Treatment of extensive stage small cell bronchogenic carcinoma. Effects of variation in intensity of induction chemotherapy.
Forty-nine consecutive previously untreated patients with extensive stage small cell bronchogenic carcinoma were treated with cyclophosphamide 1,000 mg/m2, doxorubicin 50 mg/m2, etoposide (VP-16-213) 125 mg/m2, and vincristine 1.4 mg/m2 (maximum 2 mg) as induction chemotherapy. Thirty-four patients were given high-intensity therapy, receiving these drugs on both Days 1 and 8 of two or three 21-day induction courses. Fifteen other patients were treated with moderate intensity, receiving these drugs only on Day 1 of two 21-day induction courses. The number and intensity of induction courses were determined by the time of entry into the study. There were 31 complete or partial remissions among the 33 evaluable patients treated with high-intensity therapy (94 percent), including eight complete remissions (24 percent), whereas there were 11 responses (73 percent) including three complete responses (20 percent) among the 15 patients treated with moderate-intensity therapy. There was no marked tendency for the patients in the high-intensity group to have a more favorable response to the induction chemotherapy (p = 0.22), and survival experience was very similar in the two groups (p = 0.92). Overall median survival was 12 months. Within the high-intensity group, there was no significant difference between patients receiving two or three courses of induction therapy with respect to response (p = 0.97) or survival (p = 0.32). There were six induction deaths in the high-intensity induction group (18 percent) and one induction death in the moderate-intensity group (7 percent) (p = 0.59). In addition to the expected hematologic and infectious complications, there were unexpectedly high frequencies of mucositis, reversible congestive heart failure, and severe peripheral neuropathy in patients treated with high-intensity induction. Only two patients, both in the high-intensity group, were alive and free of disease at 24 months. Increasing the intensity of induction chemotherapy with these drugs did not significantly improve response or survival in extensive stage small cell bronchogenic carcinoma.


Ancient medicine for a modern disease: traditional Amazonian medicine to treat substance use disorders.
Background: There exists an underexploited opportunity to develop innovative therapeutic approaches to SUDs based upon the complementarity between modern and traditional health systems.Objectives: Illustrate the feasibility and potentiality of such an approach through the comprehensive description of Takiwasi Center's treatment model and program, where health concepts and practices from traditional Amazonian medicine work synergistically with modern psychotherapy and medicine in an intercultural dialog to assist in the rehabilitation of people suffering from SUDs.Methods: The description was built from a review of the literature, institutional data, participatory observation and unstructured interviews with staff, researchers and patients during treatment.Results: Since the foundation of the Takiwasi Center in 1992 in the peruvian Amazon, more than a thousand patients with different socio-cultural, ethnic and religious backgrounds have received residential treatment. We present how traditional Amazonian medicine techniques and health concepts cooperate to complement modern psychology in a therapeutic community setting and propose some hypotheses about the neurobiological, psycho-emotional and spiritual healing mechanisms triggered by the program to help people identify and heal the roots of their substance misuse and addictive behavior. We also summarize quantitative outcomes during treatment showing significant improvements in a wide variety of mental health indicators.Conclusion: Takiwasi Center's program is an option for people seeking non-conventional treatment who are sensitive to traditional Amazonian medicine practices and ready to explore the roots of their addiction. From this intercultural approach, some lessons could emerge toward a broader understanding of SUDs that may result in better patient care.


[The spirit of community medicine: students learning from students].
At the University of Lausanne third-year medical students are given the task of spending a month investigating a question of community medicine. In 2009, four students evaluated the legitimacy of health insurers intervening in the management of depression. They found that health insurers put pressure on public authorities during the development of legislation governing the health system and reimbursement for treatment. This fact emerged during the scientific investigation led jointly by the team in the course of the "module of immersion in community medicine." This paper presents each step of their study. The example chosen illustrates the learning objectives covered by the module.


Structural basis of human triosephosphate isomerase deficiency: mutation E104D is related to alterations of a conserved water network at the dimer interface.
Human triosephosphate isomerase deficiency is a rare autosomal disease that causes premature death of homozygous individuals. The most frequent mutation that leads to this illness is in position 104, which involves a conservative change of a Glu for Asp. Despite the extensive work that has been carried out on the E104D mutant enzyme in hemolysates and whole cells, the molecular basis of this disease is poorly understood. Here, we show that the purified, recombinant mutant enzyme E104D, while exhibiting normal catalytic activity, shows impairments in the formation of active dimers and low thermostability and monomerizes under conditions in which the wild type retains its dimeric form. The crystal structure of the E104D mutant at 1.85 A resolution showed that its global structure was similar to that of the wild type; however, residue 104 is part of a conserved cluster of 10 residues, five from each subunit. An analysis of the available high resolution structures of TIM dimers revealed that this cluster forms a cavity that possesses an elaborate conserved network of buried water molecules that bridge the two subunits. In the E104D mutant, a disruption of contacts of the amino acid side chains in the conserved cluster leads to a perturbation of the water network in which the water-protein and water-water interactions that join the two monomers are significantly weakened and diminished. Thus, the disruption of this solvent system would stand as the underlying cause of the deficiency.


Subdural empyema after tooth extraction in which Capnocytophaga species was isolated.
We describe a patient with meningitis and a subdural empyema arising from an infection after teeth extraction in which Capnocytophaga species was detected. The patient was a 54-y-old man without any underlying diseases. A computerized tomography scan showed a subdural empyema 21 d after the extraction.


Neuronal variability in orbitofrontal cortex during economic decisions.
Neuroeconomic models assume that economic decisions are based on the activity of offer value cells in the orbitofrontal cortex (OFC), but testing this assertion has proven difficult. In principle, the decision made on a given trial should correlate with the stochastic fluctuations of these cells. However, this correlation, measured as a choice probability (CP), is small. Importantly, a neuron's CP reflects not only its individual contribution to the decision (termed readout weight), but also the intensity and the structure of correlated variability across the neuronal population (termed noise correlation). A precise mathematical relation between CPs, noise correlations, and readout weights was recently derived by Haefner and colleagues (Haefner RM, Gerwinn S, Macke JH, Bethge M. Nat Neurosci 16: 235-242, 2013) for a linear decision model. In this framework, concurrent measurements of noise correlations and CPs can provide quantitative information on how a population of cells contributes to a decision. Here we examined neuronal variability in the OFC of rhesus monkeys during economic decisions. Noise correlations had similar structure but considerably lower strength compared with those typically measured in sensory areas during perceptual decisions. In contrast, variability in the activity of individual cells was high and comparable to that recorded in other cortical regions. Simulation analyses based on Haefner's equation showed that noise correlations measured in the OFC combined with a plausible readout of offer value cells reproduced the experimental measures of CPs. In other words, the results obtained for noise correlations and those obtained for CPs taken together support the hypothesis that economic decisions are primarily based on the activity of offer value cells.


Impact of depressive symptoms on worklife expectancy: a longitudinal study on Danish employees.
Depressive symptoms are associated with sickness absence, work disability and unemployment, but little is known about worklife expectancy (WLE). This study investigates the impact of depressive symptoms on the WLE of a large sample of Danish employees. We used occupational health survey data of 11 967 Danish employees from 2010 and linked them with register data on salary and transfer payments from 2010 to 2015. Depressive symptoms were self-reported using the Major Depression Inventory. We used multistate data and a life table approach with Cox proportional hazard modelling to estimate the WLE of employees, expressed by time in work, unemployment and sickness absence. Separate analyses were conducted for sex and employees with a voluntary early retirement pension scheme. Using age as time axis, we used inverse probability weights to account for differences in educational level, sector, body mass index, smoking habits and loss of employment during sickness absence. The WLE of employees reporting depressive symptoms was shorter compared with those not reporting depressive symptoms; that is, the expected time in unemployment and sickness absence was longer, while the expected time in work was shorter. The shorter WLE was most pronounced in women; for example, a 40-year-old woman with depressive symptoms can expect 3.3 years less in work, 0.8 years more in unemployment and 0.7 years more in sickness absence. Employees with a voluntary early retirement pension scheme showed an even lower WLE. Our study showed a meaningful impact of depressive symptoms on the WLE of Danish employees using a multistate framework.


Impact of Physician-Pharmacist Collaboration on Diabetes Outcomes and Health Care Use.
To evaluate the impact of physician-pharmacist collaboration for disease-state management on diabetes outcomes in primary care by comparing outcomes between physician-managed care and pharmacist collaborative care. A retrospective, observational cohort study was conducted at Ascension Medical Group Via Christi, P.A. from January 1, 2016 to June 30, 2018. Health outcomes were analyzed in 385 patients with diabetes mellitus collaboratively managed by a physician and pharmacist (collaborative care group). Similar patients managed by physician only (usual care group) were matched to the collaborative care group using nearest neighbor matching. The primary outcome compared glycosylated hemoglobin (HbA1c) change between collaborative care and usual care groups at 12 months. The mean change in HbA1c decreased by 1.75% in the collaborative care group and 0.16% in the usual care group (P < .0001). The usual care group had a larger number of patients with HbA1c less than 8% at follow-up (P = .0049). Additional outcomes included decrease in total cholesterol (P = .0023), triglycerides (P = .0016), and an increase in PPSV23 pneumococcal vaccinations (P = .0255) in the collaborative care group. The usual care group had an increase in PCV13 pneumococcal vaccinations (P = .0075). Both emergency department visits (P = .0162) and hospitalizations (P = .0225) decreased significantly in the collaborative care group, estimating total savings of $633,015. The collaboration of pharmacists and physicians in the primary care setting is associated with improved diabetes outcomes and substantially reduces costs related to decreased health care use.


FGF9 prevents pleural fibrosis induced by intrapleural adenovirus injection in mice.
Fibroblast growth factor 9 (FGF9) is necessary for fetal lung development and is expressed by epithelium and mesothelium. We evaluated the role of FGF9 overexpression on adenoviral-induced pleural injury in vivo and determined the biological effects of FGF9 on mesothelial cells in vitro. We assessed the expression of FGF9 and FGF receptors by mesothelial cells in both human and mouse lungs. Intrapleural injection of an adenovirus expressing human FGF9 (AdFGF9) or a control adenovirus (AdCont) was performed. Mice were euthanized at days 3, 5, and 14 Expression of FGF9 and markers of inflammation and myofibroblastic differentiation was studied by qPCR and immunohistochemistry. In vitro, rat mesothelial cells were stimulated with FGF9 (20 ng/ml), and we assessed its effect on proliferation, survival, migration, and differentiation. FGF9 was expressed by mesothelial cells in human idiopathic pulmonary fibrosis. FGF receptors, mainly FGFR3, were expressed by mesothelial cells in vivo in humans and mice. AdCont instillation induced diffuse pleural thickening appearing at day 5, maximal at day 14 The altered pleura cells strongly expressed α-smooth muscle actin and collagen. AdFGF9 injection induced maximal FGF9 expression at day 5 that lasted until day 14 FGF9 overexpression prevented pleural thickening, collagen and fibronectin accumulation, and myofibroblastic differentiation of mesothelial cells. In vitro, FGF9 decreased mesothelial cell migration and inhibited the differentiating effect of transforming growth factor-β1. We conclude that FGF9 has a potential antifibrotic effect on mesothelial cells.


[3D ultrasound in core breast biopsy].
To evaluate the potential of three-dimensional ultrasound (3D US) in core biopsy of suspicious breast lesions. 3D US controlled core biopsy was performed in 107 breast masses in 100 women by using an automated biopsy system (11G coaxial needle, 12 G biopsy needle). Mean diameter of the lesions was 1.55 cm (0.5 - 3.5 cm). A linear 3D US volume scanner was used for the procedure. Localization of the lesion and placement of the needle were initially done under 2D US guidance. After core needle stroke a 3D US volume acquisition was performed to correlate lesion and needle position. In the case of eccentric needle position the needle was repositioned under 3D control. 5 specimens were taken from each lesion. The histological results from the specimens were correlated with the results from surgery or clinical follow-up (> 2.5 years). Biopsy was taken from 59 probably benign (BI-RADS 3 - 4) and 48 malignant (BI-RADS 5) lesions. 3D US revealed 61 central, 44 eccentric and 2 marginal needle positions after the initial 2D guidance. Central repositioning of the needle was achievable under 3D guidance in all patients. Histological examination of the specimens revealed 41 invasive carcinomas and one in-situ carcinoma (DCIS). In one lesion, the carcinoma was missed in the core biopsy, despite central hits of the biopsy needle. This led to a sensitivity of 98 %, specificity of 100 %, PPV of 100 %, NPV of 98.5 % and accuracy of 99 % for the diagnosis of a malignant lesion. 3D US improves needle positioning as well as the depiction of correct needle placement in freehand core biopsy.


Interaction of internal Ba2+ with a cloned Ca(2+)-dependent K+ (hslo) channel from smooth muscle.
We have studied potassium currents through a cloned Ca(2+)-dependent K+ channel (hslo) from human myometrium. Currents were recorded in inside-out macropatches from membranes of Xenopus laevis oocytes. In particular, the inactivation-like process that these channels show at high positive potentials was assessed in order to explore its molecular nature. This current inhibition conferred a bell shape to the current-voltage curves. The kinetic and voltage dependence of this process suggested the possibility of a Ba2+ block. There were the following similarities between the inactivation process observed at zero-added Ba2+ and the internal Ba2+ block of hslo channels: (a) in the steady state, the voltage dependence of the current inhibition observed at zero-added Ba2+ was the same as the voltage dependence of the Ba2+ block; (b) the time constant for recovery from current decay at zero-added Ba2+ was the same as the time constant for current recovery from Ba2+ blockade; and (c) current decay was largely suppressed in both cases by adding a Ba2+ chelator [(+)-18-crown-6-tetracarboxylic acid] to the internal solution. In our experimental conditions, we determined that the Kd for the complex chelator-Ba2+ is 1.6 x 10(-10) M. We conclude that the current decay observed at zero-added Ba2+ to the internal solution is due to contaminant Ba2+ present in our solutions (approximately 70 nM) and not to an intrinsic gating process. The Ba2+ blocking reaction in hslo channels is bimolecular. Ba2+ binds to a site (Kd = 0.36 +/- 0.05 mM at zero applied voltage) that senses 92 +/- 25% of the potential drop from the internal membrane surface.


Public Health Relevance of Cross-Contamination in the Fresh-Cut Vegetable Industry.
Although quantitative studies have revealed that cross-contamination during the washing stage of fresh produce occurs, the importance of cross-contamination in terms of public health relevance has rarely been assessed. The direct distribution of initially contaminated leafy vegetables to a multitude of servings by cutting and mixing also has not been addressed. The goal of this study was to assess the attribution of both contamination pathways to disease risk. We constructed a transparent and exploratory mathematical model that simulates the dispersion of contamination from a load of leafy greens during industrial washing. The risk of disease was subsequently calculated using a Beta-Poisson dose-response relation. The results indicate that up to contamination loads of 10(6) CFU the direct contamination route is more important than the indirect route (i.e., cross-contamination) in terms of number of illnesses. We highlight that the relevance of cross-contamination decreases with more diffuse and uniform contamination, and we infer that prevention of contamination in the field is the most important risk management strategy and that disinfection of washing water can be an additional intervention to tackle potentially high (>10(6) CFU) point contamination levels.


Carbon monoxide (CO) and hydrogen sulfide (H(2)S) in hypoxic sensing by the carotid body.
Carotid bodies are sensory organs for monitoring arterial blood oxygen (O(2)) levels, and the ensuing reflexes maintain cardio-respiratory homeostasis during hypoxia. This article provides a brief update of the role of carbon monoxide (CO) and hydrogen sulfide (H(2)S) in hypoxic sensing by the carotid body. Glomus cells, the primary site of O(2) sensing in the carotid body express heme oxygenase-2 (HO-2), a CO catalyzing enzyme. HO-2 is a heme containing enzyme and has high affinity for O(2). Hypoxia inhibits HO-2 activity and reduces CO generation. Pharmacological and genetic approaches suggest that CO inhibits carotid body sensory activity. Stimulation of carotid body activity by hypoxia may reflect reduced formation of CO. Glomus cells also express cystathionine γ-lyase (CSE), an H(2)S generating enzyme. Exogenous application of H(2)S donors, like hypoxia, stimulate the carotid body activity and CSE knockout mice exhibit severely impaired sensory excitation by hypoxia, suggesting that CSE catalyzed H(2)S is an excitatory gas messenger. Hypoxia increases H(2)S generation in the carotid body, and this response was attenuated or absent in CSE knockout mice. HO inhibitor increased and CO donor inhibited H(2)S generation. It is proposed that carotid body response to hypoxia requires interactions between HO-2-CO and CSE-H(2)S systems.


Elevated von Willebrand factor levels during heavy menstrual bleeding episodes limit the diagnostic utility for von Willebrand disease.
Heavy menstrual bleeding (HMB) is often the first bleeding symptom for female individuals with inherited bleeding disorders. Guidelines recommend performing the hemostatic evaluation at HMB presentation. Von Willebrand factor (VWF) levels increase with stress, making it unclear if VWF studies during acute bleeding are beneficial in diagnosing von Willebrand disease (VWD). To determine the utility of testing for VWD during acute HMB. This retrospective cohort study evaluated VWF levels of individuals presenting to the emergency department (ED) with HMB from January 1, 2017, to December 31, 2018, after prospective implementation of a clinical practice guideline recommending hemostatic evaluation in the ED. We compared VWF and factor VIII (FVIII) levels between acute presentation and follow-up visit after bleeding resolution. We compared the diagnostic accuracy of initial and follow-up labs. During the study period, 221 individuals were seen in the ED for acute HMB, and 39 had VWD testing at both time points. Median FVIII and VWF levels were higher during acute bleeding than at follow-up. The difference in VWF levels between visits was negligible when initial FVIII value was normal. Overall incidence of VWD was 7.5%; 69% of those with VWD had low VWF levels during acute HMB. VWD testing during acute HMB detects the majority of individuals with VWD but also leads to elevated levels of VWF, potentially limiting at the accuracy of diagnostic labs during acute bleeding episodes. Delayed testing until resolution of anemia and active bleeding may provide more accurate diagnostic evaluation for VWD.


Asymmetric motion visually evoked potentials in infantile strabismus are not an artifact of latent nystagmus.
Patients who have infantile strabismus exhibit a directional asymmetry of motion visually evoked potentials (MVEPs) recorded under conditions of monocular viewing. The majority of these patients also have latent nystagmus, raising the possibility that the MVEP asymmetry is an artifact of the nystagmus. To explore this issue, we correlated MVEPs and eye movements under conditions that eliminated or increased latent nystagmus. MVEPs and eye movements were recorded under conditions of monocular viewing in three adults who had combined infantile-onset strabismus and latent nystagmus. The subjects viewed vertically oriented grating stimuli that oscillated horizontally at temporal frequencies of 6.6 to 11.0 Hz by use of spatial frequencies of 1 to 3 cycles/degree. Quantitative eye movement recordings of latent nystagmus and horizontal pursuit/optokinetic nystagmus were also obtained. Eye movement recordings showed that the latent nystagmus was absent or markedly diminished when the viewing eye was in a 45-degree adducted position, whereas nystagmus velocity increased 10 to 40 times (to 2.2 to 4.5 degrees/second) when the viewing eye was in an abducted position (p < 0.05). MVEPs were abnormal (asymmetry indices > 0.40) when the viewing eye was in an adducted or abducted position of gaze. No correlation was found between the MVEP asymmetry index and the velocity of latent nystagmus. MVEP asymmetries in infantile strabismus remain robust under conditions that eliminate or greatly reduce the oscillations of latent nystagmus. MVEP asymmetries and ocular motor abnormalities both characterize infantile strabismus, but the ocular motor defects do not cause the MVEP asymmetries. The nasotemporal asymmetry of MVEPs and the nasotemporal asymmetry of pursuit and latent nystagmus are likely caused by deficits in related but separate binocular visual cortical circuits.


Reference databases for taxonomic assignment in metagenomics.
Metagenomics is providing an unprecedented access to the environmental microbial diversity. The amplicon-based metagenomics approach involves the PCR-targeted sequencing of a genetic locus fitting different features. Namely, it must be ubiquitous in the taxonomic range of interest, variable enough to discriminate between different species but flanked by highly conserved sequences, and of suitable size to be sequenced through next-generation platforms. The internal transcribed spacers 1 and 2 (ITS1 and ITS2) of the ribosomal DNA operon and one or more hyper-variable regions of 16S ribosomal RNA gene are typically used to identify fungal and bacterial species, respectively. In this context, reliable reference databases and taxonomies are crucial to assign amplicon sequence reads to the correct phylogenetic ranks. Several resources provide consistent phylogenetic classification of publicly available 16S ribosomal DNA sequences, whereas the state of ribosomal internal transcribed spacers reference databases is notably less advanced. In this review, we aim to give an overview of existing reference resources for both types of markers, highlighting strengths and possible shortcomings of their use for metagenomics purposes. Moreover, we present a new database, ITSoneDB, of well annotated and phylogenetically classified ITS1 sequences to be used as a reference collection in metagenomic studies of environmental fungal communities. ITSoneDB is available for download and browsing at http://itsonedb.ba.itb.cnr.it/.


Suppression of the water ice and snow albedo feedback on planets orbiting red dwarf stars and the subsequent widening of the habitable zone.
M stars comprise 80% of main sequence stars, so their planetary systems provide the best chance for finding habitable planets, that is, those with surface liquid water. We have modeled the broadband albedo or reflectivity of water ice and snow for simulated planetary surfaces orbiting two observed red dwarf stars (or M stars), using spectrally resolved data of Earth's cryosphere. The gradual reduction of the albedos of snow and ice at wavelengths greater than 1 μm, combined with M stars emitting a significant fraction of their radiation at these same longer wavelengths, means that the albedos of ice and snow on planets orbiting M stars are much lower than their values on Earth. Our results imply that the ice/snow albedo climate feedback is significantly weaker for planets orbiting M stars than for planets orbiting G-type stars such as the Sun. In addition, planets with significant ice and snow cover will have significantly higher surface temperatures for a given stellar flux if the spectral variation of cryospheric albedo is considered, which in turn implies that the outer edge of the habitable zone around M stars may be 10-30% farther away from the parent star than previously thought.


The effect of disgust on oral immune function.
Disgust motivates avoidance of pathogen sources, but whether its role in disease avoidance extends into activating the immune system is unexplored. This was tested here by comparing oral immune markers before and after a disgust induction, relative to neutral and negative induction control groups. The disgust group, but not controls, revealed an oral inflammatory response, with increased salivary tumor necrotizing factor alpha and albumin, as well as a down-regulation of immunoglobulin A (SIgA) secretion. It has been hypothesized that disgust evolved in animals to clear toxins from the oral cavity by gaping and increased salivary flow. Our data suggest down-regulated SIgA secretion may be a vestige of this response so as to conserve protein, while the inflammatory reaction may reflect an adaptive response to disease threat, selectively triggered by disgust. The broader implications of these data for a discrete neuro-gut-immune axis are examined.


Somatostatin receptor gene transfer inhibits established pancreatic cancer xenografts.
Most human pancreatic adenocarcinoma cells do not express somatostatin receptors, and somatostatin does not inhibit the growth of these cancers. We have demonstrated previously that somatostatin inhibits the growth of pancreatic cancers expressing somatostatin receptor subtype-2 (SSTR2), but not receptor-negative cancers. SSTR2 expression may be an important tumor-suppressor pathway that is lost in human pancreatic cancer. We hypothesized that SSTR2 gene transfer would restore the growth-inhibitory response of human pancreatic cancer to somatostatin. Palpable human pancreatic adenocarcinoma tumors were established on the backs of nude mice by subcutaneous injection of cultured cells (Panc-1). The animals were divided into 5 groups (n = 10/group). Group I served as an untreated control. Group II received an intramuscular injection of the long-acting somatostatin analogue Sandostatin LAR. Group III received Lac-Z expressing adenovirus via intraperitoneal injection. Group IV received SSTR2 expressing adenovirus via intraperitoneal injection. Group V received SSTR2 expressing adenovirus via intraperitoneal injection and an intramuscular injection of Sandostatin LAR. The rate of tumor growth was assessed with calipers. After 28 days, the animals were anesthetized and exsanguanated, and the tumors were excised and weighed. Plasma somatostatin and octreotide levels were measured by radioimmunoassay. Expression of cell-surface somatostatin-receptor protein and known tumor-suppressor proteins was determined by reverse transcriptase-polymerase chain reaction, Western blot, and immunohistochemistry. Systemic delivery of SSTR2-expressing adenovirus by intraperitoneal injection resulted in expression of SSTR2 protein in the subcutaneous human pancreatic cancers. Final tumor weight was significantly decreased in the groups expressing SSTR2 receptors compared to the other 3 groups. Treatment with Sandostatin LAR increased plasma octreotide levels as determined by radioimmunoassay, but had no significant effect on tumor growth. Western blot analysis revealed an up-regulation of the cyclin-dependent kinase inhibitors p27 and p16 in the SSTR2 transfected tumors. Expression of SSTR2 by human pancreatic cancer causes significant slowing of tumor growth by a mechanism independent of exogenous somatostatin. The mechanism may involve up-regulation of known tumor-suppressor proteins. Restoration of SSTR2 gene expression deserves further study as a potential gene-therapy strategy in human pancreatic cancer.


Electrophilic phosphonium cations catalyze hydroarylation and hydrothiolation of olefins.
Electrophilic phosphonium cations (EPCs) are efficient main group catalysts for the hydroarylation of olefins under mild conditions, providing a facile route to substituted aniline, bis-arylamine, phenol, furan, thiophene, pyrrole, and indole derivatives. Similarly, EPCs catalyze the hydrothiolation of aryl olefins with thiophenol affording a series of alkyl aryl thioethers. Experimental data support a mechanism for these reactions that involves initial activation of the olefin.


SLC41A1, a Na+/Mg2+ exchanger, is downregulated during exercise.
Serum magnesium (Mg) levels are closely controlled through a variety of Mg transporters and ionic channels during physiological conditions. These levels have been shown to increase during exercise. However, the effect of Mg transporter expression during exercise remains to be determined. The purpose of this study was to examine the gene expression of SLC41A1, a Na+/Mg2+ exchanger, during exercise. In the present study, male C57BL/6JNarl mice (n=16, 8 weeks old) were subjected to 3 h forced exercise on a treadmill. The mice in the control and Mg groups were injected with saline and Mg (MgSO4, 90 mg/kg, intraperitoneal), respectively. Blood samples were obtained at three time points: prior to, following and 24 h after exercise. The gene expression levels of SLC41A1 were significantly downregulated to 23.6±4.6 and 12.6±10.2% following exercise in the control and Mg groups, respectively. The expression levels returned to the basal levels 24 h after exercise in the two groups and there was no significant difference found between the two groups. The downregulated role of SLC41A1 expression and its interaction with the Mg status in exercise requires further investigation.


Effects of a Group-Based Treadmill Program on Children With Neurodevelopmental Impairment Who Are Not Yet Ambulating.
To examine the effects of a group-based treadmill program on gross motor skills related to walking and the amount of support needed for ambulation in children with neuromotor impairment who are not yet walking. Twelve children (mean age, 30.4 months; standard deviation, 7.9) participated in the program twice per week for 14 weeks. The Gross Motor Function Measure-88 Dimensions D and E (GMFM-88 D/E), the Functional Mobility Scale (FMS), the timed 10-m walk test, and the Pediatric Evaluation of Disability Inventory Mobility Scale (PEDI) were administered before and at the conclusion of the program. Data were analyzed using paired the t test and Wilcoxon matched-pairs signed rank test. Statistically significant improvements were found between pre- and posttests in the GMFM-88 D (P = .0005) and E (P = .001), in FMS scores (P = .039), and the PEDI (P = .001). A group-based treadmill program leads to positive changes in walking ability in children with neuromotor impairment.


Individual reactions to a multisensory immersive virtual environment: the impact of a wind farm on individuals.
The aim of this study was to assess the impact of a wind farm on individuals by means of an audio-visual methodology that tried to simulate biologically plausible individual-environment interactions. To disentangle the effects of auditory and visual components on cognitive performances and subjective evaluations, unimodal (Audio or Video) and bimodal (Audio + Video) approaches were compared. Participants were assigned to three experimental conditions that reproduced a wind farm by means of an immersive virtual reality system: bimodal condition, reproducing scenarios with both acoustic and visual stimuli; unimodal visual condition, with only visual stimuli; unimodal auditory condition, with only auditory stimuli. While immersed in the virtual scenarios, participants performed tasks assessing verbal fluency, short-term verbal memory, backward counting, and distance estimations (egocentric: how far is the turbine from you?; allocentric: how far is the turbine from the target?). Afterwards, participants reported their degree of visual and noise annoyance. The results revealed that the presence of a visual scenario as compared to the only availability of auditory stimuli may exert a negative effect on resource-demanding cognitive tasks but a positive effect on perceived noise annoyance. This supports the idea that humans perceive the environment holistically and that auditory and visual features are processed in close interaction.


Dihydroartemisinin and its derivative induce apoptosis in acute myeloid leukemia through Noxa-mediated pathway requiring iron and endoperoxide moiety.
Anti-apoptotic protein Mcl-1 plays an important role in protecting cell from death in acute myeloid leukemia (AML). The apoptosis blocking activity of Mcl-1 is inhibited by BH3-only protein Noxa. We found that dihydroartemisinin (DHA) and its derivative X-11 are potent apoptosis inducers in AML cells and act through a Noxa-mediate pathway; X-11 is four-fold more active than DHA. DHA and X-11-induced apoptosis is associated with induction of Noxa; apoptosis is blocked by silencing Noxa. DHA and X-11 induce Noxa expression by upregulating the transcription factor FOXO3a in a reactive oxygen species-mediated pathway. Interfering with the integrity of the endoperoxide moiety of DHA and X-11, as well as chelating intracellular iron with deferoxamine, diminish apoptosis and Noxa induction. AML cells expressing Bcl-xL, or with overexpression of Bcl-2, have decreased sensitivity to DHA and X-11-induced apoptosis which could be overcome by addition of Bcl-2/Bcl-xL inhibitor ABT-737. DHA and X-11 represent a new group of AML cells-apoptosis inducing compounds which work through Noxa up-regulation utilizing the specific endoperoxide moiety and intracellular iron.


Endothelial Cell Responses to Biomechanical Forces in Lymphatic Vessels.
Lymphatic vessels are important components of the cardiovascular and immune systems. They contribute both to the maintenance of normal homeostasis and to many pathological conditions, such as cancer and inflammation. The lymphatic vasculature is subjected to a variety of biomechanical forces, including fluid shear stress and vessel circumferential stretch. This review will discuss recent advances in our understanding of biomechanical forces in lymphatic vessels and their role in mammalian lymphatic vascular development and function. We will highlight the importance of fluid shear stress generated by lymph flow in organizing the lymphatic vascular network. We will also describe how mutations in mechanosensitive genes lead to lymphatic vascular dysfunction. Better understanding of how biomechanical and biochemical stimuli are perceived and interpreted by lymphatic endothelial cells is important for targeting regulation of lymphatic function in health and disease. Important remaining critical issues and future directions in the field will be discussed in this review. Antioxid. Redox Signal. 25, 451-465.


[Neurons in the hyperchromic state].
The paper summarizes findings concerning the ultrastructure and cytochemistry of the cortical hyperchromic neurons which appear under different experimental conditions (in intact animals, in mechanical traumatization of neuronal tissue, during formation of a local focus of destruction, upon the administration of aminazine, and in the process of autolysis). Characteristics of the development of the hyperchromic status in each of the above experimental situations are specified. The authors consider the questions concerning the life-time development of neuronal hyperchromia, a relationship of hyperchromia with a certain function of the cell and the reversibility of the ultrastructural and cytochemical shifts characteristic of hyperchromia. A conclusion is made about the development of hyperchromia during life (with the exception of autolysis), its correlation with a decreased functional activity of the cell and the possibility of hyperchromia involution. Hyperchromic cells proved to be highly resistant to autolysis.


Angiogenesis in lipoma: An experimental study in the chick embryo chorioallantoic membrane.
Lipoma is one of the most common benign mesenchymal tumors. Its ability to trigger an angiogenic response is a critical step for its growth. Because adipose tissue serves as an important conduit for the vasculature, it is conceivable that the angiogenic properties of this tissue may modulate the growth of the vasculature in a paracrine manner. We investigated in vivo the angiogenic potential of bioptic fragments of human lipoma by using the chick embryo chorioallantoic membrane (CAM), a useful model for such an investigation. The angiogenic response in pathological and control implants was assessed on histologic sections by a morphometric method, 96 h after grafting. Results showed that pathological samples were surrounded by numerous allantoic vessels with a radially arranged pattern around the implant. The vascular counts in the CAMs treated with lipoma implants were comparable to that of FGF-2. The role played in vasoproliferative response by angiogenic cytokines (FGF-2, VEGF) released by adipocytes, by endogenous cytokines, such as FGF-2, stored in the CAM extracellular matrix and by angiogenic growth factors released by perivascular mononuclear cells around the newly-formed blood vessels, were supported by this study.


Discontinuous nanoporous membranes reduce non-specific fouling for immunoaffinity cell capture.
The microfluidic isolation of target cells using adhesion-based surface capture has been widely explored for biology and medicine. However, high-throughput processing can be challenging due to interfacial limitations such as transport, reaction, and non-specific fouling. Here, it is shown that antibody-functionalized capture surfaces with discontinuous permeability enable efficient target cell capture at high flow rates by decreasing fouling. Experimental characterization and theoretical modeling reveal that "wall effects" affect cell-surface interactions and promote excess surface accumulation. These issues are partially circumvented by reducing the transport and deposition of cells near the channel walls. Optimized microfluidic devices can be operated at higher cell concentrations with significant improvements in throughput.


Lipopolysaccharide from Crypt-Specific Core Microbiota Modulates the Colonic Epithelial Proliferation-to-Differentiation Balance.
We identified a crypt-specific core microbiota (CSCM) dominated by strictly aerobic, nonfermentative bacteria in murine cecal and proximal colonic (PC) crypts and hypothesized that, among its possible functions, it may affect epithelial regeneration. In the present work, we isolated representative CSCM strains using selective media based upon our initial 16S rRNA-based molecular identification (i.e., Acinetobacter, Delftia, and Stenotrophomonas). Their tropism for the crypt was confirmed, and their influence on epithelial regeneration was demonstrated in vivo by monocolonization of germfree mice. We also showed that lipopolysaccharide (LPS), through its endotoxin activity, was the dominant bacterial agonist controlling proliferation. The relevant molecular mechanisms were analyzed using colonic crypt-derived organoids exposed to bacterial sonicates or highly purified LPS as agonists. We identified a Toll-like receptor 4 (TLR4)-dependent program affecting crypts at different stages of epithelial differentiation. LPS played a dual role: it repressed cell proliferation through RIPK3-mediated necroptosis of stem cells and cells of the transit-amplifying compartment and concurrently enhanced cell differentiation, particularly the goblet cell lineage.IMPORTANCE The LPS from crypt-specific core microbiota controls intestinal epithelium proliferation through necroptosis of stem cells and enhances cell differentiation, mainly the goblet cell lineage.


Organizing the complexes of schizophrenia.
A wide range of factors contribute to the occurrence of schizophrenia and to its outcome. The complexity to the disorder is further heightened by the several semi-independent aspects of function that constitute its course. To provide a structure for dealing with these complexities, this report employs principles of multiaxial diagnosis to begin constructing an operational systems model of schizophrenia. Findings from an intensive qualitative study of schizophrenic subjects are used to develop this model from an empirical base.


Trends in socioeconomic inequalities in premature and avoidable mortality in Canada, 1991-2016.
Recent epidemiologic findings suggest that socioeconomic inequalities in health may be widening over time. We examined trends in socioeconomic inequalities in premature and avoidable mortality in Canada. We conducted a population-based repeated cohort study using the 1991, 1996, 2001, 2006 and 2011 Canadian Census Health and Environment Cohorts. We linked individual-level Census records for adults aged 25-74 years to register-based mortality data. We defined premature mortality as death before age 75 years. For each census cohort, we estimated age-standardized rates, risk differences and risk ratios for premature and avoidable mortality by level of household income and education. We identified 16 284 045 Census records. Between 1991 and 2016, premature mortality rates declined in all socioeconomic groups except for women without a high school diploma. Absolute income-related inequalities narrowed among men (from 2478 to 1915 deaths per 100 000) and widened among women (from 1008 to 1085 deaths per 100 000). Absolute education-related inequalities widened among men and women. Relative socioeconomic inequalities in premature mortality widened progressively over the study period. For example, the relative risk of premature mortality associated with the lowest income quintile increased from 2.10 (95% confidence interval [CI] 2.02-2.17) to 2.79 (95% CI 2.66-2.91) among men and from 1.72 (95% CI 1.63- 1.81) to 2.50 (95% CI 2.36-2.64) among women. Similar overall trends were observed for avoidable mortality. Socioeconomically disadvantaged groups have not benefited equally from recent declines in premature and avoidable mortality in Canada. Efforts to reduce socioeconomic inequalities and associated patterns of disadvantage are necessary to prevent this pattern of widening health inequalities from persisting or worsening over time.


Suppressive effects of rosa damascena essential oil on naloxone- precipitated morphine withdrawal signs in male mice.
This research was done to test the effect of Rosa damascena essential oil on withdrawal signs of naloxone-precipitated morphine in male mice. Morphine dependence was induced by injection (IP) three times daily at doses of 50, 50 and 75 mg/kg, respectively, for 3 days. On day 4, after the last administration of morphine, Rosa damascena essential oil was administered at different concentrations (5, 2 and 40%, IP) 30 min before administration of naloxone (5 mg/kg, IP). The following actions were taken as signs of withdrawal and records taken for jumping as a number and scores of 0 to 3 were given for incidences of grooming, teeth chattering, rearing, writing, diarrhea, wet dog shakes and climbing during a 30 min period. Results showed that different concentrations of Rosa damascena essential oil significantly reduced signs of morphine withdrawal compared to the control group in terms of number of jumps (p < 0.05 and p < 0.01), grooming, teeth chattering, rearing, climbing, wet dog shakes and writhing, but not for diarrhea (p < 0.05). In conclusion it seems that GABAergic activity induced by flavonoids from Rosa damascena essential oil can alleviate signs of morphine withdrawal, but further studies need to be done to better understand this mechanism.


Modifications in coordination structure of Mg[TFSA]2-based supporting salts for high-voltage magnesium rechargeable batteries.
To achieve a sustainable-energy society in the future, next-generation highly efficient energy storage technologies, particularly those based on multivalent metal negative electrodes, are urgently required to be developed. Magnesium rechargeable batteries (MRBs) are promising options owing to the many advantageous chemical and electrochemical properties of magnesium. However, the substantially low working voltage of sulfur-based positive electrodes may hinder MRBs in becoming alternatives to current Li-ion batteries. We proposed halide-free noncorrosive ionic liquid-based electrolytes incorporating Mg[TFSA]2 for high-voltage MRB applications. Upon the complexation of Mg[TFSA]2 with tetraglyme (G4) and strict control of the liquid states, the electrolytes achieved excellent anodic stability up to 4.1 V vs. Mg2+/Mg even at 100 °C. The modest electrochemical activities for magnesium deposition/dissolution in the [Mg(G4)][TFSA]2/ionic liquid electrolyte can be improved by certain modifications to the coordination state of [TFSA]-. Dialkyl sulfone was found to be effective in changing the coordination state of [TFSA]- from associated to isolated (free). This coordination change successfully promoted magnesium deposition/dissolution reactions, particularly in the coexistence of ether ligand. By contrast, the coordination of Mg2+ by strongly donating agents such as dimethyl sulfoxide and alkylimidazole led to the complexes inactive electrochemically, suggesting that interaction between Mg2+ and coordination agents predominates the fundamental electrochemical activity. We also demonstrated that an enhancement in the electrochemical activity of electrolytes contributed to improvements in the cycling ability of magnesium batteries with 2.5 V-class MgMn2O4 positive electrodes.


Field Trial and Molecular Characterization of RNAi-Transgenic Tomato Plants That Exhibit Resistance to Tomato Yellow Leaf Curl Geminivirus.
RNA interference (RNAi) is a widely used approach to generate virus-resistant transgenic crops. However, issues of agricultural importance like the long-term durability of RNAi-mediated resistance under field conditions and the potential side effects provoked in the plant by the stable RNAi expression remain poorly investigated. Here, we performed field trials and molecular characterization studies of two homozygous transgenic tomato lines, with different selection markers, expressing an intron-hairpin RNA cognate to the Tomato yellow leaf curl virus (TYLCV) C1 gene. The tested F6 and F4 progenies of the respective kanamycin- and basta-resistant plants exhibited unchanged field resistance to TYLCV and stably expressed the transgene-derived short interfering RNA (siRNAs) to represent 6 to 8% of the total plant small RNAs. This value outnumbered the average percentage of viral siRNAs in the nontransformed plants exposed to TYLCV-infested whiteflies. As a result of the RNAi transgene expression, a common set of up- and downregulated genes was revealed in the transcriptome profile of the plants selected from either of the two transgenic events. A previously unidentified geminivirus causing no symptoms of viral disease was detected in some of the transgenic plants. The novel virus acquired V1 and V2 genes from TYLCV and C1, C2, C3, and C4 genes from a distantly related geminivirus and, thereby, it could evade the repressive sequence-specific action of transgene-derived siRNAs. Our findings shed light on the mechanisms of siRNA-directed antiviral silencing in transgenic plants and highlight the applicability limitations of this technology as it may alter the transcriptional pattern of nontarget genes.


Mass accommodation of H2SO4 and CH3SO3H on water-sulfuric acid solutions from 6% to 97% RH.
The uptake of H2SO4 and CH3SO3H onto particles composed of water and sulfuric acid was studied in a laminar flow reactor at atmospheric pressure. Their first-order gas-phase loss rate coefficients were determined using a chemical ionization mass spectrometer. Relative humidity was varied from 6% to 97% at 295-297.5 K. The mass accommodation coefficient, alpha, was found to be close to unity for both species. These findings show that alpha does not limit particle growth rates resulting from H2SO4 and CH3SO3H uptake. Diffusion coefficients in N2 for these two species are also reported and a significant dependence upon relative humidity was seen for H2SO4 but not for CH3SO3H. Last, production of small particles was observed due to the presence of SO2 in particle chargers. Formation of these particles can be significantly reduced by adding an OH scavenger such as propane.


Chemical Characterization, Antioxidant, Antimicrobial, Cytotoxicity and in Silico Studies of Hexane Extract and Essential Oils from Citrus limon Leaves.
The present study investigates the chemical composition, antioxidant and antimicrobial bioactivities of essential oil and hexane extract from Citrus limon leaves. The isolation of essential oil was carried out using the Clevenger apparatus. The percentage yield of essential oil and hexane extract from Citrus limon leaves was 0.59 and 0.50 %, respectively. 2,2-Diphenyl-1-picrylhydrazyl (DPPH) scavenging assay highlighted that Citrus limon leaves essential oil (CLEO) and hexane extract exhibited the significant antioxidant potential of 69.64 and 67.55 %, respectively, compared to the BHT standard. Similarly, a significant inhibition in linoleic acid peroxidation was recorded in both CLEO (81.93 %) and hexane extract (50.34 %). Characterization of chemical constituents in CLEO and extract was executed using GC/MS, where Limonene was detected as a major compound in CLEO (60.52 %) and hexane extract (73.62 %). The haemolytic activity ranged from 2.46 to 5.75 % revealing negligible cytotoxicity of CLEO and hexane extract. In silico studies agree with the in vitro antimicrobial studies, where vinimalol, taraxasterol, and moretenol present in CLEO showed strong interactions/inhibition against dihydroorotase and DNA gyrase from E. coli, and the tyrosyl-tRNA synthetase and DNA gyrase from S. aureus. Based on the current data, it may be concluded that both CLEO and hexane extract possessed significant bioactivities, such as antimicrobial and antioxidant activity, with minimal cytotoxicity.


[Interaction of antibodies of different immunoglobulin classes with specific O-antigens and Salmonella haptens].
A study was made of the neutralizing properties of antisalmonella antibodies belonging to different immunoglobulin classes in respect to specific O-antigen (Lipopolysaccharide S. anatum) and haptens of salmonellae. In comparison with IgM-antibodies, IgG-antibodies were more stable bound not only with the univalent trisaccharide determinant, but also with the polysaccharide. However, in regard to the lipopolysaccharide complex the neutralizing activity of IgM- and IgG-antibodies was about the same; IgA-antibodies possessed the greatest neutralizing activity with respect to all the antigenic preparations used. The minimal neutralizing dose of the antigen and haptens increased with the reduction of the size of their molecule. A marked heterogeneity of antibodies of each of the immunoglobulin classes by their antigen-neutralizing properties was revealed in individual sera.


Differences in management of telemedicine alerts on weekdays and public holidays: Results from the OptiLink heart failure trial.
In the OptiLink heart failure study, timely and appropriate reactions to telemedicine alerts improved clinical outcomes in heart failure patients. This analysis investigates the relation between the weekday of alert transmission and the subsequent patient contact. In patients enrolled in the intervention arm of the OptiLink heart failure study (n = 505, age 66.1 ± 10.1, 77.2% male, left-ventricular ejection fraction 26.7% ± 6.1%), fluid index threshold crossing alerts were analysed according to the weekday of the transmission. Transmissions on Mondays-Thursdays were categorized as TD1, Fridays-Sundays as well as public holidays as TD2. Of 1365 transmitted alerts, 867 (63.5%) were categorized as TD1 and 498 (36.5%) as TD2. Same day telephone contacts were more frequent in TD1 (46.2%) than in TD2 (18.3%; p < 0.001). Accordingly, the median time to contact was significantly longer in TD2 compared with TD1 (2(1-3) vs 0(0-1) days; p < 0.001). Rates of no telephone contact were no different between the groups (12.1% vs 12.4%; p = 0.866). Although signs of worsening heart failure were prevalent in 32.4% in TD1 versus 32.1% in TD2 (p = 0.996), initiation of a pharmacological intervention occurred more likely in TD1 compared with TD2 (27.9% vs 22.9%; p = 0.041). No differences existed concerning hospitalization for heart failure within 30 days after alert transmission (3.9% vs 3.4%; p = 0.636). Alert transmissions during weekends and public holidays were less likely associated with timely patient contacts and initiation of pharmacological interventions than during the week. Telemedical centres providing 24/7 remote monitoring service and specific education programmes for physicians might help to optimize patient care.


Tuberculosis treatment outcomes and interruption among patients assessing DOTS regimen in a tertiary hospital in semi-urban area of south-western Nigeria.
Tuberculosis remains one of the most infectious diseases worldwide especially with the HIV pandemic. It is a cause of high morbidity and mortality in developing countries including Nigeria. Reasons contributing to high morbidity and mortality include high defaulting rate and treatment interruption. Several studies had evaluated the treatment outcome of tuberculosis but there is paucity of published literature on the outcome of treatment interruption especially in this environment. This study thus assessed the outcome of treatments and interruption among patients assessing DOTS regimen in a tertiary hospital located in asemi urban area in south-western Nigeria. The study was a review of TB register of the federal medical centre, Owo from its inception in 2008 to 2011. All the patients that have completed at least one course of chemotherapy (defined as 8 months of anti-tuberculosis treatment- 2 months intensive phase and 6 months continuation phase) were included. Treatment outcome and interruption were defined in accordance with World Health Organisation (WHO) recommendations. Data were analysed with SPSS version 17. A total of 400 patients were included. The mean age of patients was 36.8 +/- 16.8 years and 56.3% were male. Majority, (79.7%) were adults aged 19-64 years, 12.5% were in the paediatric age group and 7.8% were elderly. Less than half, 45.3% had TB/HIV co-infection. Regarding treatment outcome of tuberculosis, 75.5% were cured, 14.8% died, 4% relapsed and 3% defaulted. A little above one-fifth, 21 (5.3%) had treatment interruption among whom 9 (42.9%) were successfully traced and completed treatment. Significantly, higher proportion of those that had treatment interruption died, 54.1% compared with their counterpart, 14.9%, (p < 0.001) and had relapse. (14.3% versus 3.4%, p = 0.01). A high rate of tracking failure among patients with treatment interruption was found in the study. In addition, mortality and morbidity were higher among patients with treatment interruption. A more concerted effort is needed in tracking/tracing patients with treatment interruption in orderto reduce morbidity and mortality among TB patients assessing treatment.


Bioactivity and Bone Cell Formation with Poly-ε-Caprolactone/Bioceramic 3D Porous Scaffolds.
This study applied poly-ε-caprolactone (PCL), a biomedical ceramic powder as an additive (nano-hydroxyapatite (nHA) or β-tricalcium diphosphate (β-TCP)), and sodium chloride (NaCl) and ammonium bicarbonate ((NH4)HCO3) as porogens; these stuffs were used as scaffold materials. An improved solvent-casting/particulate-leaching method was utilized to fabricate 3D porous scaffolds. In this study we examined the physical properties (elastic modulus, porosity, and contact angle) and degradation properties (weight loss and pH value) of the 3D porous scaffolds. Both nHA and β-TCP improved the mechanical properties (elastic modulus) of the 3D porous scaffolds. The elastic modulus (0.15~1.865 GPa) of the various composite scaffolds matched that of human cancellous bone (0.1~4.5 GPa). Osteoblast-like (MG63) cells were cultured, a microculture tetrazolium test (MTT) was conducted and alkaline phosphatase (ALP) activity of the 3D porous scaffolds was determined. Experimental results indicated that both nHA and β-TCP powder improved the hydrophilic properties of the scaffolds. The degradation rate of the scaffolds was accelerated by adding nHA or β-TCP. The MTT and ALP activity tests indicated that the scaffolds with a high ratio of nHA or β-TCP had excellent properties of in vitro biocompatibility (cell attachment and proliferation).


Advances in Cryptococcus genomics: insights into the evolution of pathogenesis.
Cryptococcus species are the causative agents of cryptococcal meningitis, a significant source of mortality in immunocompromised individuals. Initial work on the molecular epidemiology of this fungal pathogen utilized genotyping approaches to describe the genetic diversity and biogeography of two species, Cryptococcus neoformans and Cryptococcus gattii. Whole genome sequencing of representatives of both species resulted in reference assemblies enabling a wide array of downstream studies and genomic resources. With the increasing availability of whole genome sequencing, both species have now had hundreds of individual isolates sequenced, providing fine-scale insight into the evolution and diversification of Cryptococcus and allowing for the first genome-wide association studies to identify genetic variants associated with human virulence. Sequencing has also begun to examine the microevolution of isolates during prolonged infection and to identify variants specific to outbreak lineages, highlighting the potential role of hyper-mutation in evolving within short time scales. We can anticipate that further advances in sequencing technology and sequencing microbial genomes at scale, including metagenomics approaches, will continue to refine our view of how the evolution of Cryptococcus drives its success as a pathogen.


Draft genomes of 3 cyanobacteria strains and 17 co-habiting proteobacteria assembled from metagenomes.
Cyanobium and Synechococcus are prominent, globally distributed cyanobacteria genera with ecological significance. Here, we report the genomes of the marine Synechococcus sp. CCMP836 and two strains of Cyanobium (CZS25K and CZS48M) along with the genomes of 17 co-occurring proteobacteria. These genomes will improve the strain-specific ecological positions.


Urinary proteome profiling for stratifying patients with familial Parkinson's disease.
The prevalence of Parkinson's disease (PD) is increasing but the development of novel treatment strategies and therapeutics altering the course of the disease would benefit from specific, sensitive, and non-invasive biomarkers to detect PD early. Here, we describe a scalable and sensitive mass spectrometry (MS)-based proteomic workflow for urinary proteome profiling. Our workflow enabled the reproducible quantification of more than 2,000 proteins in more than 200 urine samples using minimal volumes from two independent patient cohorts. The urinary proteome was significantly different between PD patients and healthy controls, as well as between LRRK2 G2019S carriers and non-carriers in both cohorts. Interestingly, our data revealed lysosomal dysregulation in individuals with the LRRK2 G2019S mutation. When combined with machine learning, the urinary proteome data alone were sufficient to classify mutation status and disease manifestation in mutation carriers remarkably well, identifying VGF, ENPEP, and other PD-associated proteins as the most discriminating features. Taken together, our results validate urinary proteomics as a valuable strategy for biomarker discovery and patient stratification in PD.


[Sclerotherapy versus somatostatin in the treatment of upper digestive hemorrhage caused by rupture of esophageal varices].
The aim of this study was to compare the efficacy of somatostatin versus endoscopic sclerotherapy in the management of digestive bleeding caused by rupture of esophageal varices. Forty patients were evaluated; 21 were randomly assigned to receive somatostatin (initial 250 micrograms followed by a 48-hour continuous infusion of 250 micrograms/h and 250 micrograms 6/6 h bolus in the first 24 hours) and 19 to receive endoscopic sclerotherapy with ethanolamine oleate 5%. The patients were evaluated after 48 hours and after 7 days of treatment. Both groups of patients were similar in sex, age, gravity of the hemorrhage and liver dysfunction. Therapeutic failure occurred in 26.3% and 35.7% in the group of endoscopic sclerotherapy (48 h and 7 days respectively), and in 23.8% and 21.4% in the group of somatostatin. The need of blood transfusion (3.38 U in the group of endoscopic sclerotherapy and 2.42 U in the group of somatostatin) and the mortality rate (31.6% in the group of endoscopic sclerotherapy and 28.6% in the group of somatostatin) were also similar (P > 0.05). The authors conclude that somatostatin is as effective as endoscopic sclerotherapy and that it should be considered in the treatment of acute esophageal variceal bleeding.


A qualitative study exploring use of the surprise question in the care of older people: perceptions of general practitioners and challenges for practice.
The question "Would you be surprised if this patient were to die in the next 6-12 months?" has been included in UK palliative care guidance with the aim of supporting the identification and care planning of those nearing the end of life. Little is known about how the surprise question is utilised in the care of older people within primary care. This study sought to explore the perceptions and experiences of general practitioners (GPs). Semistructured interviews were conducted with 12 GPs. Each interview reflected on the care of two people, aged 80 years or older, selected by the GP as possibly being in the last year of life. Analysis followed a grounded theory approach within a framework of interpretive thematic analysis. Data discussing 22 clinical cases revealed the difficulties experienced by GPs when assessing prognosis for older people with non-malignant conditions, despite their recognition of multiple mortality risk factors and high symptom burden. GPs did not appear to include the surprise question within their usual practice and expressed concerns regarding its use to facilitate discussion of advance care plans. These concerns highlighted the subjective nature of the surprise question and potential barriers to conducting discussions of preferences for future care. Greater understanding is needed as to the difficulties experienced by GPs when assessing prognosis in older people. We propose a thematic model which could support GPs by focusing assessment on the supportive and palliative care needs of older people nearing the end of life.


[Efficacy of peristil treatment in primary and secondary duodenal dyskinesias].
Clinical studies of peristil demonstrated that this drug is effective in hypomotor and dysmotor gastroduodenal disturbances leading to reduction of clinical symptoms of primary and secondary duodenodyskinesias. A systemic prokinetic action of peristil is beneficial in patients with duodenodiskinesia combination with gastroesophageal reflux as well as hypomotor constipation syndrome. Also, peristil reduces depressive symptoms and improves quality of life in patients with primary and secondary duodenodyskinesias.


The preparation of alcohol dehydrogenase and glyceraldehyde 3-phosphate dehydrogenase from baker's yeast.
A procedure has been developed for the preparation of alcohol dehydrogenase and glyceraldehyde 3-phosphate dehydrogenase from the same sample of baker's yeast. The two enzymes were obtained in good yield in a pure crystalline form. The method minimizes the work involved in preparing the two enzymes and would be of particular advantage for preparing the enzymes in radioactive form from yeast grown in a radioactive medium.


Effects of growth hormone gene polymorphism on lipogenic gene expression levels in diaphragm tissues of Japanese black heifers.
Two SNPs, i.e. L127V and T172M, of bovine growth hormone (GH) causing the presence of GH gene haplotypes A, B, and C was previously shown to alter intramuscular fatty acid (FA) composition in Japanese Black (JB) heifers. To determine the SNP effect on somatotropic hormone concentration and lipogenesis, we measured plasma GH, insulin, and insulin-like growth factor-1 (IGF-1) concentrations. We also measured mRNA levels of fatty acid synthase (FASN), stearoyl-coA desaturase (SCD), and sterol regulatory element binding proteins-1 (SREBP-1) and FA composition in diaphragm tissues. Heifers with genotype CC had the lowest plasma insulin concentration and FASN and SCD mRNA levels among genotypes. FASN mRNA levels in haplotype A tended to positively correlate with saturated FA (SFA) content and negatively correlated with C18:2 and unsaturated FA (USFA) contents. SCD mRNA levels in haplotype A positively correlated with monounsaturated FA (MUFA) contents and negatively correlated with C18:0 content. They also tended to positively correlate with C16:1, C18:1, and USFA contents and USFA/SFA ratio and negatively correlate with SFA content. Taken together, GH gene polymorphism affects the lipogenic genes expression levels and their relationships with fatty acid compositions in diaphragm tissues of JB heifers at 31 months of age.


Nerve Visualization Using Phenoxazine-Based Near-Infrared Fluorophores to Guide Prostatectomy.
Fluorescence-guided surgery (FGS) is poised to revolutionize surgical medicine through near-infrared (NIR) fluorophores for tissue- and disease-specific contrast. Clinical open and laparoscopic FGS vision systems operate nearly exclusively at NIR wavelengths. However, tissue-specific NIR contrast agents compatible with clinically available imaging systems are lacking, leaving nerve tissue identification during prostatectomy a persistent challenge. Here, we show that combining drug-like molecular design concepts and fluorophore chemistry enabled the production of a library of NIR phenoxazine-based fluorophores for intraoperative nerve-specific imaging. The lead candidate readily delineated prostatic nerves in the canine and iliac plexus in the swine models using the clinical da Vinci Surgical System that has been popularized for minimally invasive prostatectomy procedures. These results demonstrate the feasibility of molecular engineering of NIR nerve-binding fluorophores for ready integration into the existing surigical workflow, paving the path for clinical translation to reduce morbidity from nerve injury for prostate cancer patients. This article is protected by copyright. All rights reserved.


Species and population specific gene expression in blood transcriptomes of marine turtles.
Transcriptomic data has demonstrated utility to advance the study of physiological diversity and organisms' responses to environmental stressors. However, a lack of genomic resources and challenges associated with collecting high-quality RNA can limit its application for many wild populations. Minimally invasive blood sampling combined with de novo transcriptomic approaches has great potential to alleviate these barriers. Here, we advance these goals for marine turtles by generating high quality de novo blood transcriptome assemblies to characterize functional diversity and compare global transcriptional profiles between tissues, species, and foraging aggregations. We generated high quality blood transcriptome assemblies for hawksbill (Eretmochelys imbricata), loggerhead (Caretta caretta), green (Chelonia mydas), and leatherback (Dermochelys coriacea) turtles. The functional diversity in assembled blood transcriptomes was comparable to those from more traditionally sampled tissues. A total of 31.3% of orthogroups identified were present in all four species, representing a core set of conserved genes expressed in blood and shared across marine turtle species. We observed strong species-specific expression of these genes, as well as distinct transcriptomic profiles between green turtle foraging aggregations that inhabit areas of greater or lesser anthropogenic disturbance. Obtaining global gene expression data through non-lethal, minimally invasive sampling can greatly expand the applications of RNA-sequencing in protected long-lived species such as marine turtles. The distinct differences in gene expression signatures between species and foraging aggregations provide insight into the functional genomics underlying the diversity in this ancient vertebrate lineage. The transcriptomic resources generated here can be used in further studies examining the evolutionary ecology and anthropogenic impacts on marine turtles.


Use of oseltamivir during influenza outbreaks in Ontario nursing homes, 1999-2000.
To describe the experience of Ontario long-term care facilities that used oseltamivir during influenza outbreaks in 1999/2000. Case series. Ten Ontario long-term care facilities for older people and their residents. Older residents of long-term care facilities. Oseltamivir for treatment or prophylaxis during 11 influenza outbreaks in 1999/2000. Control of outbreaks; pneumonia, hospitalization, and death complicating acute influenza. All outbreaks were due to influenza A//H3N2/Sydney/05/97. One facility elected to use oseltamivir for treatment and amantadine for prophylaxis. The remaining nine facilities (10 outbreaks) recommended oseltamivir for treatment and prophylaxis (after amantadine failure in five and as primary prophylaxis in five). Use of oseltamivir was associated with termination of the outbreak in all eight evaluable outbreaks. Overall, 178/185 (96%) case-residents met the case definition of influenza and had complete data for evaluation. Of these, 63 (35%) were treated with antibiotics, 37 (21%) were diagnosed with pneumonia, 19 (11%) were hospitalized, and 16 (9%) died. Compared with residents receiving no therapy or who became ill while taking amantadine, residents who received oseltamivir within 48 hours of the onset of symptoms were less likely to be prescribed antibiotics, to be hospitalized, or to die (P <.05 for each outcome). These differences persisted and remained statistically significant when corrected for influenza immunization status. A total of 730 residents received oseltamivir prophylaxis for a median of 9 days (range 5-12). Of these, side effects were identified in 30 (4.1%), the most common being diarrhea (12 residents, 1.6%), cough (5, 0.7%), confusion (4, 0.5%) and nausea (4, 0.5%). Oseltamivir is safe and appears to be effective when used as treatment or prophylaxis to control outbreaks of influenza in older nursing home residents.


Splanchnic venous thrombosis is a marker of cancer and a prognostic factor for cancer survival.
It is unknown if splanchnic venous thrombosis (SVT) is a marker of occult cancer and a prognostic factor for cancer survival. Using Danish medical registries, we conducted a nationwide cohort study including all patients with first-time SVT (n = 1191) between 1994 and 2011. We followed the patients for subsequent cancer diagnoses and calculated absolute risks and standardized incidence ratios (SIRs). We formed a matched comparison cohort of cancer patients without SVT, and assessed the prognostic impact of SVT on cancer survival by applying the Kaplan-Meier method and Cox regression. We followed the patients for a median of 1.6 years, and found that SVT was a marker of occult cancer. The 3-month cancer risk was 8.0% and the SIR was 33 (95% confidence interval, 27-40), compared with the general population. Increased risk was mainly found for liver cancer (risk = 3.5%; SIR = 1805), pancreatic cancer (risk = 1.5%; SIR = 256), and myeloproliferative neoplasms (risk = 0.7%; SIR = 764). The overall SIR remained increased twofold after 1 or more years of follow-up. SVT was also a prognostic factor for survival in patients with liver and pancreatic cancer. The clinical impact may be a more thorough diagnostic work-up in patients presenting with SVT.


Development of an ovine collagen-based composite biosynthetic vascular prosthesis.
The search for an ideal vascular prosthesis to bypass peripheral vascular obstructive lesions is necessary where autologous tissues are either unavailable or unsuitable. This paper will outline the development and use of vascular conduits, principally of biological origin. The clinical benefits and limitations of these materials are discussed. The development of a composite biosynthetic prosthesis (Omniflow¿) is described, together with the testing methods used to determine and predict its suitability for use as an arterial substitute. The ovine biosynthetic prosthesis has significantly improved surface and mural properties over previous attempts at producing prostheses for vascular reconstruction. Immunohistological studies on samples recovered from dogs after 4 years show that the original ovine collagen is still present after 4 years, and it is further augmented by the deposition of new, host-derived connective tissue.


Measuring the motives of informal entrepreneurs.
Background - Handling non-observed activities pose major challenges to the governments and other stakeholders. Non-observed activities refer to underground activities, illegal activities, informal sector and any other activities that result in goods or services consumed by the household. The impact of these non-observed activities shows that the volume of people involved in the informal sector will rapidly increase. Informal economic activities are technically illegal yet are not intended as antisocial, thereby remaining acceptable to many individuals within the society. This research aimed to identify the factors that lead to entrepreneurial necessity and opportunity. Methods - The data of 51 respondents who were employed as informal entrepreneurs in Klang Valley areas in Malaysia was collected with the use of a questionnaire and convenient and proportionate sampling techniques. The data were analysed using SPSS software. Results - The two primary drivers of informal entrepreneurial activity were necessity and opportunity. The inability to find a formal job was an example of being driven by necessity. Meanwhile, individuals that are driven by opportunity chose to work independently in these informal sectors. Between necessity and engagement, refinement acted as a mediator. Often, necessity and opportunity do not automatically translate into successful entrepreneurship; further refinement is required in terms of market potential, technology usage, location preferences, and capital requirements. Improved refinement results in increased entrepreneurial engagement. Conclusions - The role and contribution of the informal sector entrepreneurship in economic development need to be evaluated and not just observed as an opportunity for individuals who choose this type of career. Therefore, further research is required in a wider variety of contexts to evaluate whether the same remains true in different populations. The results of this study can be useful for the government to set policies to encourage the transition of informal to formal entrepreneurships in Malaysia.


Perceptions Regarding Influenza Vaccination during Pregnancy among Childbearing Women.
The purpose of this study was to examine womens' perceptions regarding influenza vaccination during pregnancy among Korean childbearing women. Data was collected using focus group interviews from June to September, 2010. Forty Korean women participated in 13 focus groups. After obtaining permission from participants, each session of the focus group was audio-taped and transcribed verbatim. The responses were analyzed utilizing qualitative content analysis. Forty women ranging from 26 to 43 participated in the study. The major themes were safety concerns; effects of fetal protection and infection prevention; lack of perceived needs; and encouragement as well as concerns from others. Participants raised questions on whether the vaccine was safe and effective, and concerns about the potential harmful effect of influenza vaccine to their bodies and the fetus. The major reason for influenza vaccination during pregnancy was to protect self and fetus. Also, clinician's recommendation was the facilitating factors for influenza vaccination during pregnancy. The findings suggest that concerns associated with influenza vaccination should be considered when educating childbearing women about the influenza vaccine during pregnancy.


Three-component zoom lens with fixed position of optical center.
A method is proposed for calculation of initial parameters of a three-element zoom lens with an identical position of object and image principal planes of the optical system and approximately zero Petzval sum. Such an optical system has a fixed position of its optical center, which does not depend on object distance. The proposed method makes it possible to determine focal length values of individual elements and trajectories of their movements during zooming. The analysis is presented on examples of the calculation of parameters of such optical systems. These systems could be useful in optical measuring methods, photogrammetry, and machine vision techniques.


The Effect of Two Amino acid Residue Substitutions via RNA Editing on Dark-operative Protochlorophyllide Oxidoreductase in the Black Pine Chloroplasts.
Dark-operative protochlorophyllide oxidoreductase (DPOR) is a key enzyme to produce chlorophyll in the dark. Among photosynthetic eukaryotes, all three subunits chlL, chlN, and chlB are encoded by plastid genomes. In some gymnosperms, two codons of chlB mRNA are changed by RNA editing to codons encoding evolutionarily conserved amino acid residues. However, the effect of these substitutions on DPOR activity remains unknown. We first prepared cyanobacterial ChlB variants with amino acid substitution(s) to mimic ChlB translated from pre-edited mRNA. Their activities were evaluated by measuring chlorophyll content of dark-grown transformants of a chlB-lacking mutant of the cyanobacterium Leptolyngbya boryana that was complemented with pre-edited mimic chlB variants. The chlorophyll content of the transformant cells expressing the ChlB variant from the fully pre-edited mRNA was only one-fourth of the control cells. Co-purification experiments of ChlB with Strep-ChlN suggested that a stable complex with ChlN is greatly impaired in the substituted ChlB variant. We then confirmed that RNA editing efficiency was markedly greater in the dark than in the light in cotyledons of the black pine Pinus thunbergii. These results indicate that RNA editing on chlB mRNA is important to maintain appropriate DPOR activity in black pine chloroplasts.


Ratings of Perceived Exertion and Self-reported Mood State in Response to High Intensity Interval Training. A Crossover Study on the Effect of Chronotype.
The aim of this study was to investigate the influence of chronotype on mood state and ratings of perceived exertion (RPE) before and in response to acute high intensity interval exercise (HIIE) performed at different times of the day. Based on the morningness-eveningness questionnaire, 12 morning-types (M-types; N = 12; age 21 ± 2 years; height 179 ± 5 cm; body mass 74 ± 12 kg) and 11 evening-types (E-types; N = 11; age 21 ± 2 years; height 181 ± 11 cm; body mass 76 ± 11 kg) were enrolled in a randomized crossover study. All subjects underwent measurements of Profile of Mood States (POMS), before (PRE), after 12 (POST12) and 24 h (POST24) the completion of both morning (08.00 am) and evening (08.00 p.m.) training. Additionally, Global Mood Disturbance and Energy Index (EI) were calculated. RPE was obtained PRE and 30 min POST HIIE. Two-way ANOVA with Tukey's multiple comparisons test of POMS parameters during morning training showed significant differences in fatigue, vigor and EI at PRE and POST24 between M-types and E-types. In addition, significant chronotype differences were found only in POST12 after the evening HIIE for fatigue, vigor and EI. For what concerns Borg perceived exertion, comparing morning versus evening values in PRE condition, a higher RPE was observed in relation to evening training for M-types (P = 0.0107) while E-types showed higher RPE values in the morning (P = 0.008). Finally, intragroup differences showed that E-types had a higher RPE respect to M-types before (P = 0.002) and after 30 min (P = 0.042) the morning session of HIIE. No significant changes during the evening training session were found. In conclusion, chronotype seems to significantly influence fatigue values, perceived exertions and vigor in relation to HIIE performed at different times of the day. Specifically, E-types will meet more of a burden when undertaking a physical task early in the day. Practical results suggest that performing a HIIE at those times of day that do not correspond to subjects' circadian preference can lead to increased mood disturbances and perceived exertion. Therefore, an athlete's chronotype should be taken into account when scheduling HIIE. Trial registration: ACTRN12617000432314, registered 24 March 2017, "retrospectively registered". Web address of trial: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=371862&showOriginal=true&isReview=true.


Testosterone and relationship quality across the transition to fatherhood.
Recent research points to decreasing testosterone (T) levels as well as decreasing relationship quality during the transition to fatherhood, and it has been suggested that T reflects and affects motivation and behavior with respect to mating or paternal effort. Accordingly, we hypothesized that decreases in T are associated with decreasing relationship quality in new fathers. Thirty-seven fathers and 38 men in committed romantic relationships without children (controls) were recruited. All subjects participated actively by collecting saliva samples for T assessment three times a day on two assessment days, four weeks prior to birth (day 1) and eight weeks after birth (day 2) for fathers, and three months after the first assessment for controls and by filling out questionnaires on relationship quality. Results revealed significantly lower T levels (AUCg-T) in fathers than in controls at day 2 and significant decreases in relationship quality from day 1 to day 2 in fathers, but not in controls. In particular, the new fathers reported tenderness in their relationship to have significantly decreased from pre to post birth in comparison to the controls. These results were partially moderated by T levels at day 1. We interpret our results as being in line with the "challenge hypothesis" in humans, according to which T levels are positively associated with mating effort and negatively related to paternal activities.


Applying decision analysis in therapeutic drug monitoring: using decision trees to interpret serum theophylline concentrations.
In the second of a three-part series, decision analysis is applied to therapeutic drug monitoring decisions that affect individual patients, using theophylline concentration and toxicity data to illustrate general concepts. Likelihood ratios and conditional probability curves were developed. The curves were used to determine the probability of toxicity based on the clinician's assessment of patient status and a measured serum theophylline concentration. A decision tree to "rule in" or "rule out" toxicity was constructed. Selection of a serum concentration cutoff level for classifying patients as toxic or nontoxic depends on the probabilities of the possible outcomes of the decision process and the clinician's assessment of the value of each possible outcome; therefore, no single concentration value is best for classifying patients. A decision tree was also constructed for evaluating therapeutic options when the clinician is confronted with adverse effects that may be drug related. In three prototype cases, the expected utility for discontinuing theophylline, continuing the drug at the same dosage, or lowering the dosage was determined and used to evaluate the relative worth of each therapeutic option. A more comprehensive interpretation of the serum theophylline concentration is provided by decision-analysis techniques than by observation of pharmacologic effect alone, because other factors such as merit, risk, and consequences of alternative decisions are considered.


Acute and chronic effects of the incretin enhancer vildagliptin in insulin-resistant rats.
The enzyme dipeptidyl peptidase-IV (DPP-4) inactivates the incretin hormone glucagon-like peptide-1 (GLP-1). Because GLP-1 has therapeutic effects in patients with type 2 diabetes, but its potential is limited by a short half-life, DPP-4 inhibition is a promising approach to diabetes treatment. This study examined acute (single dose) and chronic (once-a-day dosing for 21 days) effects of the DPP-4 inhibitor vildagliptin (0.03-10 mg/kg) on plasma DPP-4 activity, intact GLP-1, glucose, and insulin after an oral glucose load in insulin-resistant Zucker fatty rats and acute effects in mildly insulin-resistant high-fat-fed normal rats. A single oral dose of vildagliptin in Zucker rats produced a rapid and dose-related inhibition of DPP-4: the minimum effective dose (MED) was 0.3 mg/kg. Glucose-induced increases of intact GLP-1 were greatly but similarly enhanced by vildagliptin at doses > or =0.3 mg/kg. Postload glucose excursions decreased, and the insulinogenic index (Deltainsulin/Deltaglucose at 10 min) increased, with an MED of 0.3 mg/kg and a maximally effective dose of 3 mg/kg. The effects of vildagliptin after chronic treatment were nearly identical to those of acute administration, and vildagliptin had no effect on body weight. In fat-fed normal rats, vildagliptin (3 mg/kg) also decreased postload glucose excursions and increased the insulinogenic index, but these effects were smaller than those in Zucker rats. Thus, vildagliptin is an orally effective incretin enhancer with antihyperglycemic activity in insulin-resistant rats and exhibits no tachyphylaxis. GLP-1-mediated augmentation of glucose-induced insulin release seems to make the major contribution to the antidiabetic properties of vildagliptin.


Hydrodynamic fluctuations in thermostatted multiparticle collision dynamics.
In this work we study the behavior of mesoscopic fluctuations of a fluid simulated by Multiparticle Collision Dynamics when this is applied together with a local thermostatting procedure that constrains the strength of temperature fluctuations. We consider procedures in which the thermostat interacts with the fluid at every simulation step as well as cases in which the thermostat is applied only at regular time intervals. Due to the application of the thermostat temperature fluctuations are forced to relax to equilibrium faster than they do in the nonthermostatted, constant-energy case. Depending on the interval of application of the thermostat, it is demonstrated that the thermodynamic state changes gradually from isothermal to adiabatic conditions. In order to exhibit this effect we compute from simulations diverse correlation functions of the hydrodynamic fluctuating fields. These correlation functions are compared with those predicted by a linearized hydrodynamic theory of a simple fluid in which a thermostat is applied locally. We find a good agreement between the model and the numerical results, which confirms that hydrodynamic fluctuations in Multiparticle Collision Dynamics in the presence of the thermostat have the properties expected for spontaneous fluctuations in fluids in contact with a heat reservoir.


Extraction and purification of Aspergillus tamarii β-fructofuranosidase with transfructosylating activity using aqueous biphasic systems (PEG/phosphate) and magnetic field.
β-fructofuranosidases (FFases) are enzymes involved in sucrose hydrolysis and fructo-oligosaccharides' production which are of great interest for the food industry. FFase from Aspergillus tamarii URM4634 was extracted using PEG/Phosphate Aqueous Biphasic Systems (ABS), and the impact of magnetic field on the extraction behavior was evaluated. A 24-full experimental design was employed to study the influence of molar mass of PEG, concentrations of PEG and phosphate and pH on the selected response variables, i.e., partition coefficient (K), purification factor (PF), activity yield (Y) and selectivity (S). The influence of magnetic field during partition and NaCl concentration on the same responses was also studied. The best results of FFase extraction without magnetic field (K = 0.50, PF = 4.05, Y = 72.66% and S = 0.06) were observed at pH 8.0 using 12.5% (w/w) PEG 400 and 25% (w/w) NaH2PO4/K2HPO4. Application of the magnetic field allowed improving the performance, with the best results being obtained at the longest distance between magnets (lowest magnetic field) and absence of NaCl (K = 0.93, PF = 4.22, Y = 83.79% and S = 0.09). The outcomes obtained demonstrate that ABS combination with low intensity magnetic field can be used as an efficient FFase pre-purification method.


Coordination of locomotor activity in the lamprey: role of descending drive to oscillators along the spinal cord.
In the lamprey and most fish, locomotion is characterized by caudally propagating body undulations that result from a rostrocaudal phase lag for ipsilateral burst activity. One of the mechanisms that might contribute to rostrocaudal phase lags is a gradient of oscillator burst frequencies along the spinal cord that presumably are produced, in part, by descending drive from the brain. The purpose of the present study was to test whether a gradient of oscillator frequencies does exist along the lamprey spinal cord. First, during brain-initiated locomotor activity in in vitro brain/spinal cord preparations, the cycle times (=1/frequency) of locomotor activity generated by the functionally isolated rostral spinal cord (activity blocked in middle and caudal cord) were significantly shorter than control cycle times when the entire spinal cord was generating locomotor activity. Second, the cycle times of locomotor activity generated by the functionally isolated caudal cord (activity blocked in rostral and middle cord) were significantly longer than control cycle times for activity generated by the entire spinal cord. Thus, no one region of the spinal cord appears to dictate the overall cycle times of locomotor activity generated by the entire spinal cord, although overall cycle times tended to be closest to those of the isolated rostral spinal cord. Finally, although short- and long-distance coupling as well as oscillator frequency gradients probably contribute to rostrocaudal phase lags of spinal locomotor activity, the asymmetrical nature of short-distance coupling, in which the descending component dominates, appears to be the main factor.


Gene Expression Analysis of Toll-Like Receptor Pathways in Heterophils from Genetic Chicken Lines that Differ in Their Susceptibility to Salmonella enteritidis.
Previously conducted studies using two chicken lines (A and B) show that line A birds have increased resistance to a number of bacterial and protozoan challenges and that heterophils isolated from line A birds are functionally more responsive. Furthermore, when stimulated with Toll-like receptor (TLR) agonists, heterophils from line A expressed a totally different cytokine and chemokine mRNA expression pattern than heterophils from line B. A large-scale gene expression profile using an Agilent 44K microarray on heterophils isolated from line A and line B also revealed significantly differential expression in many immune-related genes following Salmonella enteritidis (SE) stimulation, which included genes involved in the TLR pathway. Therefore, we hypothesize the differences between the lines result from distinctive TLR pathway signaling cascades that mediate heterophil function and, thus, innate immune responsiveness to SE. Using quantitative RT-PCR on mRNA from heterophils isolated from control and SE-stimulated heterophils of each line, we profiled the expression of all chicken homologous genes identified in a reference TLR pathway. Several differentially expressed genes found were involved in the TLR-induced My88-dependent pathway, showing higher gene expression in line A than line B heterophils following SE stimulation. These genes included the TLR genes TLR4, TLR15, TLR21, MD-2, the adaptor proteins Toll-interleukin 1 receptor domain-containing adaptor protein (TIRAP), Tumor necrosis factor-receptor associated factor 3 (TRAF3), the IκB kinases transforming growth factor-β-activating kinase 1 (TAK1), IKKε and IKKα, the transcription factors NFkB2 and interferon regulatory factor 7, phosphatidylinositol-3 kinase (PI-3K), and the mitogen-activated protein kinase p38. These results indicate that higher expression of TLR signaling activation of both MyD88-dependent and TRIF-dependent pathways are more beneficial to avian heterophil-mediated innate immunity and a complicated regulation of downstream adaptors is involved in stronger induction of a TLR-mediated innate response in the resistant line A. These findings identify new targets for genetic selection of chickens to increase resistance to bacterial infections.


Long-term bacterial profile of refrigerated ground beef made from carcass tissue, experimentally contaminated with pathogens and spoilage bacteria after hot water, alkaline, or organic acid washes.
The effects of 2% (vol/vol) lactic acid (LA), 2% (vol/vol) acetic acid (AA), 12% (wt/vol) trisodium phosphate (TSP), 72 degrees C water (HW), and 32 degrees C water (W) washes on bacterial populations which were introduced onto beef carcass surfaces after wash treatments were determined up to 21 days of storage at 4 degrees C of packaged ground beef prepared from the treated and inoculated carcasses. Beef carcass necks were collected from cattle immediately after harvest and subjected to the above treatments or left untreated (control). Neck meat was then inoculated with low levels (ca. <2 log10) of Listeria innocua, Salmonella typhimurium, Escherichia coli O157:H7, and Clostridium sporogenes contained in a bovine fecal cocktail. In general, growth of these four bacteria, aerobic bacteria, lactic acid bacteria, and pseudomonads was suppressed or not observed in the ground beef when LA, AA, or TSP treatments were used as compared to the untreated control. HW or W washes offered little suppression of growth of pathogens during subsequent storage of ground beef when these bacteria were introduced onto beef tissue posttreatment. Of the treatments used, a final LA or AA wash during the processing of beef carcasses offers the best residual efficacy for suppression of pathogen proliferation in ground beef during long-term refrigerated storage or short-term abusive temperature storage if these bacteria contaminate the carcass immediately after carcass processing.


Cryogenic separation of hydrogen isotopes in single-walled carbon and boron-nitride nanotubes: insight into the mechanism of equilibrium quantum sieving in quasi-one-dimensional pores.
Quasi-one-dimensional cylindrical pores of single-walled boron nitride and carbon nanotubes efficiently differentiate adsorbed hydrogen isotopes at 33 K. Extensive path integral Monte Carlo simulations revealed that the mechanisms of quantum sieving for both types of nanotubes are quantitatively similar; however, the stronger and heterogeneous external solid-fluid potential generated from single-walled boron nitride nanotubes enhanced the selectivity of deuterium over hydrogen both at zero coverage and at finite pressures. We showed that this enhancement of the D(2)/H(2) equilibrium selectivity results from larger localization of hydrogen isotopes in the interior space of single-walled boron nitride nanotubes in comparison to that of equivalent single-walled carbon nanotubes. The operating pressures for efficient quantum sieving of hydrogen isotopes are strongly depending on both the type as well as the size of the nanotube. For all investigated nanotubes, we predicted the occurrence of the minima of the D(2)/H(2) equilibrium selectivity at finite pressure. Moreover, we showed that those well-defined minima are gradually shifted upon increasing of the nanotube pore diameter. We related the nonmonotonic shape of the D(2)/H(2) equilibrium selectivity at finite pressures to the variation of the difference between the average kinetic energy computed from single-component adsorption isotherms of H(2) and D(2). In the interior space of both kinds of nanotubes hydrogen isotopes formed solid-like structures (plastic crystals) at 33 K and 10 Pa with densities above the compressed bulk para-hydrogen at 30 K and 30 MPa.