Analysis of the unique hamster cell tropism of ecotropic murine leukemia virus PVC-211.
PVC-211 murine leukemia virus (MuLV) is a neuropathogenic variant of Friend MuLV (F-MuLV). Previous studies from our laboratory demonstrated that unlike the parental F-MuLV, PVC-211 MuLV can infect rat brain capillary endothelial cells efficiently and that it has acquired genetic changes responsible for its expanded cellular tropism. To determine if PVC-211 MuLV also has expanded its host range, we tested its infectivity on Chinese hamster ovary-derived CHO-K1 cells, which are generally resistant to ecotropic MuLV. The results indicated that PVC-211 MuLV, but not F-MuLV, was highly infectious for CHO-K1 cells. Studies using glycosylation inhibitors and glycosylation mutants of CHO-K1 cells, as well as interference studies, suggested that PVC-211 MuLV has acquired the ability to interact with the ecotropic MuLV receptor on CHO-K1 cells that has undergone glycosylation-dependent modification. Using chimeric viruses between PVC-211 MuLV and F-MuLV, we were able to localize the viral genetic element crucial for CHO-K1 cell tropism within the env gene of PVC-211 MuLV and show that glycine at position 116 and lysine at position 129 of the envelope glycoprotein SU were important. These viral determinants also appear to confer tropism for other hamster cells resistant to ordinary ecotropic MuLVs. Further studies on the interaction between PVC-211 MuLV and the receptor on hamster cells may provide novel insights into the molecular mechanisms for receptor recognition and binding by viral envelope glycoproteins.


[Syrian hamster sensitivity to tumor cell inoculation in the period of pregnancy and nursing the cubs].
The influence of pregnancy and lactation on the sensitivity of females to the transplantation of tumor cells was studied in experiments with Syrian hamsters. During the first days of the joint keeping of males and females (1--6 days before pregnancy) the latter ones were shown to be more resistant to the transplantation of tumor cells as compared with unbearing females. However, days 1--8 of pregnancy and during lactation no subtantial differences were revealed between animal groups compared in the sensitivity to the transplantation of tumor cells.


Magneto-optical Selection Rules in Bilayer Bernal Graphene.
The low-frequency magneto-optical properties of bilayer Bernal graphene are studied by the tight-binding model with the four most important interlayer interactions taken into account. Since the main features of the wave functions are well-depicted, the Landau levels can be divided into two groups based on the characteristics of the wave functions. These Landau levels lead to four categories of absorption peaks in the optical absorption spectra. Such absorption peaks own complex optical selection rules, and these rules can be reasonably explained by the characteristics of the wave functions. In addition, twin-peak structures, regular frequency-dependent absorption rates, and complex field-dependent frequencies are also obtained in this work. The main features of the absorption peaks are very different from those in monolayer graphene and have their origin in the interlayer interactions.


Nosocomial urinary tract infection. Risk factors, rates and trends.
This report aims at both estimation of the rates of overall nosocomial and urinary tract infection (UTI) and their linear trends as well as studying the potential risk factors of patients admitted to Al-Hada, Rehab and Prince Sultan military hospitals and developed nosocomial UTIs (NUTIs). A case-control study on 206 discharged patients with confirmed UTI and 618 controls without UTI was carried out between August 2001 through to July 2003 to study risk factors for nosocomial UTI as well as hospital records during the period (1998-2002) were reviewed for calculation of the overall annual nosocomial infection and nosocomial UTI rates. Multiple logistic regression analysis showed that duration of hospital stay, unit of admission, history of diabetes mellitus or debilitating diseases, and duration and number of urinary catheters were independently associated with increased risk of NUTIs. The mean incidence rate of overall nosocomial infection along the study period (1998-2002) was 2.82, while the mean incidence rate of UTI nosocomial infection was 0.85 per 100 discharged patients. Urinary tract infection represents approximately 31.7% of overall nosocomial infection throughout the study period. Urinary tract infections comprise approximately one third of nosocomial infections. The results, thus, indicated that to reduce the incidence of UTI nosocomial infection, it was important to take factors that can be managed into consideration. Therefore, the involved persons should pay more attention and set practical and effective guidelines for the hospital.


Phase I study of subcutaneously administered interleukin-2 in combination with interferon alfa-2a in patients with advanced cancer.
Although high-dose interleukin-2 (IL-2) can produce durable remissions in a subset of responding patients with renal cell carcinoma (RCC), this occurs in the setting of significant toxicity. The purpose of this study is to define the maximum-tolerated dosage (MTD) of IL-2 and interferon alfa-2a (IFN alpha-2a) that can be administered chronically on an outpatient basis. Fifty-three patients with advanced cancer of variable histology with good prognostic features were treated in six cohorts. Patients in cohorts one through five received IL-2 (1.5 or 3.0 x 10(6) million units (mU)/m2) Monday through Friday and IFN alpha-2a (1.5 or 3 x 10(6) mU/m2) daily for a 4-week cycle. In cohort six, IFN alpha-2a was given three times a week. Immunologic monitoring, including serum levels of soluble IL-2 receptor (sIL-2R) and neopterin, flow cytometry, and natural killer cell (NK) activity, were measured. Patients were evaluated for toxicity, response, and survival. Almost all patients developed grade I/II toxicities commonly associated with cytokine therapy. Symptoms were most severe with the first treatment of each week. Dose-limiting toxicities included grade III fatigue, hypotension, and creatinine elevations. The MTD was 1.5 mU/m2 daily x 5 given subcutaneously repeated weekly for IL-2 and 1.5 mU/m2 daily subcutaneously (dose level 3) for IFN. Six of 25 assessable patients with RCC (24%) achieved a partial response (PR), including four of eight patients who were previously untreated. There were no objective responses in patients with other tumors, including 12 melanoma patients. IL-2 and IFN alpha-2a can be given with tolerable toxicities on an outpatient basis and shows significant activity in patients with metastatic RCC.


Inference of Bacterial Small RNA Regulatory Networks and Integration with Transcription Factor-Driven Regulatory Networks.
Small noncoding RNAs (sRNAs) are key regulators of bacterial gene expression. Through complementary base pairing, sRNAs affect mRNA stability and translation efficiency. Here, we describe a network inference approach designed to identify sRNA-mediated regulation of transcript levels. We use existing transcriptional data sets and prior knowledge to infer sRNA regulons using our network inference tool, the Inferelator This approach produces genome-wide gene regulatory networks that include contributions by both transcription factors and sRNAs. We show the benefits of estimating and incorporating sRNA activities into network inference pipelines using available experimental data. We also demonstrate how these estimated sRNA regulatory activities can be mined to identify the experimental conditions where sRNAs are most active. We uncover 45 novel experimentally supported sRNA-mRNA interactions in Escherichia coli, outperforming previous network-based efforts. Additionally, our pipeline complements sequence-based sRNA-mRNA interaction prediction methods by adding a data-driven filtering step. Finally, we show the general applicability of our approach by identifying 24 novel, experimentally supported, sRNA-mRNA interactions in Pseudomonas aeruginosa, Staphylococcus aureus, and Bacillus subtilis Overall, our strategy generates novel insights into the functional context of sRNA regulation in multiple bacterial species.IMPORTANCE Individual bacterial genomes can have dozens of small noncoding RNAs with largely unexplored regulatory functions. Although bacterial sRNAs influence a wide range of biological processes, including antibiotic resistance and pathogenicity, our current understanding of sRNA-mediated regulation is far from complete. Most of the available information is restricted to a few well-studied bacterial species; and even in those species, only partial sets of sRNA targets have been characterized in detail. To close this information gap, we developed a computational strategy that takes advantage of available transcriptional data and knowledge about validated and putative sRNA-mRNA interactions for inferring expanded sRNA regulons. Our approach facilitates the identification of experimentally supported novel interactions while filtering out false-positive results. Due to its data-driven nature, our method prioritizes biologically relevant interactions among lists of candidate sRNA-target pairs predicted in silico from sequence analysis or derived from sRNA-mRNA binding experiments.


Model Construction and Analysis of Respiration in Halobacterium salinarum.
The archaeon Halobacterium salinarum can produce energy using three different processes, namely photosynthesis, oxidative phosphorylation and fermentation of arginine, and is thus a model organism in bioenergetics. Compared to its bacteriorhodopsin-driven photosynthesis, less attention has been devoted to modeling its respiratory pathway. We created a system of ordinary differential equations that models its oxidative phosphorylation. The model consists of the electron transport chain, the ATP synthase, the potassium uniport and the sodium-proton antiport. By fitting the model parameters to experimental data, we show that the model can explain data on proton motive force generation, ATP production, and the charge balancing of ions between the sodium-proton antiporter and the potassium uniport. We performed sensitivity analysis of the model parameters to determine how the model will respond to perturbations in parameter values. The model and the parameters we derived provide a resource that can be used for analytical studies of the bioenergetics of H. salinarum.


Osteopontin and fibronectin levels are decreased in vitreous of autoimmune uveitis and retinal expression of both proteins indicates ECM re-modeling.
Autoimmune uveitis is an intraocular inflammation that arises through autoreactive T-cells attacking the inner eye, eventually leading to blindness. However, the contributing molecular pathomechanisms within the affected tissues remain as yet elusive. The extracellular matrix (ECM) is a highly dynamic structure that varies tremendously and influences the encompassing tissue. In order to assess ECM re-modeling in autoimmune uveitis, we investigated the expression of ECM molecules fibronectin and osteopontin in vitreous and retina samples. This was carried out in the only spontaneous animal model for human autoimmue uveitis, namely equine recurrent uveitis (ERU) that resembles the human disease in clinical as well as in immunopathological aspects. ERU is a naturally occurring autoimmune disease in horses that develops frequently and has already proved its value to study disease-related pathomechanisms. Western blot analysis of fibronectin and osteopontin in healthy and uveitic vitreous revealed significant reduction of both proteins in uveitis. Immunohistochemical expression of fibronectin in healthy retinas was restricted to the inner limiting membrane abutting vimentin positive Müller cell endfeet, while in uveitic sections, a disintegration of the ILM was observed changing the fibronectin expression to a dispersed pattern extending toward the vitreous. Retinal expression of osteopontin in control tissue was found in a characteristic Müller cell pattern illustrated by co-localization with vimentin. In uveitic retinas, the immunoreactivity of osteopontin in gliotic Müller cells was almost absent. The ability of Müller cells to express fibronectin and osteopontin was additionally shown by immunocytochemistry of primary cultured equine Müller cells and the equine Müller cell line eqMC-7. In conclusion, severe ECM re-modeling in autoimmune uveitis reported here, might affect the adhesive function of fibronectin and thus the anchoring of Müller cell endfeet to the ILM. Furthermore, the absence of osteopontin in gliotic Müller cells might represent reduced neuroprotection, an osteopontin attribute that is intensively discussed.


Activated human NK and CD8+ T cells express both TNF-related apoptosis-inducing ligand (TRAIL) and TRAIL receptors but are resistant to TRAIL-mediated cytotoxicity.
The expression of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and TRAIL receptors was investigated in resting and cytokine-activated purified primary human natural killer (NK) and CD8(+) T cells. Resting NK and CD8(+) T cells expressed the mRNA for all TRAIL receptors, but TRAIL-R4 was the only receptor clearly detectable on the surface of both cell types. NK cells were activated by interleukin 2 (IL-2) or IL-15, whereas CD8(+) T cells were activated by phytohemagglutinin (PHA) + IL-2 followed by IL-2 alone for up to 10 days. On activation, both cell types rapidly expressed TRAIL-R2 and TRAIL-R3, whose expression peaked at day 10 of culture. TRAIL-R1, however, was never expressed at any time point examined, whereas the expression of TRAIL-R4, which showed a progressive increase in CD8(+) T cells, remained constant in NK cells. Notwithstanding the expression of TRAIL-R2, recombinant TRAIL did not show any cytotoxic activity on either NK or CD8(+) T cells. Both resting and activated NK and CD8(+) T cells were found to express high levels of the 2 isoforms of c-FLIP (cellular Fas-associated death domain protein [FADD]-like IL-1-converting enzyme [FLICE]-inhibitory protein). Small interference RNA-mediated inhibition of c-FLIP expression in NK cells abrogated their resistance to the apoptotic effect of soluble TRAIL. Thus, once activated the major cytotoxic effector cells are potentially sensitive to TRAIL but are physiologically protected from its apoptotic action by intracellular level of c-FLIP.


Complications of long-term drainage of fetal pleural effusion: case report and review of the literature.
Severe fetal pleural effusion and ascites in the second trimester are associated with poor prognosis. We present a case where long-term drainage of several pleural effusion by a double reverse pig tail stent was achieved. Although the ultimate outcome was successful, complications seen in this case include accidental placement of the proximal opening of the catheter, first into the myometrium, then between amnion and chorion; development of oligohydramnios; intrathoracic migration of the catheter. Review of the literature reveals a multitude of other complications associated with this procedure, specifically difficulties at the time of placement and failure of function due to obstruction, migration of the catheter, or removal by the fetus. It is important to consider these complications in the counseling and management of the patients. Ongoing research is required to further improve the design of the catheters.


Occult bacteraemia in cardiac implantable electronic device patients: a review of diagnostic workflow and mandatory therapy.
: Cardiac implantable electronic device (CIED) implantation has greatly increased, with an associated exponential increase in CIED infections (CDIs). Cardiac device related infective endocarditis (CDRIE) has high morbidity and mortality: approximately 10-21%. Therefore, a prompt diagnosis and radical treatment of CDRIE are needed; transvenous lead extraction (TLE) is the mainstay for the complete healing, even if associated with wide logistic problems, high therapeutic costs and high mortality risk for patients. Some criticisms about the value of Duke criteria and their limitations for the diagnosis of CDRIE are known. The significance of classic laboratory data, transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE), considered in the Duke score, are reviewed and critically discussed in this article, with regard to the specific field of the diagnosis of CDI. The need for new techniques for achieving the diagnostic reliability has been well perceived by physicians, and additional techniques have been introduced in the new European Society of Cardiology (ESC) and British Heart Rhythm Society (BHRS) guidelines on infective endocarditis. These suggested techniques, such as 18-Fluorodeoxyglucose PET/computed tomography (FDG-PET/CT), white blood cell PET (WBC PET) and lung multislice CT (MSCT), are also discussed in the study. This short review is intended as an extensive summary of the diagnostic workflow in cases of CDI and will be useful for readers who want to know more about this issue.


Algorithms for calculating detector efficiency normalization coefficients for true coincidences in 3D PET.
Accurate normalization of lines of response in 3D PET is a prerequisite for quantitative reconstruction. Most current methods are component based, calculating a series of geometric and intrinsic detector efficiency factors. We have reviewed the theory behind several existing algorithms for calculating detector efficiency factors in 2D and 3D PET, and have extended them to create a range of new algorithms. Three of the algorithms described are 'fully 3D' in that they make use of data from all detector rings for the calculation of the efficiencies of any one line of response. We have assessed the performance of the new and existing methods using simulated and real data, and have demonstrated that the fully 3D algorithms allow the rapid acquisition of crystal efficiency normalization data using low-activity sources. Such methods enable the use of scatter-free scanning line sources or the use of very short acquisitions of cylindrical sources for routine normalization.


A review of treatment-emergent adverse events during olanzapine clinical trials in elderly patients with dementia.
Olanzapine and other antipsychotics are not approved by the U.S. Food and Drug Administration to treat behavioral disturbances associated with dementia, but they are often prescribed to these patients. Although antipsychotics may be efficacious in this population, elderly patients with dementia may be particularly vulnerable to adverse events. This article reviews the safety of olanzapine in elderly patients with dementia. Data from 6 studies comparing olanzapine to placebo, risperidone, or conventional antipsychotics in elderly patients with dementia were analyzed for mortality, cerebrovascular adverse events (CVAEs), and other adverse events. These trials represent all Lilly olanzapine-comparator trials in this population. The data included integration of 5 double-blind, placebo-controlled studies (olanzapine, N = 1184; placebo, N = 478; median age = 79 years; 1 study also compared olanzapine with risperidone, N = 196) and an open-label study comparing olanzapine (N = 150) with conventional antipsychotics (N = 143). Incidence of mortality was significantly higher in olanzapine- (3.5%) than in placebo-treated patients (1.5%; p = .024). There were no significant differences in the crude incidence of mortality between olanzapine- (2.9%) and risperidone- (2.0%) or olanzapine- (14.8%) and conventional antipsychotic-treated patients (16.1%; p = .871). Risk factors associated with mortality in olanzapine-treated patients included age >/= 80, concurrent benzodiazepine use, treatment-emergent sedation, or treatment-emergent pulmonary conditions. Incidence of CVAEs was approximately 3 times higher in olanzapine- (1.3%) than in placebo-treated patients (0.4%). There were no significant differences in the incidence of CVAEs between olanzapine- (2.5%) and risperidone- (2.0%; p = 1.0) or olanzapine- (3.4%) and conventional antipsychotic-treated patients (4.3%; p = .765). These findings should be considered if prescribers elect to treat behavioral disturbances associated with dementia in the elderly with olanzapine or other antipsychotics.


Six methods for direct radioiodination of mouse epidermal growth factor compared: effect of nonequivalence in binding behavior between labeled and unlabeled ligand.
Mouse epidermal growth factor (EGF) was radioiodinated by six different direct iodination methods. The 125I-labeled EGF preparations were distinguished by analyzing the binding of the radioligand to the EGF receptor (EGFR)-containing human placental membranes. The receptor-binding affinity of EGF labeled with Chloramine T was less than the affinity of unlabeled EGF, which precluded an accurate determination of the specific radioactivity of the 125I-labeled EGF preparation by "self-displacement analysis." Scatchard analysis of competitive binding data (increasing concentrations of unlabeled EGF) obtained with commercially prepared 125I-labeled EGF (Chloramine T method), according to the specific radioactivity stated by the manufacturer, resulted in a substantial underestimation of the apparent number of receptors. Iodination of EGF with Iodogen or Iodo-beads, reagents claimed to be more gentle because of their solid state, also yielded 125I-labeled EGF preparations that were not equivalent to the native EGF in receptor binding. In contrast, equivalence in the ligand-receptor interaction between labeled and unlabeled EGF could be achieved by iodinating EGF with iodine monochloride (ICl), Protag-125, or lactoperoxidase-glucose oxidase-coupled beads (Enzymobeads). Scatchard plots of saturation and competitive binding data obtained with these 125I-labeled EGF preparations produced identical results for apparent receptor number and apparent dissociation constants. Such radioiodinated EGF preparations yield relevant binding data in competition studies of labeled and unlabeled EGF.


Subjective responses to oral tobacco products: scale validation.
Several noncombusted oral tobacco products have been introduced that are primarily marketed to cigarette smokers. An important component of evaluating these products involves assessment of subjective responses to the product. To date, few studies have been undertaken to examine the validity of subjective response questionnaires for oral tobacco products. The goal of this study is to examine the extent subjective responses to a product are related to product preference and extent of product use. Data from a study examining oral tobacco product preference were used. Smokers were asked to sample a variety of oral tobacco products that differed in formulation (snus versus dissolvables) and dose of nicotine. At the end of the sampling period, subjects were asked to choose the product that they would use to completely substitute for cigarettes for the next 2 weeks. During the sampling period, subjects completed a Product Evaluation Scale (PES) that describes subjective responses to the product. During the treatment phase, they kept record of amount of product use. Subjective responses to the product on the PES were related to product choice and to some extent, the amount of product use. Product choice was associated with different characteristics of the product and smoker needs. The PES may be a useful tool for the evaluation or oral tobacco products.


Old proverbs in new skins - an FMRI study on defamiliarization.
We investigated how processing fluency and defamiliarization (the art of rendering familiar notions unfamiliar) contribute to the affective and esthetic processing of reading in an event-related functional magnetic-resonance-imaging experiment. We compared the neural correlates of processing (a) familiar German proverbs, (b) unfamiliar proverbs, (c) defamiliarized variations with altered content relative to the original proverb (proverb-variants), (d) defamiliarized versions with unexpected wording but the same content as the original proverb (proverb-substitutions), and (e) non-rhetorical sentences. Here, we demonstrate that defamiliarization is an effective way of guiding attention, but that the degree of affective involvement depends on the type of defamiliarization: enhanced activation in affect-related regions (orbito-frontal cortex, medPFC) was found only if defamiliarization altered the content of the original proverb. Defamiliarization on the level of wording was associated with attention processes and error monitoring. Although proverb-variants evoked activation in affect-related regions, familiar proverbs received the highest beauty ratings.


Postoperative hyperthermia of unknown origin treated with dantrolene sodium.
An 11-year-old girl was scheduled for alveolar cleft bone grafting with an iliac bone under general anesthesia. Anesthesia was performed with 70% nitrous oxide, 30% oxygen, and propofol. On the first and second postoperative day, persistent hyperthermia was observed. Because the administration of diclofenac sodium had not been effective for the hyperthermia, dantrolene sodium was given. Her body temperature gradually dropped and returned to normal level on the fifth postoperative day. The hyperthermia in the present case might have been caused by a rapidly elevated muscle metabolism in response to pain and stress after the propofol anesthesia. The oral administration of dantrolene sodium successfully lowered the patient's high body temperature.


Mitochondrial dysfunction in Parkinsonian mesenchymal stem cells impairs differentiation.
Sporadic cases account for 90-95% of all patients with Parkinson's Disease (PD). Atypical Parkinsonism comprises approximately 20% of all patients with parkinsonism. Progressive Supranuclear Palsy (PSP) belongs to the atypical parkinsonian diseases and is histopathologically classified as a tauopathy. Here, we report that mesenchymal stem cells (MSCs) derived from the bone marrow of patients with PSP exhibit mitochondrial dysfunction in the form of decreased membrane potential and inhibited NADH-dependent respiration. Furthermore, mitochondrial dysfunction in PSP-MSCs led to a significant increase in mitochondrial ROS generation and oxidative stress, which resulted in decrease of major cellular antioxidant GSH. Additionally, higher basal rate of mitochondrial degradation and lower levels of biogenesis were found in PSP-MSCs, together leading to a reduction in mitochondrial mass. This phenotype was biologically relevant to MSC stemness properties, as it heavily impaired their differentiation into adipocytes, which mostly rely on mitochondrial metabolism for their bioenergetic demand. The defect in adipogenic differentiation was detected as a significant impairment of intracellular lipid droplet formation in PSP-MSCs. This result was corroborated at the transcriptional level by a significant reduction of PPARγ and FABP4 expression, two key genes involved in the adipogenic molecular network. Our findings in PSP-MSCs provide new insights into the etiology of 'idiopathic' parkinsonism, and confirm that mitochondrial dysfunction is important to the development of parkinsonism, independent of the type of the cell.


Effects of hearing the past, present, or future during music performance.
Three experiments were performed to explore the effects of mismatches between actions (key-presses) and the contents of auditory feedback (pitch events) during music performance. Pianists performed melodies from memory during altered auditory feedback that was synchronized with key-presses but matched the pitch of other sequence events. Feedback direction was manipulated by presenting pitches that matched events intended for the past (delays; Experiments 1 and 3) or the future (prelays; Experiments 2 and 3). Feedback distance was manipulated by varying the absolute separation between the current event and the location of the feedback pitch. All alterations disrupted the accuracy of performance (pitch errors) more so than timing. Serial-ordering errors indicated confusions among proximal and metrically similar events, consistent with the predictions of an incremental planning model (Palmer & Pfordresher, 2003). Patterns of serial-ordering errors suggested that performers compensate for the disruptive effects of altered feedback by changing event activations during planning.


Mechanism of hyaluronan degradation by Streptococcus pneumoniae hyaluronate lyase. Structures of complexes with the substrate.
Hyaluronate lyase enzymes degrade hyaluronan, the main polysaccharide component of the host connective tissues, predominantly into unsaturated disaccharide units, thereby destroying the normal connective tissue structure and exposing the tissue cells to various endo- and exogenous factors, including bacterial toxins. The crystal structures of Streptococcus pneumoniae hyaluronate lyase with tetra- and hexasaccharide hyaluronan substrates bound in the active site were determined at 1.52- and 2.0-A resolution, respectively. Hexasaccharide is the longest substrate segment that binds entirely within the active site of these enzymes. The enzyme residues responsible for substrate binding, positioning, catalysis, and product release were thereby identified and their specific roles characterized. The involvement of three residues in catalysis, Asn(349), His(399), and Tyr(408), is confirmed, and the details of proton acceptance and donation within the catalytic machinery are described. The mechanism of processivity of the enzyme is analyzed. The flexibility (allosteric) behavior of the enzyme may be understood in terms of the results of flexibility analysis of this protein, which identified two modes of motion that are also proposed to be involved in the hyaluronan degradation process. The first motion describes an opening and closing of the catalytic cleft located between the alpha- and beta-domains. The second motion demonstrates the mobility of a binding cleft, which may facilitate the binding of the negatively charged hyaluronan to the enzyme.


Impact of Hospital "Best Practice" Mandates on Prescription Opioid Dispensing After an Emergency Department Visit.
Washington State mandated seven hospital "best practices" in July 2012, several of which may affect emergency department (ED) opioid prescribing and provide a policy template for addressing the opioid prescription epidemic. We tested the hypothesis that the mandates would reduce opioid dispensing after an ED visit. We further assessed for a selective effect in patients with prior risky or chronic opioid use. We performed a retrospective, observational analysis of ED visits by Medicaid fee-for-service beneficiaries in Washington State, between July 1, 2011, and June 30, 2013. We used an interrupted time-series design to control for temporal trends and patient characteristics. The primary outcome was any opioid dispensing within 3 days after an ED visit. The secondary outcome was total morphine milligram equivalents (MMEs) dispensed within 3 days. We analyzed 266,614 ED visits. Mandates were associated with a small reduction in opioid dispensing after an ED visit (-1.5%, 95% confidence interval [CI] = -2.8% to -0.15%). The mandates were associated with decreased opioid dispensing in 42,496 ED visits by patients with prior risky opioid use behavior (-4.7%, 95% CI = -7.1% to -2.3%) and in 20,238 visits by patients with chronic opioid use (-3.6%, 95% CI = -5.6% to -1.7%). Mandates were not associated with reductions in MMEs per dispense in the overall cohort or in either subgroup. Washington State best practice mandates were associated with small but nonselective reductions in opioid prescribing rates. States should focus on alternative policies to further reduce opioid dispensing in subgroups of high-risk and chronic users.


Neglected for too long? - CD8+ Tregs release NOX2-loaded vesicles to inhibit CD4+ T cells.
Tregs are critical for control of self-reactive T cells that escape thymic selection and end up in the periphery. Treg subsets suppress effector T cell populations through the secretion of immunosuppressive molecules and inhibitory cytokines as well as cell contact-dependent mechanisms. In this issue of the JCI, Wen and colleagues describe another mechanism by which Tregs suppress effector T cell populations. Specifically, the authors reveal that CD8+ T cells in close contact with target T cells release NADPH oxidase 2-containing microvesicles that inhibit TCR activation by elevating ROS and thereby reducing phosphorylation of the TCR-associated kinase ZAP70. Together, the results of this study provide important insight into CD8+ Treg function and into the development of autoimmunity in older individuals.


Nerve guides manufactured from photocurable polymers to aid peripheral nerve repair.
The peripheral nervous system has a limited innate capacity for self-repair following injury, and surgical intervention is often required. For injuries greater than a few millimeters autografting is standard practice although it is associated with donor site morbidity and is limited in its availability. Because of this, nerve guidance conduits (NGCs) can be viewed as an advantageous alternative, but currently have limited efficacy for short and large injury gaps in comparison to autograft. Current commercially available NGC designs rely on existing regulatory approved materials and traditional production methods, limiting improvement of their design. The aim of this study was to establish a novel method for NGC manufacture using a custom built laser-based microstereolithography (μSL) setup that incorporated a 405 nm laser source to produce 3D constructs with ∼ 50 μm resolution from a photocurable poly(ethylene glycol) resin. These were evaluated by SEM, in vitro neuronal, Schwann and dorsal root ganglion culture and in vivo using a thy-1-YFP-H mouse common fibular nerve injury model. NGCs with dimensions of 1 mm internal diameter × 5 mm length with a wall thickness of 250 μm were fabricated and capable of supporting re-innervation across a 3 mm injury gap after 21 days, with results close to that of an autograft control. The study provides a technology platform for the rapid microfabrication of biocompatible materials, a novel method for in vivo evaluation, and a benchmark for future development in more advanced NGC designs, biodegradable and larger device sizes, and longer-term implantation studies.


The reproductive system of Osedax (Annelida, Siboglinidae): ovary structure, sperm ultrastructure, and fertilization mode.
Osedax is a genus of siboglinid annelids in which the females live on dead vertebrate bones on the seafloor. These females have a posterior end that lies within the bone and contains the ovarian tissue, as well as the "roots" involved with bone degradation and nutrition. The males are microscopic and live as "harems" in the lumen of the gelatinous tube that surrounds the female trunk, well away from the ovary. Females are known to spawn fertilized primary oocytes, suggesting internal fertilization. However, little is known about sperm transfer, sperm storage, or the location of fertilization, and the morphology of the female reproductive system has not been described and compared with the reproductive systems of other siboglinids. A 3D-reconstruction of the ovisac of Osedax showed ovarian tissue with multiple lobes and mature oocytes stored in a "uterus" before being released through the single oviduct. The oviduct emerges as a gonopore on the trunk and travels along the trunk to finally open to the seawater as a thin cylindrical tube among the crown of palps. Light and transmission electron microscopy of mature Osedax sperm revealed elongate heads consisting of a nucleus with helical grooves occupied by mitochondria. In contrast to other Siboglinidae, Osedax sperm are not packaged into spermatophores or spermatozeugmata, and Osedax females lack a discrete region for sperm storage. Transmission electron microscopy and fluorescence microscopy allowed detection of sperm associated with ovarian tissue of the female ovisac of four different Osedax species. This provides the first evidence for the site of internal fertilization in Osedax. A heart body was found in the circulatory system, as seen in other siboglinids and some other annelids. The possible presence of nephridia in the anterior ovisac region was also documented. These morphological features provide new insights for comparing the regionalization of Osedax females in relation to other siboglinids.


A critical appraisal of analyzing nasal provocation test results in allergen immunotherapy trials.
The statistical analysis of nasal provocation tests is very complex. We compared the conventional analysis with the maximally selected test statistics and the hierarchical ordered logistic model. We re-analyzed data from a trial with 112 patients suffering from grass pollen allergy. The patients had been randomized to receive either intralymphatic immunotherapy (ILIT) or subcutaneous immunotherapy (SCIT). The conventional analysis indicated that the logarithmized ratio between the pre- and the post-treatment threshold concentration was significantly lower for ILIT than for SCIT. The maximally selected test statistics was used to test different threshold symptom scores that would imply positive clinical symptoms at the given allergen concentration. A threshold score of 3 maximised the difference in improvement between the ILIT and the SCIT groups. The hierarchical ordered logistic model does not take threshold allergen concentrations as the basis for analysis, but the single scores measured at each concentration. This approach simultaneously considers the treatment effect (ILIT versus SCIT), the time effect (pre- versus post-treatment), and the dose effect (different allergen concentrations). The hierarchical ordered logistic model revealed that the clinical improvement was greater after ILIT than after SCIT. As the choice of method can affect the outcome, guidelines for analysis are highly needed.


Rational Design of Topical Semi-Solid Dosage Forms-How Far Are We?
Specific aspects of semi-solid dosage forms for topical application include the nature of the barrier to be overcome, aspects of susceptibility to physical and chemical instability, and a greater influence of sensory perception. Advances in understanding the driving forces of skin penetration as well as the design principles and inner structure of formulations, provide a good basis for the more rational design of such dosage forms, which still often follow more traditional design approaches. This review analyses the opportunities and constraints of rational formulation design approaches in the industrial development of new topical drugs. As the selection of drug candidates with favorable physicochemical properties increases the speed and probability of success, models for drug selection based on theoretical and experimental approaches are discussed. This paper reviews how progress in the scientific understanding of mechanisms and vehicle-influence of skin penetration can be used for rational formulation design. The characterization of semi-solid formulations is discussed with a special focus on modern rheological approaches and analytical methods for investigating and optimizing the chemical stability of active ingredients in consideration of applicable guidelines. In conclusion, the combination of a good understanding of scientific principles combined with early consideration of regulatory requirements for product quality are enablers for the successful development of innovative and robust semi-solid formulations for topical application.


Dietary carbohydrate, muscle glycogen content, and endurance performance in well-trained women.
This study examined the ability of well-trained eumenorrheic women to increase muscle glycogen content and endurance performance in response to a high-carbohydrate diet (HCD; approximately 78% carbohydrate) compared with a moderate-carbohydrate diet (MD; approximately 48% carbohydrate) when tested during the luteal phase of the menstrual cycle. Six women cycled to exhaustion at approximately 80% maximal oxygen uptake (VO(2 max)) after each of the randomly assigned diet and exercise-tapering regimens. A biopsy was taken from the vastus lateralis before and after exercise in each trial. Preexercise muscle glycogen content was high after the MD (625.2 +/- 50.1 mmol/kg dry muscle) and 13% greater after the HCD (709.0 +/- 44.8 mmol/kg dry muscle). Postexercise muscle glycogen was low after both trials (MD, 91.4 +/- 34.5; HCD, 80.3 +/- 19.5 mmol/kg dry muscle), and net glycogen utilization during exercise was greater after the HCD. The subjects also cycled longer at approximately 80% VO(2 max) after the HCD vs. MD (115:31 +/- 10:47 vs. 106:35 +/- 8:36 min:s, respectively). In conclusion, aerobically trained women increased muscle glycogen content in response to a high-dietary carbohydrate intake during the luteal phase of the menstrual cycle, but the magnitude was smaller than previously observed in men. The increase in muscle glycogen, and possibly liver glycogen, after the HCD was associated with increased cycling performance to volitional exhaustion at approximately 80% VO(2 max).


Efficacy and Safety of Oral TDF-Based Pre-exposure Prophylaxis for Men Who Have Sex With Men: A Systematic Review and Meta-Analysis.
Background: Pre-exposure prophylaxis (PrEP) is used as an HIV prevention method by people at substantial risk of HIV infection. This systematic review and meta-analysis evaluates current clinical evidence for use of oral TDF-based PrEP among men who have sex with men. Methods: A comprehensive literature search in PubMed, web of science, Google Scholar and ClinicalTrials.gov was performed. A random-effects meta-analysis was conducted using the event rate (ER) for estimation of the incidence of HIV and grade 3 or 4 adverse events (AE) among PrEP arm and using risk ratio (RR) for comparison of incidence of HIV and grade 3 or 4 AE between PrEP recipients and PrEP non-users. Blood-based adherence levels were also divided into three categories with reference to previous meta-analysis. Subgroup meta-analysis was also performed to evaluate whether blood-based adherence levels moderated the effect of TDF-based PrEP on HIV incidence. Narrative review was used due to inconsistent measurements of risk behavior and drug resistance. This review is registered on the PROSPERO database (CRD42017077965). Results: Fourteen studies were included in the review. Oral TDF-based PrEP significantly reduced HIV incidence with minimum drug resistance and tolerable safety risks (HIV incidence, ER = 1.1%, 95% CI 0.6-2.0%, p < 0.001, RR = 0.244, 95% CI 0.111-0.537, p < 0.001 and grade 3 or 4 AEs, ER = 13.0%, 95% CI 9.9-16.9%, p < 0.001, RR = 1.059, 95% CI 0.824-1.362, p = 0.653). Oral TDF-based PrEP was more effective in reducing HIV incidence with high levels of blood-based PrEP adherence (ER, 0.4%) compared to moderate adherence (2.9%; p < 0.001). Most studies found no association between PrEP use and self-reported sexual behavior. Conclusion: Oral TDF-based PrEP is an effective intervention to prevent against HIV infection among MSM. Well-designed implementation science studies that integrate sociobehavioral and biomedical interventions are needed to identify optimal PrEP delivery models in different populations to translate biomedical efficacy into real-world efficacy.


Inhibitory effect of alcohol on osteogenic differentiation in human bone marrow-derived mesenchymal stem cells.
Alcohol-induced osteoporosis is characterized by a considerable suppression of osteogenesis. The objective of this investigation was to determine the effect of alcohol on gene expression, protein synthesis, and mineralization in human bone marrow-derived mesenchymal stem cells induced toward osteogenic differentiation in vitro. Human bone marrow-derived mesenchymal stem cells induced toward osteogenesis were cultured in the presence or absence of 50 mM alcohol. Stem cells were characterized by using SH2 antibody to the cell-surface antigen CD105/endoglin, and their proliferation in the presence of alcohol was quantified. The expression of genes for early, middle, and late markers of the osteogenic lineage was quantified by Northern analysis, and bone matrix protein synthesis was assayed. The effect of alcohol on cell-mediated matrix mineralization in terminally differentiated cultures was determined by von Kossa staining. Fluorescence-activated cell sorting analysis of human mesenchymal stem cells separated with a Percoll gradient proved 99% homogeneity by using SH2 antibody to the surface antigen CD105. Dose-dependent inhibition of proliferation of these stem cells occurred at concentrations greater than 50 mM alcohol. Gene expression of osteoblast-specific factor 2/core binding factor a1 (Osf2/Cbfa1), type I collagen, alkaline phosphatase, and osteocalcin (early, middle, and late markers for osteogenesis, respectively) was analyzed with and without osteogenic induction and treatment with 50 mM alcohol. After induction, Osf2/Cbfa1 levels were unresponsive to alcohol. To determine the effect of alcohol on human mesenchymal stem cell progression along the osteogenic pathway, messenger RNA (mRNA) levels for type I collagen, alkaline phosphatase, and osteocalcin were examined after osteogenic induction. After osteogenic induction, alcohol down-regulated the gene expression of type I collagen and significantly reduced its synthesis. Alcohol did not alter mRNA expression of alkaline phosphatase, a midstage marker for osteogenesis, but significantly decreased its activity compared with osteogenic induction alone. After induction, osteocalcin remained unchanged by alcohol at both the mRNA and protein levels. Histochemistry revealed decreased alkaline phosphatase staining and fewer alkaline phosphatase-positive cells in alcohol-treated human mesenchymal stem cell cultures. von Kossa staining revealed a reduction in the number of mineralizing nodules in stem cell cultures after alcohol treatment. Collectively, the data suggest that alcohol alters osteogenic differentiation in human bone marrow-derived mesenchymal stem cell cultures during lineage progression and provide further insight into alcohol-induced reduced bone formation.


[The fractal structure of homeopathic preparations].
It was demonstrated (by the MFL method) in experiments the collective dynamical structural states of the liquid medium are the basis of the biological activity of homeopathic preparations (HP). The dynamical structure of water and HP determines the specific structure of the proton potentials in these media and the EM radiation of very low level and uniform spectrum. The vibration structure in medium (specific molecular dynamics, proton potential structure and spectrum of very low level eradiation) have fractal organization--spectrum of processes from high-frequency region (intramolecular vibrations) to low-frequency region (creation and destruction of clatrates) consists of consequence of corresponding regions with the repetition of frequency correlation in every region.


Photoperiod and bromocriptine treatment effects on expression of prolactin receptor mRNA in bovine liver, mammary gland and peripheral blood lymphocytes.
Recent evidence suggests that photoperiod influences immune function. Interestingly, photoperiod has profound effects on concentrations of prolactin (PRL), a hormone also known to be involved in fluctuations of the immune system. However, the impact of photoperiod on PRL receptor (PRL-R) expression is poorly understood, particularly in tIssues of the immune system. Two experiments were performed to increase the general understanding of how photoperiod interacts with the immune system. Our first objective was to determine the effects of photoperiod on PRL-R mRNA expression and cellular immune function. Lymphocytes were isolated from blood collected from calves (n=10) and PRL-R mRNA expression of both long and short forms was quantified using real-time PCR. Lymphocytes expressed PRL-R mRNA, suggesting that PRL could act directly on these cells. To determine the relationship between photoperiod and PRL-R mRNA expression in other tIssues, hepatic and mammary biopsies were collected after calves were exposed to long days (LDPP; 16 h light:8 h darkness) or short days (SDPP; 8 h light:16 h darkness). Relative to LDPP, SDPP decreased circulating PRL, but increased expression of both forms of PRL-R mRNA in liver, mammary gland and lymphocytes. Short days also increased lymphocyte proliferation compared with long days. Reversal of photoperiodic treatments reversed the effects on circulating PRL, PRL-R mRNA expression and lymphocyte proliferation. Our second objective was to manipulate PRL concentration in photoperiod-treated animals, using bromocriptine. Concentrations of PRL in LDPP animals injected daily with bromocriptine for 1 week were decreased compared with LDPP controls, to a level similar to SDPP animals. Receptor expression was increased in LDPP+bromocriptine-treated animals relative to LDPP controls, as was lymphocyte proliferation. Overall, our results indicate that photoperiodic effects on PRL-R mRNA expression were inverse to those on circulating PRL, with short days stimulating expression of both forms of PRL-R mRNA. Expression of PRL-R mRNA changed in the same direction as lymphocyte proliferation with regard to photoperiod treatment, suggesting a link between photoperiodic effects on PRL sensitivity and immune function. Thus, PRL signaling may mediate photoperiodic effects on immune function.


Attitudes toward cosmetic surgery patients: the role of culture and social contact.
Cosmetic surgery is increasingly popular globally, but how cosmetic surgery patients are socially evaluated is largely unknown. The present research documents attitudes toward these patients in multiple cultures (Hong Kong, Japan, and the United States). Across these cultures, attitudes toward cosmetic surgery patients were predominantly negative: Participants ascribed more negative attributes to cosmetic surgery patients and found cosmetic surgery not acceptable. Also, participants in Hong Kong and Japan were not willing to form social relationships, particularly intimate ones, with these patients. These attitudes were less negative in the United States than in Hong Kong and Japan, partly because social contact, which reduced negativity in attitudes toward cosmetic surgery patients, was more prevalent in the United States. These findings bear important implications for the subjective well-being of cosmetic surgery patients, who very often expect improvement in their social relationships through the surgery.


The course of pain hypersensitivity according to painDETECT in patients with rheumatoid arthritis initiating treatment: results from the prospective FRAME-cohort study.
Evidence is emerging that pain in rheumatoid arthritis (RA) exists without underlying inflammation. Our objective was to evaluate the prognostic value of pain classification at treatment initiation using the painDETECT questionnaire (PDQ). Outcomes were change in DAS28-CRP and RAMRIS synovitis score. RA patients initiating a disease-modifying anti-rheumatic drug (DMARD) or initiating/ switching a biological agent were included. Follow-up time was 4 months. Clinical examination, imaging (MRI, dynamic contrast-enhanced MRI (DCE-MRI)), and patient-reported outcomes were undertaken. The PDQ was used to differentiate pain mechanisms. Mean change (95% CI) was calculated using ANCOVA. Multivariable regression models were used to determine a prognostic value. A total of 102 patients were included; 75 were enrolled for MRI. Mean changes in baseline variables were greatest in the high PDQ classification group (> 18), while limited in the intermediate group (13-18). The 12 patients with high baseline PDQ score all changed pain classification group. No prognostic value of PDQ pain classification was found in relation to change of DAS28-CRP, RAMRIS score, or VAS pain. In the unadjusted model, RAMRIS score at baseline was associated with change in DAS28-CRP. The exploratory variables of DCE-MRI did not differ from other inflammatory variables. In RA patients a high PDQ score (non-nociceptive pain) at baseline was not associated with worse outcomes, in fact these patients had numerically greater improvement in DAS28-CRP. However, pain classification by PDQ was not independently associated with change in DAS28-CRP, RAMRIS score, or VAS pain in the prognostic models. Furthermore, patients classified with a high baseline PDQ score changed pain classification group. Patients with unclear pain mechanism had reduced numerically treatment response. The study was approved by the Regional Ethics Committee of the Capital of Denmark April 18 2013; identification number H-3-2013-049 .


Relationship between cognition and the severity of chronic tinnitus: Validation of the Japanese version of the Tinnitus Cognitions Questionnaire.
The Tinnitus Cognitions Questionnaire (TCQ) is a scale designed to assess the positive and negative cognitions associated with tinnitus. The purpose of this study was to validate the Japanese version of the TCQ and to analyze the relationship between cognition and the severity of chronic tinnitus. This was a cross-sectional, multicenter study. Patients with chronic tinnitus persisting for longer than 3 months were included. Participants completed the TCQ, the Tinnitus Handicap Inventory (THI), and the Hospital Anxiety and Depression Scale (HADS). They also completed the TCQ a second time 3-7 days later. The questionnaire was translated into Japanese. A factor analysis was performed and the convergent and discriminant validity, internal consistency, and test-retest reliability were evaluated. The total sample consisted of 75 participants. We obtained high Cronbach's α coefficients for the total score and subscales, ranging from 0.933 to 0.974. The total score and subscale interclass correlation coefficients for test-retest reliability ranged from 0.631 to 0.963. The factor analysis yielded a two-factor structure: negative and positive subscales. The convergent and discriminative validity was sufficiently clear. The negative subscale of the TCQ was strongly correlated with the THI and the HADS. The Japanese version of the TCQ was validated here. It also exhibited a two-factor structure that was well matched with previous data. And it was a highly consistent and reliable measure that can be used to evaluate cognitions in patients with chronic tinnitus. Negative cognition for tinnitus was greatly related to handicap and psychological state.


Evaluation of Thromboelastometry in Sepsis in Correlation With Bleeding During Invasive Procedures.
Prolongation of prothrombin time (PT) is often encountered in patients with sepsis. On the other hand, thromboelastometry as a global coagulation test might yield normal results. The aim of our study was to evaluate whether prolonged PT in the presence of normal thromboelastometry parameters is associated with severe bleeding in patients with sepsis undergoing invasive procedures. In patients with sepsis undergoing low-risk bleeding invasive procedures (central venous catheter placement, dialysis catheter insertion, drain insertion, and so on) or high-risk bleeding invasive procedures (surgical tracheostomy, surgical laparotomy, thoracotomy, and so on), coagulation was assessed by thromboelastometry using EXTEM test (test for evaluation of the extrinsic pathway of coagulation, contains activator of extrinsic pathway) and with PT. For period of years 2013 to 2016, we assessed occurrence of severe bleeding during those procedures and 24 hours later in patients with prolonged PT and normal thromboelastometry results. This retrospective study was performed at Department of Anaesthesiology and Intensive Care Medicine of Motol University Hospital in Prague. Data from 76 patients with sepsis were analyzed. Median value of international normalized ratio (INR) was 1.59 (min-1.3 and max-2.56), and median value of prothrombin ratio (PR) was 1.5 (min-1.23 and max-2.55) with normal thromboelastometry finding. Despite prolonged INR/PR, no severe bleeding was observed during invasive procedures. Our data show that sepsis may be accompanied by normal thromboelastometry results, despite prolonged values of PT, and invasive procedures were performed without severe bleeding. This approach to coagulation assessment in sepsis may reduce administration of fresh frozen plasma to the patients. The study was registered at Clinical Trials.gov with assigned number NCT02971111.


Ultrasonography, biochemical and hematological profiles in liver disease caused by intravenous administration of dimethylnitrosamine in dogs.
The results of liver function tests and ultrasonographical findings were analysed in 7 dogs that were intravenously injected dimethylnitrosamine (DMNA 2 mg/kg body weight) on 2 consecutive days each week for 10 weeks. Typical clinical signs and similar changes in liver enzyme concentrations that develop in dogs with natural cirrhosis were observed in this canine model. Severe anaemia and a significant reduction in the platelet numbers occurred in the dogs that died in the 5th week, while in all the other dogs these parameters decreased slightly. Serum total protein and the albumin/globulin ratio decreased gradually while the alkaline phosphatase, alanine amino transferase, aspartate amino transferase and gamma glutamyl transpeptidase activities increased significantly (p < 0.05) in all dogs after beginning the administration of DMNA. Ultrasound findings of a coarsened and heterogeneous echo pattern with increased echogenicity that are characteristic of canine cirrhosis were noticed at the same time when the changes in liver enzymes became evident. Present results suggest that ultrasonography in conjunction with liver function tests may be useful in the evaluation of experimentally induced liver cirrhosis.


Curative effect of the Egyptian marine Erugosquilla massavensis extract on carbon tetrachloride-induced oxidative stress in rat liver and erythrocytes.
The purpose of the present work was to investigate the effect of marine crustacean extract (MCE) from marine mantis shrimp Erugosquilla massavensis and silymarin on oxidative stress induced by carbon tetrachloride (CCl4) in rat liver and erythrocytes. Male rats were randomly divided into 3 main groups, (1) control group which administered olive oil orally for 2 days, followed by distilled water for 7 consecutive days, (2) MCE group in which rats administered orally MCE, 250 mg/kg body weight for 9 consecutive days and (3) CCl4-treated group in which rats given CCl4 orally (2.5 ml/kg body weight) for 2 days. This group then subdivided into 5 subgroups. All subgroups treated orally for 7 consecutive days with distilled water (subgroup I), silymarin, 150 mg/kg body weight (subgroup II) and MCE at three tested doses 50, 100 and 250 mg/kg body weight (subgroups III, IV and V). The MCE and silymarin produced significant hepatoprotective effect by decreasing the activity of serum aminotransferases (ASAT and ALAT) and alkaline phosphatase (ALP) as well as malondialdehyde (MDA) level, and increasing the serum total protein, glutathione reduced (GSH) levels and the activities of glutathione-S-transferase (GST) and catalase (CAT). The MCE and silymarin also showed the same antioxidant effect on erythrocytes. The results of the present study, suggested that, the MCE could protect the liver and erythrocytes injuries perhaps, by its antioxidative effect, hence eliminating the deleterious effect of toxic metabolites from CCl4.


Neoplastic disease and tumor immunology from the perspective of host-parasite relationships.
Neoplasia is considered within the biologic framework of host-parasite relationships, and the arguments favoring this perspective are discussed. By viewing neoplastic processes as dynamic interactions between transformed clones, host defense mechanisms, and the environmental circumstances impinging directly on the neoplastic event, the experimentalist and clinician are better prepared conceptually for a balanced assessment of all factors determining the development and outcome of confrontations with neoplastic clones. The frame of reference placing progressive neoplasia into the category of host-parasite associations also prepares the ground for techinical approaches to the study and observation of oncologic phenomena appropriate to their essential nature. The correct evaluation and most promising future development of the current emphasis on immunologic parameters of neoplasia demands especially an awareness of the role of immunologic variables in other host-parasite relationships.


The structure of multiplicative motions in natural imagery.
A theoretical investigation of the frequency structure of multiplicative image motion signals is presented, e.g., as associated with translucency phenomena. Previous work has claimed that the multiplicative composition of visual signals generally results in the annihilation of oriented structure in the spectral domain. As a result, research has focused on multiplicative signals in highly specialized scenarios where highly structured spectral signatures are prevalent, or introduced a nonlinearity to transform the multiplicative image signal to an additive one. In contrast, in this paper, it is shown that oriented structure is present in multiplicative cases when natural domain constraints are taken into account. This analysis suggests that the various instances of naturally occurring multiple motion structures can be treated in a unified manner. As an example application of the developed theory, a multiple motion estimator previously proposed for translation, additive transparency, and occlusion is adapted to multiplicative image motions. This estimator is shown to yield superior performance over the alternative practice of introducing a nonlinear preprocessing step.


Gpr75 knockout mice display age-dependent cone photoreceptor cell loss.
GPR75 is an orphan G protein-coupled receptor for which there is currently limited information and its function in physiology and disease is only recently beginning to emerge. This orphan receptor is expressed in the retina but its function in the eye is unknown. The earliest studies on GPR75 were conducted in the retina, where the receptor was first identified and cloned and mutations in the receptor were identified as a possible contributor to retinal degenerative disease. Despite these sporadic reports, the function of GPR75 in the retina and in retinal disease has yet to be explored. To assess whether GPR75 has a functional role in the retina, the retina of Gpr75 knockout mice was characterized. Knockout mice displayed a mild progressive retinal degeneration, which was accompanied by oxidative stress. The degeneration was because of the loss of both M-cone and S-cone photoreceptor cells. Housing mice under constant dark conditions reduced oxidative stress but did not prevent cone photoreceptor cell loss, indicating that oxidative stress is not a primary cause of the observed retinal degeneration. Studies here demonstrate an important role for GPR75 in maintaining the health of cone photoreceptor cells and that Gpr75 knockout mice can be used as a model to study cone photoreceptor cell loss.


Lubricant base stock potential of chemically modified vegetable oils.
The environment must be protected against pollution caused by lubricants based on petroleum oils. The pollution problem is so severe that approximately 50% of all lubricants sold worldwide end up in the environment via volatility, spills, or total loss applications. This threat to the environment can be avoided by either preventing undesirable losses, reclaiming and recycling mineral oil lubricants, or using environmentally friendly lubricants. Vegetable oils are recognized as rapidly biodegradable and are thus promising candidates as base fluids in environment friendly lubricants. Lubricants based on vegetable oils display excellent tribological properties, high viscosity indices, and flash points. To compete with mineral-oil-based lubricants, some of their inherent disadvantages, such as poor oxidation and low-temperature stability, must be corrected. One way to address these problems is chemical modification of vegetable oils at the sites of unsaturation. After a one-step chemical modification, the chemically modified soybean oil derivatives were studied for thermo-oxidative stability using pressurized differential scanning calorimetry and a thin-film micro-oxidation test, low-temperature fluid properties using pour-point measurements, and friction-wear properties using four-ball and ball-on-disk configurations. The lubricants formulated with chemically modified soybean oil derivatives exhibit superior low-temperature flow properties, improved thermo-oxidative stability, and better friction and wear properties. The chemically modified soybean oil derivatives having diester substitution at the sites of unsaturation have potential in the formulation of industrial lubricants.


Proton resonance frequency chemical shift thermometry: experimental design and validation toward high-resolution noninvasive temperature monitoring and in vivo experience in a nonhuman primate model of acute ischemic stroke.
Applications for noninvasive biologic temperature monitoring are widespread in biomedicine and of particular interest in the context of brain temperature regulation, where traditionally costly and invasive monitoring schemes limit their applicability in many settings. Brain thermal regulation, therefore, remains controversial, motivating the development of noninvasive approaches such as temperature-sensitive nuclear MR phenomena. The purpose of this work was to compare the utility of competing approaches to MR thermometry by using proton resonance frequency chemical shift. We tested 3 methodologies, hypothesizing the feasibility of a fast and accurate approach to chemical shift thermometry, in a phantom study at 3T. A conventional, paired approach (difference [DIFF]-1), an accelerated single-scan approach (DIFF-2), and a new, further accelerated strategy (DIFF-3) were tested. Phantom temperatures were modulated during real-time fiber optic temperature monitoring, with MR thermometry derived simultaneously from temperature-sensitive changes in the water proton chemical shift (∼0.01 ppm/°C). MR thermometry was subsequently performed in a series of in vivo nonhuman primate experiments under physiologic and ischemic conditions, testing its reproducibility and overall performance. Chemical shift thermometry demonstrated excellent agreement with phantom temperatures for all 3 approaches (DIFF-1: linear regression R(2) = 0.994; P < .001; acquisition time = 4 minutes 40 seconds; DIFF-2: R(2) = 0.996; P < .001; acquisition time = 4 minutes; DIFF-3: R(2) = 0.998; P < .001; acquisition time = 40 seconds). These findings confirm the comparability in performance of 3 competing approaches to MR thermometry and present in vivo applications under physiologic and ischemic conditions in a primate stroke model.


Oxytocin levels and sex differences in autism spectrum disorder with severe intellectual disabilities.
There were few reports of oxytocin (OXT) concentrations of autism spectrum disorder (ASD) patients with severe intellectual disabilities. We measured serum OXT concentrations in 79 hospitalized patients with severe intellectual disabilities (16-60 years old, 50 males and 29 females, 54 ASD patients) and investigated the associations between serum OXT concentration, symptom scores, sex differences, and autism spectrum disorder. There were no significant effects of diagnosis, severity of intellectual disabilities, and total score of the Japanese version of the Aberrant Behavior Checklist (ABC-J), the Childhood Autism Rating Scale-Tokyo Version (CARS-TV), and the Japanese version of the Repetitive Behavior Scale-Revised (RBS-R). However, there were sex differences in the correlations between OXT concentrations and subscale scores in the ASD group. The male ASD group (n = 39) showed negative correlations between RBS-R Self-injurious and Sameness subscale scores and serum OXT concentrations. In the female ASD group(n = 15), CARS-TV Nonverbal communication subscale scores and RBS-R Compulsive subscale scores were seen to positively correlate with serum OXT concentrations. These findings suggest that OXT functions differ in males and females with severe intellectual disabilities and that OXT partly affects autism and related to some of the repetitive behaviors and nonverbal communication, in ASD patients with severe intellectual disabilities.


Space-use behaviour of woodland caribou based on a cognitive movement model.
Movement patterns offer a rich source of information on animal behaviour and the ecological significance of landscape attributes. This is especially useful for species occupying remote landscapes where direct behavioural observations are limited. In this study, we fit a mechanistic model of animal cognition and movement to GPS positional data of woodland caribou (Rangifer tarandus caribou; Gmelin 1788) collected over a wide range of ecological conditions. The model explicitly tracks individual animal informational state over space and time, with resulting parameter estimates that have direct cognitive and ecological meaning. Three biotic landscape attributes were hypothesized to motivate caribou movement: forage abundance (dietary digestible biomass), wolf (Canis lupus; Linnaeus, 1758) density and moose (Alces alces; Linnaeus, 1758) habitat. Wolves are the main predator of caribou in this system and moose are their primary prey. Resulting parameter estimates clearly indicated that forage abundance is an important driver of caribou movement patterns, with predator and moose avoidance often having a strong effect, but not for all individuals. From the cognitive perspective, our results support the notion that caribou rely on limited sensory inputs from their surroundings, as well as on long-term spatial memory, to make informed movement decisions. Our study demonstrates how sensory, memory and motion capacities may interact with ecological fitness covariates to influence movement decisions by free-ranging animals.


Learning neural networks with noisy inputs using the errors-in-variables approach.
Currently, most learning algorithms for neural-network modeling are based on the output error approach, using a least squares cost function. This method provides good results when the network is trained with noisy output data and known inputs. Special care must be taken, however, when training the network with noisy input data, or when both inputs and outputs contain noise. This paper proposes a novel cost function for learning NN with noisy inputs, based on the errors-in-variables stochastic framework. A learning scheme is presented and examples are given demonstrating the improved performance in neural-network curve fitting, at the cost of increased computation time.


Associations of dairy product consumption with mortality in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Italy cohort.
The relation of dairy product consumption to health and mortality is controversial. We investigated associations of consumption of various dairy products with mortality in the Italian cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC)-Italy study. Dairy product consumption was assessed by validated semiquantitative FFQs. Multivariable Cox models stratified by center, age, and sex and adjusted for confounders estimated associations of milk (total, full fat, and reduced fat), yogurt, cheese, butter, and dairy calcium consumption with mortality for cancer, cardiovascular disease, and all causes. Nonlinearity was tested by restricted cubic spline regression. After a median follow-up of 14.9 y, 2468 deaths were identified in 45,009 participants: 59% from cancer and 19% from cardiovascular disease. No significant association of consumption of any dairy product with mortality was found in the fully adjusted models. A 25% reduction in risk of all-cause mortality was found for milk intake from 160 to 120 g/d (HR: 0.75; 95% CI: 0.61, 0.91) but not for the highest (>200 g/d) category of intake (HR: 0.95; 95% CI: 0.84, 1.08) compared with nonconsumption. Associations of full-fat and reduced-fat milk consumption with all-cause and cause-specific mortality were similar to those for milk as a whole. In this Italian cohort characterized by low to average milk consumption, we found no evidence of a dose-response association between milk consumption and mortality and also no association of consumption of other dairy products investigated with mortality.


Current income profile for academic pediatric emergency medicine faculty.
To survey academic pediatric emergency medicine (PEM) programs for information on financial compensation and patient care activities of PEM faculty and compare the results to the financial data published by the AAEM, AAAP, and MGMA. A survey was mailed to program directors requesting information on medical school affiliation, ED census, recruitment, patient care activity and annual income for each academic rank. The survey also included questions on CME benefits, and income adjustment mechanisms/bonus plans for PEM faculty. The survey income data were stratified by program size and geographic region and then compared to income data from the AAMC, AAAP, and MGMA. Of 47 eligible programs, 37 (78.7%) responded,and four were excluded. Mean number of clinical hours per week for academic faculty and clinical faculty were 27.9 +/- 3.5 and 32.4 +/- 3.9, respectively, (P = 0.000). Clinical appointments in academic departments were offered by 82% of the programs. Mean annual income for all academic ranks was $121,503 +/- $15,795, and is nearly $37,000 less than the annual income for academic adult emergency medicine (AEM) faculty. Compared to medium and large programs, small programs are offering higher salaries to recent fellowship graduates (P = 0.004). When income data were stratified by program size or geographic region, no significant difference in average annual income was observed. Bonus or incentive plans were available only in 45.5% of the programs. Direct patient care responsibility of PEM academic faculty has not changed significantly in the past 13 years, despite the availability of clinical appointments within most of the surveyed programs. Our data indicate that the annual income for PEM faculty in academic institutions is significantly less than AEM faculty. No significant difference was observed between programs at the assistant, associate, or full professor level when stratified by size or geographic region. Bonus/incentive plans for exceptional patient care or scholarly activity were available in less than half of the surveyed programs.


[Femoral hernia in elderly and senile patients, peculiarities of surgical tactics].
The results of surgical treatment of 74 elderly and senile patients, suffering femoral hernia (FH), were analyzed. In 39 (52.7%) of them intestinal incarceration was noted. The most effective procedures have appeared those, which incorporate application of polypropylene implants for the femoral ring strengthening while hernioplasty performing in elderly and senile patients. Application of transabdominal preperitoneal endovideohemioplasty constitutes a perspective direction in surgical treatment of FH.


Persistent cognitive and motor deficits after successful antimalarial treatment in murine cerebral malaria.
Human cerebral malaria causes neurological and behavioral deficits which persist long after resolution of infection and clearance of parasites with antimalarial drugs. Previously, we demonstrated that during active infection, mice with cerebral malaria demonstrated negative behavioral outcomes. Here we used a chloroquine treatment model of cerebral malaria to determine whether these abnormal outcomes would be persistent in the mouse model. C57BL/6 mice were infected with Plasmodium berghei ANKA, and treated for ten days. After cessation of chloroquine, a comprehensive assessment of cognitive and motor function demonstrated persistence of abnormal behavioral outcomes, 10 days after successful eradication of parasites. Furthermore, these deficits were still evident forty days after cessation of chloroquine, indicating persistence long after successful treatment, a hallmark feature of human cerebral malaria. Thus, cognitive tests similar to those used in these mouse studies could facilitate the development of adjunctive therapies that can ameliorate adverse neurological outcomes in human cerebral malaria.


Asymptomatic carriage of Streptococcus pneumoniae detected by qPCR on the palm of hands of populations in rural Senegal.
Aside from malaria, infectious diseases are an important cause of death in sub-Saharan Africa and continue to pose major public health problems in African countries, notably pneumonia. Streptococcus pneumoniae remains the most common bacterial cause of pneumonia in all age groups. The skin is one of the main infection sites followed by the oropharynx. The skin carriage of certain pathogenic bacteria such as S. pneumoniae is often ignored or under-diagnosed. Finally, the mode of transmission of these infections remains uncertain. Here, we hypothesized that skin could play a role in the transmission of these infections. We collected 649 cotton swabs from a healthy population in Dielmo and Ndiop, rural Senegal. The sampling was carried out on the palm of the hands. After DNA extraction and actin control, qPCR targeting eight different bacteria was performed on 614 skin samples. We detected Streptococcus pneumoniae in 33.06% (203/614), Staphylococcus aureus in 18.08% (111/614) and Streptococcus pyogenes in 1.95% (12/614) of samples. A skin S. pneumoniae carriage was detected in more than a third of a rural population in rural Africa, highlighting the need to develop hand disinfection programs in order to reduce the burden of infections.


Novel isosteric, isopolar phosphonate analogs of oligonucleotides: preparation and properties.
A synthetic approach leading to novel-type modified oligothymidylates containing an isosteric, isopolar, enzyme-stable C3'-O-P-CH(2)-O-C4'' phosphonate alternative to phosphodiester internucleotide bond was elaborated. The suitable monomers were prepared from 4'-phosphonomethoxy derivatives of alpha-L-threo and beta-D-erythro-2',5'-dideoxythymidine, which were considered interesting as structurally related to nucleoside 5'-monophosphates. The phosphotriester method was applied to the automated synthesis of both homooligomeric phosphonate 15-mer chains and alternating phosphonate-phosphate constructs. The fully modified homooligomers did not hybridize while homooligomers with alternating sequences containing alpha-L-threo-configured units (but not beta-D-erythro-) showed a significant decrease in T(m) values in comparison with natural dT(15). For a comparative study, phosphodiester 4'-CH(3)-substituted oligothymidylate was synthesized and physical studies (NMR, CD, MDS modeling) were undertaken to shed more light on the changes in conformational behavior arising from the chosen structural alterations.


Rapid evolution in response to introduced predators I: rates and patterns of morphological and life-history trait divergence.
Introduced species can have profound effects on native species, communities, and ecosystems, and have caused extinctions or declines in native species globally. We examined the evolutionary response of native zooplankton populations to the introduction of non-native salmonids in alpine lakes in the Sierra Nevada of California, USA. We compared morphological and life-history traits in populations of Daphnia with a known history of introduced salmonids and populations that have no history of salmonid introductions. Our results show that Daphnia populations co-existing with fish have undergone rapid adaptive reductions in body size and in the timing of reproduction. Size-related traits decreased by up to 13 percent in response to introduced fish. Rates of evolutionary change are as high as 4,238 darwins (0.036 haldanes). Species introductions into aquatic habitats can dramatically alter the selective environment of native species leading to a rapid evolutionary response. Knowledge of the rates and limits of adaptation is an important component of understanding the long-term effects of alterations in the species composition of communities. We discuss the evolutionary consequences of species introductions and compare the rate of evolution observed in the Sierra Nevada Daphnia to published estimates of evolutionary change in ecological timescales.


Screening of different probiotic strains for their in vitro ability to metabolise oxalates: any prospective use in humans?
Oxalate is the salt-forming ion of oxalic acid and can generate oxalate salts combining with various cations, such as sodium, potassium, magnesium, and calcium. Approximately 75% of all kidney stones are composed primarily of calcium oxalate (CaOx) and hyperoxaluria, a condition involving high urinary oxalate concentration, is considered a primary risk factor for kidney stone formation, known as nephrolithiasis. Current therapeutic strategies often fail in their compliance or effectiveness, and CaOx stone recurrence is still common. After an initial stone, there is a 50% chance of forming a second stone within 7 years if the condition is left untreated. The potential therapeutic application of some probiotics, mainly lactobacilli and bifidobacteria, in reducing hyperoxaluria in vivo through intestinal oxalate degrading activity is compelling and initial reports are promising. This study was undertaken to screen different Lactobacillus and Bifidobacterium strains for their capacity to degrade oxalate in vitro using reverse-phase high-performance liquid chromatography (HPLC). The oxalate-degrading activity of 13 lactobacilli and 5 bifidobacteria was tested using a novel HPLC method after growth in a broth culture added with 10 mM ammonium oxalate. Experiments were repeated 3 times. Oxalobacter formigenes (DSM 4420) was used as positive reference to validate HPLC oxalate-degrading capability assays. Lactobacillus strains were more efficient than bifidobacteria in degrading oxalates. L. paracasei LPC09 (DSM 24243) gave the best result, as 68.5% of ammonium oxalate was converted at the end of incubation, whereas the following best converters belong to the L. gasseri and L. acidophilus species. The relatively low conversion rate observed for most bifidobacteria can probably be attributed to intrinsic oxalate toxicity toward this genus. Humans lack the enzymes needed to directly metabolise oxalate, and this potentially toxic compound is, therefore, managed using alternative pathways. As oxalate-degrading bacteria are present in the endogenous microbiota of the human intestine, although with significant individual differences, it is possible to hypothesise that the administration of selected oxalate-degrading probiotics could be an alternative and innovative approach to reducing the intestinal absorption of oxalate and the resulting urinary excretion.


Association Between Pancreatic Cystic Lesions and High-grade Intraepithelial Neoplasia and Aging: An Autopsy Study.
This study aimed to clarify clinicopathological features of pancreatic cysts. Pancreata from 280 autopsies (median, 83 years; male, 146; female, 134) were sectioned every 5 mm. Cysts (<10 mm) were diagnosed as a simple cyst or low-grade, intermediate-grade, or high-grade dysplasia. We found 236 cysts in 93 patients (33.2%). The number and diameter of cysts increased according to the age. Of the 236 cysts, 9 (3.8%) were with high-grade dysplasia. Cysts with high-grade dysplasia arose in the pancreata of older patients with larger numbers of cysts. In contrast, 15 noncystic lesions with high-grade dysplasia were also detected. Hence, in total, 24 high-grade dysplastic lesions in 15 patients (5.4%) were noted. Of the 15 patients with high-grade dysplastic lesions, in 10 patients, the condition was accompanied by pancreatic cysts, whereas 5 patients did not have any cysts in the pancreas; therefore, patients with cyst showed higher incidence of high-grade dysplasia (10.8%; P = 0.0047) than patients without cyst (2.7%). All cysts with high-grade dysplasia were located in the branch duct of the pancreatic head/body, whereas 20% of noncystic lesions with high-grade dysplasia were located in the main pancreatic duct. Cystic lesions with high-grade dysplasia may have different characteristics compared with noncystic high-grade dysplasia.


Prevalence and Characteristics of Pediatric Healthcare Workers without Immunity to Varicella zoster Virus.
This study aimed to determine the proportion of varicella non-immune pediatric healthcare workers (HCWs) of the Pediatrics Department of King Chulalongkorn Memorial Hospital and to determine cost-effective strategies for identifying non-immune personnel. A cross-sectional study using a self-administered questionnaire to determine HCWs' histories of chickenpox or 2-dose varicella vaccination was conducted. From a total of 699 HCWs, 653 HCWs (93%), including 145 physicians (22%), 297 nurses (46%), and 211 administrative staff (32%), responded to questionnaires. There were 475 HCWs (73%) who had a history of chickenpox, 58 (9%) who had completed the 2-dose varicella vaccine schedule, and 120 (18%) whose varicella-zoster virus (VZV) immunity status was uncertain. In total, 107 HCWs (89%) were tested for VZV IgG, 90 of whom had immunity, and 17 were determined to be non-immune. After combining history and VZV IgG test results, the prevalence of non-immune HCWs was 2.6% (95%CI 1.4-3.8), with those ≤40 years of age at higher risk of non-immunity. Implementing a strategy that involves testing of only those with an unknown VZV status and vaccination for only those determined to be non-immune costs 1,801 United States dollar (USD), less than the total cost (4,601 USD) for vaccinating all HCWs with uncertain status.


Ecotoxicological Risk of World War Relic Munitions in the Sea after Low- and High-Order Blast-in-Place Operations.
Submerged munitions from World War I and II are threatening human activities in the oceans, including fisheries and shipping or the construction of pipelines and offshore facilities. To avoid unforeseen explosions, remotely controlled "blast-in-place" (BiP) operations are a common practice worldwide. However, after underwater BiP detonations, the toxic and carcinogenic energetic compounds (ECs) will not completely combust but rather distribute within the marine ecosphere. To shed light on this question, two comparable World War II mines in Denmark's Sejerø Bay (Baltic Sea) were blown up by either low-order or high-order BiP operations by the Royal Danish Navy. Water and sediment samples were taken before and immediately after the respective BiP operation and analyzed for the presence of ECs with sensitive GC-MS/MS and LC-MS/MS technology. EC concentrations increased after high-order BiP detonations up to 353 ng/L and 175 μg/kg in water and sediment, respectively, while low-order BiP detonations resulted in EC water and sediment concentrations up to 1,000,000 ng/L (1 mg/L) and >10,000,000 μg/kg (>10 g/kg), respectively. Our studies provide unequivocal evidence that BiP operations in general lead to a significant increase of contamination of the marine environment and ecotoxicological risk with toxic ECs. Moreover, as compared to high-order BiP detonations, low-order BiP detonations resulted in a several 1000-fold higher burden on the marine environment.


[Characteristics of PET cerebral functional imaging during "Deqi" of acupuncture in healthy volunteers].
To observe the characteristics of needling sensation of "Deqi" (feelings of soreness, numbness, distending and heaviness, SNDH) by using positron emission tomography (PET) based on changes of glucose metabolism in different functional brain areas. Eighteen normal volunteers [9 men and 9 women, mean age (23.23-1- 3. 32) years] were randomly divided into control, Waiguan (SJ 5) and non-acupoint groups (n=6 in each group). SJ 5 and non-acupoint (the midpoint between SJ 5 and the running course of the Small Intestine Meridian on the right forearm) were punctured by using a sterilized filiform needle. PET scan of the brain began 40 min after intravenous 18 F-fluorodeoxyglucose (FDG) injection (0. 11 mCi/kg body weight, left opisthenar vein). Needling sensations including "Deqi"(n= 5), tingling (n 5) and no-apparently-specific-feeling (NASF) were acquired by acupuncture stimulation and grouped. The needling sensations were evaluated by using Visual Analog Scale(VAS). The acquired image data of different needling-sensation groups were analyzed using SPM 2. 0 software in the Matlab Platform. After receiving acupuncture stimulation of SJ 5, 5 volunteers in the Waiguan (SJ 5) group experienced fee- lings of SNDH, with the mean VAS score being 4.23 +/- 1. 50, and 5 volunteers of the non-acupoint group had a tingling feeling, with the mean VAS score being 5.73 2.40. The VAS score of the tingling group was significantly higher than that of SNDH group (P<0. 05). Compared with the NASF control group, the activated cerebral areas were Brodmann area (BA) 7, 13, 20, 22, 39, 42 and BA 45 in the SNDH group, mainly involving the left temporal lobe, superior temporal gyrus, etc. and being obviously different to those of the control group (P<0. 001,k>10 voxels). The activated cerebral areas in the tingling group were BA 18, 19, 22, 24, 25, 32, 36, 40 and BA 45, predominantly involving the left limbic lobe, hippocampal gyrus, etc. and being apparently different to those of the control group (P<0. 001,k> 10 voxels). Acupuncture of Waiguan (SJ 5) mainly produces feelings of soreness, numbness, distending and heaviness, and the activated cerebral areas mainly involve the left temporal lobe, superior temporal gyrus, etc. ; while acupuncture of its neighboring non-acupoint chiefly induces a feeling of tingling in the healthy subjects, and the activated regions predominately involve the left limbic lobe, hippocampal gyrus, etc.


Enhanced pain modulation among triathletes: a possible explanation for their exceptional capabilities.
Triathletes and ironman triathletes engage in an extremely intense sport that involves hours of considerable pain, as well as physical and psychological stress, every day. The basic pain modulation properties of these athletes has not been established and therefore it is not clear whether they present with unique features that enable them to engage in such efforts. The aim was to investigate the existence of possible alterations in pain perception and modulation of triathletes, as well as possible underlying factors. Participants were 19 triathletes and 17 non-athletes who underwent measurement of pain threshold, pain tolerance, suprathreshold perceived pain intensity, temporal summation of pain, and conditioned pain modulation (CPM). Participants also completed the fear of pain and the pain catastrophizing questionnaires, and rated the amount of perceived stress. Triathletes exhibited higher pain tolerance (P<.0001), lower pain ratings (P<.001), and lower fear of pain values (P<.05) than controls. The magnitude of CPM was significantly greater in triathletes (P<.05), and negatively correlated with fear of pain (P<.05) and with perceived mental stress during training and competition (P<.05). The results suggest that triathletes exhibit greater pain tolerance and more efficient pain modulation than controls, which may underlie their perseverance in extreme physical efforts and pain during training/competitions. This capability may be enhanced or mediated by psychological factors, enabling better coping with fear of pain and mental stress.


Effects of dexamethasone and cAMP on tyrosine aminotransferase expression in cultured fetal rat hepatocytes.
Fetal hepatocyte cultures were used to investigate tyrosine aminotransferase (TyrAT) expression during development. Previous studies showed that TyrAT is synthesized by hepatocytes isolated from 15-day-gestation fetuses maintained in culture for two or more day, then exposed to dexamethasone. TyrAT expression was essentially undetectable on the first day of culture of hepatocytes derived from 15-day-gestation, or less mature, fetuses. Dexamethasone and cAMP are potent inducers of TyrAT and they synergistically induce TyrAT to extremely high levels when added simultaneously to cultured fetal hepatocytes. The effects of dibutyryl-cAMP (Bt2cAMP) alone and in combination with dexamethasone on TyrAT expression are investigated. Hepatocytes isolated from 15-day-gestation fetuses exposed to both inducers possessed detectable levels of TyrAT activity and mRNA on day 1 of culture, and this increased by day 3. In contrast, hepatocytes exposed to either inducing agent alone were essentially negative on day 1, but positive on day 3. This was shown to be a consequence of transcription. When 13-day-gestation hepatocytes were maintained in culture under identical conditions detectable levels of TyrAT mRNA were evident on day 1, and this increased by day 3. Immunocytochemical studies revealed that the appearance and subsequent increase in TyrAT production elicited by dexamethasone and Bt2cAMP were due to changes in the proportion of hepatocytes expressing the enzyme. Therefore, in the presence of both dexamethasone and Bt2cAMP, TyrAT expression can be detected in some cells at an earlier stage of liver development than reported previously.


Pretherapeutic resting-state fMRI profiles are associated with MR signature volumes after stereotactic radiosurgical thalamotomy for essential tremor.
OBJECTIVEEssential tremor (ET) is the most common movement disorder. Drug-resistant ET can benefit from standard stereotactic deep brain stimulation or radiofrequency thalamotomy or, alternatively, minimally invasive techniques, including stereotactic radiosurgery (SRS) and high-intensity focused ultrasound, at the level of the ventral intermediate nucleus (Vim). The aim of the present study was to evaluate potential correlations between pretherapeutic interconnectivity (IC), as depicted on resting-state functional MRI (rs-fMRI), and MR signature volume at 1 year after Vim SRS for tremor, to be able to potentially identify hypo- and hyperresponders based only on pretherapeutic neuroimaging data.METHODSSeventeen consecutive patients with ET were included, who benefitted from left unilateral SRS thalamotomy (SRS-T) between September 2014 and August 2015. Standard tremor assessment and rs-fMRI were acquired pretherapeutically and 1 year after SRS-T. A healthy control group was also included (n = 12). Group-level independent component analysis (ICA; only n = 17 for pretherapeutic rs-fMRI) was applied. The mean MR signature volume was 0.125 ml (median 0.063 ml, range 0.002-0.600 ml). The authors correlated baseline IC with 1-year MR signatures within all networks. A 2-sample t-test at the level of each component was first performed in two groups: group 1 (n = 8, volume < 0.063 ml) and group 2 (n = 9, volume ≥ 0.063 ml). These groups did not statistically differ by age, duration of symptoms, baseline ADL score, ADL point decrease at 1 year, time to tremor arrest, or baseline tremor score on the treated hand (TSTH; p > 0.05). An ANOVA was then performed on each component, using individual subject-level maps and continuous values of 1-year MR signatures, correlated with pretherapeutic IC.RESULTSUsing 2-sample t-tests, two networks were found to be statistically significant: network 3, including the brainstem, motor cerebellum, bilateral thalamus, and left supplementary motor area (SMA) (pFWE = 0.004, cluster size = 94), interconnected with the red nucleus (MNI -2, -22, -32); and network 9, including the brainstem, posterior insula, bilateral thalamus, and left SMA (pFWE = 0.002, cluster size = 106), interconnected with the left SMA (MNI 24, -28, 44). Higher pretherapeutic IC was associated with higher MR volumes, in a network including the anterior default-mode network and bilateral thalamus (ANOVA, pFWE = 0.004, cluster size = 73), interconnected with cerebellar lobule V (MNI -12, -70, -22). Moreover, in the same network, radiological hyporesponders presented with negative IC values.CONCLUSIONSThese findings have clinical implications for predicting MR signature volumes after SRS-T. Here, using pretherapeutic MRI and data processing without prior hypothesis, the authors showed that pretherapeutic network interconnectivity strength predicts 1-year MR signature volumes following SRS-T.


Localisation of the Schizosaccharomyces pombe rho1p GTPase and its involvement in the organisation of the actin cytoskeleton.
The Schizosaccharomyces pombe rho1p GTPase directly activates the (1-3) beta-D-glucan synthase and participates in the regulation of cell wall growth and morphogenesis in this fission yeast. Indirect immunofluorescence experiments using rho1p tagged with hemagglutinin have revealed that rho1p was located at the growing tips during interphase and at the septum prior to cytokinesis, localising to the same areas as actin patches. In S. pombe cdc10-129 mutant cells, arrested in G1, HA-rho1p accumulates at one tip whereas in cdc25-22 mutants, arrested in G2, HA-rho1p accumulates at both tips. In tea1-1 and tea2-1 cdc11-119 mutant cells, HA-rho1p is localised to the new growing tips. Overexpression of different rho1 mutant alleles caused different effects on cortical actin patch distribution, (1-3) beta-D-glucan synthase activation, and sensitivity to cell wall specific antifungal drugs. These results indicate that multiple cellular components are activated by rho1p. Overexpression of the dominant negative rho1T20N allele was lethal as was the rho1+ deletion. Moreover, when rho1+ expression was repressed in actively growing S. pombe, cells died in about 10 to 12 hours. Under these conditions, normal cell morphology was maintained but the level of (1-3) beta-D-glucan synthase activity decreased and the actin patches disappeared. Most cells lysed after cytokinesis during the process of separation, and lysis was not prevented by an osmotic stabiliser. We conclude that rho1p localisation is restricted to growth areas and regulated during the cell cycle and that rho1p is involved in cell wall growth and actin cytoskeleton organisation in S. pombe.