Attenuation of morphine withdrawal syndrome by various dosages of curcumin in comparison with clonidine in mouse: possible mechanism.
Herbal medical compounds and their major constituent have been used in the management and treatment of opioid withdrawal syndrome and pain. This study was carried out to clarify the effect of curcumin, the major compound of turmeric, on morphine withdrawal syndrome in mouse model and its possible mechanisms of pain relieving activity by assessing in writhing test as a model of visceral pain. Due to two separate protocols (withdrawal syndrome and pain), 144 male albino mice were divided in two major groups. In withdrawal syndrome group, test effect of various dosages of curcumin (10, 20, and 40 mg/kg) was assessed on withdrawal signs and compared with positive and negative control and standard treatment (clonidine 0.4 mg/kg) groups. In pain groups, to determine the mechanism of pain relieving activity of curcumin, various dosages of curcumin (10, 20, and 40 mg/kg) in three separated groups, were used against acetic acid induced writhing (which is a constriction) test. The most effective dose (40 mg/kg) was used in writhing test and compared with groups pretreated with antagonist of major neurotransmitters involved in pain; and compared with group pretreated with vehicle (DMSO, 0.05%) as control. Curcumin attenuates withdrawal syndrome in a dose dependent manner in comparison with the dependent positive control group (P<0.05). It also indicated that pretreatment with naloxone and cyproheptadine significantly attenuate antinociception effect of curcumin (P<0.05). This study advocate that antinociception of curcumin was mediated by opioidergic and adrenergic system.


Outcomes in work-related injuries: a comparison of older and younger workers.
The "graying of the workforce" has generated concerns about the physical capacity of older workers to maintain their health and productivity on the job, especially after an injury occurs. There is little detailed research on age-related differences in work outcomes after an occupational injury. A self-report survey about occupational, health, and financial outcomes, and related factors was administered 2-8 weeks post-injury to workers aged < 55 and > or = 55 who had lost time due to a work injury. Despite more severe injuries in older workers, most outcomes were similar in both age groups. In multivariate models, age was unrelated or inversely related to poor outcomes. Injury severity, physical functioning, and problems upon return to work were associated with adverse work injury outcomes. Older workers appear to fare better than younger workers after a work injury; their relative advantage may be primarily due to longer workplace attachment and the healthy worker effect.


Use of an electronic barcode system for patient identification during blood transfusion: 3-year experience in a regional hospital.
To evaluate the use of an electronic barcode system for patient identification during blood transfusion. Retrospective study. Regional hospital, Hong Kong. For all patients requiring blood transfusion between May 1999 and April 2002, with the exception of patients in the psychiatric wards and the accident and emergency department, a portable, hand-held scan-and-print electronic device was used to verify and document patients' identity at two critical points of transfusion: blood sampling for the compatibility test and blood administration. Scope of use of the electronic device, cost, effectiveness, staff compliance, problems and solution for improvement. In the first 3 years of hospital-wide use of the new device, no incidents of blood transfusion to wrong patients, or wrong labelling of blood samples, occurred with 41,00 blood sampling procedures and administration of 27 000 units of blood. Blood sampling took 6 minutes to complete with the use of the electronic device-similar to that taken by the conventional second-checker system. Among hospital staff, the compliance rate of using the new device approached 90%. Battery problems occurred in 12% of episodes of use of the device. The electronic barcode system was effective in reducing human error related to bedside transfusion procedures. The future goal is to tailor-make a more efficient device with additional functions.


Perceptions of Provider Communication Among Vulnerable Patients With Diabetes: Influences of Medical Mistrust and Health Literacy.
Patient-provider communication is modifiable and is linked to diabetes outcomes. The association of communication quality with medical mistrust is unknown. We examined these factors within the context of a low-literacy/numeracy-focused intervention to improve diabetes care, using baseline data from diverse patients enrolled in a randomized trial of a health communication intervention. Demographics, measures of health communication (Communication Assessment Tool [CAT], Interpersonal Processes of Care survey [IPC-18]), health literacy (Short Test of Functional Health Literacy in Adults), depression, medical mistrust, and glycemic control were ascertained. Adjusted proportional odds models were used to test the association of mistrust with patient-reported communication quality. The interaction effect of health literacy on mistrust and communication quality was also assessed. A total of 410 patients were analyzed. High levels of mistrust were observed. In multivariable modeling, patients with higher mistrust had lower adjusted odds of reporting a higher CAT score (adjusted odds ratio [AOR] = 0.67, 95% confidence interval [CI] [0.52, 0.86], p = .003) and higher scores on the Communication (AOR = 0.69, 95% CI [0.55, 0.88], p = .008), Decided Together (AOR = 0.74, 95% CI [0.59, 0.93], p = .02), and Interpersonal Style (AOR = 0.69, 95% CI [0.53, 0.90], p = .015) subscales of the IPC-18. We observed evidence of an interaction effect of health literacy for the association between mistrust and the Decided Together subscale of the IPC-18 such that patients with higher mistrust and lower literacy perceived worse communication relative to mistrustful patients with higher literacy. In conclusion, medical mistrust was associated with poorer communication with providers in this public health setting. Patients' health literacy level may vary the effect of mistrust on interactional aspects of communication. Providers should consider the impact of mistrust on communication with vulnerable diabetes populations and focus efforts on mitigating its influence.


A novel SNP analysis method to detect copy number alterations with an unbiased reference signal directly from tumor samples.
Genomic instability in cancer leads to abnormal genome copy number alterations (CNA) as a mechanism underlying tumorigenesis. Using microarrays and other technologies, tumor CNA are detected by comparing tumor sample CN to normal reference sample CN. While advances in microarray technology have improved detection of copy number alterations, the increase in the number of measured signals, noise from array probes, variations in signal-to-noise ratio across batches and disparity across laboratories leads to significant limitations for the accurate identification of CNA regions when comparing tumor and normal samples. To address these limitations, we designed a novel "Virtual Normal" algorithm (VN), which allowed for construction of an unbiased reference signal directly from test samples within an experiment using any publicly available normal reference set as a baseline thus eliminating the need for an in-lab normal reference set. The algorithm was tested using an optimal, paired tumor/normal data set as well as previously uncharacterized pediatric malignant gliomas for which a normal reference set was not available. Using Affymetrix 250K Sty microarrays, we demonstrated improved signal-to-noise ratio and detected significant copy number alterations using the VN algorithm that were validated by independent PCR analysis of the target CNA regions. We developed and validated an algorithm to provide a virtual normal reference signal directly from tumor samples and minimize noise in the derivation of the raw CN signal. The algorithm reduces the variability of assays performed across different reagent and array batches, methods of sample preservation, multiple personnel, and among different laboratories. This approach may be valuable when matched normal samples are unavailable or the paired normal specimens have been subjected to variations in methods of preservation.


The post-orgasmic prolactin increase following intercourse is greater than following masturbation and suggests greater satiety.
Research indicates that prolactin increases following orgasm are involved in a feedback loop that serves to decrease arousal through inhibitory central dopaminergic and probably peripheral processes. The magnitude of post-orgasmic prolactin increase is thus a neurohormonal index of sexual satiety. Using data from three studies of men and women engaging in masturbation or penile-vaginal intercourse to orgasm in the laboratory, we report that for both sexes (adjusted for prolactin changes in a non-sexual control condition), the magnitude of prolactin increase following intercourse is 400% greater than that following masturbation. The results are interpreted as an indication of intercourse being more physiologically satisfying than masturbation, and discussed in light of prior research reporting greater physiological and psychological benefits associated with coitus than with any other sexual activities.


Implementing reusable software components for SNOMED CT diagram and expression concept representations.
SNOMED CT is a vital component in the future of semantic interoperability in healthcare as it provides the meaning to EHRs via its semantically rich, controlled terminology. Communicating the concepts of this terminology to both humans and machines is crucial therefore formal guidelines for diagram and expression representations have been developed by the curators of SNOMED CT. This paper presents a novel, model-based approach to implementing these guidelines that allows simultaneous editing of a concept via both diagram and expression editors. The implemented extensible software component can be embedded both both desktop and web applications.


Sensitization of capsaicin-sensitive lung vagal afferents by anandamide in rats: role of transient receptor potential vanilloid 1 receptors.
Anandamide (AEA), an arachidonic acid derivative produced during inflammatory conditions, is an endogenous agonist of both transient receptor potential vanilloid 1 (TRPV1) receptors and cannabinoid CB1 receptors. Sensitization of capsaicin-sensitive lung vagal afferent (CSLVA) fibers by chemical mediators is important in the pathogenesis of hyperreactive airway diseases. We investigated the effect of the intravenous infusion of AEA (2 mg x kg(-1) x ml(-1), 0.5 ml/min for 2 min) on the sensitivity of CSLVA fibers to chemical and mechanical stimulation in anesthetized rats. In artificially ventilated rats, AEA infusion only mildly elevated the baseline activity of CSLVA fibers. However, CSLVA fiber responses to right atrial injection of capsaicin, AEA, or adenosine and to lung inflation (tracheal pressure = 30 cmH(2)O) were all markedly potentiated during AEA infusion, which reverted 20 min after termination of the infusion. The potentiating effect on the sensitivity of CSLVA fibers to adenosine injection or lung inflation was completely blocked by pretreatment with capsazepine (a TRPV1 receptor antagonist) but was unaffected by pretreatment with AM281 (a CB1 receptor antagonist). In spontaneously breathing rats, right atrial injection of adenosine evoked an apneic response that is presumably mediated through CSLVA fibers. Similarly, the adenosine-evoked apneic response was potentiated during AEA infusion, and this potentiating effect was also completely prevented by pretreatment with capsazepine. These results suggest that AEA infusion at the dose tested produces a mild activation of TRPV1 receptors and this nonspecifically increases CSLVA fiber sensitivity to chemical and mechanical stimulation.


Decreased Amino Acid Concentrations are Involved in Congenital Heart Disease.
Congenital heart disease (CHD) is the most common malformation in China. In this study, we determined whether amino acids (AAs) in the amniotic fluid (AF) of patients with CHD changed and clarified whether AAs would affect the insulin-like growth factor type 1 receptor (IGF1R). Fifty-seven AF samples from pregnant women carrying CHD-affected (n = 17) or normal (n = 40) fetuses were collected. The AA concentrations were measured in AF by liquid chromatography-tandem mass spectrometry. The IGF axis-related and epigenetic marker proteins in AF after serial treatments were quantified using a multiple reaction monitoring approach. IGF1R and P300 were also confirmed by Western blot in AF without any treatment. Most AAs decreased in the AF of patients with CHD. P300 and IGF1R decreased significantly in the CHD group. When H9C2 cells were cultured in one-half AA concentrations, the expression of P300 and IGF1R was reduced. Histone acetylation of the IGF1R promoter also decreased. Our data suggest that AAs decreased in the AF of patients with CHD. AAs may partly regulate the IGF1R through P300, which may be involved in heart development.


Cross-Domain Recognition by Identifying Joint Subspaces of Source Domain and Target Domain.
This paper introduces a new method to solve the cross-domain recognition problem. Different from the traditional domain adaption methods which rely on a global domain shift for all classes between the source and target domains, the proposed method is more flexible to capture individual class variations across domains. By adopting a natural and widely used assumption that the data samples from the same class should lay on an intrinsic low-dimensional subspace, even if they come from different domains, the proposed method circumvents the limitation of the global domain shift, and solves the cross-domain recognition by finding the joint subspaces of the source and target domains. Specifically, given labeled samples in the source domain, we construct a subspace for each of the classes. Then we construct subspaces in the target domain, called anchor subspaces, by collecting unlabeled samples that are close to each other and are highly likely to belong to the same class. The corresponding class label is then assigned by minimizing a cost function which reflects the overlap and topological structure consistency between subspaces across the source and target domains, and within the anchor subspaces, respectively. We further combine the anchor subspaces to the corresponding source subspaces to construct the joint subspaces. Subsequently, one-versus-rest support vector machine classifiers are trained using the data samples belonging to the same joint subspaces and applied to unlabeled data in the target domain. We evaluate the proposed method on two widely used datasets: 1) object recognition dataset for computer vision tasks and 2) sentiment classification dataset for natural language processing tasks. Comparison results demonstrate that the proposed method outperforms the comparison methods on both datasets.


Dependability modeling and assessment in UML-based software development.
Assessment of software nonfunctional properties (NFP) is an important problem in software development. In the context of model-driven development, an emerging approach for the analysis of different NFPs consists of the following steps: (a) to extend the software models with annotations describing the NFP of interest; (b) to transform automatically the annotated software model to the formalism chosen for NFP analysis; (c) to analyze the formal model using existing solvers; (d) to assess the software based on the results and give feedback to designers. Such a modeling→analysis→assessment approach can be applied to any software modeling language, be it general purpose or domain specific. In this paper, we focus on UML-based development and on the dependability NFP, which encompasses reliability, availability, safety, integrity, and maintainability. The paper presents the profile used to extend UML with dependability information, the model transformation to generate a DSPN formal model, and the assessment of the system properties based on the DSPN results.


Anisotropic cascade of field-induced phase transitions in the frustrated spin-ladder system BiCu2PO6.
BiCu(2)PO(6) is a frustrated two-leg spin-ladder compound with a spin gap that can be closed with a magnetic field of approximately 20 T. This quantum phase transition and its related phase diagram as a function of magnetic field and temperature (H, T) are investigated up to 60 T by means of specific heat, magnetocaloric effect, magnetization, and magnetostriction measurements. In contrast to other gapped quantum magnets, BiCu(2)PO(6) undergoes a series of unexpected first- and second-order phase transitions when an external magnetic field is applied along the crystallographic c axis. The application of a magnetic field along the b axis induces two second-order phase transitions. We propose that the anisotropy and complex phase diagram result from the interplay between strong geometrical frustration and spin-orbit interaction necessary for the description of this fascinating magnetic system.


Cysteine mutagenesis reveals novel structure-function features within the predicted third extracellular loop of the type IIa Na(+)/P(i) cotransporter.
The transport function of the rat type IIa Na(+)/P(i) cotransporter is inhibited after binding the cysteine modifying reagent 2-aminoethyl methanethiosulfonate hydrobromide (MTSEA) to a cysteine residue substituted for a serine at position 460 (S460C) in the predicted third extracellular loop. This suggests that Ser-460 lies in a functionally important region of the protein. To establish a "structure-function" profile for the regions that flank Ser-460, the substituted cysteine accessibility method was employed. 18 mutants were constructed in which selected amino acids from Arg-437 through Leu-465 were substituted one by one for a cysteine. Mutants were expressed in Xenopus oocytes and transport function (cotransport and slippage) and kinetics were assayed by electrophysiology with or without prior treatment with cysteine modifying (methanethiosulfonate, MTS) reagents. Except for mutant I447C, mutants with cysteines at sites from Arg-437 through Thr-449, as well as Pro-461, were inactive. Cotransport function of mutants with Cys substitutions at sites Arg-462 through Leu-465 showed low sensitivity to MTS reagents. The preceding mutants (Cys substitution at Thr-451 to Ser-460) showed a periodic accessibility pattern that would be expected for an alpha-helix motif. Apart from loss of transport function, exposure of mutants A453C and A455C to MTSEA or 2-(triethylammonium)ethyl MTS bromide (MTSET) increased the uncoupled slippage current, which implicated the mutated sites in the leak pathway. Mutants from Ala-453 through Ala-459 showed less pH dependency, but generally stronger voltage dependency compared with the wild type, whereas those flanking this group were more sensitive to pH and showed weaker voltage dependence of cotransport mode kinetics. Our data indicate that parts of the third extracellular loop are involved in the translocation of the fully loaded carrier and show a membrane-associated alpha-helical structure.


Whole grain intake and cardiovascular disease: a review.
Prospective epidemiologic and feeding studies find possible health benefits of whole cereal grain foods (which include the bran, germ, and endosperm in their naturally occurring proportions), especially for prevention of atherosclerotic cardiovascular diseases and type 2 diabetes. We review 17 articles that consistently found a 20% to 40% reduction in long-term risk of these diseases comparing habitual consumers of whole grains to those who rarely eat these foods. Another 12 studies found a similar risk reduction according to amount of cereal fiber consumed. Feeding studies show improvements in risk factors for these diseases when whole grain foods are consumed. Some authors have tried to explain the reduced risk by invoking cereal fiber, with no attention to nonfiber constituents. We interpret the data as supportive of a synergy of the whole grain constituents, including fiber as only one such constituent.


Alexander Technique Lessons, Acupuncture Sessions or usual care for patients with chronic neck pain (ATLAS): study protocol for a randomised controlled trial.
Chronic neck pain is a common condition in the adult population. More research is needed to evaluate interventions aiming to facilitate beneficial long-term change. We propose to evaluate the effect of Alexander Technique lessons and acupuncture in a rigorously conducted pragmatic trial with an embedded qualitative study. We will recruit 500 patients who have been diagnosed with neck pain in primary care, who have continued to experience neck pain for at least three months with 28% minimum cut-off score on the Northwick Park Neck Pain Questionnaire (NPQ). We will exclude patients with serious underlying pathology, prior cervical spine surgery, history of psychosis, rheumatoid arthritis, ankylosing spondylitis, osteoporosis, haemophilia, cancer, HIV or hepatitis, or with alcohol or drug dependency currently or in the last 12 months, or actively pursuing compensation or with pending litigation.The York Trials Unit will randomly allocate participants using a secure computer-based system. We will use block randomisation with allocation to each intervention arm being unambiguously concealed from anyone who might subvert the randomisation process.Participants will be randomised in equal proportions to Alexander Technique lessons, acupuncture or usual care alone. Twenty 30-minute Alexander Technique lessons will be provided by teachers registered with the Society of Teachers of the Alexander Technique and twelve 50-minute sessions of acupuncture will be provided by acupuncturists registered with the British Acupuncture Council. All participants will continue to receive usual GP care.The primary outcome will be the NPQ at 12 months, with the secondary time point at 6 months, and an area-under-curve analysis will include 3, 6 and 12 month time-points. Adverse events will be documented. Potential intervention effect modifiers and mediators to be explored include: self-efficacy, stress management, and the incorporation of practitioner advice about self-care and lifestyle. Qualitative material will be used to address issues of safety, acceptability and factors that impact on longer term outcomes. This study will provide robust evidence on whether there are significant clinical benefits to patients, economic benefits demonstrating value for money, and sufficient levels of acceptability and safety. Current Controlled Trials ISRCTN15186354.


An evaluation of the inhibitory effects against rotavirus infection of edible plant extracts.
Rotaviruses are the single most important cause of severe diarrhea in young children worldwide. The developments of specific, potent and accessible antiviral treatments that restrain rotavirus infection remain important to control rotavirus disease. 150 plant extracts with nutritional applications were screened in vitro on MA-104 cells for their antiviral activity against rhesus rotavirus (RRV). One extract (Aspalathus linearis (Burm.f.) R.Dahlgren) was also tested for its effect on the loss of transepithelial resistance (TER) of Caco-2 cells caused by simian rotavirus (SA-11) infection. Aqueous extracts of Nelumbo nucifera Gaertn. fruit, Urtica dioica L. root, Aspalathus linearis (Burm.f.) R.Dahlgren leaves, Glycyrrhiza glabra L. root and Olea europaea L. leaves were found to have strong significant antiviral activity with a 50% inhibitory concentration (IC50) < 300 μg/ml. The pure compound 18ß-glycyrrhetinic acid from Glycyrrhiza glabra was found to have the strongest antiviral activity (IC50 46 μM), followed by luteolin and vitexin from Aspalathus linearis (IC50 respectively 116 μM and 129 μM) and apigenin-7-O-glucoside from Melissa officinalis (IC50 150 μM). A combination of Glycyrrhiza glabra L. + Nelumbo nucifera Gaertn. and Urtica dioica L. + Nelumbo nucifera Gaertn. showed synergy in their anti-viral activities. Aspalathus linearis (Burm.f.) R.Dahlgren showed no positive effect on the maintenance of the TER. These results indicate that nutritional intervention with extracts of Nelumbo nucifera Gaertn., Aspalathus linearis (Burm.f.) R.Dahlgren, Urtica dioica L., Glycyrrhiza glabra L. and Olea europaea L. might be useful in the treatment of diarrhea caused by rotavirus infection.


Design, synthesis and biological study of hybrid drug candidates of nitric oxide releasing cucurbitacin-inspired estrone analogs for treatment of hepatocellular carcinoma.
Development of hybrid drug candidates is well known strategy for designing antitumor agents. Herein, a novel class of nitric oxide donating cucurbitacin inspired estrone analogs (NO-CIEAs) were designed and synthesized as multitarget agents. Synthesized analogs were initially evaluated for their anti-hepatocellular carcinoma activities. Among the tested analogs, NO-CIEAs 17 and 20a exhibited more potent activity against HepG2 cells (IC50 = 4.69 and 12.5 µM, respectively) than the reference drug Erlotinib (IC50 = 25 µM). Interestingly, NO-CIEA 17 exerted also a high potent activity against Erlotinib-resistant HepG2 cell line (HepG2-R) (IC50 = 8.21 µM) giving insight about its importance in drug resistance therapy. Intracellular measurements of NO revealed that NO-CIEAs 17 and 20a showed a significant increase in NO production in tumor cells after 1 h of incubation comparable to the reference prodrug JS-K. Flow cytometric analysis showed that both NO-CIEAs 17 and 20a mainly arrested the HepG2 cells in the G0/G1 phase. Also, In-Cell Based ELISA screening showed that NO-CIEA 17 resulted in a potential inhibitory activity towards the EGFR and MAPK (25% and 29% inhibition compared to untreated control cells, respectively). This data suggests the binding ability of NO-CIEA 17 to the EGFR and ERK to be well correlated along with the docking and cellular studies. Also, treatment of HepG2-R cells with NO-CIEA 17 showed a potential reduction of MRP2 expression in a dose dependent manner providing a significant impact on the chemotherapeutic resistance. Overall, the current study provides a potential new approach for the discovery of a novel antitumor agent against HCC.


The development and standardization of the Children Activity Scales (ChAS-P/T) for the early identification of children with Developmental Coordination Disorders.
Previous studies have emphasized the importance of early identification of children with Developmental Coordination Disorder (DCD) to prevent the development of secondary academic, emotional and social manifestations of the disorder. The aim of this study was to develop a valid parent and teacher questionnaire--the Children Activity Scales for parents (ChAS-P) and for teachers (ChAS-T)--to identify children aged 4-8 years at risk for DCD and to examine the reliability and validity of these questionnaires. The questionnaires' content and face validity were established, and then cut-off scores were determined based on responses of 355 teachers and 216 parents. Internal consistencies were also calculated. Factor analyses were performed, and construct validity was determined by examining the questionnaires' ability to discriminate between 30 children aged 5-6.5 years diagnosed with DCD and 30 typically developing children. Concurrent validity was examined by comparing questionnaire scores with those of the Movement Assessment Battery for Children (M-ABC). High values were obtained for internal consistency (0.96-0.94) for the ChAS-T and the ChAS-P respectively. Factor analysis revealed four distinct factors within the ChAS-P and three within the ChAS-T, reinforcing the theoretical validity of the items selected and appropriateness for identifying DCD. Construct validity was indicated by finding significant differences between the groups' scores on the ChAS-T and the ChAS-P. Significant correlations between the children's scores on the questionnaires and those of the M-ABC confirmed their concurrent validity. Initial results suggest that the ChAS-T and Chas-P are reliable tools to identify children at risk for DCD.


Randomized controlled pilot study of 2 weeks' treatment with high cutoff membrane for hemodialysis patients with elevated C-reactive protein.
Chronic inflammation in hemodialysis (HD) patients is associated with cardiovascular complications and mortality. Circulating immune active proteins in the molecular range 15-45 kD that cannot be efficiently cleared by high-flux (HF) dialysis may be causally involved. We intended to test the feasibility of using a high cutoff (HCO) dialyzer in chronic HD patients and its influence on inflammation and monocyte activation. The Gambro HCO1100 dialyzer was compared to a conventional HF membrane in a randomized double-blind crossover trial in 19 chronic HD patients selected for the presence of elevated serum C-reactive protein levels. Patients were treated for six consecutive dialysis sessions (2 weeks) with each membrane. Safety analysis recorded adverse events and albumin losses through the protein-leaking membranes. Efficacy analysis observed reductions in the number of proinflammatory (CD14+CD16+) monocyte subpopulations in circulating blood. Treatment with the HCO membrane was well tolerated, although the number of adverse events was slightly higher. Despite significant serum albumin loss (from 34.1 ± 2.7 to 29.6 ± 3.0 g/L; P < 0.01), there was no need to supplement albumin, and rising activity of cholinesterase during HCO treatment indicated compensation by enhanced hepatic synthesis. The HCO membrane cleared high amounts of proinflammatory cytokines, but did not reduce predialysis inflammatory monocytes and markers. Although the time of HD session was extended, the study was hampered by a lower Kt/V in the HCO compared to the HF period. Treatment of chronic HD patients with this HCO dialyzer for 2 weeks is tolerable in terms of albumin loss and able to clear proinflammatory cytokines; however, this was not sufficient to decrease monocyte activation. Therefore, a more selective, less albumin-leaking membrane is desirable to allow prolonged high-efficient dialysis with more effective cytokine clearance.


Distribution of maternal immunoglobulins in the mouse uterus and embryo in the days after implantation.
The distribution of maternal immunoglobulins in the mouse uterus and embryo in the days after implantation has been studied on sections incubated with sheep Fab anti-mouse immunoglobulins labeled with peroxidase. At the time of implantation the blastocyst is already surrounded by immunoglobulins that are also present in the blastocoel and early endoderm; uterine glands contain large amounts of immunoglobulins. Later, immunoglobulins are concentrated in the vacuolated endoderm, then the visceral yolk sac and the embryonic gut. They are also present in the various cavities of the embryo. Trophoblast cells progressively contain increasing amounts of immunoglobulins. In the decidua, immunoglobulins coat the cells and also occasionally appear as cytoplasmic granules. The early presence of maternal immunoglobulins may represent the transfer of serum proteins as a means of nutrition for the embryo. It is also very likely to have an immunological significance in the protection of the embryo.


A systematic review of psychological therapies for nonulcer dyspepsia.
We conducted a systematic review to determine the effectiveness of psychological interventions including psychodrama, cognitive behavioral therapy, relaxation therapy, guided imagery, or hypnosis in the improvement of dyspepsia symptoms in patients with nonulcer dyspepsia (NUD). Trials were identified through electronic searches of the Cochrane Controlled Trials Register (CCTR), MEDLINE, EMBASE, CINAHL, and PsycLIT, using appropriate subject headings and text words and searching bibliographies of retrieved articles. All randomized controlled trials (RCTs) or quasi-randomized studies were eligible. The four eligible trials all used different psychological interventions including applied relaxation therapy, psychodynamic psychotherapy, cognitive therapy, and hypnotherapy. Trials did not present data in a form that could be synthesized. All reported an improvement in the dyspepsia symptom scores at the end of treatment and at 1 yr in the intervention arm compared with controls. All studies only achieved statistically significant results through adjusting for baseline differences between groups. This reflects the small sample sizes of the trials. There were also problems with assumptions made in the statistical analyses used to achieve statistical significance. The studies highlighted problems with recruitment and compliance. There was insufficient evidence on the efficacy of psychological therapies in NUD. This emphasizes the need for appropriately powered well-designed trials in this area.


Citeromyces siamensis sp. nov., a novel halotolerant yeast isolated in Thailand.
Two halotolerant yeast strains, H130(T) and H149, were isolated from dry salted squid and fermented soybeans, respectively, in Thailand. Both isolates grew by multilateral budding, produced asci that had one roughened spherical ascospore and contained ubiquinone Q-8. These characteristics were shared by Citeromyces matritensis, the only species of the genus Citeromyces. Strains H130(T) and H149 were differentiated from C matritensis by their ability to assimilate L-sorbose and L-lysine and to grow at 37 degrees C. The novel isolates were more tolerant to higher concentrations of cations (3 M NaCl or 0.8 M LiCI) and to higher osmotic pressure (60% glucose) than C. matritensis. A phylogenetic analysis of 18S rRNA gene sequence data indicated that the two novel isolates represented a sister species to C. matritensis. Furthermore, DNA-DNA hybridization data indicated that the isolates were clearly distinct from the type strain of C. matritensis (IFO 0954(T). Based on the above characteristics, strains H130(T) and H149 are proposed to represent a novel species within the genus Citeromyces, Citeromyces siamensis; the type strain is H130(T) (= IFO 11052(T) = JCM 11522(T) = TISTR 5777(T) = CBS 9153(T)).


Importance of Risk Factors for Febrile Neutropenia Among Patients Receiving Chemotherapy Regimens Not Classified as High-Risk in Guidelines for Myeloid Growth Factor Use.
Clinical practice guidelines recommend prophylaxis in patients with cancer receiving a colony-stimulating factor (CSF) when the risk of febrile neutropenia (FN) is high (>20%). For patients receiving chemotherapy regimens not documented as high-risk, the decision regarding CSF prophylaxis use can be challenging, because some patients may be at high risk based on a combination of the regimen and individual risk factors. A retrospective cohort design and US private health care claims data were used. Study subjects received chemotherapy regimens classified as "low" or "intermediate," or unclassified, in terms of FN risk, and were stratified by cancer and regimen. For each subject, the first chemotherapy course, and each cycle and FN episode within the course, were identified. FN incidence proportions were estimated by the presence and number of risk factors and chronic comorbidities. Across the 17 tumor/regimen combinations considered (n=160,304 in total), 74% to 98% of patients had 1 or more risk factor for FN and 41% to 89% had 2 or more. Among patients with 1 or more risk factor, FN incidence ranged from 7.2% to 29.0% across regimens, and the relative risk of FN (vs those without risk factors) ranged from 1.1 (95% CI, 0.8-1.3) to 2.2 (95% CI, 1.5-3.0). FN incidence increased in a graded and monotonic fashion with the number of risk factors and comorbidities. In this retrospective evaluation of patients with cancer receiving chemotherapy regimens not classified as high-risk for FN in US clinical practice, most patients had 1 or more FN risk factor and many had 2 or more. FN incidence was found to be elevated in these patients, especially those with multiple risk factors.


Targeting epigenetic pathway with gold nanoparticles for acute myeloid leukemia therapy.
Leukemia remains a fatal disease for most patients and novel therapeutic strategies are urgently needed. Aberrant DNA methylation is an epigenetic modification that is important in the initiation and progression of leukemia. Here, we demonstrated NCL/miR-221/NFκB/DNMT1 axis as a new molecular pathway promoting aggressive acute myeloid leukemia (AML) leukemogenesis and successfully designed and prepared a nuclear localization signal (NLS) peptide-targeted gold nanoparticles with co-loaded anti-221 and AS1411 (NPsN-AS1411/a221), which can specifically target NCL/miR-221/NFκB/DNMT1 signaling pathway in AML. NPsN-AS1411/a221 synergistically abrogate endogenous miR-221 promoting cancerous growth by inhibiting the expression of p27Kip1 suppressor gene, as well as effectively deregulate the DNMT1 expression through NFκB signaling which led to a reduction of global DNA methylation and the restoration of tumor suppressor p15INK4B via its promoter DNA hypomethylation. Functionally, NPsN-AS1411/a221 remarkably blockage leukemia proliferation and clonogenic potential in NCL/miR-221/NFκB/DNMT1 positive AML cell lines. More importantly, NPsN-AS1411/a221 cooperatively extend the overall survival, lower the white blood cells, reverse splenomegaly, inhibit blasts in bone marrow and metastatic to lung in a preclinical AML animal model. Altogether, our studies provide a proof of concept for multiple-functional drug delivery system that based on the specific gene network involved in tumor growth, and highlight the clinical potential of NCL/miR-221/NFκB/DNMT1-targeted AML nanotherapy.


Oncology meets immunology: the cancer-immunity cycle.
The genetic and cellular alterations that define cancer provide the immune system with the means to generate T cell responses that recognize and eradicate cancer cells. However, elimination of cancer by T cells is only one step in the Cancer-Immunity Cycle, which manages the delicate balance between the recognition of nonself and the prevention of autoimmunity. Identification of cancer cell T cell inhibitory signals, including PD-L1, has prompted the development of a new class of cancer immunotherapy that specifically hinders immune effector inhibition, reinvigorating and potentially expanding preexisting anticancer immune responses. The presence of suppressive factors in the tumor microenvironment may explain the limited activity observed with previous immune-based therapies and why these therapies may be more effective in combination with agents that target other steps of the cycle. Emerging clinical data suggest that cancer immunotherapy is likely to become a key part of the clinical management of cancer.


Targeted reduction in expression of Trypanosoma cruzi surface glycoprotein gp90 increases parasite infectivity.
A previous study had shown that the expression of gp90, a stage-specific surface glycoprotein of Trypanosoma cruzi metacyclic trypomastigotes, is inversely correlated with the parasite's ability to invade mammalian cells. By using antisense oligonucleotides complementary to a region of the gp90 gene implicated in host cell adhesion, we investigated whether the selective inhibition of gp90 synthesis affected the capacity of metacyclic forms to enter target cells. Parasites were incubated for 24 h with 20 microM PS1, a phosphorothioate oligonucleotide based on a sequence of the gp90 coding strand; PS2, the antisense counterpart of PS1; or PO2, the unmodified version of PS2 containing phosphodiester linkages, and the expression of surface molecules was analyzed by flow cytometry and immunoblotting using specific monoclonal antibodies. PS2 but not PS1 or PO2 inhibited the expression of gp90. Inhibition by PS2 was dose dependent. Northern blot analysis revealed that steady-state gp90 mRNA levels were diminished in PS2-treated parasites compared to untreated controls. Treatment with PS2 did not affect the expression of other metacyclic stage surface glycoproteins involved in parasite-host cell interaction, such as gp82 and the mucin-like gp35/50. Expression of gp90 was also inhibited by other phosphorothioate oligonucleotides targeted to the gp90 gene (PS4, PS5, PS6, and PS7) but not by PS3, with the same base composition as PS2 but a mismatched sequence. Parasites treated with PS2, PS4, or PS5 entered HeLa cells in significantly higher numbers than untreated controls, whereas the invasive capacity of PS1- and PS3-treated parasites was unchanged, confirming the inverse association between infectivity and gp90 expression.


Semiautomatic detection of scoliotic rib borders from posteroanterior chest radiographs.
3-D assessment of scoliotic deformities relies on an accurate 3-D reconstruction of bone structures from biplanar X-rays, which requires a precise detection and matching of anatomical structures in both views. In this paper, we propose a novel semiautomated technique for detecting complete scoliotic rib borders from PA-0° and PA-20° chest radiographs, by using an edge-following approach with multiple-path branching and oriented filtering. Edge-following processes are initiated from user starting points along upper and lower rib edges and the final rib border is obtained by finding the most parallel pair among detected edges. The method is based on a perceptual analysis leading to the assumption that no matter how bent a scoliotic rib is, it will always present relatively parallel upper and lower edges. The proposed method was tested on 44 chest radiographs of scoliotic patients and was validated by comparing pixels from all detected rib borders against their reference locations taken from the associated manually delineated rib borders. The overall 2-D detection accuracy was 2.64 ± 1.21 pixels. Comparing this accuracy level to reported results in the literature shows that the proposed method is very well suited for precisely detecting borders of scoliotic ribs from PA-0° and PA-20° chest radiographs.


The effects of attention-deficit/hyperactivity disorder on employment and household income.
Many children with attention-deficit/hyperactivity disorder (ADHD) continue to exhibit symptoms of the disorder into adolescence and adulthood. Although ADHD may have a profound impact on activities of daily living, including educational achievement and work performance, limited research exists on ADHD's impact on individual income loss and overall economic effect. Evaluate ADHD's impact on individual employment and income, and quantify costs of ADHD on workforce productivity for the US population. Two telephone surveys were conducted between April 18, 2003, and May 11, 2003, to collect demographic, educational, employment, and income information. Two groups of adults aged 18-64 years were interviewed: those diagnosed with ADHD (n = 500) derived from a national list of mail-paneled members who identified themselves or a household member as having been diagnosed with ADHD, and an age- and gender-matched control group (n = 501) derived from a random digital-dialing sample of a national cross-section not diagnosed with ADHD. Statistically fewer subjects in the ADHD group achieved academic milestones beyond some high school (P < .05). In addition, fewer subjects with ADHD were employed full time (34%) compared with controls (59%; P < .001). Except for the subgroup of subjects aged 18-24 years, average household incomes were significantly lower among individuals with ADHD compared with controls, regardless of academic achievement or personal characteristics. On the basis of these findings, loss of workforce productivity associated with ADHD was estimated between $67 billion and $116 billion. Decreased individual income among adults with ADHD contributes to substantial loss in US workforce productivity.


Melittin - A bee venom component - Enhances muscle regeneration factors expression in a mouse model of skeletal muscle contusion.
Melittin is a major peptide component of sweet bee venom that possesses anti-allergic, anti-inflammatory, anti-arthritis, anti-cancer, and neuroprotective properties. However, the therapeutic effects of melittin on muscle injury have not been elucidated. We investigated the therapeutic effects of melittin on muscle injury in a mouse model of muscle contusion. The biceps femoris muscle of the mice was injured using drop mass method, and the animals were treated with melittin (4, 20, or 100 μg/kg) for 7 days. Melittin significantly increased: locomotor activity in open field test, and treadmill running activity in a dose-dependent manner to level comparable to the positive control, diclofenac (30 mg/kg). Melittin treatment attenuated the pro-inflammatory cytokine MCP-1, TNF-α and IL-6. The expression of muscle regeneration biomarkers, including MyoD (muscle differentiation marker), myogenin, smooth muscle actin, and myosin heavy chain was markedly increased in the injured muscle tissue of melittin-treated mice, as determined by western blotting and quantitative real-time polymerase chain reaction. These results demonstrate that melittin inhibits inflammatory response and improves muscle damage by regenerating muscles in a mouse model of muscle contusion. Taken together, the results of present study suggest that melittin is a promising candidate for the muscle injury treatment.


Aggressive giant cell tumour of bone.
The surgical treatment of Stage III or aggressive giant cell tumour of the bone, whether to perform intralesional or en-bloc resection, remains controversial. The aim of this study is to identify the effectiveness of en-bloc resection for local control and final oncological outcome of the disease. The data of 20 consecutive patients with Stage III giant cell tumour were retrospectively reviewed to determine the local control and oncological outcome after treatment with wide resection. The majority of the patients presented late with mean duration of symptoms of 24 months, and four patients presented with recurrences. All patients were treated with wide resection except for two patients who underwent ablative surgery due to major neurovascular involvement. Ten patients required free vascularised tissue transfer to cover massive soft tissue defect. Local recurrence occurred in one patient who was again treated with wide resection and vascularised flap. Six patients had pulmonary metastases. Two patients with resectable disease were treated with thoracoscopic surgery and they remained disease-free 36 months after surgery. Two patients with multiple lung metastases were treated with chemotherapy and the disease remained non-progressive. The remaining two patients who refused chemotherapy showed radiological progression, and one succumbed to the disease with massive haemoptysis. Aggressive giant cell tumour of bone should be treated with wide resection for better local control, and treatment of pulmonary metastases is mandatory for overall prognosis.


Cell signalling is the music of life.
Cell signalling is an immensely important topic in biological and biomedical sciences, and one which has an ever-increasing literature. As more and more is known about it, and more components are discovered, it is getting harder and harder to visualise how it all might work to create an holistic mechanism in the cell. To achieve a better understanding of a complex issue such as this, it is often useful to use an analogy which is familiar to the researcher to encourage better understanding. In this essay it is suggested that music, and the instruments used to produce it, can be used as such an analogy. Various elements and issues in cell signalling are discussed and musical comparisons are made. Clearly, the true understanding of cell signalling will come from systems biology and mathematical modelling, but it is proposed that this analogy might prove useful. The phrasing used may be considered a little loose and flamboyant for a scientific topic of such importance, but it is hoped that the discussion will not only be interesting but might also be useful in fostering debate and facilitating teaching in this area of molecular biology.


Benefits of CT urography in patients presenting to the emergency department with suspected ureteric colic.
Ureteric colic is a common presentation in the emergency department and accounts for approximately 1% of all hospital admissions. Diagnosis depends on a typical history, clinical examination and the presence of haematuria. Intravenous urography has traditionally been used as the means of investigation, but over recent years this has been superseded by CT urography. This latter investigation gives potentially more information and may detect alternative or additional pathology which would otherwise be missed on intravenous urography. 100 consecutive patients attending the emergency department with a provisional diagnosis of ureteric colic undergoing CT urography were studied to detect the incidence of alternative or incidental pathology. Stone disease was found in 58% of patients, with obstruction present in 43%. The most common site of obstruction was the vesicoureteric junction. Significant incidental or alternative pathology was found in 16% of patients. It was estimated that, in 12%, these findings would not have been detected by intravenous urography. The use of non-contrast CT urography is recommended in the initial investigation of patients with ureteric colic.


Self-monitoring of intraocular pressure using Icare HOME tonometry in clinical practice.
Purpose: To determine the value of self-monitoring of diurnal intraocular pressure (IOP) by Icare Home rebound tonometer in patients with glaucoma and ocular hypertension. Methods: Patients with open-angle glaucoma or ocular hypertension, controlled IOP at office visits, and at least 3 years of follow-up in the glaucoma clinic were included. Progression of glaucoma was based on medical records and defined by documented structural and/or visual field change. Patients were trained to correctly perform self-tonometry and instructed to measure diurnal IOP in a home setting for 3 days. IOP characteristics (mean, peak IOP, fluctuation of IOP as range, and SD of IOP) were documented and compared between the progressive and stable eyes. Results: Ninety-four patients (50 females) with a mean (SD) age of 57.1 (14.7) years were included. Among the 94 eyes from 94 subjects, 72 (76.6%) eyes had primary open-angle glaucoma, ten (10.6%) had pigmentary glaucoma, four (4.3%) had exfoliative glaucoma, and eight (8.5%) eyes had ocular hypertension. Thirty-six eyes showed progression and 58 eyes were stable. Patients with progression were older than those with stable disease (mean (SD) 65.8 (8.4) years vs 51.7 (15.3) years, P<0.001). The progression group had higher average IOP (mean (SD) 15.8 (4.0) mmHg vs 13.3 (3.7) mmHg, P=0.002), peak IOP (mean (SD) 21.8 (5.8) mmHg vs 18.6 (4.8) mmHg, P=0.01), and greater IOP fluctuation range (mean (SD) 11.6 (4.8) vs 9.1 (3.5) mmHg, P=0.011) compared to non-progression group. Conclusion: Self-monitoring of IOP using Icare Home tonometry provides more complete data on variability of IOP to assist in the management of glaucoma.


Intermittent Pneumatic Compression Boot Use Elevates Blood Lactate During Subsequent Exercise.
The purpose of the present study was to investigate the influence of intermittent pneumatic compression (IPC) boot use between submaximal cycling trials on heart rate (HR) and blood lactate concentrations. Ten healthy participants (9M; 1F) performed two consecutive 60 minute rides at 60% of functional threshold power with a 30 minute rest between rides. The rest period was spent in a supine position using IPC boots (BOOT) or sitting in a similar position without boots (CON). HRs were collected every 15 minutes during cycling rides, and lactate was measured at the 30-minute mark during both rides. An identical trial was performed 7 days later with conditions (BOOT or CON) crossed. There were no between-trial differences (p > 0.05) in HR; between-trial differences were found for lactate concentrations during the second ride (3.9 ± 1.0 mmol/L BOOT vs. 2.7 ± 1.5 mmol/L CON, p < 0.05). The use of IPC boots between cycling trials as compared to laying in a supine position did not affect heart rate responses but did stimulate higher lactate concentrations during subsequent exercise.


Fetal pancreas transplantation in miniature swine. V. The functional and immunodulatory effects of ultraviolet light on fetal pig islets.
We have used the pig as a large animal model for studies of fetal pancreas transplantation. Fetal pig pancreas (FPP) has also been proposed as a potential source of endocrine cells for the treatment of diabetes mellitus. Among the approaches to prevent rejection, the irradiation of donor islets with ultraviolet B light has been used for its immunomodulating properties. Our goal was to study in vitro the effects of UV-B irradiation of FPP on the function and immunogenicity of the tissue. FPP were collagenase-digested and cultured for 1-29 days prior to UV-B irradiation. Static incubation tests were used to measure glucose-theophylline stimulated insulin release. Data obtained at 300 J/m2 revealed no impairment of insulin release (78% to 129% of controls, P = ns). At 500 J/m2, a significant reduction of glucose-theophylline stimulated insulin release was observed with 50-60-day-old FPP (35% to 66% of controls, P < 0.05), but not with 80-day-old FPP (93% of controls, P = ns). At both doses, prolonged observation in culture did not show any alteration of the growth and proliferation of islet cell clusters. UV-irradiated (300 J/m2) adult and fetal pig islet allografts released C-peptide and survived > 200 days. The immunogenicity of irradiated tissues was determined in vitro with allogeneic mixed islet-lymphocyte cultures (MILC). Proliferative responses of allogeneic lymphocytes to UV-irradiated FPP were very significantly decreased by 52-91% at both 300 and 500 J/m2 doses. This effect was observed from 1 to 10 days following UV irradiation and was not modulated by exposure of the tissues to gamma-interferon. We conclude that UVB-irradiation of FPP at a dose of 300 J/m2 does not alter its endocrine function and growth and is effective in reducing tissue immunogenicity. This treatment may be a useful approach for fetal islet transplantation in large animal models.


8.5 W VECSEL output at 1270 nm with conversion efficiency of 59%.
We report on 1270 nm vertical-external-cavity surface-emitting lasers (VECSELs) with up to 59% conversion efficiency and maximum output power of 8.5 W (pump limited), at 5°C heat sink temperature. These VECSELs comprised wafer-fused gain mirrors in the flip-chip (thin-disk) heat dissipation scheme. The reflected pump light from the gain mirror surface was found to depend considerably on temperature and pump power.


Oxygen-sensing PHDs regulate bone homeostasis through the modulation of osteoprotegerin.
The bone microenvironment is composed of niches that house cells across variable oxygen tensions. However, the contribution of oxygen gradients in regulating bone and blood homeostasis remains unknown. Here, we generated mice with either single or combined genetic inactivation of the critical oxygen-sensing prolyl hydroxylase (PHD) enzymes (PHD1-3) in osteoprogenitors. Hypoxia-inducible factor (HIF) activation associated with Phd2 and Phd3 inactivation drove bone accumulation by modulating osteoblastic/osteoclastic cross-talk through the direct regulation of osteoprotegerin (OPG). In contrast, combined inactivation of Phd1, Phd2, and Phd3 resulted in extreme HIF signaling, leading to polycythemia and excessive bone accumulation by overstimulating angiogenic-osteogenic coupling. We also demonstrate that genetic ablation of Phd2 and Phd3 was sufficient to protect ovariectomized mice against bone loss without disrupting hematopoietic homeostasis. Importantly, we identify OPG as a HIF target gene capable of directing osteoblast-mediated osteoclastogenesis to regulate bone homeostasis. Here, we show that coordinated activation of specific PHD isoforms fine-tunes the osteoblastic response to hypoxia, thereby directing two important aspects of bone physiology: cross-talk between osteoblasts and osteoclasts and angiogenic-osteogenic coupling.


A review of ELTD1, a pro-angiogenic adhesion GPCR.
Epidermal growth factor, latrophilin and seven-transmembrane domain-containing 1 (ELTD1), an orphan G-protein-coupled receptor (GPCR) belonging to the adhesion GPCR family, has recently been identified as a potential cancer biomarker and a novel regulator of angiogenesis. In this mini-review, we present an overview of the current literature on ELTD1 and present bioinformatics data showing ELTD1's sequence conservation, its expression in cancer cell lines and its mutational frequency in human cancers. Additionally, we present sequence homology alignment results confirming ELTD1 to be a hybrid comprising motifs shared with individual members in both adhesion GPCR subfamilies 1 and 2. Finally, we discuss why tumour endothelial ELTD1 expression may confer a good prognosis yet still represent a therapeutic target.


Gist memory in the unconscious-thought effect.
The unconscious-thought effect (UTE) occurs when people are better able to make complex decisions after a period of distraction rather than immediately or after a period of conscious deliberation. This finding has often been interpreted as evidence of unconscious thinking. In two experiments, we provided the first evidence that the UTE is accompanied by enhanced memory for the gist of decision-relevant attributes and demonstrated that the cognitive demands of a distraction task moderate its effect on decision making and gist memory. It was only following a low-demand distraction task that participants chose the best alternative more often and displayed enhanced gist memory for decision-relevant attributes. These findings suggest that the UTE occurs only if cognitive resources are available and that it is accompanied by enhanced organization of information in memory, as shown by the increase in gist memory.


Cerebral blood flow alterations in progressive communicating hydrocephalus: transcranial Doppler ultrasonography assessment in an experimental model.
In many cases communicating hydrocephalus is the result of impairments in cerebrospinal fluid absorption in the arachnoid villi at the cranial convexity. Reported methods of creating experimental hydrocephalus have not sought to produce an arachnoidal adhesion in the cranial convexity. In this study the authors investigate alterations in cerebral blood flow (CBF) in experimental communicating hydrocephalus induced by the injection of kaolin into the subarachnoid space at the convexity in neonatal rats. In neonatal rats, kaolin was injected into the subarachnoid space at the cranial convexity. Assessment of CBF alterations was performed using transcranial Doppler ultrasonography preinjection and at 10 days, 4 weeks, and 8 weeks postinjection. Light microscopy examination was also performed at 4 weeks and 8 weeks postinjection. Conspicuous lateral ventricle enlargements of different dimensions were observed in kaolin-injected rats at 4 to 8 weeks postinjection. The third and fourth ventricles were dilated to a lesser extent. Resistance to CBF and increased mean CBF velocity were apparent 8 weeks after kaolin injection. Further, destruction and even loss of ependymal layers were more prominent at the chronic stage. The present model may be considered a progressive communicating hydrocephalus because of marked changes in blood flow dynamics and destruction of the ependymal layer at the chronic stage.


A national-scale dataset for threats impacting Australia's imperiled flora and fauna.
Australia is in the midst of an extinction crisis, having already lost 10% of terrestrial mammal fauna since European settlement and with hundreds of other species at high risk of extinction. The decline of the nation's biota is a result of an array of threatening processes; however, a comprehensive taxon-specific understanding of threats and their relative impacts remains undocumented nationally. Using expert consultation, we compile the first complete, validated, and consistent taxon-specific threat and impact dataset for all nationally listed threatened taxa in Australia. We confined our analysis to 1,795 terrestrial and aquatic taxa listed as threatened (Vulnerable, Endangered, or Critically Endangered) under Australian Commonwealth law. We engaged taxonomic experts to generate taxon-specific threat and threat impact information to consistently apply the IUCN Threat Classification Scheme and Threat Impact Scoring System, as well as eight broad-level threats and 51 subcategory threats, for all 1,795 threatened terrestrial and aquatic threatened taxa. This compilation produced 4,877 unique taxon-threat-impact combinations with the most frequently listed threats being Habitat loss, fragmentation, and degradation (n = 1,210 taxa), and Invasive species and disease (n = 966 taxa). Yet when only high-impact threats or medium-impact threats are considered, Invasive species and disease become the most prevalent threats. This dataset provides critical information for conservation action planning, national legislation and policy, and prioritizing investments in threatened species management and recovery.


Predictive biomarkers for anti-epidermal growth factor receptor therapy: beyond KRAS testing.
In an era of personalized medicine, an increased effort is being made to identify patients likely to benefit from targeted therapy. By limiting treatment to selected patients, both unnecessary cost and toxicity may be avoided. Restricting the use of anti-epidermal growth factor receptor (anti-EGFR)-targeted agents in metastatic colorectal cancer to only patients with KRAS exon 2 wild-type tumors has become well-established in clinical practice. However, lack of KRAS exon 2 mutations does not necessarily predict response, and a significant proportion of patients with KRAS wild-type tumors do not benefit from therapy with cetuximab or panitumumab. Further characterization is needed of the subset of patients with KRAS exon 2 wild-type tumors who are likely to benefit from anti-EGFR therapy. Recent data suggest that patients with KRAS mutations at loci other than exon 2, and those with other RAS mutations, might not benefit from EGFR-directed therapy. This article briefly reviews established work on KRAS exon 2 mutations, but focuses primarily on emerging data on non-exon 2 KRAS mutations and additional RAS and BRAF mutations and how this information may impact clinical decision-making.


'Who's the guy in the room?' Involving fathers in antenatal care screening for sickle cell disorders.
Fathers are increasingly invited to take part in antenatal care of which screening for sickle cell trait is a part. Expectations about involvement reflect changing perceptions of fatherhood and negotiation of gendered identities. Current policy supports male involvement, but is less clear on what basis and with what consequences. In exploring this, our qualitative study, using semi-structured interviews, presents the experiences of fathers who have recently undergone antenatal screening for sickle cell. The sample was generated in discussion with eight non-governmental organisations. We recruited 24 fathers from nine UK cities. Our analysis outlines the importance of 'presence', in which fathers rely on nurturing definitions of fatherhood to display their sense of responsibility. Fathers, however, struggled to find a meaningful role as traditional masculinities became juxtaposed with new and complex forms of gender organisation, creating the potential for estrangement. To conclude, screening policy makes an appeal to emergent masculinities. It also generates risks and compromises choice, due to the normative values implicit in the screening process, reinforced by the more controlling aspects of health surveillance. This creates confusion among fathers, who are not sure why they have been invited into the antenatal space.


Age and Outcomes of Medial Meniscal-Bearing Unicompartmental Knee Arthroplasty.
National joint registries report increasing revision rates with decreasing patient age for all types of joint arthroplasty. This study aimed to explore the effect of age on function and revision risk in patients undergoing medial meniscal-bearing UKA. A prospectively followed cohort of 1000 consecutive medial meniscal-bearing UKAs at a designer center was analyzed. All knees were implanted for recommended indications and had mean 10-year follow-up. Patients were grouped by age at surgery (<55, 55 to <65, 65 to <75, 75+). Oxford Knee Scores (OKS) were assessed at 5 and 10 years. Component-time revision incidence rates and Kaplan-Meier implant survival were calculated. Mean patient age at surgery was 66.6 years (range, 33-88). All age-groups had significant (P < .001) improvement in OKS over time, and at 5 years achieved a median OKS of 44. At 10 years, median OKS, from youngest group to eldest, were 44, 45, 42, and 39, with the eldest group having a significantly lower OKS (P < .01). Ten-year implant survival rates were 97%, 94%, 94%, and 93%, respectively, and was not significantly associated with age at UKA. Medial meniscal-bearing UKA provides good functional outcomes in all age-groups; however, in older patients (75+), the functional outcome deteriorated at 10 years presumably due to deteriorating health. Contrary to registry observations, the revision rate was not higher in younger patients. These results suggest that, with correct indications, patient age should not be considered a contraindication to medial meniscal-bearing UKA.


Performance of commercial platforms for rapid genotyping of polymorphisms affecting warfarin dose.
Initiation of warfarin therapy is associated with bleeding owing to its narrow therapeutic window and unpredictable therapeutic dose. Pharmacogenetic-based dosing algorithms can improve accuracy of initial warfarin dosing but require rapid genotyping for cytochrome P-450 2C9 (CYP2C9) *2 and *3 single nucleotide polymorphisms (SNPs) and a vitamin K epoxide reductase (VKORC1) SNP. We evaluated 4 commercial systems: INFINITI analyzer (AutoGenomics, Carlsbad, CA), Invader assay (Third Wave Technologies, Madison, WI), Tag-It Mutation Detection assay (Luminex Molecular Diagnostics, formerly Tm Bioscience, Toronto, Canada), and Pyrosequencing (Biotage, Uppsala, Sweden). We genotyped 112 DNA samples and resolved any discrepancies with bidirectional sequencing. The INFINITI analyzer was 100% accurate for all SNPs and required 8 hours. Invader and Tag-It were 100% accurate for CYP2C9 SNPs, 99% accurate for VKORC1 -1639/3673 SNP, and required 3 hours and 8 hours, respectively. Pyrosequencing was 99% accurate for CYP2C9 *2, 100% accurate for CYP2C9 *3, and 100% accurate for VKORC1 and required 4 hours. Current commercial platforms provide accurate and rapid genotypes for pharmacogenetic dosing during initiation of warfarin therapy.


Using positional distribution to identify splicing elements and predict pre-mRNA processing defects in human genes.
We present an intuitive strategy for predicting the effect of sequence variation on splicing. In contrast to transcriptional elements, splicing elements appear to be strongly position dependent. We demonstrated that exonic binding of the normally intronic splicing factor, U2AF65, inhibits splicing. Reasoning that the positional distribution of a splicing element is a signature of its function, we developed a method for organizing all possible sequence motifs into clusters based on the genomic profile of their positional distribution around splice sites. Binding sites for serine/arginine rich (SR) proteins tended to be exonic whereas heterogeneous ribonucleoprotein (hnRNP) recognition elements were mostly intronic. In addition to the known elements, novel motifs were returned and validated. This method was also predictive of splicing mutations. A mutation in a motif creates a new motif that sometimes has a similar distribution shape to the original motif and sometimes has a different distribution. We created an intraallelic distance measure to capture this property and found that mutations that created large intraallelic distances disrupted splicing in vivo whereas mutations with small distances did not alter splicing. Analyzing the dataset of human disease alleles revealed known splicing mutants to have high intraallelic distances and suggested that 22% of disease alleles that were originally classified as missense mutations may also affect splicing. This category together with mutations in the canonical splicing signals suggest that approximately one third of all disease-causing mutations alter pre-mRNA splicing.


Outcomes of treatment of children and adolescents with recurrent non-Hodgkin's lymphoma and Hodgkin's disease with dexamethasone, etoposide, cisplatin, cytarabine, and l-asparaginase, maintenance chemotherapy, and transplantation: Children's Cancer Group Study CCG-5912.
To determine the toxicity and response rate in children treated with dexamethasone, etoposide, cisplatin, high-dose cytarabine, and L-asparaginase (DECAL) for recurrent non-Hodgkin's lymphoma (NHL) and Hodgkin's disease (HD). Ninety-seven children with recurrent NHL (n = 68) or HD (n = 29) were enrolled. Treatment consisted of two cycles of DECAL, then bone marrow transplantation or up to four cycles of ifosfamide, mesna, and etoposide alternating with DECAL maintenance therapy. After two cycles of DECAL induction therapy, complete response (CR) or partial response (PR) was reported in 19 (65.5%; 10 CRs and nine PRs) of 29 patients with HD and 29 (41.6%; 23 CRs and six PRs) of 68 patients with NHL. When only 24 patients with HD and 58 patients with NHL who were assessable for response were considered, the response rates were 79.2% (19 of 24 patients) and 50.0% (29 of 58 patients), respectively. Five-year event-free survival was 26% +/- 9% and 23% +/- 5% in patients with HD and NHL, respectively. Five-year survival was 31% +/- 14% and 30% +/- 6%, respectively. Although median time to treatment failure was significantly longer in patients with HD (EFS, P =.002; survival, P =.011), this difference did not translate into a higher long-term survival. Grade 3 or 4 toxic effects were observed during induction in 70 (72%) of 97 patients and during maintenance in 45 (70%) of 64 courses of DECAL therapy. Pancytopenia and systemic infections in particular were frequently observed. Other toxic effects were uncommon. Although not a formal part of the therapy or the study design, 42 patients who responded to therapy who underwent bone marrow transplant did not show any benefit from this approach. DECAL is an effective and tolerable salvage regimen for treating patients with recurrent NHL and HD.


Livestock Susceptibility to Infection with Middle East Respiratory Syndrome Coronavirus.
Middle East respiratory syndrome (MERS) cases continue to be reported, predominantly in Saudi Arabia and occasionally other countries. Although dromedaries are the main reservoir, other animal species might be susceptible to MERS coronavirus (MERS-CoV) infection and potentially serve as reservoirs. To determine whether other animals are potential reservoirs, we inoculated MERS-CoV into llamas, pigs, sheep, and horses and collected nasal and rectal swab samples at various times. The presence of MERS-CoV in the nose of pigs and llamas was confirmed by PCR, titration of infectious virus, immunohistochemistry, and in situ hybridization; seroconversion was detected in animals of both species. Conversely, in sheep and horses, virus-specific antibodies did not develop and no evidence of viral replication in the upper respiratory tract was found. These results prove the susceptibility of llamas and pigs to MERS-CoV infection. Thus, the possibility of MERS-CoV circulation in animals other than dromedaries, such as llamas and pigs, is not negligible.


Surveying the lipogenesis landscape in Yarrowia lipolytica through understanding the function of a Mga2p regulatory protein mutant.
Lipogenic organisms represent great starting points for metabolic engineering of oleochemical production. While previous engineering efforts were able to significantly improve lipid production in Yarrowia lipolytica, the lipogenesis landscape, especially with respect to regulatory elements, has not been fully explored. Through a comparative genomics and transcriptomics approach, we identified and validated a mutant mga2 protein that serves as a regulator of desaturase gene expression and potent lipogenesis factor. The resulting strain is enriched in unsaturated fatty acids. Comparing the underlying mechanism of this mutant to other previously engineered strains suggests that creating an imbalance between glycolysis and the TCA cycle can serve as a driving force for lipogenesis when combined with fatty acid catabolism overexpressions. Further comparative transcriptomics analysis revealed both distinct and convergent rewiring associated with these different genotypes. Finally, by combining metabolic engineering targets, it is possible to further engineer a strain containing the mutant mga2 gene to a lipid production titer of 25g/L.


Computational Models Accurately Predict Multi-Cell Biomarker Profiles in Inflammation and Cancer.
Individual computational models of single myeloid, lymphoid, epithelial, and cancer cells were created and combined into multi-cell computational models and used to predict the collective chemokine, cytokine, and cellular biomarker profiles often seen in inflamed or cancerous tissues. Predicted chemokine and cytokine output profiles from multi-cell computational models of gingival epithelial keratinocytes (GE KER), dendritic cells (DC), and helper T lymphocytes (HTL) exposed to lipopolysaccharide (LPS) or synthetic triacylated lipopeptide (Pam3CSK4) as well as multi-cell computational models of multiple myeloma (MM) and DC were validated using the observed chemokine and cytokine responses from the same cell type combinations grown in laboratory multi-cell cultures with accuracy. Predicted and observed chemokine and cytokine responses of GE KER + DC + HTL exposed to LPS and Pam3CSK4 matched 75% (15/20, p = 0.02069) and 80% (16/20, P = 0.005909), respectively. Multi-cell computational models became 'personalized' when cell line-specific genomic data were included into simulations, again validated with the same cell lines grown in laboratory multi-cell cultures. Here, predicted and observed chemokine and cytokine responses of MM cells lines MM.1S and U266B1 matched 75% (3/4) and MM.1S and U266B1 inhibition of DC marker expression in co-culture matched 100% (6/6). Multi-cell computational models have the potential to identify approaches altering the predicted disease-associated output profiles, particularly as high throughput screening tools for anti-inflammatory or immuno-oncology treatments of inflamed multi-cellular tissues and the tumor microenvironment.


Quantitative subproteomic analysis of age-related changes in mouse liver peroxisomes by iTRAQ LC-MS/MS.
Aging is a complex multifactorial phenomenon, which is believed to result from the accumulation of cellular damage to biological macromolecules. Peroxisomes recently emerged as another important source of reactive oxygen species (ROS) production in addition to mitochondria. However, the role of these organelles in the process of aging is still not clear. The aim of this study was to characterize the changes in protein expression profiles of young (10 weeks old) versus old (18 months old) mouse liver peroxisome-enriched fractions. We have applied shotgun proteomic approach based on liquid chromatography and tandem mass spectrometry (LC-MS/MS) combined with iTRAQ (isobaric tags for relative and absolute quantitation) labeling that allows comparative quantitative multiplex analysis. Our analysis led to identification and quantification of 150 proteins, 8 out of which were differentially expressed between two age groups at a statistically significant level (p<0.05), with folds ranging from 1.2 to 4.1. These proteins involved in peroxisomal β-oxidation, detoxification of xenobiotics and production of ROS. Noteworthy, differences in liver proteome have been observed between as well as within different age groups. In conclusion, our subproteomic quantitative study suggests that mouse liver proteome is sufficiently maintained until certain age.


Objectively assessing bioartificial organs.
The metrics used, thus far, to assess bioartificial organ function are shown to be subjective and requiring validation. Therefore, four categories of correlations are proposed based on, respectively, device, in vitro and in vivo evaluations, and clinical function. Examples are presented whereby the correlations among individual indicators are used as a means to expedite the development of immunoisolated cells. Specifically, a case study illustrating the validation of in vitro indicators of in vivo graft function for the bioartificial pancreas (microencapsulated islets) is summarized. This has revealed thresholds with respect to given metrics relating to in vivo device function, the necessity to couple bioartificial organ design with transplant site selection, as well as the lack of objectivity involved in the evaluation and establishment of hypotheses. Specific quantitative indicators illustrate the need for quality-controlled measures, for example, relating to the tolerance of microcapsule diameter and membrane thickness distributions. Qualitative indices representing fibrosis and device properties (e.g., sphericity) are also used to describe the need for in vitro experiments in the development of bioartificial organs.


Total chemical synthesis of a D-enzyme: the enantiomers of HIV-1 protease show reciprocal chiral substrate specificity [corrected].
The D and L forms of the enzyme HIV-1 protease have been prepared by total chemical synthesis. The two proteins had identical covalent structures. However, the folded protein-enzyme enantiomers showed reciprocal chiral specificity on peptide substrates. That is, each enzyme enantiomer cut only the corresponding substrate enantiomer. Reciprocal chiral specificity was also evident in the effect of enantiomeric inhibitors. These data imply that the folded forms of the chemically synthesized D- and L-enzyme molecules are mirror images of one another in all elements of the three-dimensional structure. Enantiomeric proteins are expected to display reciprocal chiral specificity in all aspects of their biochemical interactions.


Divergence-Free SPH for Incompressible and Viscous Fluids.
In this paper we present a novel Smoothed Particle Hydrodynamics (SPH) method for the efficient and stable simulation of incompressible fluids. The most efficient SPH-based approaches enforce incompressibility either on position or velocity level. However, the continuity equation for incompressible flow demands to maintain a constant density and a divergence-free velocity field. We propose a combination of two novel implicit pressure solvers enforcing both a low volume compression as well as a divergence-free velocity field. While a compression-free fluid is essential for realistic physical behavior, a divergence-free velocity field drastically reduces the number of required solver iterations and increases the stability of the simulation significantly. Thanks to the improved stability, our method can handle larger time steps than previous approaches. This results in a substantial performance gain since the computationally expensive neighborhood search has to be performed less frequently. Moreover, we introduce a third optional implicit solver to simulate highly viscous fluids which seamlessly integrates into our solver framework. Our implicit viscosity solver produces realistic results while introducing almost no numerical damping. We demonstrate the efficiency, robustness and scalability of our method in a variety of complex simulations including scenarios with millions of turbulent particles or highly viscous materials.


Sea bass Dicentrarchus labrax nervous necrosis virus isolates with distinct pathogenicity to sea bass larvae.
Reproduction of nodavirus disease was performed by experimental infection of sea bass eggs during fertilization or at larval stage 4 with 2 genetically distinguishable nodavirus strains (Sb1 and Sb2) isolated from sea bass collected along the Atlantic and Mediterranean French coast. The pathogenicity of the virus strains was assigned after detection of the virus by ELISA and immunohistochemistry (IHC). The Atlantic (Sb1) strain was more pathogenic than the Mediterranean (Sb2) strain during the fertilization step whilst both strains were pathogenic following experimental exposure of 4 d old larvae. Virus lesions developed in the brain 4 to 6 d following experimental exposure. Experimental ELISA proved very sensitive for detecting the nodavirus in Sb1 or Sb2 experimentally infected larvae, as well as in naturally infected sea bass larvae collected in French hatcheries or in barramundi larvae reared in the Pacific area. The development of an ELISA specific for the 2 nodavirus strains isolated from the sea bass should be useful for the detection of the virus, in addition to other techniques recommended by the Office International des Epizooties (OIE).


Memory impairment in young women at increased risk of depression: influence of cortisol and 5-HTT genotype.
Memory deficits are common in depressed patients and may persist after recovery. The aim of the present study was to determine whether memory impairments were present in young women at increased familial risk of depression and whether memory performance was related either to cortisol secretion or to allelic variation in the promoter region of the serotonin transporter gene (5-HTT). Young women (n=35, age range 16-21 years) with no personal history of depression but with a depressed parent (FH+) carried out the Rey Auditory Verbal Learning Test (RAVLT). They also provided samples for the measurement of waking salivary cortisol and for 5-HTT genotyping. An age-matched control group of women (n=31) with no family history of depression were similarly studied. The FH+ participants had decreased immediate recall and recognition memory compared to controls. The impairment in recall, but not recognition, correlated negatively with increased cortisol secretion in FH+ subjects. There was no significant effect of 5-HTT allelic status on either memory or waking cortisol secretion. Impairments in declarative memory are present in young women at increased genetic risk of depression and may be partly related to increased cortisol secretion. Further studies are needed to explore the neural mechanisms underlying the memory impairments and whether they predict the development of clinical illness.


Neovascularization of the Xenopus embryo.
The receptor tyrosine kinase, Flk-1 or VEGFR-2, and its ligand, vascular endothelial growth factor (VEGF) are required for the development of the embryonic vasculature. Targeted disruption of either gene in mice results in the failure of vascular system formation. The Xenopus homologues of flk-1 and VEGF have been cloned and their expression has been examined throughout early embryonic development. These studies indicate that flk-1 is expressed in groups of endothelial precursor cells which will form the major blood vessels of the embryo, including the posterior cardinal veins, the dorsal aorta, the vitelline veins, and the endocardium. VEGF expression is found in tissues adjacent to the mesenchyme containing the flk-1-expressing endothelial precursors. Expression of both flk-1 and VEGF is transient, appearing as the primary vascular plexus is forming and declining steadily after the onset of functional embryonic circulation. After establishment of the primary vascular structures, flk-1 expression is also observed in the intersegmental veins which form by an angiogenic mechanism. Overall, these results support a role for VEGF/flk-1 signaling in both vasculogenesis and angiogenesis in the Xenopus embryo. When VEGF is expressed ectopically in Xenopus embryos by microinjection of either plasmid DNA or synthetic mRNA, large, disorganized vascular structures are produced. This result indicates that ectopic VEGF is capable of altering the architecture of the developing vascular network.


Neural Correlates of Hand-Object Congruency Effects during Action Planning.
Selecting hand actions to manipulate an object is affected both by perceptual factors and by action goals. Affordances may contribute to "stimulus-response" congruency effects driven by habitual actions to an object. In previous studies, we have demonstrated an influence of the congruency between hand and object orientations on response times when reaching to turn an object, such as a cup. In this study, we investigated how the representation of hand postures triggered by planning to turn a cup was influenced by this congruency effect, in an fMRI scanning environment. Healthy participants were asked to reach and turn a real cup that was placed in front of them either in an upright orientation or upside-down. They were instructed to use a hand orientation that was either congruent or incongruent with the cup orientation. As expected, the motor responses were faster when the hand and cup orientations were congruent. There was increased activity in a network of brain regions involving object-directed actions during action planning, which included bilateral primary and extrastriate visual, medial, and superior temporal areas, as well as superior parietal, primary motor, and premotor areas in the left hemisphere. Specific activation of the dorsal premotor cortex was associated with hand-object orientation congruency during planning and prior to any action taking place. Activity in that area and its connectivity with the lateral occipito-temporal cortex increased when planning incongruent (goal-directed) actions. The increased activity in premotor areas in trials where the orientation of the hand was incongruent to that of the object suggests a role in eliciting competing representations specified by hand postures in lateral occipito-temporal cortex.


Colony Stimulating Factor-1 Receptor Expressing Cells Infiltrating the Cornea Control Corneal Nerve Degeneration in Response to HSV-1 Infection.
Herpes simplex virus type-1 (HSV-1) is a leading cause of neurotrophic keratitis, characterized by decreased or absent corneal sensation due to damage to the sensory corneal innervation. We previously reported the elicited immune response to infection contributes to the mechanism of corneal nerve regression/damage during acute HSV-1 infection. Our aim is to further establish the involvement of infiltrated macrophages in the mechanism of nerve loss upon infection. Macrophage Fas-Induced Apoptosis (MAFIA) transgenic C57BL/6 mice were systemically treated with AP20187 dimerizer or vehicle (VEH), and their corneas, lymph nodes, and blood were assessed for CD45+CD11b+GFP+ cell depletion by flow cytometry (FC). Mice were ocularly infected with HSV-1 or left uninfected. At 2, 4, and/or 6 days post infection (PI), corneas were assessed for sensitivity and harvested for FC, nerve structure by immunohistochemistry, viral content by plaque assay, soluble factor content by suspension array, and activation of signaling pathways by Western blot analysis. C57BL6 mice were used to compare to the MAFIA mouse model. MAFIA mice treated with AP20187 had efficient depletion of CD45+CD11b+GFP+ cells in the tissues analyzed. The reduction of CD45+CD11b+GFP+ cells recruited to the infected corneas of AP20187-treated mice correlated with preservation of corneal nerve structure and function, decreased protein concentration of inflammatory cytokines, and decreased STAT3 activation despite no changes in viral content in the cornea compared to VEH-treated animals. Our results suggest infiltrated macrophages are early effectors in the nerve regression following HSV-1 infection. We propose the neurodegeneration mechanism involves macrophages, local up-regulation of IL-6, and activation of STAT3.


Blood-tissue exchange via transport and transformation by capillary endothelial cells.
The escape of solutes from the blood during passage along capillaries in heart and skeletal muscle occurs via diffusion through clefts between endothelial cells and, for some solutes, via adsorption to or transport across the luminal plasmalemma of the endothelial cell. To quantitate the rates of permeation via these two routes of transport across capillary wall, we have developed a linear model for transendothelial transport and illustrated its suitability for the design and analysis of multiple simultaneous indicator dilution curves from an organ. Data should be obtained for at least three solutes: 1) an intravascular reference, albumin; 2) a solute transported by endothelial cells; and 3) another reference solute, of the same molecular size as solute 2, which neither binds nor traverses cell membranes. The capillary-tissue convection-permeation model is spatially distributed and accounts for axial variation in concentrations, transport through and around endothelial cells, accumulation and consumption within them, exchange with the interstitium and parenchymal cells, and heterogeneity of regional flows. The upslope of the dilution curves is highly sensitive to unidirectional rate of loss at the luminal endothelial surface. There is less sensitivity to transport across the antiluminal surface, except when endothelial retention is low. The model is useful for receptor kinetics using tracers during steady-state conditions and allows distinction between equilibrium binding and reaction rate limitations. Uptake rates at the luminal surface are readily estimated by fitting the model to the experimental dilution curves. For adenosine and fatty acids, endothelial transport accounts for 30-99% of the transcapillary extraction.


An endohedral single-molecule magnet with long relaxation times: DySc2N@C80.
The magnetism of DySc(2)N@C(80) endofullerene was studied with X-ray magnetic circular dichroism (XMCD) and a magnetometer with a superconducting quantum interference device (SQUID) down to temperatures of 2 K and in fields up to 7 T. XMCD shows hysteresis of the 4f spin and orbital moment in Dy(III) ions. SQUID magnetometry indicates hysteresis below 6 K, while thermal and nonthermal relaxation is observed. Dilution of DySc(2)N@C(80) samples with C(60) increases the zero-field 4f electron relaxation time at 2 K to several hours.


Gap junctions compensate for sublinear dendritic integration in an inhibitory network.
Electrically coupled inhibitory interneurons dynamically control network excitability, yet little is known about how chemical and electrical synapses regulate their activity. Using two-photon glutamate uncaging and dendritic patch-clamp recordings, we found that the dendrites of cerebellar Golgi interneurons acted as passive cables. They conferred distance-dependent sublinear synaptic integration and weakened distal excitatory inputs. Gap junctions were present at a higher density on distal dendrites and contributed substantially to membrane conductance. Depolarization of one Golgi cell increased firing in its neighbors, and inclusion of dendritic gap junctions in interneuron network models enabled distal excitatory synapses to drive network activity more effectively. Our results suggest that dendritic gap junctions counteract sublinear dendritic integration by enabling excitatory synaptic charge to spread into the dendrites of neighboring inhibitory interneurons.


Is Empathy for Pain Unique in Its Neural Correlates? A Meta-Analysis of Neuroimaging Studies of Empathy.
Empathy is an essential component of our social lives, allowing us to understand and share other people's affective and sensory states, including pain. Evidence suggests a core neural network-including anterior insula (AI) and mid-cingulate cortex (MCC)-is involved in empathy for pain. However, a similar network is associated to empathy for non-pain affective states, raising the question whether empathy for pain is unique in its neural correlates. Furthermore, it is yet unclear whether neural correlates converge across different stimuli and paradigms that evoke pain-empathy. We performed a coordinate-based activation likelihood estimation (ALE) meta-analysis to identify neural correlates of empathy, assess commonalities and differences between empathy for pain and for non-pain negative affective states, and differences between pain-empathy evoking stimuli (i.e., facial pain expressions vs. acute pain inflictions) and paradigms (i.e., perceptual/affective vs. cognitive/evaluative paradigms). Following a systematic search, data from 128 functional brain imaging studies presenting whole-brain results of an empathy condition vs. baseline/neutral condition were extracted. Synthesizing neural correlates of empathy confirmed a core network comprising AI, MCC, postcentral gyrus, inferior parietal lobe, thalamus, amygdala, and brainstem. There was considerable overlap in networks for empathy for pain and empathy for non-pain negative affective states. Important differences also arose: empathy for pain uniquely activated bilateral mid-insula and more extensive MCC. Regarding stimuli, painful faces and acute pain inflictions both evoked the core empathy regions, although acute pain inflictions activated additional regions including medial frontal and parietal cortex. Regarding paradigms, both perceptual/affective and cognitive/evaluative paradigms recruited similar neural circuitry, although cognitive/evaluative paradigms activated more left MCC regions while perceptual/affective paradigms activated more right AI. Taken together, our findings reveal that empathy for pain and empathy for non-pain negative affective states share considerable neural correlates, particularly in core empathy regions AI and MCC. Beyond these regions, important differences emerged, limiting generalizability of findings across different affective/sensory states. Within pain-empathy studies, the core regions were recruited robustly irrespective of stimuli or instructions, allowing one to tailor designs according to specific needs to some extent, while ensuring activation of core regions.


Fourier spectroscopy, past, present, and future.
Several comments concerning the analytical relationship between measured interferograms and spectra serve to clarify some common misconceptions. A brief history traces fourier spectroscopy, beginning with Fellgett's thesis and culminating with the Connes' measurements. Special note is made of the fact that astronomy has served as the challenge and motivation for almost all the progress. The discussion of the present situation mentions both the commercial tangle and the general clouds that now hang over science. A simple pedantic experiment, which is described in some detail, may prove helpful in diminishing the hesitations of future scientists. The applications of fourier spectrometry in the infrared, both near and far, are already well in hand. Further application at shorter wavelengths, both visible and ultraviolet, will also be fruitful. Even though Fellgett's advantage is not applicable, the Jacquinot and Connes advantages will prove most important. In particular, capabilities surpassing those of the conventional coudé spectrograph present an intermediate step on the path to the eventual consummation of a giant flux collector worthy of fourier spectrometry.


Attention-Deficit/Hyperactivity Disorder and Successful Completion of Anesthesia Residency: A Case Report.
Cognitive and physical disabilities among anesthesia residents are not well studied. Cognitive disabilities may often go undiagnosed among trainees, and these trainees may struggle during their graduate medical education. Attention-deficit/hyperactivity disorder (ADHD) is an executive function disorder that may manifest as lack of vigilance, an inability to adapt to the rapid changes associated with anesthesia cases, distractibility, an inability to prioritize activities, and even periods of hyperfocusing, among other signs. Programs are encouraged to work closely with residents with such disabilities to develop an educational plan that includes accommodations for their unique learning practices while maintaining the critical aspects of the program. The authors present the management of a case of an anesthesia resident with a diagnosis of ADHD, the perspectives of the trainee, program director, clinical competency director, and the office of general counsel. This article also provides follow-up in the five years since completion of residency.


Biotransformation of dissolved and sediment-bound fluoranthene in the polychaete, Capitella sp. I.
Polycyclic aromatic hydrocarbons (PAHs) are widely distributed in the marine environment and have physicochemical properties that make them likely to bioaccumulate. The main purpose of this study was to investigate fluoranthene (FLU) uptake, biotransformation and elimination in the deposit-feeding polychaete Capitella sp. I exposed via different routes. Individual worms were exposed to either dissolved FLU or to both dissolved and sediment-bound FLU. The 14C-FLU was used as a tracer to determine the amounts of unmetabolized FLU (parent), water-soluble (aqueous)- and water-insoluble (polar) FLU metabolites and FLU residues (unextractable fraction) in sediment, water, and worm tissue. Capitella was capable of accumulating and biotransforming FLU regardless of route of exposure, thus suggesting that biotransformation activity is not restricted to gut tissues. Although both feeding and nonfeeding worms were able to biotransform FLU extensively, feeding worms eliminated/transformed parent FLU faster than both aqueous and polar FLU metabolites after transfer to clean conditions, whereas nonfeeding worms barely excreted FLU in any form. The high biotransformation capability of Capitella sp. I. along with the dependency of elimination on exposure route, demonstrates the potential importance of these processes in controlling the fate and effects of PAH and possibly other organic toxicants in contaminated marine sediments.