bouquets were determined by learning the beam configuration features from 60 clinical lung IMRT plans designed by experienced planners. A k-medoids cluster analysis method was used to classify the beam configurations in the dataset. The appropriate number of clusters was determined by maximizing the value of average silhouette width of the classification. Once the number of clusters had been determined, the beam arrangements in each medoid of the clusters were designated as the standardized beam bouquet for the cluster. This standardized bouquet set was used to re-plan 20 cases randomly selected from the clinical database. The dosimetric quality of the plans using the beam bouquets was evaluated against the corresponding clinical plans by a paired t-test. The classification with six clusters has the largest average silhouette width value and hence would best represent the beam bouquet patterns in the dataset. The results shows that plans generated with a small number of standardized bouquets (e.g. 6) have comparable quality to that of clinical plans. These standardized beam configuration bouquets will potentially help improve plan efficiency and facilitate automated planning.


Liver MRI susceptibility-weighted imaging (SWI) compared to T2* mapping in the presence of steatosis and fibrosis.
To show that both susceptibility-weighted imaging (SWI) and T2*-mapping are dependent on liver steatosis, which should be taken into account when using these parameters to grade liver fibrosis and cirrhosis. In this prospective study, a total of 174 patients without focal liver disease underwent multiparametric MRI at 3 T including SWI, T1- and T2* mapping, proton density fat fraction (PDFF) quantification and MR elastography. SWI, T2* and T1 were measured in the liver (4 locations), as well as in paraspinal muscles, to calculate the liver-to-muscle ratio (LMR). Liver and LMR values were compared among patients with different steatosis grades (PDFF < 5%, 5-10%, 10-20% and >20%), patients with normal, slightly increased and increased liver stiffness (<2.8 kPa, 2.8-3.5 kPa and >3.5 kPa, respectively). ANOVA with Bonferroni-corrected post hoc tests as well as a multivariate analysis were used to compare values among groups and parameters. SWI and T2* both differed significantly among groups with different steatosis grades (p < 0.001). However, SWI allowed a better differentiation among liver fibrosis grades (p < 0.001) than did T2* (p = 0.05). SWI LMR (p < 0.001) and T2* LMR (p = 0.036) showed a similar performance in differentiating among liver fibrosis grades. SWI and T2*-mapping are strongly dependent on the liver steatosis grades. Nevertheless, both parameters are useful predictors for liver fibrosis when using a multiparametric approach.


Obsessive-Compulsive and Depressive Symptoms in Professional Tennis Players.
A moderate sport activity is considered beneficial for both physical and mental health. On the contrary, different studies have shown that professional players may be more vulnerable to suffer from psychological and/or psychiatric disorders. Given the limited information available, the present study aimed to investigate the possible presence of depressive and obsessive-compulsive symptoms or disorders in a group of professional tennis players. Twenty-five current or former professional tennis players (18 men and 7 women; mean age ± SD: 42.32 ± 13.45 years), were recruited within the Italian Tennis Federation during an international competition and during a master meeting of coaches. They were compared with a control group, recruited from university students, doctors and nurses. All of them underwent a psychiatric interview with a structured scale and a psychopathological assessment carried out with the Mini-International Neuropsychiatric Interview (MINI), the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) and the Self Assessment Scale for Depression (SAD). The Y-BOCS total and subscale scores were significantly higher in both current and past athletes than controls. Current athletes showed higher scores at Y-BOCS total, subscales and some items. The majority of the current athletes also showed superstitions and magical thinking. The present study demonstrated that professional tennis players show a relevant increase of obsessive-compulsive symptoms and supertistions than controls. Interestingly, current athletes resulted more severe than past ones. Taken together, our findings support the notion that agonistic sport activities of high level require intensive training and compliance to strict daily routines that might represent a sort of vulnerability toward the onset of full-blown obsessive-compulsive disorder (as well as other disorders) in more fragile individuals. Not suprisingly, sport psychological support experts are increasingly needed.


Method for Determining the Optimal Number of Clusters Based on Agglomerative Hierarchical Clustering.
It is crucial to determine the optimal number of clusters for the clustering quality in cluster analysis. From the standpoint of sample geometry, two concepts, i.e., the sample clustering dispersion degree and the sample clustering synthesis degree, are defined, and a new clustering validity index is designed. Moreover, a method for determining the optimal number of clusters based on an agglomerative hierarchical clustering (AHC) algorithm is proposed. The new index and the method can evaluate the clustering results produced by the AHC and determine the optimal number of clusters for multiple types of datasets, such as linear, manifold, annular, and convex structures. Theoretical research and experimental results indicate the validity and good performance of the proposed index and the method.


Metabolic control analysis of monoclonal antibody synthesis.
A general route for protein synthesis in eukaryotic cells has been proposed and applied to monoclonal antibody (MAb) synthesis. It takes into account transcription of the gene, binding of ribosomes to mRNA, and polypeptide elongation including binding to SRP (signal recognition particles) and SRP-receptor, competing translocation, folding and glycosylation, assembly of the heavy and light chains in a tetrameric protein and Golgi processing and secretion. A comprehensive model was built on the basis of the proposed pathway. The model takes into account the mechanism of each step. Metabolic control analysis (MCA) principles were applied to the general pathway using the proposed model, and control coefficients were calculated. The results show a shared flux control (of both pathway flux and flux ratio at the branch) among different steps, i.e., transcription, folding, glycosylation, translocation and building blocks synthesis. The steps sharing the control depend on the concentration of building blocks, pathway flux and levels of OST (oligosacharyl transferase), BiP (heavy chain binding protein) and PDI (protein disulfide isomerase). Model predictions compare well with experimental data for MAb synthesis, explaining the control structure of the route and the heterogeneity of the product and also addressing future targets for improvement of the production rate of MAbs.


EEG-driven photic stimulation effect on plasma cortisol and beta-endorphin.
The effect of EEG-driven photic stimulation on stress-related endocrine function was studied. Subjects were 16 healthy males divided into a photic stimulation group (n = 8) and a control group (n = 8). Electrodermal and emotional lability measures were assessed by nonspecific skin conductance response and the Maudsley Personality Inventory, respectively. Plasma cortisol and beta-endorphin concentrations were measured both before and after EEG-driven photic stimulation as well as the resting condition. Subjects with electrodermal, emotional, or both lability showed comparable decreases of plasma beta-endorphin on photic stimulation as did the stable subjects. Under resting control conditions, however, they showed significant increases of beta-endorphin compared to both stable subjects as well as the photic stimulation condition. In addition, labile subjects showed significant alpha enhancement on photic stimulation compared to stable subjects and to the resting control condition. The data suggest that increases of plasma beta-endorphin in labile control subjects may denote a stress response to the conditions of these experiments, and that any decrease by EEG-driven photic stimulation may indicate a reduction of responsiveness to an acute stress.


An analog VLSI chip emulating sustained and transient response channels of the vertebrate retina.
A silicon retina that emulates the sustained and the transient responses in the vertebrate retina was fabricated. The circuit of the chip consists of two layers of resistive network that have different length constants. The output emulating the sustained response possesses a Laplacian-Gaussian-like receptive field and, therefore, carries out a smoothing and contrast-enhancement on the input images. This receptive field was realized by subtracting voltages distributing over the two resistive networks. The output emulating the transient response was obtained by subtracting consecutive images that were smoothed out by the resistive network and is sensitive to moving objects. The outputs of these two channels can be obtained alternately from the silicon retina in real time, within time delays not exceeding a few tens of milliseconds, with indoor illumination. The outputs of the chip are offset-suppressed analog voltages since the uncontrollable mismatches of transistor characteristics are compensated for with the aid of sample/hold circuits embedded in each pixel circuit. The silicon retina fabricated in the present study can be readily used in current engineering applications, e.g., robot vision.


Variation in phenotypic plasticity across age-at-maturity genotypes in wild Atlantic salmon.
Evolution of phenotypic plasticity requires genotype-environment interaction. The discovery of two large-effect loci in the vgll3 and six6 genomic regions associated with the number of years the Atlantic salmon spend feeding at sea before maturation (sea age), provides a unique opportunity to study evolutionary potential of phenotypic plasticity. Using data on 1246 Atlantic salmon caught in the River Surna in Norway, we show that variation in mean sea age among years (smolt cohorts 2013-2018) is influenced by genotype frequencies as well as interaction effects between genotype and year. Genotype-year interactions suggest that genotypes may differ in their response to environmental variation across years, implying genetic variation in phenotypic plasticity. Our results also imply that plasticity in sea age will evolve as an indirect response to selection on mean sea age due to a shared genetic basis. Furthermore, we demonstrate differences between years in the additive and dominance functional genetic effects of vgll3 and six6 on sea age, suggesting that evolutionary responses will vary across environments. Considering the importance of age at maturity for survival and reproduction, genotype-environment interactions likely play an important role in local adaptation and population demography in Atlantic salmon.


Identifying a Novel Eight-NK Cell-related Gene Signature for Ovarian Cancer Prognosis Prediction.
Ovarian cancer (OVC) is the most common and costly tumor in the world with unfavorable overall survival and prognosis. This study is aimed to explore the prognostic value of natural killer cells related genes for OVC treatment. RNA-seq and clinical information were acquired from the TCGA-OVC dataset (training dataset) and the GSE51800 dataset (validation dataset). Genes linked to NK cells were obtained from the immPort dataset. Moreover, ConsensusClusterPlus facilitated the screening of molecular subtypes. Following this, the risk model was established by LASSO analysis, and immune infiltration and immunotherapy were then detected by CIBERSORT, ssGSEA, ESTIMATE, and TIDE algorithms. Based on 23 NK cell-related genes with prognosis, TCGA-OVC samples were classified into two clusters, namely C1 and C2. Of these, C1 had better survival outcomes as well as enhanced immune infiltration and tumor stem cells. Additionally, it was more suitable for immunotherapy and was also sensitive to traditional chemotherapy drugs. The eight-gene prognosis model was constructed and verified via the GSE51800 dataset. Additionally, a high infiltration level of immune cells was observed in low-risk patients. Low-risk samples also benefited from immunotherapy and chemotherapy drugs. Finally, a nomogram and ROC curves were applied to validate model accuracy. The present study identified a RiskScore signature, which could stratify patients with different infiltration levels, immunotherapy, and chemotherapy drugs. Our study provided a basis for precisely evaluating OVC therapy and prognosis.


Modelling Behaviour of a Carbon Epoxy Composite Exposed to Fire: Part II-Comparison with Experimental Results.
Based on a phenomenological methodology, a three dimensional (3D) thermochemical model was developed to predict the temperature profile, the mass loss and the decomposition front of a carbon-reinforced epoxy composite laminate (T700/M21 composite) exposed to fire conditions. This 3D model takes into account the energy accumulation by the solid material, the anisotropic heat conduction, the thermal decomposition of the material, the gas mass flow into the composite, and the internal pressure. Thermophysical properties defined as temperature dependant properties were characterised using existing as well as innovative methodologies in order to use them as inputs into our physical model. The 3D thermochemical model accurately predicts the measured mass loss and observed decomposition front when the carbon fibre/epoxy composite is directly impacted by a propane flame. In short, the model shows its capability to predict the fire behaviour of a carbon fibre reinforced composite for fire safety engineering.


Faster Reaching in Chronic Spastic Stroke Patients Comes at the Expense of Arm-Trunk Coordination.
The velocity of reaching movements is often reduced in patients with stroke-related hemiparesis; however, they are able to voluntarily increase paretic hand velocity. Previous studies have proposed that faster speed improves movement quality. To investigate the combined effects of reaching distance and speed instruction on trunk and paretic upper-limb coordination. The hypothesis was that increased speed would reduce elbow extension and increase compensatory trunk movement. A single session study in which reaching kinematics were recorded in a group of 14 patients with spastic hemiparesis. A 3-dimensional motion analysis system was used to track the trajectories of 5 reflective markers fixed on the finger, wrist, elbow, acromion, and sternum. The reaching movements were performed to 2 targets at 60% and 90% arm length, respectively, at preferred and maximum velocity. The experiment was repeated with the trunk restrained by a strap. All the patients were able to voluntarily increase reaching velocity. In the trunk free, faster speed condition, elbow extension velocity increased but elbow extension amplitude decreased and trunk movement increased. In the trunk restraint condition, elbow extension amplitude did not decrease with faster speed. Seven patients scaled elbow extension and elbow extension velocity as a function of reach distance, the other 7 mainly increased trunk compensation with increased task constraints. There were no clear clinical characteristics that could explain this difference. Faster speed may encourage some patients to use compensation. Individual indications for therapy could be based on a quantitative analysis of reaching coordination.


Plant metabolism, the diverse chemistry set of the future.
New technologies are redefining how plant biology will meet societal challenges in health, nutrition, agriculture, and energy. Rapid and inexpensive genome and transcriptome sequencing is being exploited to discover biochemical pathways that provide tools needed for synthetic biology in both plant and microbial systems. Metabolite detection at the cellular and subcellular levels is complementing gene sequencing for pathway discovery and metabolic engineering. The crafting of plant and microbial metabolism for the synthetic biology platforms of tomorrow will require precise gene editing and delivery of entire complex pathways. Plants sustain life and are key to discovery and development of new medicines and agricultural resources; increased research and training in plant science will accelerate efforts to harness the chemical wealth of the plant kingdom.


A transient rise in cytosolic calcium follows stimulation of quiescent cells with growth factors and is inhibitable with phorbol myristate acetate.
We have used aequorin as an indicator for the intracellular free calcium ion concentration [( Ca++]i) of Swiss 3T3 fibroblasts. Estimated [Ca++]i of serum-deprived, subconfluent fibroblasts was 89 (+/-20) nM, almost twofold higher than that of subconfluent cells growing in serum, whose [Ca++]i was 50 (+/-19) nM. Serum, partially purified platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF) stimulated DNA synthesis by the serum-deprived cells, whereas epidermal growth factor (EGF) did not. Serum immediately and transiently elevated the [Ca++]i of serum-deprived cells, which reached a maximal value of 5.3 microM at 18 s poststimulation but returned to near prestimulatory levels within 3 min. Moreover, no further changes in [Ca++]i were observed during 12 subsequent h of continuous recording. PDGF produced a peak rise in [Ca++]i to approximately 1.4 microM at 115 s after stimulation, and FGF to approximately 1.2 microM at 135 s after stimulation. EGF caused no change in [Ca++]i. The primary source of calcium for these transients was intracellular, since the magnitude of the serum-induced rise in [Ca++]i was reduced by only 30% in the absence of exogenous calcium. Phorbol 12-myristate 13-acetate (PMA) had no effect on resting [Ca++]i. When, however, quiescent cells were treated for 30 min with 100 nM PMA, serum-induced rises in [Ca++]i were reduced by sevenfold. PMA did not inhibit growth factor-induced DNA synthesis and was by itself partially mitogenic. We suggest that if calcium is involved as a cytoplasmic signal for mitogenic activation of quiescent fibroblasts, its action is early, transient, and can be partially substituted for by PMA. Activated protein kinase C may regulate growth factor-induced increases in [Ca++]i.


Increased fatty acid synthase expression in prostate biopsy cores predicts higher Gleason score in radical prostatectomy specimen.
Fatty acid synthase (FAS) is highly expressed in various types of cancer, and elevated expression of FAS has been suggested to be a predictor of tumor aggressiveness and poor prognosis. We examined whether FAS expression in prostate biopsy cores could predict the pathological characteristics of radical prostatectomy (RP) specimens. Paraffin-embedded prostate biopsy cores, obtained from 102 patients who subsequently underwent RP, were immunostained with polyclonal anti-FAS antibody. The staining intensity was categorized into non-staining, weak, moderate, and strong. Tumors with moderate or strong immunostaining were considered to show high FAS expression, and other tumors were considered to show low FAS expression. The relation between the FAS expression status in biopsy cores and pathological parameters in RP specimens was analyzed. The FAS expression in the biopsy cores of 64 of the 102 tumors (63%) was high, whereas it was low in the biopsy cores of the other 38 tumors (37%). High FAS expression was significantly associated with Gleason Score (GS) ≥ 7 in RP specimens (p< 0.0001). In multivariable logistic regression analyses, GS ≥7 in biopsy cores (p <0.0001), higher preoperative PSA (p = 0.0194), and high FAS expression (p = 0.0004) were independent predictors of GS ≥ 7 in the RP specimen. Increased FAS expression in prostate biopsy cores could be a novel parameter for predicting higher GS in RP specimens. The treatment strategy for patients with high FAS expression in prostate biopsy cores should be carefully determined.


Salidroside Delays Cellular Senescence by Stimulating Mitochondrial Biogenesis Partly through a miR-22/SIRT-1 Pathway.
Calorie restriction (CR) is a nongenetic intervention with a robust effect on delaying aging in mammals and other organisms. A mild stimulation on mitochondrial biogenesis induced by CR seems to be an important action mode for its benefits. Here, we reported that a component isolated from Rhodiola rosea L., salidroside, delays replicative senescence in human fibroblasts, which is related to its stimulation on mitochondrial biogenesis by activating SIRT1 partly resulted from inhibition on miR-22. Salidroside increased the mitochondrial mass that accompanied an increment of the key regulators of mitochondrial biogenesis including PGC-1α, NRF-1, and TFAM and reversed the mitochondrial dysfunction in presenescent 50PD cells, showing a comparable effect to that of resveratrol. SIRT1 is involved in the inducement of mitochondrial biogenesis by salidroside. The declined expression of SIRT1 in 50PD cells compared with the young 30PD cells was prevented upon salidroside treatment. In addition, pretreatment of EX-527, a selective SIRT1 inhibitor, could block the increased mitochondrial mass and decreased ROS production induced by salidroside in 50PD cells, resulting in an accelerated cellular senescence. We further found that salidroside reversed the elevated miR-22 expression in presenescent cells according to a miRNA array analysis and a subsequent qPCR validation. Enforced miR-22 expression by using a Pre-miR-22 lentiviral construct induced the young fibroblasts (30PD) into a senescence state, accompanied with increased senescence-related molecules including p53, p21, p16, and decreased SIRT1 expression, a known target of miR-22. However, salidroside could partly impede the senescence progression induced by lenti-Pre-miR-22. Taken together, our data suggest that salidroside delays replicative senescence by stimulating mitochondrial biogenesis partly through a miR22/SIRT1 pathway, which enriches our current knowledge of a salidroside-mediated postpone senility effect and provides a new perspective on the antidecrepitude function of this naturally occurring compound in animals and humans.


Emerging therapeutic interventions for idiopathic pulmonary fibrosis.
Idiopathic pulmonary fibrosis (IPF) is a devastating and relentlessly progressive lung disorder. Previously, it was thought to be a chronic inflammatory disease; however, it is now considered to be an epithelial-fibroblastic disease. In accordance with this paradigm change, efforts toward the development of novel therapeutic targets for IPF have acquired a new direction. Currently available therapies are largely ineffective in reversing the lung damage, and lung transplantation is the only effective treatment for end-stage disease. Limitations in advancement of IPF therapeutics are due to a poor understanding of its pathogenesis, unavailability of reliable animal models and slow disease progression. Recent research on IPF has resulted in the identification of a plethora of novel targets that are in various stages of development and offers hope that in the near future that there will be better therapeutic options available for the treatment of IPF. This review discusses existing therapies and highlights some of the recent, novel therapeutics being explored in the current clinical landscape for the treatment of this chronic, disabling disorder. The review also discusses the pathogenic rationale behind current therapies. Targeting one fibrotic signaling pathway at a time may not have any significant effect on the control of IPF. It is therefore recommended that future IPF management focuses on targeting multiple pro-fibrotic pathways associated with its complex pathogenesis.


Community integration and related factors among people with mental illness in Japan: Multiple regression analysis stratified by social isolation level.
Community integration is an essential for people with mental illness that affects their health and quality of life. The objective of this study is to find the factors useful in improving community integration of people with mental illness. The study method was self-reporting questionnaires for people with mental illness living in the community. The decision tree analysis revealed that people with mental illness into high or low social isolation level strata. Multiple regression analyses stratified by using two social isolation levels were conducted. Common factors among the strata were living environment of formal care accessibility and daily life activity. Specific factors for social isolation low-level stratum were self-efficacy for coping with symptoms, self-efficacy for social relationships, healthy lifestyle habits, treatment, exchange daily life information with friends and family members. Specific factors for social isolation high-level stratum were self-efficacy for daily living, self-efficacy for treatment-related behavior and satisfaction with formal care. All specific factors were positively associated with community integration. The findings suggest the devising interventions to enhance community integration by social isolation level among people with mental illness.


V-Gel® Guided Endotracheal Intubation in Rabbits.
Background: General anesthesia in rabbits is associated with higher morbidity and mortality relative to other mammalian species commonly anesthetized. Unique challenges related to endotracheal intubation (ETI) in rabbits contribute to this risk. Objective: To improve the safety of ETI in rabbits, we developed two new ETI methods using a supraglottic airway device (v-gel®) to facilitate ETI and compared them to traditional "blind" technique. We hypothesized that relative to blind ETI, v-gel® guided ETI provides more successful placement of the endotracheal tube (ETT) in a shorter time. Outcomes included number of intubation attempts, time for achievement of ETI, endoscopic findings, and serial arterial blood gas (ABG) analysis. Study Design: Prospective, randomized, and crossover study. Methods: Ten female, New Zealand White rabbits aged 1-2 years old, weighing 4.3 ± 0.4 kg, were anesthetized four times. Each time, ETI was performed with one of the following techniques: Method 1: v-gel® guided, polypropylene catheter facilitated, intubation using a cuffed ETT; Method 2: v-gel® guided intubation using an uncuffed ETT directly inserted through the device airway channel; Method 3 and 4: Blind intubation with uncuffed or cuffed ETT. Upper airway endoscopy was performed before intubation attempts and after extubation. Serial ABG analysis was performed during the peri-intubation process. Results: V-gel® guided techniques allowed successful ETI on the initial attempt for 9/10 subjects using Method 1 and 10/10 using Method 2. Relative to the v-gel® guided techniques, the blind techniques required more intubation attempts. A median of 2 attempts (range 1-4, p < 0.007) were required for the uncuffed ETT, and a median of 4 (range 1-4, p < 0.001) attempts were performed for the cuffed ETT. The time to perform successful ETI was positively correlated with the number of attempts (ρ = 0.82), while successful ETI was negatively correlated with number of attempts (ρ = -0.82). Endoscopic findings showed mild to moderate laryngeal trauma. In the absence of oxygen supplementation, ABG analysis demonstrated low PaO2, while PaCO2 remained consistent. Conclusions: Facilitated ETI using the v-gel® guided techniques allows for the rapid establishment of a secure airway to provide ventilatory support for rabbits undergoing general anesthesia.


Manipulation of Cannabinoid Biosynthesis via Transient RNAi Expression.
Cannabis sativa L. produces unique phytocannabinoids, which are used for their pharmaceutical benefits. To date, there are no reports of in vivo engineering targeting the cannabinoid biosynthesis genes to greater elucidate the role each of these genes play in synthesis of these medically important compounds. Reported here is the first modulation of cannabinoid biosynthesis genes using RNAi via agroinfiltration. Vacuum infiltrated leaf segments of the Cannbio-2 C. sativa strain, transfected with different RNAi constructs corresponding to THCAS, CBDAS, and CBCAS gene sequences, showed significant downregulation of all cannabinoid biosynthesis genes using real-time quantitative PCR. Using RNAi, significant off-targeting occurs resulting in the downregulation of highly homologous transcripts. Significant (p < 0.05) downregulation was observed for THCAS (92%), CBDAS (97%), and CBCAS (70%) using pRNAi-GG-CBDAS-UNIVERSAL. Significant (p < 0.05) upregulation of CBCAS (76%) and non-significant upregulation of THCAS (13%) were observed when transfected with pRNAi-GG-CBCAS, suggesting the related gene's ability to synthesize multiple cannabinoids. Using this approach, increased understanding of the relationship between cannabinoid biosynthesis genes can be further elucidated. This RNAi approach enables functional genomics screens for further reverse genetic studies as well as the development of designer cannabis strains with over-expression and/or downregulation of targeted cannabinoid biosynthesis genes. Functional genomics screens, such as these, will further provide insights into gene regulation of cannabinoid biosynthesis in Cannabis.


Synthesis and utility of 2-(benzoyloxyimino)-2-deoxy-alpha-D-lyxo-hexopyranosyl bromide as a novel alpha-D-talosaminide building block.
A novel alpha-D-talosaminyl donor, 2-(benzoyloxyimino)-2-deoxy-alpha-D-lyxo-hexopyranosyl bromide has been synthesized in a total yield of 32% over 6 steps from D-galactose. The utility of the donor was evaluated for the elaboration of alpha-D-TalNAc-(1-->6)-alpha-D-Gal, alpha-D-TalNAc-(1-->6)-alpha-D-Glc, and alpha-D-TalNAc-(1-->3)-L-serine derivatives by a simple 3-step sequence, comprising alpha-selective glycosylation of appropriately protected acceptors of D-galactose, D-glucose, and L-serine, talo-selective hydroboration of the oxyimino function to an amino group, and N-acetylation.


[Physiopuncture therapy of trigeminal neuralgia].
137 patients with typical trifacial neuralgia (TN) were divided into four groups. 30 patients of group 1 received EHF therapy, 30 patients of group 2 were exposed to laser, 67 patients of group 3 were treated with combination of laser with EHF-puncture, 10 patients of group 4 were controls on conventional physiotherapy. Patients of all the groups were given drug of choice--carbamazepin. The highest response was registered in group 3, 21(31.3%) patients of which could stop carbamazepin, while 40(59.7%) patients reduced carbamazepin dose by 50-70%. Positive results were due to restoration of self-regulation in pain and antipain systems which are disturbed in TN patients.


Cost-effectiveness of Different Diabetic Retinopathy Screening Modalities.
Current screening strategies aimed at detection of diabetic retinopathy (DR) historically have poor compliance, but advancements in technology can enable improved access to care. Nearly 80% of all persons with diabetes live in low- and middle-income countries (LMICs), highlighting the importance of a cost effective screening program. Establishing mechanisms to reach populations with geographic and financial barriers to access is essential to prevent visual disability. Teleretinal programs leverage technology to improve access and reduce cost. The quality of currently employed screening modalities depends on many variables including the instrument used, use of pupillary mydriasis, number of photographic fields, and the qualifications of the photographer and image interpreter. Recent telemedicine and newer technological approaches have been introduced, but data for these technologies is yet limited. We present results of a systematic review of studies evaluating cost-effectiveness of DR screening, and discuss potential relevance for LMICs.


Polymorphisms in genes within the IGF-axis influence antenatal and postnatal growth.
Two pregnancy cohorts were used to investigate the association between single-nucleotide polymorphisms (SNPs) in genes within the insulin-like growth factor (IGF)-axis and antenatal and postnatal growth from birth to adolescence. Longitudinal analyses were conducted in the Raine pregnancy cohort (n = 1162) using repeated measures of fetal head circumference (HC), abdominal circumference (AC) and femur length (FL) from 18 to 38 weeks gestation and eight measures of postnatal height and weight (1-17 years). Replications of significant associations up to birth were undertaken in the Generation R Study (n = 2642). Of the SNPs within the IGF-axis genes, 40% (n = 58) were associated with measures of antenatal growth (P ⩽ 0.05). The majority of these SNPs were in receptors; IGF-1R (23%; n = 34) and IGF-2R (13%; n = 9). Fifteen SNPs were associated with antenatal growth (either AC or HC or FL) in Raine (P ⩽ 0.005): five of which remained significant after adjusting for multiple testing. Four of these replicated in Generation R. Associations were identified between 38% (n = 55) of the IGF-axis SNPs and postnatal height and weight; 21% in IGF-1R (n = 31) and 9% in IGF-2R (n = 13). Twenty-six SNPs were significantly associated with both antenatal and postnatal growth; 17 with discordant effects and nine with concordant effects. Genetic variants in the IGF-axis appear to play a significant role in antenatal and postnatal growth. Further replication and new analytic methods are required in order to better understand this key metabolic pathway integrating biologic knowledge about the interaction between IGF-axis components.


Microarray analysis of DNA damage repair gene expression profiles in cervical cancer cells radioresistant to 252Cf neutron and X-rays.
The aim of the study was to obtain stable radioresistant sub-lines from the human cervical cancer cell line HeLa by prolonged exposure to 252Cf neutron and X-rays. Radioresistance mechanisms were investigated in the resulting cells using microarray analysis of DNA damage repair genes. HeLa cells were treated with fractionated 252Cf neutron and X-rays, with a cumulative dose of 75 Gy each, over 8 months, yielding the sub-lines HeLaNR and HeLaXR. Radioresistant characteristics were detected by clone formation assay, ultrastructural observations, cell doubling time, cell cycle distribution, and apoptosis assay. Gene expression patterns of the radioresistant sub-lines were studied through microarray analysis and verified by Western blotting and real-time PCR. The radioresistant sub-lines HeLaNR and HeLaXR were more radioresisitant to 252Cf neutron and X-rays than parental HeLa cells by detecting their radioresistant characteristics, respectively. Compared to HeLa cells, the expression of 24 genes was significantly altered by at least 2-fold in HeLaNR cells. Of these, 19 genes were up-regulated and 5 down-regulated. In HeLaXR cells, 41 genes were significantly altered by at least 2-fold; 38 genes were up-regulated and 3 down-regulated. Chronic exposure of cells to ionizing radiation induces adaptive responses that enhance tolerance of ionizing radiation and allow investigations of cellular radioresistance mechanisms. The insights gained into the molecular mechanisms activated by these "radioresistance" genes will lead to new therapeutic targets for cervical cancer.


Inhibition of thymidine transport in dnaA mutants of Escherichia coli.
DnaA protein is the initiator of chromosomal DNA replication in Escherichia coli. We report here our evidence that thymidine transport across cytoplasmic membranes in temperature-sensitive dnaA mutants is greatly decreased at a permissive temperature for growth of the mutants. Complementation analysis with a plasmid containing the wild type dnaA gene and P1 phage-mediated transduction confirmed that mutations in the dnaA gene were responsible for the phenotype. A low level of nucleoside transport in the dnaA mutant was specific for thymidine; transport activities for other nucleosides were much the same as those in wild type cells. Membrane vesicles prepared from the dnaA mutant showed much the same activity of thymidine transport as did those from the wild type cells. No significant difference in the activity of thymidine kinase, which is known to facilitate thymidine transport, was seen between the mutant and the wild type cells. An increase in the pool of dTTP, a negative regulator for thymidine kinase, was observed in the dnaA mutant. Based on these observations, we suggest that inhibition of thymidine transport in dnaA mutants is caused by increases in the dTTP pool.


Surgical treatment of malformations of the uterus.
The reproductive history in 13 patients with uterine malformations was reviewed. Following plastic repair, there was a high incidence of pregnancy salvage. Of 19 pregnancies, 14 resulted in term deliveries, four in premature deliveries and one in abortion; there are 14 living children. The surgical repair in two patients with primary sterility was the contributing factor in achieving pregnancies with full term deliveries.


Sensitive research with adolescents: just how upsetting are self-report surveys anyway?
Distress related to answering personal survey questions about drug use, suicidal behavior, and physical and sexual abuse were examined in multiple convenience samples of adolescents. Samples varied in consent procedures utilized (active vs. passive parental consent), data collection setting (school vs. juvenile justice), developmental level (middle school vs. high school). Participation rates differed across consent procedures (e.g., 93% with passive vs. 62% with active parental consent). Results indicated that small percentages of adolescents in every sample reported frequently feeling upset while completing the survey (range 2.5% to 7.6%). Age, race, gender, and data collection strategy did not emerge as significant predictors of feeling upset. Instead, as hypothesized, adolescents reporting a history of suicidal ideation or attempt, illicit drug use, or experiences of physical or sexual victimization endorsed more frequent feelings of upset while completing the survey than peers without these experiences. Taken together, however, these sensitive event experiences explained only 6.6% of the variance in adolescents' upset ratings. The scientific and ethical implications of these findings are discussed with regard to adolescent participation in survey research about sensitive topics.


[Vesicostomy in children].
To evaluate the upper urinary tract morphology and function in children undergoing vesicostomy for different causes. We report on 27 children aged 1 month to 12 years who had undergone a Blocksom vesicostomy procedure. Twenty had a neuropathic bladder and 3 had posterior urethral valves. In the 20 children with neuropathic bladder, renal function improved in 95% and the associated vesicoureteral reflux improved in 56%. The morphology of the upper urinary tract returned to normal prior to the definitive operation in all cases. Only one of the patients with posterior urethral valves has preserved satisfactory renal function two years following vesicostomy. The most common complication was prolapse (14.8%). In our view, vesicostomy is the best urinary diversion procedure in the cases described herein. Vesicostomy closure must be performed following definitive treatment of the underlying condition, except in those cases with neuropathic bladder who require augmentation cystoplasty to keep upper urinary tract pressures low.


Rapid synthesis of quantum-confined CsPbBr3 perovskite nanowires using a microfluidic reactor.
Microfluidics has been considered as an effective platform in the mechanism study and large-scale manufacturing of nanomaterials. In this work, we report the facile synthesis of quantum-confined CsPbBr3 nanowires (NWs) by using a continuous-flow microfluidic reactor. The optimized reaction temperature is around 50 °C, and one "synthesis run" by microfluidics requires only ten minutes. This study reveals that the formation of CsPbBr3 NWs takes place by a hybrid growth mechanism of seed-mediated growth and oriented attachment growth. This microfluidic approach benefits the alignment of the short quantum-confined NWs and promotes their oriented attachment to form long NWs, while conventional flask synthesis results in large and irregular nanorods under the same reaction conditions. This work not only provides a new synthetic path for the preparation of CsPbX3 NWs but also sheds some light on the fundamental study of CsPbX3 NWs.


Economic analysis as an aid to subsidisation decisions: the development of Australian guidelines for pharmaceuticals.
Factors governing the entry of new drugs into clinical practice are changing, with increasing emphasis on economic issues. In future, organisations that subsidise the use of pharmaceuticals are likely to require sponsors to provide evidence of the cost-effectiveness of their products. The first national government to signal such an intention is the Commonwealth Government of Australia, which from January 1993 will require economic analyses in support of applications for listing of new pharmaceutical products on its schedule of pharmaceutical benefits. This move is underpinned by legislation that requires the country's Pharmaceutical Benefits Advisory Committee (PBAC) to consider costs and effectiveness when recommending listing of new drugs. The approach that has been recommended to the Committee is based on advice from a group of consultants, health economists and clinicians. The PBAC will use economic analyses as an aid to decision-making that will remain within a clinical framework; the viewpoint will be societal, and analyses will include costs that fall outside the pharmaceutical benefits scheme. The preferred approach is comparative cost-effectiveness analysis with a particular emphasis on the marginal costs of obtaining additional health benefits with new drugs, compared with existing therapies. The use of analyses that are restricted to potential cost savings with new drugs is discouraged, as is the inclusion of indirect costs and benefits. To facilitate the conduct of economic analyses, it is planned to hold meetings with specialist clinicians to obtain consensus on a range of intermediate clinical outcome indicators, and to publish lists of 'standard' Australian costs that will be updated regularly. The approach being followed in Australia has implications for both the government and the pharmaceutical industry. The responsibility for monitoring the effects of this new policy lie with the government. The success, or otherwise, of the policy should not be gauged simply by the effects on the price of new drugs which, historically, have been relatively low in Australia. A full evaluation will require that more effort be put into clinical outcomes research and the development of population databases, an area in which Australia lags behind other countries.


Stabilization of the p53-DNA Complex by the Nuclear Protein Dmp1α.
We recently reported the existence of a physical interaction between the Myb-like transcription factor Dmp1 (Dmtf1) and p53 in which Dmp1 antagonized polyubiquitination of p53 by Mdm2 and promoted its nuclear localization. Dmp1 significantly stabilized p53-DNA complexes on promoters that contained p53-consensus sequences, which were either supershifted or disrupted with antibodies to Dmp1. Lysates from mice injected with doxorubicin showed that Dmp1 bound to p21Cip1, Bbc3, and Thbs1 gene regulatory regions in a p53-dependent fashion. Our data suggest that acceleration of DNA-binding of p53 by Dmp1 is a critical process for Dmp1 to increase the p53 function in Arf-deficient cells.


Comparison of nerve regeneration in vascularized and conventional grafts: nerve electrophysiology, norepinephrine, prostacyclin, malondialdehyde, and the blood-nerve barrier.
We compared the efficacy of vascularized (VASC) and conventional (CONV) sciatic nerve grafts in restoring nerve blood flow (NBF), conduction, the blood-nerve barrier, norepinephrine (NE), and 6-keto prostaglandin F1 alpha (6-KPGF; the stable prostacyclin metabolite) in the sciatic nerve of the rat. We also measured malondialdehyde (MDA) content. NBF was much greater in VASC grafts, but the increase was confined to non-nutritive flow. There was a statistically non-significant increase in nerve action potential amplitude in the grafted segments of VASC nerves at 1 and 2 months post graft. The [14C]sucrose permeability surface area (PA) product was increased in both CONV and VASC at 1 and 3 months and was not different to each other. NE and 6-KPGF, the major vasoconstrictor and dilator of nerve microvessels were better restored in VASC than CONV reaching statistically significance for 6-KPGF (P less than 0.001). MDA used as an index of oxygen free radical generation was not significantly different in the 3 groups. The better restoration of 6-KPGF and perhaps NE suggest that VASC grafts may be more effective in restoring vasoreactivity of peripheral nerve following graft.


Blood pressure parameters and morbid and mortal outcomes in nondialysis-dependent chronic kidney disease.
Observational and interventional studies provide conflicting evidence regarding optimal blood pressure (BP) control in persons with chronic kidney disease (CKD). Recent publications provide additional information to inform therapeutic decision-making. Targeting SBP to less than 120 mmHg, versus less than 140 mmHg, decreased cardiovascular events and all-cause mortality in persons with nondiabetic CKD. A meta-analysis of trials testing blood pressure management among nondialysis-dependent CKD patients (15 924 total patients) found more intensive therapies generally reduced mortality in all subgroups. Observational studies demonstrate that low SBP is associated with higher mortality in CKD. A recent report suggests that this is because of death from cardiovascular and noncardiovascular and nonmalignant causes, whereas higher BP is associated with death from cardiovascular causes. The shape of association between BP and cardiovascular and noncardiovascular events also appears to vary depending on baseline risk factors. Furthermore, BP measurement methodology may differ importantly between observational and interventional studies. We review and summarize observational and interventional literature relating BP parameters to key clinical outcomes in persons with CKD. Apart from the inherent differences between these study designs, the disparate findings from trials and observational studies may be because of differences in patient characteristics and BP measurement techniques.


Psychological and social outcomes of befriending interventions for adults with intellectual disabilities: A systematic review.
Befriending is an intervention intended to provide companionship and support to socially isolated populations. This review aimed to understand the key characteristics and psychological and social outcomes of befriending interventions for adults with intellectual disabilities. Systematic searches of electronic databases (PsycINFO, MedLine and Web of Science) identified 11 studies for inclusion. A narrative synthesis of the findings was completed, along with critical appraisal of study quality. Increased community participation, positive changes to social networks and mood were frequently reported outcomes for befriendees. Increased knowledge, new experiences and opportunities to 'give back' were most reported for befrienders. The review highlighted that existing research in this field is limited in scope and methodologically diverse. Future research should focus upon the effectiveness and long-term impact of befriending interventions, understanding the mechanisms of change, and eliciting the views of people with intellectual disabilities on their experiences.


Translocation of RNA-coated gold particles through the nuclear pores of oocytes.
In the present study, various sized gold particles coated with tRNA, 5S RNA, or poly(A) were used to localize and characterize the pathways for RNA translocation to the cytoplasm. RNA-coated gold particles were microinjected into the nucleus of Xenopus oocytes. The cells were fixed after 15, 60 min, or 6 h, and the particle distribution was later observed by electron microscopy. Similar results were obtained with all classes of RNA used. After nuclear injection, particles ranging from 20-230 A in diameter were observed within central channels of the nuclear pores and in the cytoplasm immediately adjacent to the pores. Particles of this size would not be expected to diffuse through the pores, suggesting that some form of mediated transport occurred. In addition, it was found that the translocation process is saturable. At least 97% of the pores analyzed appeared to be involved in the translocation process. Gold coated with nonphysiological polynucleotides (poly[I] or poly[dA]) were also translocated. When nuclei were injected with either BSA-, ovalbumin-, polyglutamic acid-, or PVP-coated gold, the particles were essentially excluded from the pores. These results indicate that the accumulation of RNA-gold within the pores and adjacent cytoplasm was not due to non-specific effects. We conclude that the translocation sites for gold particles coated with different classes of RNA are located in the centers of the nuclear pores and that particles at least 230 A in diameter can cross the envelope. Tracer particles injected into the cytoplasm were observed within the nuclear pores in areas near the site of injection. However, only a small percentage of the particles actually entered the nucleus. It was also determined, by performing double injection experiments, that individual pores are bifunctional, that is, capable of transporting both proteins and RNA.


IDENTIFICATION OF TWO LETHAL CASES OF ELEPHANT ENDOTHELIOTROPIC HERPESVIRUS HEMORRHAGIC DISEASE IN SUMATRAN ELEPHANT CALVES IN INDONESIA.
As many as a dozen cases of lethal acute hemorrhagic disease (HD) in young captive-born Sumatran sub-species Asian elephant (Elephas maximus sumatranus roman) calves raised naturally in camps in Sumatra have been observed in recent years. To address whether these deaths, like many others documented worldwide, might be associated with acute systemic infection by elephant endotheliotropic herpesvirus (EEHV), diagnostic polymerase chain reaction (PCR) tests followed by subtype deoxyribonucleic acid (DNA) sequencing analysis were carried out on pathologic tissue samples from two lethal HD cases that occurred within 6 days of one another in calves at the same camp. Viral DNA from five selected PCR loci was found to be present at high levels in both calves and proved to be the same EEHV1A virus species that has been described most commonly previously in numerous lethal or surviving symptomatic cases in North America, Europe, India, and Thailand. Furthermore, the two cases were identical at all five PCR loci tested (covering a total of 3,050 base pairs) and were therefore likely to have been infected from the same epidemiologic source herdmate. However, the strain involved (which was subtype-D2 in the vGPCR1 locus) differed from all previously characterized EEHV1A strains. In conclusion, these two calves are the first two confirmed HD cases in Sumatra alongside several other suspected HD cases in Sumatra that have succumbed to the same devastating EEHV1A-HD that has afflicted young Asian elephants worldwide over the past 25 yr. Because the progeny of some of the 1,500 remaining red-listed critically endangered Sumatra subspecies elephants are bred naturally in camps from wild parents it seems very likely that the EEHV1A herpesvirus identified here in these HD camp cases is also present in the free-ranging Sumatran elephant population, and this will have to be taken into account in future wildlife management policies and decisions.


Relative expression of matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-2 in mouse renal cell carcinoma cells regulates their metastatic potential.
To clarify the significance of the balance between matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinase-2 (TIMP-2) in the progression of renal cell carcinoma, we transfected both the MMP-2 and TIMP-2 genes simultaneously into RenCa, a mouse renal cell carcinoma cell line that does not express detectable levels of either MMP-2 or TIMP-2 mRNAs, and established several clones with various MMP-2:TIMP-2 expression ratios. On the basis of the quantitative evaluation of the MMP-2: TIMP-2 mRNA expression ratio by Northern blot analysis, we selected a clone overexpressing MMP-2 alone (RenCa/M), a clone overexpressing TIMP-2 alone (RenCa/T), and two kinds of clones overexpressing both, i.e., one with a high (RenCa/MTh) and one with a low (RenCa/MTl) MMP-2: TIMP-2 ratio, to compare the tumor cell phenotypes. In an in vitro tumor cell invasion assay, the MMP-2:TIMP-2 ratios of the RenCa sublines were directly correlated with their invasive potential. The invasive abilities of the parental RenCa cells induced by conditioned media from RenCa sublines were also correlated with the MMP-2:TIMP-2 ratios of the sublines. The cell adhesion assay showed the inverse correlation between the MMP-2 expression levels in the sublines and their cell adhesion to several extracellular matrix components. Furthermore, when injected i.v. or into the renal subcapsule in syngeneic mice, RenCa sublines formed metastatic nodules in the lungs, and the number of nodules was correlated with the MMP-2:TIMP-2 ratio of each clone. In contrast, despite the growth-inhibitory effects of TIMP-2 overexpression, MMP-2 overexpression had no effect on either proliferation in vitro of RenCa sublines or on their growth as tumors in vivo. These results suggest that the MMP-2:TIMP-2 expression ratio is a critical factor in the invasion and metastasis of renal cell carcinoma.


Genetic influences on the development of grip strength in adolescence.
Enhanced physical strength is a secondary sex characteristic in males. Sexual dimorphism in physical strength far exceeds sex differences in stature or total body mass, suggesting a legacy of intense sexual selection. Upper-body strength is a particularly promising marker of intrasexual competitiveness in young men. Consequently, it is assumed that sex-influenced gene expression contributes to the development of physical strength. It is unclear, however, whether the underlying sources of individual differences in strength development are comparable across sex. We obtained three measurements of hand-grip strength (HGS) over a six-year period spanning adolescence in male and female same-sex twins (N = 2,513). Biometrical latent growth models were used to partition the HGS variance at age 11 (intercept) and its growth over time (slope) into genetic and environmental components. Results demonstrated that variance around the intercept was highly heritable in both males and females (88% and 79%, respectively). In males, variance around the slope exceeded that of the intercept, while the reverse held for females. Additive genetic effects accounted for most (80%) of the variance around the slope in males, but were of less importance in females (heritability = 28%). Absolute genetic variance around the slope was nearly nine-fold higher in males. This striking disparity suggests that the developmental processes shaping HGS growth are different between the sexes. We propose that this might account for the sex-specific pattern of associations between HGS and external measures (e.g., digit ratio and physical aggression) typically reported in the literature. Our results underscore the role of endogenous androgenic influences in the development of physical strength.


Acute and maintenance treatment of chronic depression.
Chronic forms of depression account for approximately one third of all depressions. They are underrecognized and undertreated. This article defines the types of chronic depressions (dysthymic disorder, double depression, chronic major depression, and major depression in incomplete remission). A review of treatments for patients with these conditions is provided. The basic principles of treatment of chronic depression involve longer treatment and higher doses than are usually required for acute major depression. The impact of psychosocial disability and severity of depressive symptoms can be ameliorated with appropriate treatment. Newer treatments, such as the combination of psychotherapy and pharmacotherapy, may prove to be of greatest benefit for individuals with chronic mood disorders.


Integrated transcriptome analysis of mouse spermatogenesis.
Differentiation of primordial germ cells into mature spermatozoa proceeds through multiple stages, one of the most important of which is meiosis. Meiotic recombination is in turn a key part of meiosis. To achieve the highly specialized and diverse functions necessary for the successful completion of meiosis and the generation of spermatozoa thousands of genes are coordinately regulated through spermatogenesis. A complete and unbiased characterization of the transcriptome dynamics of spermatogenesis is, however, still lacking. In order to characterize gene expression during spermatogenesis we sequenced eight mRNA samples from testes of juvenile mice from 6 to 38 days post partum. Using gene expression clustering we defined over 1,000 novel meiotically-expressed genes. We also developed a computational de-convolution approach and used it to estimate cell type-specific gene expression in pre-meiotic, meiotic and post-meiotic cells. In addition, we detected 13,000 novel alternative splicing events around 40% of which preserve an open reading frame, and found experimental support for 159 computational gene predictions. A comparison of RNA polymerase II (Pol II) ChIP-Seq signals with RNA-Seq coverage shows that gene expression correlates well with Pol II signals, both at promoters and along the gene body. However, we observe numerous instances of non-canonical promoter usage, as well as intergenic Pol II peaks that potentially delineate unannotated promoters, enhancers or small RNA clusters. Here we provide a comprehensive analysis of gene expression throughout mouse meiosis and spermatogenesis. Importantly, we find over a thousand of novel meiotic genes and over 5,000 novel potentially coding isoforms. These data should be a valuable resource for future studies of meiosis and spermatogenesis in mammals.


Directed Evolution of Pseudomonas fluorescens Lipase Variants With Improved Thermostability Using Error-Prone PCR.
Lipases catalyze the hydrolysis of fats and oils, and have been widely used in various industrial fields. However, bacterial lipases have a lower thermostability in industrial processes, which was a limiting factor in their industrial application. In this study, we obtained an improve variant of Pseudomonas fluorescens lipase (PFL) with enhanced thermostability using classical error-prone PCR. Wild-type PFL showed an optimal temperature and pH of 50°C and pH 7.5, respectively. Due to the low thermostability of PFL, a library containing over 3000 individual mutants as constructed using error-prone PCR. Screening for thermotolerance yielded the mutants L218P and P184C/M243C with Tm values of 62.5 and 66.0°C, which was 2.5 and 6°C higher than that of the WT, respectively. The combination of the two mutants (P184C/M243C/L218P) resulted in an approximately additive effect with a Tm value of 68.0°C. Although the increase of Tm was not substantial, the mutant also had dramatically increased methanol tolerance. Structural analysis revealed that the introduction of a disulfide bond between P184C and M243C and the substitution of Pro to reduce the flexibility of a loop increased the thermostability of PFL, which provides a theoretical foundation for improving the thermostability and methanol tolerance of lipase family I.1 to resist the harsh conditions of industrial processes.


Predicting drug-drug interactions involving multiple mechanisms using physiologically based pharmacokinetic modeling: a case study with ruxolitinib.
Physiologically based pharmacokinetic modeling was applied to characterize the potential drug-drug interactions for ruxolitinib. A ruxolitinib physiologically based pharmacokinetic model was constructed using all baseline PK data in healthy subjects, and verified by retrospective predictions of observed drug-drug interactions with rifampin (a potent CYP3A4 inducer), ketoconazole (a potent CYP3A4 reversible inhibitor) and erythromycin (a moderate time-dependent inhibitor of CYP3A4). The model prospectively predicts that 100-200 mg daily dose of fluconazole, a dual inhibitor of CYP3A4 and 2C9, would increase ruxolitinib plasma concentration area under the curve by ∼two-fold, and that as a perpetrator, ruxolitinib is highly unlikely to have any discernible effect on digoxin, a sensitive P-glycoprotein substrate. The analysis described here illustrates the capability of physiologically based pharmacokinetic modeling to predict drug-drug interactions involving several commonly encountered interaction mechanisms and makes the case for routine use of model-based prediction for clinical drug-drug interactions. A model verification checklist was explored to harmonize the methodology and use of physiologically based pharmacokinetic modeling.


Polarization effects in fourier spectroscopy. I: coherency matrix representation.
A general analytical method using the formalisms of polarization coherency and Jones's matrices is provided for the evaluation of all polarization effects in fourier spectroscopy. The method applies to any incident state of arbitrary (complete, random, or partial) polarization. Inversely, it may also be used for determining the intensity and state of polarization of the source of light. TE- and TM-mode reflectivity and transmissivity for beam splitters and the dependence of these quantities on the incident polarization are obtained. It is demonstrated that three different efficiencies for these optical components must be introduced. Interferometer efficiency expressions for the source beam and the detector beam are also derived and shown to be essentially different from the previous efficiencies. Polarization effects of beam splitters, reflectors, and their composite combinations (interferometers) are investigated in detail. General conditions for complete or restricted polarization compensation are derived. Theoretical SNR expressions for both the source beam and the detector beam are also obtained; these formulas specifically account for the incident state of polarization, the polarization effects of the interferometer, and make use of the exact expressions for the appropriate interferometer efficiency. In an Appendix, a brief comparison is made between some usual representations of the state of wave polarization.


Mullerian mixed tumour of the uterine corpus: a clinical histopathological review of 28 patients.
Clinical and histopathological features of 28 patients with Mullerian mixed tumours of the uterine corpus presenting to the Birmingham and Midland Hospital for Women between 1972 and 1977 are reviewed. The 5-year survival value for this group of patients was 25% with 53.5% of patients dying within 12 months of diagnosis. The most important finding of prognostic value was the extent of the tumour at the time of diagnosis and where this was localized to the uterus, there was a 50% 5-year survival. The presence of specific types of heterotopic elements or numbers of mitotic elements were not correlated with outcome. Five patients had previously received radium for induction of a radiation menopause and the relevance of this treatment and other factors in the aetiology of the tumour are discussed.


The beneficial effects of Tai Chi exercise on endothelial function and arterial stiffness in elderly women with rheumatoid arthritis.
Rheumatoid arthritis (RA) has been known to be associated with increased risk of cardiovascular disease (CVD). The aim of this study was to investigate the effects of Tai Chi exercise on CVD risk in elderly women with RA. In total, 56 female patients with RA were assigned to either a Tai Chi exercise group (29 patients) receiving a 3-month exercise intervention once a week or a control group (27 patients) receiving general information about the benefits of exercise. All participants were assessed at baseline and at 3 months for RA disease activity (Disease Activity Score 28 and Routine Assessment of Patient Index Data 3), functional disability (Health Assessment Questionnaire), CVD risk factors (blood pressure, lipids profile, body composition, and smoking), and three atherosclerotic measurements: carotid intima-media thickness, flow-mediated dilatation (FMD), and brachial-ankle pulse wave velocity (baPWV). FMD, representative of endothelial function, significantly increased in the Tai Chi exercise group (initial 5.85 ± 2.05 versus 3 months 7.75 ± 2.53%) compared with the control group (initial 6.31 ± 2.12 versus 3 months 5.78 ± 2.13%) (P = 1.76 × 10(-3)). Moreover, baPWV, representative of arterial stiffness, significantly decreased in the Tai Chi exercise group (initial 1693.7 ± 348.3 versus 3 months 1600.1 ± 291.0 cm/s) compared with the control group (initial 1740.3 ± 185.3 versus 3 months 1792.8 ± 326.1 cm/s) (P = 1.57 × 10(-2)). In addition, total cholesterol decreased significantly in the Tai Chi exercise group compared with the control group (-7.8 ± 15.5 versus 2.9 ± 12.2 mg/dl, P = 2.72 × 10(-2)); other changes in RA-related characteristics were not significantly different between the two groups. Tai Chi exercise remained significantly associated with improved endothelial function (FMD; P = 4.32 × 10(-3)) and arterial stiffness (baPWV; P = 2.22 × 10(-2)) after adjustment for improvement in total cholesterol level. Tai Chi exercise improved endothelial dysfunction and arterial stiffness in elderly women with RA, suggesting that it can be a useful behavioral strategy for CVD prevention in patients with RA.


Differential effects of selective inhibitors targeting the PI3K/AKT/mTOR pathway in acute lymphoblastic leukemia.
Aberrant PI3K/AKT/mTOR signaling has been linked to oncogenesis and therapy resistance in various malignancies including leukemias. In Philadelphia chromosome (Ph) positive leukemias, activation of PI3K by dysregulated BCR-ABL tyrosine kinase (TK) contributes to the pathogenesis and development of resistance to ABL-TK inhibitors (TKI). The PI3K pathway thus is an attractive therapeutic target in BCR-ABL positive leukemias, but its role in BCR-ABL negative ALL is conjectural. Moreover, the functional contribution of individual components of the PI3K pathway in ALL has not been established. We compared the activity of the ATP-competitive pan-PI3K inhibitor NVP-BKM120, the allosteric mTORC1 inhibitor RAD001, the ATP-competitive dual PI3K/mTORC1/C2 inhibitors NVP-BEZ235 and NVP-BGT226 and the combined mTORC1 and mTORC2 inhibitors Torin 1, PP242 and KU-0063794 using long-term cultures of ALL cells (ALL-LTC) from patients with B-precursor ALL that expressed the BCR-ABL or TEL-ABL oncoproteins or were BCR-ABL negative. Dual PI3K/mTOR inhibitors profoundly inhibited growth and survival of ALL cells irrespective of their genetic subtype and their responsiveness to ABL-TKI. Combined suppression of PI3K, mTORC1 and mTORC2 displayed greater antileukemic activity than selective inhibitors of PI3K, mTORC1 or mTORC1 and mTORC2. Inhibition of the PI3K/mTOR pathway is a promising therapeutic approach in patients with ALL. Greater antileukemic activity of dual PI3K/mTORC1/C2 inhibitors appears to be due to the redundant function of PI3K and mTOR. Clinical trials examining dual PI3K/mTORC1/C2 inhibitors in patients with B-precursor ALL are warranted, and should not be restricted to particular genetic subtypes.


Cognitive load privileges memory-based over data-driven processing, not group-level over person-level processing.
In the current paper, we argue that categorization and individuation, as traditionally discussed and as experimentally operationalized, are defined in terms of two confounded underlying dimensions: a person/group dimension and a memory-based/data-driven dimension. In a series of three experiments, we unconfound these dimensions and impose a cognitive load. Across the three experiments, two with laboratory-created targets and one with participants' friends as the target, we demonstrate that cognitive load privileges memory-based over data-driven processing, not group- over person-level processing. We discuss the results in terms of their implications for conceptualizations of the categorization/individuation distinction, for the equivalence of person and group processes, for the ultimate 'purpose' and meaningfulness of group-based perception and, fundamentally, for the process of categorization, broadly defined.


Retrograde transport of radiolabelled botulinum neurotoxin type A to the CNS after intradetrusor injection in rats.
To investigate the potential distribution of radiolabelled botulinum neurotoxin type A (BoNT/A) in the CNS after bladder injection in normal rats, by using the gamma-emitting radionuclide technetium-99 m ((99m) Tc). BoNT/A was radiolabelled by pretreatment with 2-iminothiolane and incubation with (99m) Tc-gluconate. The labelled toxin (99m) Tc-BoNT/A was purified using size exclusion HPLC. Twenty-four female Wistar rats were evenly injected in the bladder wall with either (99m) Tc-ΒοΝΤ/Α (n = 12) or free (99m) Tc (n = 12). Four rats from each group were killed at 1, 3 and 6 h after injection, respectively. The bladder, L6-S1 spinal cord segment and L6-S1 dorsal root ganglia (DRG) were harvested and their radioactivity counted in a gamma scintillation detector. Results were calculated as % injected dose (I.D.) per gram of tissue. The paired t-test was used for comparison of means of (99m) Tc-ΒοΝΤ/Α radioactivity vs free (99m) Tc in the tissues of interest. Radiolabelled BoNT/A had a high radiochemical stability of 70% after 24 h. Gradual accumulation of (99m) Tc-ΒοΝΤ/Α was observed in the DRG up to 6 h after injection (P = 0.04 and P = 0.029 compared with 1 h and 3 h, respectively), while no accumulation was detected for free (99m) Tc. Consequently, (99m) Tc-ΒοΝΤ/Α radioactivity in the DRG was higher than free (99m) Tc radioactivity (3.18 ± 0.67% I.D./g vs 0.19 ± 0.10% I.D./g [P = 0.002] 6 h after injection). Values for (99m) Tc-ΒοΝΤ/Α radioactivity in the spinal cord were higher than those for free (99m) Tc, but not significantly. The bladder retained higher dosages of (99m) Tc-ΒοΝΤ/Α than free (99m) Tc at all time points. Significant accumulation of the radiolabelled toxin in the lumbosacral DRG, together with a less significant uptake in the respective spinal cord segment as opposed to free radioactivity provide first evidence of the retrograde transport of BoNT/A to the CNS after bladder injection in rats.


Vitamin B 6 -responsive histidine deficiency in mutants of Salmonella typhimurium.
A mutant of Salmonella typhimurium LT-2 that requires either vitamin B(6) or histidine for growth was found to synthesize vitamin B(5) in amounts comparable to the parent strain, but to be deficient in imidazoleacetol phosphate transaminase (L-histidinolphosphate: 2-oxoglutarate aminotransferase, EC 188.8.131.52), an enzyme required for histidine biosynthesis. The mutant apotransaminase required a 50-fold higher concentration of pyridoxal 5'-phosphate for half-maximum activation than the corresponding wild-type enzyme; the fully activated mutant enzyme also displays a much lower maximum rate of catalysis than the enzyme from the parent strain. Such mutational changes in bacteria resemble those in certain vitamin B(6)-responsive genetic diseases in man and provide useful experimental material for the study of factors involved in coenzyme binding and enzymatic catalysis.


Neurophobia among resident physicians in the emergency service.
Neurophobia is defined as the fear towards clinical neurology caused by the inability to apply theoretical knowledge to practical clinical situations. This phenomenon is not restricted to medical students and has never been studied before in the Emergency Department. We aimed to study how resident doctors perceive their knowledge in neurology and urgent neurological conditions as well as possible causes for said fears. Cross-sectional multicentric study using self-administered surveys sent to medical residents within the Aragon Health Service. They were questioned about their fear of neurology and other medical specialties, possible causes, and perception of knowledge in neurological pathologies and subareas in the emergency service. We obtained 134 responses. 27.6% (37) suffered from neurophobia. Despite neurology being considered the most difficult discipline, it did also arouse the third most interest among the students. The areas where they showed the most confidence were headaches and vascular pathology. The areas where they felt the most insecure were neuromuscular diseases, neuro-ophthalmology, and spinal cord injury. In none of the areas surveyed, the percentage of respondents who felt secure exceeded 50%. Neurophobia is prevalent among trainee doctors working in the emergency department. Their confidence correlates with the degree of exposure to patients. Neurologist must play an active role in the education of new specialist and promote the collaboration with emergency departments.


Rare transformation to double hit lymphoma in Waldenstrom's macroglobulinemia.
Waldenström macroglobulinemia (WM) is a lymphoproliferative lymphoma that is characterized by monoclonal immunoglobulin M (IgM) protein and bone marrow infiltration. Its incidence is rare and rarer still is its ability to transform to a B-cell lymphoma, particularly the aggressive diffuse large B-cell lymphoma, which bodes a poor prognosis. When transformation includes mutations of MYC, BCL-2 and/or BCL-6, it is known as a 'double hit' or 'triple hit' lymphoma respectively. This paper presents a rare case of WM with mutations positive for MYC and BCL2, making it a case of double hit B-cell lymphoplasmacytic lymphoma with plasmatic differentiation without morphological transformation to aggressive histology like DLBCL. The paper also broadens to include discussions on current topics in the classification, diagnosis, possible causes of transformation, and treatment of WM, including transformation to double hit lymphoma. The significance of this case lies in that the presence of double hit lymphoma-like genetic mutations in WM have not been previously described in the literature and potentially such changes are harbinger of extra-nodal presentation, aggressive growth, and possibly poor prognosis, if data from other double-hit lymphoma are extrapolated.


Epithelial mesenchymal transition regulator TWIST1 transcription factor stimulates glucose uptake through upregulation of GLUT1, GLUT3, and GLUT12 in vitro.
TWIST1 is a major regulator of epithelial mesenchymal transition process, essential in cancer metastasis. Cancer cells increase glucose uptake capabilities to meet their high energy requirements. In this study, we explored the potential role of TWIST1 on glucose transport into the 293T cells in an insulin-dependent and insulin-independent manner. For this purpose, the ectopic expression of TWIST1 was successfully performed by electroporation. The altered mRNA expressions of GLUT-1, -3, -4, and -12, insulin receptor (InsR), and insulin receptor substrate (IRS)-1 and -2 were assessed in control and TWIST1-overexpressing cells. Glucose uptake rates of the cells were evaluated by fluorometric glucose uptake assay. Our findings showed that the transcriptional expression levels of GLUT-1, -3, and -12 genes were significantly upregulated by TWIST1. However, TWIST1 did not alter the mRNA and protein expressions of the InsR, its substrates (IRS-1 and -2), and GLUT-4 genes in 293T cells which are main factors for insulin-stimulated glucose uptake pathway. Also, the glucose transport activities were significantly increased in TWIST1-overexpressing cells compared to controls due to fetal bovine serum (FBS) stimulation, but there was a slight non-significant difference in insulin stimulation. Thus, our data suggest that TWIST1 could promote glucose uptake independently of insulin and is possible to be evaluated as a metabolic marker in cancer. Further investigations are needed to clarify the precise molecular mechanisms underlying the cells' glucose uptake and consumption during tumorigenesis.


Mutantelec: An In Silico mutation simulation platform for comparative electrostatic potential profiling of proteins.
The electrostatic potential plays a key role in many biological processes like determining the affinity of a ligand to a given protein target, and they are responsible for the catalytic activity of many enzymes. Understanding the effect that amino acid mutations will have on the electrostatic potential of a protein, will allow a thorough understanding of which residues are the most important in a protein. MutantElec, is a friendly web application for in silico generation of site-directed mutagenesis of proteins and the comparison of electrostatic potential between the wild type protein and the mutant(s), based on the three-dimensional structure of the protein. The effect of the mutation is evaluated using different approach to the traditional surface map. MutantElec provides a graphical display of the results that allows the visualization of changes occurring at close distance from the mutation and thus uncovers the local and global impact of a specific change. © 2017 Wiley Periodicals, Inc.


Socioeconomic status and mental illness stigma: the impact of mental illness controllability attributions and personal responsibility judgments.
Prior research has suggested that higher levels of socioeconomic status (SES) may be linked with heightened mental illness stigma (MIS). It has been posited that this link is due to the resource-rich environment high-SES individuals live in, which predisposes them to seeing the certain phenomena as being more controllable in nature than low-SES individuals. The current study intended to address the attributional mechanisms behind the SES-MIS link. In a sample of 932 participants, we collected self-reported SES along with the controllability attributions and personal responsibility judgments participants make for individuals with mental illnesses. Analyses indicated that SES was significantly associated with greater MIS levels, and that this link was significantly mediated by controllability attributions and personal responsibility judgments. Findings suggest that high-SES individuals are more likely to see mental illness as due to internal, controllable factors, which leads to blaming the individual for mental illness onset and, ultimately, greater mental illness stigma. These results provide support for more socioeconomically diverse committees and panels where mental health funding decisions are made due to inherent attributional biases which may be present along the SES spectrum.


Quantitative assessment of procedural competence. A prospective study of training in endoscopic retrograde cholangiopancreatography.
Endoscopic retrograde cholangiopancreatography (ERCP) is a technically demanding procedure that can cause substantial complications. Competence in performing ERCP and the learning curve for achieving competence are poorly understood. To evaluate the number of supervised ERCPs that physicians must do to achieve procedural competence. Competence was defined as a 0.8 probability of successfully completing specific technical components of ERCP and an overall grading of competence as judged by the attending physician. Prospective study. University training program for gastroenterologists. 17 gastroenterology fellows at various stages of training. Experienced therapeutic endoscopists prospectively graded gastroenterology fellows during 1796 consecutive ERCPs. Fellows were graded on their overall level of competence for the procedure and on specific technical components of ERCP. Grading data were available for 1450 ERCPs (81%). The number of ERCPs done before adequate skill was achieved was 160 for cholangiography, 140 for pancreatography, 160 for deep cannulation of the pancreatic duct, 120 for stone extraction, and 60 for stent insertion. Fellows achieved overall competence after completing 180 to 200 ERCPs. The predicted probability of overall competence was 0.8 after 137 ERCPs and 0.9 after 185 ERCPs. At least 180 ERCPs were required before these gastroenterology fellows could be considered competent in ERCP. This number is much greater than that previously recommended, and these findings have substantial implications for training guidelines and issues of competence and certification in ERCP. The methods used to define and evaluate competence in ERCP could also be used to assess competence in other medical procedures.


Breaking the blue wall of silence: risk factors for experiencing police sexual misconduct among female offenders.
We assessed the prevalence of and risk factors for trading sex with a police officer among women recruited from drug courts in St Louis, Missouri. In 2005 to 2008, we recruited women into an HIV intervention study, which surveyed participants about multiple sociodemographic, lifestyle, and risk factors. Regression analyses assessed risk factors for trading sex, a form of police sexual misconduct (PSM). Of the 318 participants, 78 (25%) reported a lifetime history of PSM. Among women who experienced PSM, 96% had sex with an officer on duty, 77% had repeated exchanges, 31% reported rape by an officer, and 54% were offered favors by officers in exchange for sex; 87% said officers kept their promise. Only 51% of these respondents always used a condom with an officer. Multivariable models identified 4 or more arrests (adjusted odds ratio [AOR] = 2.8; 95% confidence interval [CI] = 1.29, 5.97), adult antisocial personality (AOR = 9.0; 95% CI = 2.08, 38.79), and lifetime comorbid cocaine and opiate use (AOR = 2.9 [1.62, 5.20]) as risk factors; employment (AOR = 0.4; 95% CI = 0.22, 0.77) lowered the risk of PSM. Community-based interventions are critical to reduce risk of abuse of vulnerable women by police officers charged with protecting communities.


New applications for the world's smallest high-precision capacitance dilatometer and its stress-implementing counterpart.
We introduce a new stress dilatometer with exactly the same size and mass as the world's smallest miniature capacitance dilatometer (height × width × depth = 15 × 14 × 15 mm3, mass: 12 g). To develop this new device, only a single part of the most recently developed mini-dilatometer, the so-called "body," needs to be replaced. Therefore, the new mini-dilatometer with an interchangeable body can be used for high-resolution measurements of thermal expansion and magnetostriction with and without large stress. We also report two novel applications of both mini-dilatometer cell types. Our new setup was installed for the first time in a cryogen-free system (PPMS DynaCool). The first new setup allows the rotation of both dilatometers in situ at any angle between -90° ≥ μ ≥ +90° in the temperature range from 320 to 1.8 K. We also installed our mini-cells in a dilution refrigerator insert of a PPMS DynaCool, in which dilatometric measurements are now possible in the temperature range from 4 to 0.06 K. Because of the limited sample space, such measurements could not be performed so far. For both new applications, we can resolve the impressive length changes to 0.01 Å.


CXCR2-Expressing Tumor Cells Drive Vascular Mimicry in Antiangiogenic Therapy-Resistant Glioblastoma.
Glioblastoma (GBM) was shown to relapse faster and displayed therapeutic resistance to antiangiogenic therapies (AATs) through an alternative tumor cell-driven mechanism of neovascularization called vascular mimicry (VM). We identified highly upregulated interleukin 8 (IL-8)-CXCR2 axis in tumor cells in high-grade human glioma and AAT-treated orthotopic GBM tumors. Human GBM tissue sections and tissue array were used to ascertain the clinical relevance of CXCR2-positive tumor cells in the formation of VM. We utilized U251 and U87 human tumor cells to understand VM in an orthotopic GBM model and AAT-mediated enhancement in VM was modeled using vatalanib (anti-VEGFR2) and avastin (anti-VEGF). Later, VM was inhibited by SB225002 (CXCR2 inhibitor) in a preclinical study. Overexpression of IL8 and CXCR2 in human datasets and histological analysis was identified as a bonafide candidate to validate VM through in vitro and animal model studies. AAT-treated tumors displayed a higher number of CXCR2-positive GBM-stem cells with endothelial-like phenotypes. Stable knockdown of CXCR2 expression in tumor cells led to decreased tumor growth as well as incomplete VM structures in the animal models. Similar data were obtained following SB225002 treatment. The present study suggests that tumor cell autonomous IL-8-CXCR2 pathway is instrumental in AAT-mediated resistance and VM formation in GBM. Therefore, CXCR2 can be targeted through SB225002 and can be combined with standard therapies to improve the therapeutic outcomes in clinical trials.


Effect of Active Surgical Co-Management by Medical Hospitalists in Urology Inpatient Care: A Retrospective Cohort Study.
This study aimed to evaluate the use of active surgical co-management (SCM) by medical hospitalists for urology inpatient care. Since March 2019, a hospitalist-SCM program was implemented at a tertiary-care medical center, and a retrospective cohort study was conducted among co-managed urology inpatients. We assessed the clinical outcomes of urology inpatients who received SCM and compared passive SCM (co-management of patients by hospitalists only on request; March 2019 to June 2020) with active SCM (co-management of patients based on active screening by hospitalists; July 2020 to October 2021). We also evaluated the perceptions of patients who received SCM toward inpatient care quality, safety, and subjective satisfaction with inpatient care at discharge or when transferred to other wards. We assessed 525 patients. Compared with the passive SCM group (n=205), patients in the active SCM group (n=320) required co-management for a significantly shorter duration (p=0.012) and tended to have a shorter length of stay at the urology ward (p=0.062) and less frequent unplanned readmissions within 30 days of discharge (p=0.095) while triggering significantly fewer events of rapid response team activation (p=0.002). No differences were found in the proportion of patients transferred to the intensive care unit, in-hospital mortality rates, or inpatient care questionnaire scores. Active surveillance and co-management of urology inpatients by medical hospitalists can improve the quality and efficacy of inpatient care without compromising subjective inpatient satisfaction.


Preservation of hatchery waste by lactic acid fermentation. 2. Large-scale fermentation and feeding trial to evaluate feeding value.
Two waste streams from a Leghorn hatchery were preserved and recycled by fermentation with a by-product carbohydrate and extrusion processing into new feed ingredients that were evaluated with broiler chickens. Cockerel chicks (CC) and a 60:40 ratio of CC:shell waste (CC:SW) were fermented in 189-L barrels for 21 d following grinding, then mixing with a liquid culture (0.2%) and carbohydrate source at 15 and 16.66%, respectively. At 2 wk, pH was 4.44 and 5.09 for the CC and CC:SW products compared with higher values of 6.54 and 6.98 for the raw ingredients at the onset. Negligible hydrogen sulfide and no ammonia gas were recorded during the fermentation period. At 21 d, the fermented CC and CC:SW were extruded, dried, and ground to meals containing CP and TMEn levels of 47.4%, 3,187 kcal/kg, and 33.1%, 2,696 kcal/kg, respectively. Broiler chickens were fed a control diet and the CC (5 and 10%) and CC:SW (2.5 and 5%) ingredient diets with corn and soybean meal for 6 wk to evaluate feeding value and carcass yield. Body weight, gain and feed conversion at 42 d for birds fed diets supplemented with CC or CC:SW at all levels were comparable to those of the control. Diets supplemented with hatchery by-product had no negative effect on carcass measurements except ready to cook carcass and wing yield, which were significantly greater for the 10% CC:SW birds than for the control. These data indicate that nutrient dense hatchery by-products can be preserved with fermentation up to 21 d and support broiler live performance and carcass yield as dietary ingredients equal to or better than a corn-soybean meal control.


The first metal-rich binary chalcogenides of the lanthanides: Dy(2)Te and Gd(2)Te.
Two new tellurides have been synthesized in Ta with particular attention to the use of finely divided Dy (Gd) and a sequence of reactive sintering reactions of pressed pellets up to approximately 1060 degrees C. Both phases disproportionate to Ln and LnTe at only slightly higher temperatures so that arc-melting procedures are relatively unproductive. The two compounds crystallize with a Sc(2)Te-type structure. Single-crystal X-ray diffraction results for Dy(2)Te were detailed in the orthorhombic space group Pnma (No. 62), Z =12, a = 21.922(4) A, b = 4.0650(6) A, and c = 11.428(2) A (Guinier data). There is good evidence for the existence of additional metal-rich binary chalcogenides of the heavy lanthanides. Extended Hückel calculations were performed within the tight binding approximation to aid the understanding of the metal-metal bonding in this system. In terms of metal-metal overlap populations, the isotypic Sc(2)Te is more 1D in aggregation, while the larger atoms and orbitals and stronger bonding in Dy(2)Te make it somewhat more 3D. Electrical resistivity and magnetic susceptibility measurements on polycrystalline Dy(2)Te indicate it is metallic and ferromagnetic (T(c)= 161.3 K) with an effective moment at higher temperatures close to that of ground-state Dy(3+). The connections between heavy lanthanide-rich chalcogenide chemistry and that of the early transition metals seem significant.


The nucleotide sequence of Saccharomyces cerevisiae chromosome IV.
The complete DNA sequence of the yeast Saccharomyces cerevisiae chromosome IV has been determined. Apart from chromosome XII, which contains the 1-2 Mb rDNA cluster, chromosome IV is the longest S. cerevisiae chromosome. It was split into three parts, which were sequenced by a consortium from the European Community, the Sanger Centre, and groups from St Louis and Stanford in the United States. The sequence of 1,531,974 base pairs contains 796 predicted or known genes, 318 (39.9%) of which have been previously identified. Of the 478 new genes, 225 (28.3%) are homologous to previously identified genes and 253 (32%) have unknown functions or correspond to spurious open reading frames (ORFs). On average there is one gene approximately every two kilobases. Superimposed on alternating regional variations in G+C composition, there is a large central domain with a lower G+C content that contains all the yeast transposon (Ty) elements and most of the tRNA genes. Chromosome IV shares with chromosomes II, V, XII, XIII and XV some long clustered duplications which partly explain its origin.


Can immediate second resection be an alternative to standardized second transurethral resection of bladder tumors?
This study analyzed the impact of an immediate second transurethral resection of bladder tumor (TURBT) protocol on residual tumor status at the initial TURBT session and the recurrence rate in the primary resection area. We prospectively evaluated and randomized 47 consecutive patients who underwent TURBT sessions for bladder cancer. In accordance with the inclusion criteria, of the 47 consecutive patients, 19 (Group I) underwent immediate second resection of the tumor bed after complete TUR and 28 (Group II) did not. After standard TURBT, Group I underwent a second cystoscopy and resection of the bed of the tumor or an ignored tumor, which was performed by a different urologist. After 4-6 weeks, delayed second TURB was performed, and all pathological results were evaluated. Tumors were detected in two patients during the immediate second resection. Of these, one was a misdiagnosed tumor, whereas the other was diagnosed at the bed of the tumor by pathological examination. Tumors were detected in nine patients at the delayed second TURB, of which only one was part of Group I, while the others were part of Group II (p = 0.04). The results of this study demonstrated that residual tumors may remain after initial TURB, either in the tumor bed or in a different location within the bladder. Although this was a pilot study enrolling only a small number of patients, our initial results supported the assertion that immediate second resection can be an alternative to standard second TURBT.


Targeted Nanotechnology in Glioblastoma Multiforme.
Gliomas, and in particular glioblastoma multiforme, are aggressive brain tumors characterized by a poor prognosis and high rates of recurrence. Current treatment strategies are based on open surgery, chemotherapy (temozolomide) and radiotherapy. However, none of these treatments, alone or in combination, are considered effective in managing this devastating disease, resulting in a median survival time of less than 15 months. The efficiency of chemotherapy is mainly compromised by the blood-brain barrier (BBB) that selectively inhibits drugs from infiltrating into the tumor mass. Cancer stem cells (CSCs), with their unique biology and their resistance to both radio- and chemotherapy, compound tumor aggressiveness and increase the chances of treatment failure. Therefore, more effective targeted therapeutic regimens are urgently required. In this article, some well-recognized biological features and biomarkers of this specific subgroup of tumor cells are profiled and new strategies and technologies in nanomedicine that explicitly target CSCs, after circumventing the BBB, are detailed. Major achievements in the development of nanotherapies, such as organic poly(propylene glycol) and poly(ethylene glycol) or inorganic (iron and gold) nanoparticles that can be conjugated to metal ions, liposomes, dendrimers and polymeric micelles, form the main scope of this summary. Moreover, novel biological strategies focused on manipulating gene expression (small interfering RNA and clustered regularly interspaced short palindromic repeats [CRISPR]/CRISPR associated protein 9 [Cas 9] technologies) for cancer therapy are also analyzed. The aim of this review is to analyze the gap between CSC biology and the development of targeted therapies. A better understanding of CSC properties could result in the development of precise nanotherapies to fulfill unmet clinical needs.


Metal uptake in a peri-urban Lactuca sativa cultivated area.
In this study, two Lactuca sativa crops grown in a net-protected site and an unprotected site were compared. The results showed metals were accumulated by Lactuca sativa. Higher metal accumulation in lettuce grown in the unprotected parcel was established, and the only significant differences in their physicochemical properties were cation exchange capacity and exposure to sunlight. Exposure to the sun may translate into higher soil-plant flux of water and/or higher decomposition rate of organic matter, which may augment the mobilization of metals into the plant, and therefore lead to higher noxious metal accumulation on the crops. Also, EDTA was explored as a possible extractant that could predict the bioavailablity of metals to the lettuce. Our results did not show a good agreement between the metal transferred from soil to leaves and the EDTA extracted metals, although some tendencies were found for the metal transfer from soil to roots. It is predicted that many developing countries will continue and/or increase the use of waste water for the irrigation of crops despite the health risks. Different solutions have been explored to diminish the availability of the metals in the soils. Our study shows that an action as simple as placing a net over the parcel could help diminish the accumulation of metals into the crops of a rapidly expanding peri-urban agricultural system.