Influence of aromatic hydrocarbon receptor-mediated events on the genotoxicity of cigarette smoke condensate.
The role of aromatic hydrocarbon receptor (AhR)-mediated events on the genotoxicity of mainstream cigarette smoke condensate was investigated. In vitro studies with mouse hepatoma cells stably transfected with a DRE-dependent luciferase reporter indicate that cigarette smoke condensate is able to transform AhR to an active form which is capable of initiating gene transcription. Micronucleus formation in two hepatoma cell lines was used as an index of genotoxicity. Cigarette smoke condensate was observed to induce a higher frequency of micronuclei in Hepa1c1c7 cells relative to TAOc1BP(r)c1 cells, which express approximately 10-fold less AhR. Furthermore, the frequency of micronuclei was potentiated when Hepa1c1c7 cells were pretreated with 2,3,7,8-tetrachlorodibenzo-p-dioxin, a high affinity ligand of AhR. These in vitro studies were followed by an in vivo experiment with Ahr+/+ and Ahr-/- mice. Animals were dosed for three consecutive days with cigarette smoke condensate (0.5-10 microg/kg/day, i.p. injection). The frequency of micronuclei in reticulocytes and total erythrocytes was determined in peripheral blood samples collected 24 h after the last administration. While condensate was found to increase the incidence of micronucleated reticulocytes in Ahr+/+ mice, no increase was observed in the null allele animals. Furthermore, the frequency of micronucleated erythrocytes, a measure of basal chromosome-damaging activity, was slightly but significantly higher in Ahr+/+ relative to Ahr-/- mice. Together, these data suggest that cigarette smoke contains chemicals which transform the AhR to an active transcription factor and AhR-regulated enzyme induction plays an important role in mediating the genotoxicity of this complex environmental pollutant.


Expression cloning of NaDC-2, an intestinal Na(+)- or Li(+)-dependent dicarboxylate transporter.
A cDNA coding for a Na(+)-dicarboxylate cotransporter from Xenopus laevis intestine, NaDC-2, was isolated by functional expression cloning in Xenopus oocytes. NaDC-2 encodes a 622-residue polypeptide with a predicted mass of 68.6 kDa. The sequence and secondary structure of NaDC-2 are related to the mammalian renal Na(+)-dicarboxylate and Na(+)-sulfate cotransporters. NaDC-2 mRNA is expressed only in the intestine. Oocytes injected with NaDC-2 cRNA exhibit increased transport of succinate, citrate, and glutarate. Transport of succinate by NaDC-2 is stimulated by Na+ or Li+, with Michaelis-Menten constant values for succinate of 0.3 mM (in Na+) and 0.7 mM (in Li+). Na+ and Li+ activation curves show sigmoid kinetics, with Hill coefficients of 1.4 (nNa) and 1.7 (nLi), indicating that multiple cations are involved in the transport of succinate. The transport of succinate by NaDC-2 is insensitive to pH, whereas the transport of citrate is inhibited at high pH. The differences in functional properties between NaDC-2 and the structurally related Na(+)-dicarboxylate cotransporters NaDC-1 and hNaDC-1 will form the basis of detailed structure-function studies.


The drop-jump screening test: difference in lower limb control by gender and effect of neuromuscular training in female athletes.
A valgus lower limb alignment has been noted during noncontact anterior cruciate ligament injuries. A video drop-jump test can indicate an athlete's ability to control lower limb axial alignment in the coronal plane. Female athletes have decreased knee separation distances on landing and acceleration; male athletes have a neutrally aligned lower limb position. A neuromuscular training program will significantly increase knee separation distance in female athletes. Cohort study; Level of evidence, 2. The authors tested 325 female and 130 male athletes aged 11 to 19 years. The distance between the hips, knees, and ankles was measured during a drop-jump test. The separation distance between the knees and ankles was normalized by the hip separation distance. A neuromuscular training program (Sportsmetrics) was completed by 62 female athletes, and their jump-landing characteristics were reexamined. A marked decrease in knee separation distance was found on takeoff in 80% of female athletes and in 72% of male athletes. There was no difference between male and female athletes in the normalized knee and ankle separation distance during the landing and takeoff phases. The knee separation distance on landing was 23 +/- 9 cm in the female athletes and 22 +/- 8 cm in the male athletes. The normalized knee separation distance was 51% +/- 19% in the female athletes and 51% +/- 15% in the male athletes. After training, statistically significant increases were found in the female athletes in the knee separation distance on landing (29 +/- 8 cm, P < .0001) and in the normalized knee separation distance (68% +/- 18%, P < .0001). The trained female athletes had significantly greater knee separation distance and normalized knee separation distance than did the males (P < .0001). The majority of untrained female and male athletes demonstrated a valgus alignment appearance on the video test. After neuromuscular training, female athletes had improved knee separation distances and a more neutral lower limb alignment on landing and takeoff.


EEG rhythms lateralization patterns in children with unilateral hearing loss are different from the patterns of normal hearing controls during speech-in-noise listening.
Unilateral hearing loss constitutes a field of growing interest in the scientific community. In fact, this kind of patients represent a unique and physiological way to investigate how neuroplasticity overcame unilateral deafferentation by implementing particular strategies that produce apparently next- to- normal hearing behavioural performances. This explains why such patients have been underinvestigated for a long time. Thanks to the availability of techniques able to study the cerebral activity underlying the mentioned behavioural outcomes, the aim of the present research was to elucidate whether different electroencephalographic (EEG) patterns occurred in unilateral hearing loss (UHL) children in comparison to normal hearing (NH) controls during speech-in-noise listening. Given the intrinsic lateralized nature of such patients, due to the unilateral side of hearing impairment, the experimental question was to assess whether this would reflect a different EEG pattern while performing a word in noise recognition task varying the direction of the noise source. Results showed a correlation between the period of deafness and the cortical activity asymmetry toward the hearing ear side in the frontal, parietal and occipital areas in all the experimental conditions. Concerning alpha and beta activity in the frontal and central areas highlighted that in the NH group, the lateralization was always left-sided during the Quiet condition, while it was right-sided in noise conditions; this evidence was not, however, detected also in the UHL group. In addition, focusing on the theta and alpha activity in the frontal areas (Broca area) during noise conditions, while the activity was always left-lateralized in the NH group, it was ipsilateral to the direction of the background noise in the UHL group, and of a weaker extent than in NH controls. Furthermore, in noise conditions, only the UHL group showed a higher theta activity in the temporal areas ipsilateral to the side where the background noise was directed to. Finally, in the case of bilateral noise (background noise and word signal both coming from the same two sources), the theta and alpha activity in the frontal areas (Broca area) was left-lateralized in the case of the NH group and lateralized towards the side of the better hearing ear in the case of the UHL group. Taken together, this evidence supports the establishment of a particular EEG pattern occurrence in UHL children taking place in the frontal (Broca area), temporal and parietal lobes, probably physiologically established in order to deal with different sound and noise source directions.


Attainment of treat-to-target endpoints in SLE patients with high disease activity in the atacicept phase 2b ADDRESS II study.
Low disease activity (LDA) and remission are emerging treat-to-target (T2T) endpoints in SLE. However, the rates at which these endpoints are met in patients with high disease activity (HDA) are unknown. Atacicept, which targets B lymphocyte stimulator and a proliferation-inducing ligand, improved disease outcomes in SLE patients with HDA (SLEDAI-2K ≥10) at baseline in the phase 2b ADDRESS II study. This is a post hoc analysis of T2T endpoints in these patients. Patients received weekly atacicept (75 or 150 mg s.c.) or placebo for 24 weeks (1:1:1 randomization). Attainment of three T2T endpoints, LDA (SLEDAI-2K ≤ 2), Lupus Low Disease Activity State (LLDAS) and remission (clinical SLEDAI-2K = 0, prednisone-equivalent ≤5mg/day and Physician's Global Assessment <0.5), was assessed and compared with SLE Responder Index (SRI)-4 and SRI-6 response. Of 306 randomized patients, 158 (51.6%) had baseline HDA. At week 24, 37 (23.4%) HDA patients attained LDA, 25 (15.8%) LLDAS and 17 (10.8%) remission. Each of these endpoints was more stringent than SRI-4 (n = 87; 55.1%) and SRI-6 (n = 67; 42.4%). Compared with placebo (n = 52), at week 24, patients treated with atacicept 150 mg (n = 51) were more likely to attain LDA [odds ratio (OR) 3.82 (95% CI: 1.44, 10.15), P = 0.007], LLDAS [OR 5.03 (95% CI: 1.32, 19.06), P = 0.018] or remission [OR 3.98 (95% CI: 0.78, 20.15), P = 0.095]. At week 24, LDA, LLDAS and remission were more stringent than SRI-4 and SRI-6 response, were attainable in the HDA population and discriminated between treatment with atacicept 150 mg and placebo. These results suggest that T2T endpoints are robust outcome measures in SLE clinical trials and support further evaluation of atacicept in SLE. ClinicalTrials.gov, http://clinicaltrials.gov, NCT01972568.


Vocabulary use across genres: implications for students with complex communication needs.
This study examined the vocabulary words and multiword sequences used by 124 typically developing kindergarten and 1st-grade students when they wrote about self-selected topics. The study extends previous research by examining the vocabulary used in different genres. A total of 457 writing samples were analyzed. The samples were classified according to 9 genres and were analyzed using the Child Language Analysis ( MacWhinney, 2006) software program. The authors found that 140 words represented 70% of the vocabulary produced. The most common genre types were narrative recounts and opinions. The patterns of frequency for words and multiword sequences varied across genres. The degree of variation was greater for particular vocabulary words. For instance, the word going was used predominantly in 1 genre. In contrast, the word mom was used in every genre except 3. The structure words tended to be used with high frequency across genres. The word lists generated can be used to inform vocabulary selection, organization, and instruction for students with complex communication needs who are beginning writers.


Effect of repetitive transcranial magnetic stimulation on depression and cognition in individuals with traumatic brain injury: a systematic review and meta-analysis.
Repetitive transcranial magnetic stimulation (rTMS) is an FDA-approved therapy in major depressive disorder. However, its treatment efficacy on depression after traumatic brain injury (TBI) remains inconclusive. We conducted a meta-analysis to assess the effectiveness of executing rTMS over dorsolateral prefrontal cortex (DLPFC) on depression, cognitive impairment and post-concussion syndrome in individuals with traumatic brain injury. This study contained seven randomized controlled trials that published before April 5, 2020 in PubMed, Embase, Scopus, Cochrane, and Web of Science databases. The rTMS had significant anti-depressant effect (SMD = 1.03, p = 0.02), but the effects dissipated at 1-month follow-up (SMD = 0.39, p = 0.62). In the subgroup analysis, only applying rTMS to left DLPFC area of post-TBI patients showed significant anti-depressant effect (SMD = 0.98, p = 0.04). Moreover, current data observed that rTMS on post-TBI patients possessed substantial improvement in visuospatial memory (SMD = 0.39, p < 0.0001), but wasn't in processing speed (SMD = - 0.18, p = 0.32) and selective attention (SMD = 0.21, p = 0.31). In addition, the effect of rTMS is not superior to sham on postconcussion syndrome. In conclusion, the short-term antidepressant effect of left DLPFC rTMS in patients with TBI was significant. However, the effectiveness of rTMS on cognition and postconcussion syndrome in patients with post-TBI depression was limited.


Whole body vibration in helicopters: risk assessment in relation to low back pain.
Helicopter pilots are exposed to whole body vibration (WBV) in their working environment. WBV has been associated with low back pain (LBP) and helicopter pilots have a high prevalence for LBP compared with other professions. The aim of this study was to develop a test protocol for measuring helicopters with ISO 2631-1 and to perform a whole body vibration risk assessment based on the European Vibration Directive in a number of commonly used military and civilian helicopters. Both absolute values and individual difference in current helicopter types are of interest in order to evaluate the possible role of vibration in LBP in helicopter pilots. In operationally relevant maneuvers, six helicopters were tested. In order to standardize measurements, each continuous flight was split into 15 separate maneuvers. A model of a working day exposure pattern was used to calculate A(8) vibration magnitudes for each helicopter. The vibration A(8) exposure estimates ranged from 0.32-0.51 m x s(-2) during an 8-h working day A(8). This compares with EU and ISO lower bounds risk criteria of 0.5 and 0.43 m x s(-2) A(8), respectively. Despite the vibration levels being relatively low, helicopter pilots report a high incidence of LBP. It is possible that helicopter pilot postures increase the risk of LBP when combined with WBV. The test protocol used in this study could be generally applied for other rotary winged aircraft testing to allow for comparison of WBV results. Data from different flight phases could be used to model different exposure profiles.


Incidence, Costs and Predictors of Non-Union, Delayed Union and Mal-Union Following Long Bone Fracture.
Fracture healing complications are common and result in significant healthcare burden. The aim of this study was to determine the rate, costs and predictors of two-year readmission for surgical management of healing complications (delayed, mal, non-union) following fracture of the humerus, tibia or femur. Humeral, tibial and femoral (excluding proximal) fractures registered by the Victorian Orthopaedic Trauma Outcomes Registry over five years (n = 3962) were linked with population-level hospital admissions data to identify two-year readmissions for delayed, mal or non-union. Study outcomes included hospital length-of-stay (LOS) and inpatient costs. Multivariable logistic regression was used to determine demographic and injury-related factors associated with admission for fracture healing complications. Of the 3886 patients linked, 8.1% were readmitted for healing complications within two years post-fracture, with non-union the most common complication and higher rates for femoral and tibial shaft fractures. Admissions for fracture healing complications incurred total costs of $4.9 million AUD, with a median LOS of two days. After adjusting for confounders, patients had higher odds of developing complications if they were older, receiving compensation or had tibial or femoral shaft fractures. Patients who are older, with tibial and femoral shaft fractures should be targeted for future research aimed at preventing complications.


One-step synthesis of high quality kesterite Cu2ZnSnS4 nanocrystals - a hydrothermal approach.
The present work demonstrates a systematic approach for the synthesis of pure kesterite-phase Cu2ZnSnS4 (CZTS) nanocrystals with a uniform size distribution by a one-step, thioglycolic acid (TGA)-assisted hydrothermal route. The formation mechanism and the role of TGA in the formation of CZTS compound were thoroughly studied. It has been found that TGA interacted with Cu(2+) to form Cu(+) at the initial reaction stage and controlled the crystal-growth of CZTS nanocrystals during the hydrothermal reaction. The consequence of the reduction of Cu(2+) to Cu(+) led to the formation Cu2- x S nuclei, which acted as the crystal framework for the formation of CZTS compound. CZTS was formed by the diffusion of Zn(2+) and Sn(4+) cations to the lattice of Cu2- x S during the hydrothermal reaction. The as-synthesized CZTS nanocrystals exhibited strong light absorption over the range of wavelength beyond 1000 nm. The band gap of the material was determined to be 1.51 eV, which is optimal for application in photoelectric energy conversion device.


Effect of Celecoxib Administration on the Skin of 40-Week-Old Mice.
Various side effects associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs) in analgesia have been reported. Among the NSAIDs, celecoxib has fewer side effects and is often used in therapeutic applications. However, the effect of celecoxib on aged skin is unknown. In this study, we investigated the effects of celecoxib administration on the skin of aged mice. We analyzed a 40-week-old mouse model and a 10-week-old mouse as the control group. The animals were orally administered celecoxib for four consecutive days and then killed and dissected the day after the last dose. In aged mice treated with celecoxib, the water content of the stratum corneum, which is one of the markers of dry skin, was lower than that in the control and young mice groups. In addition, serum hyaluronic acid, creatinine, and inflammatory cytokines in the collected blood samples of aged mice were elevated compared to those in other mice groups, suggesting the onset of acute renal injury. Therefore, it was considered that acute renal injury occurred from the administration of celecoxib to aged mice, whereas dry skin developed by the promotion of inflammatory cytokine secretion and release into the bloodstream in this group.


Sorption of 4-ethylguaiacol and 4-ethylphenol on yeast cell walls, using a synthetic wine.
4-Ethylphenol (4-EP) and 4-ethylguaiacol (4-EG) are the identified volatile phenolic compounds associated with off-odour in wine. The aim of this work was to investigate the kinetics and thermodynamics of sorption of 4-EG and 4-EP by yeast cell walls, using a synthetic wine. Results showed that the sorption capacity by yeast cell walls for 4-EG was greater than that for 4-EP and that the kinetics of 4-EG were quicker, although the unions were weaker than in the case of 4-EP. The retention of these compounds was by means of specific chemical sorption. The process of sorption of these compounds to the yeast walls could be due to their binding to the residual lipids, as well as to interaction of 4-EP and 4-EG (positively charged compounds), with the functional groups of the mannoproteins and the free amino acids of the surface of the cell walls.


Application of StyleGAN Architecture for Generating Venous Leg Ulcer Images.
Leg ulcers caused by impaired venous blood return are the most typical chronic wound form and have a significant negative impact on the lives of people living with these wounds. Thus, it is important to provide early assessment and appropriate treatment of the wounds to promote their healing in the normal trajectory. Gathering quality wound data is an important component of good clinical care, enabling monitoring of healing progress. This data can also be useful to train machine learning algorithms with a view to predicting healing. Unfortunately, a high volume of good-quality data is needed to create datasets of suitable volume from people with wounds. In order to improve the process of gathering venous leg ulcer (VLU) data we propose the generative adversarial network based on StyleGAN architecture to synthesize new images from original samples. We utilized a dataset that was manually collected as part of a longitudinal observational study of VLUs and successfully synthesized new samples. These synthesized samples were validated by two clinicians. In future work, we plan to further process these new samples to train a fully automated neural network for ulcer segmentation.


The effects of intrauterine malnutrition on maternal-fetal cholesterol transport and fetal lipid synthesis in mice.
Intrauterine malnutrition is associated with increased susceptibility to chronic diseases in adulthood. Growth-restricted infants display a less favorable lipid profile already shortly postnatal. Maternal low protein diet (LPD) during gestation is a well-defined model of fetal programming in rodents and affects lipid metabolism of the offspring. Effects of LPD throughout gestation on physiologic relevant parameters of lipid metabolism are unclear. We aimed to determine effects of LPD on maternal-fetal cholesterol fluxes and fetal lipid synthesis in mice. Pregnant mice (dams) were fed with a control (18% casein) or an LPD (9% casein) from E0.5 onward. We quantified maternal-fetal cholesterol transport and maternal cholesterol absorption at E19.5 using stable isotopes. We determined fetal lipid biosynthesis at E19.5, after administration of (1-C)-acetate from E17.5 onward. LPD did not change fetal and maternal plasma and hepatic concentrations of cholesterol and triglycerides. LPD affected neither the magnitudes of maternal-fetal cholesterol flux, maternal cholesterol absorption, nor fetal synthesis of cholesterol and palmitate (both groups, approximately 14% and approximately 13%, respectively). We conclude that LPD throughout gestation in mice does not affect maternal-fetal cholesterol transport, fetal cholesterol or fatty acid synthesis, indicating that programming effects of LPD are not mediated by short-term changes in maternal-fetal lipid metabolism.


Full cervical cord tractography: A new method for clinical use.
Despite recent improvements in diffusion-weighted imaging, spinal cord tractography is not used in routine clinical practice because of difficulties in reconstructing tractograms, with a pertinent tri-dimensional-rendering, in a long post-processing time. We propose a new full tractography approach to the cervical spinal cord without extensive manual filtering or multiple regions of interest seeding that could help neurosurgeons manage various spinal cord disorders. Four healthy volunteers and two patients with either cervical intramedullary tumors or spinal cord injuries were included. Diffusion-weighted images of the cervical spinal cord were acquired using a Philips 3 Tesla machine, 32 diffusion directions, 1,000 s/mm2 b-value, 2 × 2 × 2 mm voxel size, reduced field-of-view (ZOOM), with two opposing phase-encoding directions. Distortion corrections were then achieved using the FSL software package, and tracking of the full cervical spinal cord was performed using the DSI Studio software (quantitative anisotropy-based deterministic algorithm). A unique region of avoidance was used to exclude everything that is not of the nervous system. Fiber tracking parameters used adaptative fractional anisotropy from 0.015 to 0.045, fiber length from 10 to 1,000 mm, and angular threshold of 90°. In all participants, a full cervical cord tractography was performed from the medulla to the C7 spine level. On a ventral view, the junction between the medulla and spinal cord was identified with its pyramidal bulging, and by an invagination corresponding to the median ventral sulcus. On a dorsal view, the fourth ventricle-superior, middle, and inferior cerebellar peduncles-was seen, as well as its floor and the obex; and gracile and cuneate tracts were recognized on each side of the dorsal median sulcus. In the case of the intramedullary tumor or spinal cord injury, the spinal tracts were seen to be displaced, and this helped to adjust the neurosurgical strategy. This new full tractography approach simplifies the tractography pipeline and provides a reliable 3D-rendering of the spinal cord that could help to adjust the neurosurgical strategy.


Two-component sensor required for normal symbiotic colonization of euprymna scolopes by Vibrio fischeri.
The light organ of the squid Euprymna scolopes is specifically colonized to a high density by the marine bacterium Vibrio fischeri. To date, only a few factors contributing to the specificity of this symbiosis have been identified. Using a genetic screen for random transposon mutants defective in initiating the symbiotic association or in colonizing the light organ to high density, we identified a mutant of V. fischeri that exhibited an apparent defect in symbiosis initiation. This mutant was not defective in motility, luminescence, or growth in minimal medium, suggesting that it lacks an essential, previously unidentified symbiotic function. By sequence analysis, we showed that the locus inactivated in this mutant encodes a predicted 927-amino-acid protein with a high degree of similarity to the sensor component of hybrid two-component regulatory systems. We have therefore designated this locus rscS, for regulator of symbiotic colonization-sensor. Sequence analysis revealed two hydrophobic regions which may result in the formation of a periplasmic loop involved in signal recognition; PhoA fusion data supported this proposed membrane topology. We have investigated the start site of rscS transcription by primer extension and identified a putative promoter region. We hypothesize that RscS recognizes a signal associated with the light organ environment and responds by stimulating a putative response regulator that controls protein function or gene expression to coordinate early colonization events. Further studies on RscS, its cognate response regulator, and the signaling conditions will provide important insight into the interaction between V. fischeri and E. scolopes.


Nanostructure of supported lipid bilayers in water.
Biologically functional supported lipid bilayers (SLBs) used in the rising field of nanobiotechnology require fine tuning of the SLB interface with the substrate, e.g., a sensor surface. Depending on the application, membrane functionality implies a homogeneous and dense bilayer and a certain degree of diffusivity in order to allow for a rearrangement in response to, e.g., protein binding. Here, progress in the preparation, characterization, and application of SLBs obtained in the past three to five years are highlighted. Synchrotron techniques, which allow to reveal structural features within the membrane on a length scale of approximately 0.5 nm are discussed in more detail, as well as the relation of structural features to dynamical membrane properties obtained by complementary optical techniques.


Exercise for the management of type 2 diabetes mellitus: factors to consider with current guidelines.
It has long been established that exercise is powerful medicine for those with type 2 diabetes mellitus (T2DM), such that it should represent a priority in the treatment and management of that condition. In spite of this, exercise adherence among those with T2DM is low, with lack of time and fear of doing harm commonly cited as reasons for not being more active. Published guidelines for aerobic exercise in those with T2DM recommend only moderate intensity, due to the elevated risk of untoward outcomes with more vigorous exercise in persons with chronic disease. However, considerable research evidence has appeared in the literature since the publication of those guidelines in 2010 addressing the safety and efficacy of more vigorous forms of exercise (i.e., interval training) in those with T2DM. Many such studies have reported improvements in glucose control as great as or greater than those associated with moderate intensity exercise, with significantly reduced time requirements, and mechanisms of improved glucose control via interval training may be unique to this mode of exercise. Resistance training, too, appears to confer significant improvements in glucose control in those with T2DM through unique mechanisms. These recent findings may be of interest to physicians and exercise practitioners, as they may provide for greater adherence to more optimal exercise prescriptions that are better suited to each patient's time availability and motivational level.


[Effect of the induction of beta-lactamase synthesis in Pseudomonas aeruginosa strains on their resistance to penicillin].
It was found that clinical strains of Ps. aeruginosa produced inducable beta-lactamase in the presence of penicillins, such as benzylpenicillin, ampicillin, carbenicillin. The amount of beta-lactamase depended on the strain and the inductor type and increased with the inductor concentration increase. Benzylpenicillin was the most active inductor of the enzyme synthesis by Ps. aeruginosa, strain 649. In concentrations of 5000 gamma/ml it provided at least 100 times higher amounts of beta-lactamase as compared to the initial level. The dynamics of induction of the enzyme synthesis by Ps. aeruginosa, strain 649 on addition of benzylpenicillin (5000 gamma/ml of the medium) at various stages of the culture growth was studied. Maximum accumulation of induced beta-lactamase was observed on addition of benzylpenicillin to the medium 2 hours after the culture inoculation. The induced enzyme was mainly found in the bacterialcells. The culture treatment with toluol increased the amounts of the determinable induced enzyme 4-26 times, 30 to 80 percent of the induced enzyme were liberated from the cells into the supernatant. Dependence of the level of the culture resistance to benzylpenicillin and ampicillin on the induction rate of beta-lactamase synthesis provided by the penicillins was found. No such dependence was observed with respect to the culture resistance to carbenicillin.


Studies of transfer RNA tertiary structure of singlet-singlet energy transfer.
Five species of tRNAs bearing two different fluorescent groups were synthesized. These were suitable for intramolecular distance measurements by singlet-singlet energy transfer. The efficiency of energy transfer was determined from the sensitized emission of the energy acceptor. With the assumption that the relative orientation of donor and acceptor is random, the apparent distances between the 5'-end and the 3'-end, the 4-thiouridine and the 3'-end, the pseudouridine and 3'-end, the pseudouridine and the dihydrouridine in Escherichia coli formyl methionine tRNA, and between the 2-thiouridine (in the anticodon) and the 3'-end in E. coli glutamate tRNA were calculated to be 24 A, 38 A, 55 A, 36 A, and >65 A, respectively.


Pulmonary rehabilitation in patients with idiopathic pulmonary fibrosis: comparison with chronic obstructive pulmonary disease.
Background: While the efficacy of pulmonary rehabilitation (PR) in chronic obstructive pulmonary disease (COPD) has been well established, emerging evidence also suggests its benefit in idiopathic pulmonary fibrosis (IPF). However, the differences and similarities between how PR affects diseases with different physiologies remain unknown. Objective: This study aimed to compare the efficacy of PR in COPD and IPF patients by performing multifactorial evaluation with various exercise capacity measurements, and dyspnea and health-related quality of life (QoL) assessment. Methods: Twenty-two IPF patients (%vital capacity: 72%) and 27 COPD patients (%forced expiratory volume1: 43%) were recruited. Subjects who completed a 10-week outpatient PR program were analyzed. We assessed five exercise capacity indicators (6-minute walking distance, incremental shuttle walking distance, endurance time, peak work rate, and peak values for oxygen uptake [peak VO2]), dyspnea (Baseline Dyspnea Index: BDI), and health-related QoL (St. George's Respiratory Questionnaire: SGRQ) at baseline and immediately following completion of the PR program. Results: After 10 weeks of PR, all exercise capacity measurements, except VO2, as well as BDI and SGRQ score improved significantly (p<0.05) in both disease groups. The magnitude of the observed changes in each outcome, assessed by the effect size, was comparable between IPF and COPD patients. This was also true for endurance time, the measurement most responsive to PR, with a large effect size. Conclusions: PR can result in comparable improvements in exercise capacity, including endurance time, and dyspnea and HRQoL in both IPF and COPD patients after 10 weeks of exercise training. (Sarcoidosis Vasc Diffuse Lung Dis 2017; 34: 283-289).


Mechanisms for the time-dependent decay of inward currents through cloned Kir2.1 channels expressed in Xenopus oocytes.
1. The decay of inward currents was characterized using the giant patch-clamp technique in the cloned inward rectifier K+ channels Kir2.1 expressed in Xenopus laevis oocytes. 2. The degree of decay was increased by strong hyperpolarization and reduced by increases in external [K+]. This voltage (membrane potential, Vm)- and K+-dependent decay is referred to as inactivation. The dissociation constant for the protective effects of external K+ ions against inactivation was about 5 mM and was not Vm dependent. 3. Internal K+ ions also showed mildly protective effects against inactivation when external K+ sites were not saturated. Results from variations in [K+] suggest that the hyperpolarization-induced inactivation of the Kir2.1 channels is not dependent on the driving force for K+ ions. 4. In the mutant which demonstrates higher external K+ affinity, the degree of inactivation was reduced. These results suggest that binding of K+ ions in the external channel pore mouth stabilizes channel opening. 5. Internal Mg2+ and polyamines induced time-dependent decay of inward currents in a dose-dependent but Vm-independent manner between -150 and -60 mV. The order of potency for Mg2+- and polyamine-induced decay was different from that for inward rectification. Furthermore, mutations with reduced inward rectification did not show parallel reduction of Mg2+- and polyamine-induced decay. These results suggest that the effects of internal Mg2+ and polyamines on Kir2.1 channels involve different binding sites. 6. This study provides evidence for Vm-dependent processes controlling the inactivation of the Kir2.1 channels.


A Putative Microcin Amplifies Shiga Toxin 2a Production of Escherichia coli O157:H7.
Escherichia coli O157:H7 is a foodborne pathogen implicated in various multistate outbreaks. It encodes Shiga toxin on a prophage, and Shiga toxin production is linked to phage induction. An E. coli strain, designated 0.1229, that amplified Stx2a production when cocultured with E. coli O157:H7 strain PA2 was identified. Growth of PA2 in 0.1229 cell-free supernatants had a similar effect, even when supernatants were heated to 100°C for 10 min, but not after treatment with proteinase K. The secreted molecule was shown to use TolC for export and the TonB system for import. The genes sufficient for production of this molecule were localized to a 5.2-kb region of a 12.8-kb plasmid. This region was annotated, identifying hypothetical proteins, a predicted ABC transporter, and a cupin superfamily protein. These genes were identified and shown to be functional in two other E. coli strains, and bioinformatic analyses identified related gene clusters in similar and distinct bacterial species. These data collectively suggest that E. coli 0.1229 and other E. coli strains produce a microcin that induces the SOS response in target bacteria. Besides adding to the limited number of microcins known to be produced by E. coli, this study provides an additional mechanism by which stx2a expression is increased in response to the gut microflora.IMPORTANCE How the gut microflora influences the progression of bacterial infections is only beginning to be understood. Antibiotics are counterindicated for E. coli O157:H7 infections, limiting treatment options. An increased understanding of how the gut microflora directs O157:H7 virulence gene expression may lead to additional treatment options. This work identified E. coli strains that enhance the production of Shiga toxin by O157:H7 through the secretion of a proposed microcin. Microcins are natural antimicrobial peptides that target specific species, can act as alternatives to antibiotics, and mediate microbial competition. This work demonstrates another mechanism by which non-O157 E. coli strains may increase Shiga toxin production and adds to our understanding of microcins, a group of antimicrobials less well understood than colicins.


New Approaches to Targeting B Cells for Myasthenia Gravis Therapy.
Current therapies for myasthenia gravis (MG) are limited, and many investigations have recently focused on target-specific therapies. B cell-targeting monoclonal antibody (mAb) therapies for MG are increasingly attractive due to their specificity and efficacy. The targeted B cell biomarkers are mainly the cluster of differentiation (CD) proteins that mediate maturation, differentiation, or survival of pathogenic B cells. Additional B cell-directed therapies include non-specific peptide inhibitors that preferentially target specific B cell subsets. The primary goals of such therapies are to intercept autoantibodies and prevent the generation of an inflammatory response that contributes to the pathogenesis of MG. Treatment of patients with MG using B cell-directed mAbs, antibody fragments, or selective inhibitors have exhibited moderate to high efficacy in early studies, and some of these therapies appear to be highly promising for further drug development. Numerous other biologics targeting various B cell surface molecules have been approved for the treatment of other conditions or are either in clinical trials or preclinical development stages. These approaches remain to be tested in patients with MG or animal models of the disease. This review article provides an overview of B cell-targeted treatments for MG, including those already available and those still in preclinical and clinical development. We also discuss the potential benefits as well as the shortcomings of these approaches to development of new therapies for MG and future directions in the field.


Drug treatments for schizophrenia - past, present and future.
The typical antipsychotic drugs, which have been the mainstay of treatment for schizophrenia for many years, are potent antagonists of D2 receptors. However, their lack of selectivity for D2 receptors in the mesolimbic areas compared with the nigrostriatal areas of the brain has resulted in an association at therapeutic doses with extrapyramidal side-effects, an increased risk for tardive dyskinesia and increased prolactin levels. Together with other significant side-effects, this profile has limited their acceptability for antipsychotic treatment, resulting in poor compliance, increased risk of relapse and increased severity of disease. A new generation of antipsychotics, the 'atypicals', which show greater selectivity for mesolimbic D2 receptors combined with effects on 5-HT2 receptors, have demonstrated antipsychotic efficacy, with a significantly lower incidence of extrapyramidal effects than seen with haloperidol, and often at placebo level. The first atypical antipsychotic, clozapine, has been restricted to use in treatment-resistant schizophrenia because of an association with agranwlocytosis. Two other drugs are now available, olanzapine and sertindole, and two others, quetiapine and ziprasidone, are in late-stage development. The profile of these drugs is reviewed, together with future treatment possibilities.


Comparative and functional genomics of lactococci.
Whole-genome nucleotide sequencing has revolutionized the genetic, biochemical and molecular biology research on bacteria and indeed, many higher organisms. The genome sequences of the strains of two subspecies of Lactococcus lactis, L. lactis subsp. lactis and L. lactis subsp. cremoris, have been determined. These genomic sequences have permitted two important new approaches to be applied in the research of L. lactis. The analysis of the regulation of expression of all genes under specific circumstances at a given point in time is now possible by DNA microarray technology. The elucidation of the full protein complement of the organism as a function of intrinsic or external factors has been made possible by high-throughput protein identification and analysis techniques combined with the gene-derived know-how of the total protein encoding capacity of the genome. These techniques from the genomics arena, transcriptomics and proteomics, have been recently implemented in the study of various aspects of growth and functioning of L. lactis. In this paper we discuss a number of similarities and differences between the two lactococcal genome sequences and review the current status of genomics research in L. lactis. We also propose future directions with respect to both answering fundamental questions more quickly and more completely, as well as opening new avenues for biotechnological applications.


Antibody-dependent cellular cytotoxicity against HIV-coated target cells by peripheral blood monocytes from HIV seropositive asymptomatic patients.
Cytotoxic effector cells like cytotoxic T cells, NK cells, monocytes/macrophages, and neutrophils can lyse directly HIV-infected or HIV-coated cells in the absence or presence of anti-HIV antibodies. Therefore, these cytotoxic mechanisms can be invoked either in the control of HIV infection at early stages of the disease or in the generalized immunosuppression observed at later stages of the disease. The relationship between anti-HIV effector mechanisms and disease, however, remains elusive. The present study investigates in HIV+ seropositive asymptomatic patients peripheral blood monocytes (PBM)-mediated antibody dependent cellular cytotoxicity (ADCC) against HIV-coated target cells in the presence of heterologous or autologous anti-HIV serum. To test for specific ADCC against HIV Ag, a T4+ CEM.TR line resistant to TNF and macrophage-mediated cytotoxicity was selected in vitro. ADCC was performed in an 18-h 51Cr-release assay using CEM.TR cells coated with inactivated HIV. Unlike PBM from normal controls, significant ADCC was observed by PBM from HIV+ seropositive patients in the presence of pooled HIV+ antiserum. The ADCC activity was specific for HIV and was dependent on the E:T ratio and the antiserum dilution used. Upon activation of PBM with rIFN-gamma, both normal and HIV+ PBM-mediated ADCC against HIV-coated CEM.TR. Furthermore, ADCC activity by PBM from HIV+ seropositive patients in the presence of their autologous serum was examined. Significant ADCC activity was observed and was dependent on the E:T ratio and serum dilution used. The findings demonstrating anti-HIV ADCC activity by PBM from HIV+ seropositive individuals and their autologous sera support the notion that monocyte-mediated ADCC may be operative in vivo.


Stochasticity, heterogeneity, and variance in longevity in human populations.
Inter-individual variance in longevity (or any other demographic outcome) may arise from heterogeneity or from individual stochasticity. Heterogeneity refers to differences among individuals in the demographic rates experienced at a given age or stage. Stochasticity refers to variation due to the random outcome of demographic rates applied to individuals with the same properties. The variance due to individual stochasticity can be calculated from a Markov chain description of the life cycle. The variance due to heterogeneity can be calculated from a multistate model that incorporates the heterogeneity. We show how to use this approach to decompose the variance in longevity into contributions from stochasticity and heterogeneous frailty for male and female cohorts from Sweden (1751-1899), France (1816-1903), and Italy (1872-1899), and also for a selection of period data for the same countries. Heterogeneity in mortality is described by the gamma-Gompertz-Makeham model, in which a gamma distributed "frailty" modifies a baseline Gompertz-Makeham mortality schedule. Model parameters were estimated by maximum likelihood for a range of starting ages. The estimates were used to construct an age×frailty-classified matrix model, from which we compute the variance of longevity and its components due to heterogeneous frailty and to individual stochasticity. The estimated fraction of the variance in longevity due to heterogeneous frailty (averaged over time) is less than 10% for all countries and for both sexes. These results suggest that most of the variance in human longevity arises from stochasticity, rather than from heterogeneous frailty.


Dietary flexibility of Australopithecus afarensis in the face of paleoecological change during the middle Pliocene: Faunal evidence from Hadar, Ethiopia.
One approach to understanding the context of changes in hominin paleodiets is to examine the paleodiets and paleohabitats of contemporaneous mammalian taxa. Recent carbon isotopic studies suggest that the middle Pliocene was marked by a major shift in hominin diets, characterized by a significant increase in C4 foods in Australopithecus-grade species, including Australopithecus afarensis. To contextualize previous isotopic studies of A. afarensis, we employed stable isotopes to examine paleodiets of the mammalian fauna contemporaneous with A. afarensis at Hadar, Ethiopia. We used these data to inform our understanding of paleoenvironmental change through the deposition of the Hadar Formation. While the majority of the taxa in the Hadar fauna were C4 grazers, most show little change in the intensity of C4 food consumption over the 0.5 million-year interval sampled. Two taxa (equids and bovins) do show increases in C4 consumption through the Hadar Formation and into the younger, overlying Busidima Formation. Changes in the distributions of C4-feeders, C3-feeders and mixed-C3/C4-feeders in the sampled intervals are consistent with evidence of dietary reconstructions based on ecomorphology, and with habitats reconstructed using community structure analyses. Meanwhile, A. afarensis is one of many mammalian taxa whose C4 consumption does not show directional change over the intervals sampled. In combination with a wide range of carbon and oxygen isotopic composition for A. afarensis as compared to the other large mammal taxa, these results suggest that the C3/C4 dietary flexibility of A. afarensis was relatively unusual among most of its mammalian cohort.


Model-based linkage analyses confirm chromosome 19q13.3 as a susceptibility locus for intracranial aneurysm.
In previous studies of familial intracranial aneurysm (IA), parametric linkage analyses have been undertaken for five unrelated families, four providing maximum logarithm of odds (LOD) scores with dominant models and one with a recessive model. Each family was linked to a distinct locus, indicating locus heterogeneity. This study aimed to examine whether Japanese IA families consistent with autosomal-dominant mode of inheritance support linkage to these loci. We performed genomewide linkage analysis using the GENEHUNTER program. Affected-only parametric linkage analysis was used for 41 affected members in nine unrelated IA families with dominant models, which were selected from 29 families used for a nonparametric (model-free) linkage analysis in our previous study. We failed to support the linkage to previously reported autosomal-dominant loci. Instead, we found linkage to chromosome 19q13.3 with a maximum multipoint LOD score of 4.10. The LOD-1 interval (regions with LOD scores of >1) was 8.0 cM between D19S198 and D19S902. A genomewide scan for IA families with dominant models in Japan confirmed the locus at chromosome 19q13.3, which has also been reported as a candidate locus in a Finnish population.


Influence of secondary structure and hydrogen-bonding arrangement on the mechanical properties of peptidic-polyurea hybrids.
Bio-inspired materials design is an important strategy used in the fabrication of tunable and mechanically enhanced polymeric systems. An important aspect of bio-inspiration is to understand how components, such as hierarchy and self-assembly, affect the properties of the designed materials. In this investigation, we explore the use of polypeptide secondary structure and hydrogen bonding arrangement, in order to determine their effects on the thermal and mechanical properties of fully synthetic peptidic polyureas. Specifically, we incorporate either short β-sheet forming peptide blocks of poly(β-benzyl-l-aspartate)5 or poly(ε-carbobenzyloxy-l-lysine)5 or longer peptide blocks of poly(β-benzyl-l-aspartate)20 or poly(ε-carbobenzyloxy-l-lysine)20 as α-helix forming domains into non-chain extended polyureas based on 1,6-hexamethylene diisocyanate and poly(dimethysiloxane). Secondary structure was found to be influenced by the weight fraction of peptide, e.g. increasing peptide weight fractions increased sheet or helical ordering. Additionally, the polyurea microstructure was comprised of nanofibrils with a secondary structure dependent fiber width, attributed to the peptidic motif alignment within the nanothreads. Analysis of the thermomechanical and tensile response revealed multiple trends, such as increased toughness attributed to β-sheet ordering and increased modulus with increased peptide weight fraction. It is anticipated that this observed interplay between peptide organization and mechanics will be applicable to engineering and biomaterial development due to the simplicity of the synthetic protocol and the promising mechanical tunability guided by the peptide segment.


Detection of mesenchymal stem cells senescence by prelamin A accumulation at the nuclear level.
Human mesenchymal stem cells (MSC), during in vitro expansion, undergo a progressive loss of proliferative potential that leads to the senescent state, associated with a reduction of their "medicinal" properties. This may hampers their efficacy in the treatment of injured tissues. Quality controls on MSC-based cell therapy products should include an assessment of the senescent state. However, a reliable and specific marker is still missing. From studies on lamin-associated disorders, has emerged the correlation between defective lamin A maturation and cellular senescence. Primary cultured hMSC lines (n = 3), were analyzed by immunostaining at different life-span stages for the accumulation of prelamin A, along with other markers of cellular senescence. During culture, cells at the last stage of their life span displayed evident signs of senescence consistent with the positivity of SA-β-gal staining. We also observed a significant increase of prelamin A positive cells. Furthermore, we verified that the cells marked by prelamin A were also positive for p21(Waf1) while negative for Ki67. Overall data support that the detection of prelamin A identifies senescent MSC, providing an easy and reliable tool to be use alone or in combination with known senescence markers to screen MSC before their use in clinical applications.


Prognostic relevance of magnesium alterations in patients with a myocardial infarction and left ventricular dysfunction: insights from the EPHESUS trial.
Magnesium changes are common in myocardial infarction (MI) complicated with left ventricular systolic dysfunction (LVSD) and/or heart failure (HF). The relation between serum magnesium and clinical outcomes is insufficiently elucidated in this population. The EPHESUS trial randomized 6632 patients to either eplerenone or placebo. Hypomagnesemia and hypermagnesemia were defined as a serum magnesium <0.66 and >1.10 mmol/L, respectively. Linear mixed models and time-dependent Cox regression analysis were used to determine the effect of eplerenone on magnesium changes and the prognostic importance of magnesium. The co-primary outcomes were all-cause mortality and a composite of cardiovascular (CV) mortality and CV hospitalization. A total of 5371 patients had a post-baseline magnesium measurement. At baseline, 231 (4.3%) patients had hypomagnesemia and 271 (5.0%) patients had hypermagnesemia. During a median follow-up of 16 months, 682 (13%) developed hypomagnesemia and 512 (9.5%) hypermagnesemia. Eplerenone treatment did not result in a different magnesium level during follow-up (P = 0.14). After covariate adjustment hypo- and hypermagnesemia were not associated with a higher risk of CV events. Magnesium levels did not modulate the effect of a high potassium (>5 mmol/L) or low potassium (<4 mmol/L) on the clinical outcome. Baseline magnesium levels did not influence the treatment effect of eplerenone (P-interaction > 0.1 for all primary and secondary endpoints). In patients with MI complicated by LVSD or HF, magnesium alterations were not associated with clinical outcomes nor did they influence the effect of eplerenone. Serum magnesium did not modulate the effect of potassium changes on clinical outcome or the treatment effect of eplerenone. NCT00232180.


Translating Clinical Questions by Physicians Into Searchable Queries: Analytical Survey Study.
Staying up to date and answering clinical questions with current best evidence from health research is challenging. Evidence-based clinical texts, databases, and tools can help, but clinicians first need to translate their clinical questions into searchable queries. MacPLUS FS (McMaster Premium LiteratUre Service Federated Search) is an online search engine that allows clinicians to explore multiple resources simultaneously and retrieves one single output that includes the following: (1) evidence from summaries (eg, UpToDate and DynaMed), (2) preappraised research (eg, EvidenceAlerts), and (3) non-preappraised research (eg, PubMed), with and without validated bibliographic search filters. MacPLUS FS can also be used as a laboratory to explore clinical questions and evidence retrieval. Our primary objective was to examine how clinicians formulate their queries on a federated search engine, according to the population, intervention, comparison, and outcome (PICO) framework. Our secondary objective was to assess which resources were accessed by clinicians to answer their questions. We performed an analytical survey among 908 clinicians who used MacPLUS FS in the context of a randomized controlled trial on search retrieval. Recording account log-ins and usage, we extracted all 1085 queries performed during a 6-month period and classified each search term according to the PICO framework. We further categorized queries into background (eg, "What is porphyria?") and foreground questions (eg, "Does treatment A work better than B?"). We then analyzed the type of resources that clinicians accessed. There were 695 structured queries, after exclusion of meaningless queries and iterations of similar searches. We classified 56.5% (393/695) of these queries as background questions and 43.5% (302/695) as foreground questions, the majority of which were related to questions about therapy (213/695, 30.6%), followed by diagnosis (48/695, 6.9%), etiology (24/695, 3.5%), and prognosis (17/695, 2.5%). This distribution did not significantly differ between postgraduate residents and medical faculty physicians (P=.51). Queries included a median of 3 search terms (IQR 2-4), most often related to the population and intervention or test, rarely related to the outcome, and never related to the comparator. About half of the resources accessed (314/610, 51.5%) were summaries, 24.4% (149/610) were preappraised research, and 24.1% were (147/610) non-preappraised research. Our results, from a large sample of real-life queries, could guide the development of educational interventions to improve clinicians' retrieval skills, as well as inform the design of more useful evidence-based resources for clinical practice. ClinicalTrials.gov NCT02038439; https://www.clinicaltrials.gov/ct2/show/NCT02038439.


Attitudes towards cancer predictive testing and transmission of information to the family.
Before the organisation of breast cancer predictive testing in France, consultands' attitudes towards this kind of testing and towards passing on information about the family cancer risk to their relatives were investigated. This survey was carried out from January 1994 to January 1995 at six specialised cancer genetic clinics located in different parts of France Female consultands who were first degree relatives of cancer patients and who had at least one case of breast cancer in their family, affecting either themselves or a first degree relative or both, participated in this study. Among the 248 eligible consultands attending the clinics during the study period, 84.3% answered a post-consultation questionnaire. Among the 209 respondents, 40.7% (n = 85) were cancer patients and 59.3% (n = 124) were healthy consultands. A high consensus in favour of genetic testing was noted, since 87.7% of the sample stated that they would ask for breast cancer gene testing if this test became available. The underlying assumption of 96.6% of the women was that their health surveillance would be improved after a positive test. A high awareness of the anxiety that would be generated in a family after a positive result was observed and found to be associated (p < 0.05) with the anxiety and depressive profiles of the patients. Half of the healthy respondents said they would not change their attitude towards screening if the results of predictive testing turned out to be negative. Only 13.7% of the 161 patients who stated that the oncogeneticists asked them to contact their relatives firmly refused to do so, mainly because of difficult family relationships.


The fatty acid synthase of the basidiomycete Omphalotus olearius is a single polypeptide.
Fatty acids are essential components of almost all biological membranes. Additionally, they are important in energy storage, as second messengers during signal transduction, and in post-translational protein modification. De novo synthesis of fatty acids is essential for almost all organisms, and entails the iterative elongation of the growing fatty acid chain through a set of reactions conserved in all kingdoms. During our work on the biosynthesis of secondary metabolites, a 450-kDa protein was detected by SDS-PAGE of enriched fractions from mycelial lysates from the basidiomycete Omphalotus olearius. Protein sequencing of this protein band revealed the presence of peptides with homology to both alpha and beta subunits of the ascomycete fatty acid synthase (FAS) family. The FAS encoding gene of O. olearius was sequenced. The positions of its predicted 21 introns were verified. The gene encodes a 3931 amino acids single protein, with an equivalent of the ascomycetous beta subunit at the N-terminus and the a subunit at the C-terminus. This is the first report on an FAS protein from a homobasidiomycete and also the first fungal FAS which is comprised of a single polypeptide.


Improved brief assessment of cognition in aging and dementia.
To enhance the score interpretation and practicality of the Cambridge Cognitive Examination (CAMCOG) neuropsychological test, the authors used item response theory (IRT) to calibrate the difficulty of the items using the scores of 797 subjects. Forty-seven items fitted the IRT model. Score agreement with equally difficult short forms was excellent. The practicality and interpretability of the CAMCOG was improved, while the diagnostic accuracy of the short forms was similar to that of the original 60-item instrument.


Predicting liver SBRT eligibility and plan quality for VMAT and 4π plans.
It is useful to predict planned dosimetry and determine the eligibility of a liver cancer patient for SBRT treatment using knowledge based planning (KBP). We compare the predictive accuracy using the overlap volume histogram (OVH) and statistical voxel dose learning (SVDL) KBP prediction models for coplanar VMAT to non-coplanar 4π radiotherapy plans. In this study, 21 liver SBRT cases were selected, which were initially treated using coplanar VMAT plans. They were then re-planned using 4π IMRT plans with 20 inversely optimized non-coplanar beams. OVH was calculated by expanding the planning target volume (PTV) and then plotting the percent overlap volume v with the liver vs. r v , the expansion distance. SVDL calculated the distance to the PTV for all liver voxels and bins the voxels of the same distance. Their dose information is approximated by either taking the median or using a skew-normal or non-parametric fit, which was then applied to voxels of unknown dose for each patient in a leave-one-out test. The liver volume receiving less than 15 Gy (V<15Gy), DVHs, and 3D dose distributions were predicted and compared between the prediction models and planning methods. On average, V<15Gy was predicted within 5%. SVDL was more accurate than OVH and able to predict DVH and 3D dose distributions. Median SVDL yielded predictive errors similar or lower than the fitting methods and is more computationally efficient. Prediction of the 4π dose was more accurate compared to VMAT for all prediction methods, with significant (p < 0.05) results except for OVH predicting liver V<15Gy (p = 0.063). In addition to evaluating plan quality, KBP is useful to automatically determine the patient eligibility for liver SBRT and quantify the dosimetric gains from non-coplanar 4π plans. The two here analyzed dose prediction methods performed more accurately for the 4π plans than VMAT.


Doping location-dependent energy transfer dynamics in Mn-doped CdS/ZnS nanocrystals.
Dynamics of energy transfer and charge carrier localization in Mn-doped CdS/ZnS core/shell nanocrystals correlated with doping location and concentration are studied via transient absorption measurement of exciton relaxation dynamics. The strong dependence of exciton-Mn energy transfer rate on doping location was directly resolved in the transient bleach recovery and electron intraband absorption data by using layer-by-layer synthesized Mn-doped nanocrystals. With 1.2 nm decrease in doping radius in the ZnS shell, energy transfer rate increases by 6 fold. We identified that hole trapping is the major competing process that inhibits the energy transfer in Mn-doped CdS/ZnS nanocrystals. From the branching ratio of the energy transfer and hole trapping, combined with luminescence quantum yield measurement, we also obtained doping location-dependent radiative relaxation quantum yield of Mn(2+) ions that is as high as 0.95.


Secondary metabolites of Thymelaea hirsuta, a plant collected from the Sicilian Island of Lampedusa.
An investigation of the secondary metabolites was carried out on Thymelaea hirsuta collected from Lampedusa, the largest island of the Pelagie archipelago, located about 100 km from the North African coast and 200 km from the coast of Sicily. Ten compounds were isolated and found to belong to different classes of natural products as chromenes, cyclohexanones, furanyl, bis-furanyl and furanone polyphenols, and acrylates. Compounds 7, 8, 9 and 10 were slightly phytotoxic to lettuce reaching phytotoxicity of 1 (7, 8 and 9) and 2 (10) using a 1-5 point scale. None of the compounds were active against Agrostis stolonifera L., a perennial grass of the Poaceae family. Tested against three Colletotrichum species (C. acutatum, C. fragarie and C. gloeosporioides) pathogenic for agricultural plants, only compound 6 had activity against all three species, but it was not as active as captan, the commercial fungicide used as a positive control.


Trends in the use of pre-operative radiation for adenocarcinoma of the pancreas in the United States.
The benefit and timing of radiation therapy (RT) for patients undergoing a resection for pancreatic adenocarcinoma remains unclear. This study identifies trends in the use of radiation over a 10-year period and factors associated with the use of pre-operative radiation, in particular. The Surveillance, Epidemiology and End Results registry was used to identify patients aged ≥18 years with pancreatic adenocarcinoma who underwent a surgical resection between 2000 and 2010. Logistic regression was used to identify time trends and factors associated with the use of pre-operative radiation. The overall use of radiation decreased with time among the 8474 patients who met the inclusion criteria. However, the use of pre-operative radiation increased from 1.8% to 3.9% (P ≤ 0.05). Factors significantly associated with receipt of pre-operative radiation were younger age, treatment in more recent years and having an advanced T-stage tumour. The 5-year hazard of death was significantly less for those who received pre-operative radiation versus surgery alone [hazard ratio (HR) 0.64, 95% confidence interval (CI) 0.55-0.74] and for those who received post-operative radiation versus surgery alone (HR 0.69, 95% CI 0.65-0.73). The use of pre-operative radiation significantly increased during the study period. However, the overall use of pre-operative radiation therapy remains low in spite of the potential benefits.


[Oxygen sensing film based on organically modified sol-gel with ruthenium complexes and their fluorescent spectra studies].
A new kind of organically modified sol-gel (ormosil) as a matrix for oxygen-sensitive sensor, in which dimethyldimethoxysilane was selected as an organic modifier in the precursor is described. The fluorescent behaviors of different ruthenium complexes in solution and ormosil film were studied. The sensing film with different kind ruthenium complex as an indicator developed in this paper was characterized in terms of efficiently quenched by oxygen. A new ormosil provides a more desirable environment for oxygen response through increasing film hydrophobicity by the content of the nonbridging Si-CH3 groups has been discussed. The sensing film with tris-(4,7-diphenyl-1,10-phenanthroline) ruthenium(II) as an indicator is selected because of its characteristic with high quenching efficiency, fast response time, high luminescence intensity and long-term stability.


Utilization of a Smartphone Platform for Electronic Informed Consent in Acute Stroke Trials.
The informed consent process is a major limitation for enrollment in acute stroke clinical investigations. We aim to describe the novel application of smartphone electronic informed consenting (e-Consent) in trials of cerebral thrombectomy. The e-Consent tool consists of a secure/Health Insurance Portability and Accountability Act compliant smartphone platform based on REDCap (Research Electronic Data Capture; Vanderbilt University, TN) that uses a survey project located on a static webpage. A link to the webpage is sent via text message or email to the legally authorized representative. The e-Consent form is filled and a freehand electronic signature added in the smartphone browser; a record ID and an e-Consent Process Attestation form are automatically generated. The e-Consent application was piloted in a randomized trial comparing endovascular versus medical therapy in late presenting patients (DAWN [Clinical Mismatch in the Triage of Wake Up and Late Presenting Strokes Undergoing Neurointervention With Trevo]). Trial enrollment began in January 2015; e-Consent was approved by the local institutional review board in December 2016, and the study was stopped in February 2017. During the trial period, Grady Memorial Hospital performed 273 thrombectomies with 47 patients being consented and 38 patients enrolled in the DAWN trial. Of the randomized patients, 29 (76%) were transferred from outside hospitals. A total of 6 surrogates were e-Consented, with 2 patients being screen failures. Enrolled e-Consented patients (n=4) had similar age (73±14 versus 69±12 years; P=0.65) and National Institutes of Health Stroke Scale (16±5 versus 16±5; P=0.88) as compared with conventionally consented (n=25). Time from door-to-randomization was decreased with e-Consenting (28±9 versus 57±24 minutes; P=0.002). e-Consenting streamlined the consenting process in a randomized trial of patients with emergent large vessel occlusion strokes.


ANKRD11 variants: KBG syndrome and beyond.
Mutations affecting the transcriptional regulator Ankyrin Repeat Domain 11 (ANKRD11) are mainly associated with the multisystem developmental disorder known as KBG syndrome, but have also been identified in individuals with Cornelia de Lange syndrome (CdLS) and other developmental disorders caused by variants affecting different chromatin regulators. The extensive functional overlap of these proteins results in shared phenotypical features, which complicate the assessment of the clinical diagnosis. Additionally, re-evaluation of individuals at a later age occasionally reveals that the initial phenotype has evolved toward clinical features more reminiscent of a developmental disorder different from the one that was initially diagnosed. For this reason, variants in ANKRD11 can be ascribed to a broader class of disorders that fall within the category of the so-called chromatinopathies. In this work, we report on the clinical characterization of 23 individuals with variants in ANKRD11. The subjects present primarily with developmental delay, intellectual disability and dysmorphic features, and all but two received an initial clinical diagnosis of either KBG syndrome or CdLS. The number and the severity of the clinical signs are overlapping but variable and result in a broad spectrum of phenotypes, which could be partially accounted for by the presence of additional molecular diagnoses and distinct pathogenic mechanisms.


Variation in mesiodistal crown width and amount of tooth exposure between right and left maxillary anterior teeth.
Facial aesthetic depends greatly on the presence of teeth specially maxillary anterior. Four-hundred-six patients (191 males and 215 females) were examined to investigate the variation of mesiodistal crown width and amount of tooth display between right and left maxillary anterior teeth. The result of this survey indicated that right and left maxillary anterior teeth are not always identical. A difference of up to 1 mm in mesiodistal width and the amount of tooth exposure between the right and left maxillary central incisors is considered to be within the range of normal appearance. Right and left maxillary lateral incisors and canines have the same range of difference as that of central incisors.


Ocrelizumab for the treatment of relapsing-remitting multiple sclerosis.
Despite recent advances in pharmacological management, multiple sclerosis (MS), an autoimmune disease of the central nervous system, remains a leading cause of disability. In relapsing-remitting (RR)MS, neurologists most commonly utilize immunomodulatory or immunosuppressive agents to benefit their patients. With the introduction of humanized monoclonal antibodies (mAbs) ablation of distinct immune populations has become possible. Depletion of B cells by anti-CD20 mAbs has repeatedly proven to be a very rapid and effective means to diminish disease activity in RRMS. We discuss the biological rationale, development, and recent clinical study results of the second generation anti-CD20 mAb ocrelizumab. Expert commentary: The topline results of two phase-III randomized clinical trials demonstrate superiority of ocrelizumab over interferon beta in RRMS patients with regards to clinical and paraclinical outcome parameters. The short term adverse events profile appears favorable. However, long-term effects of repeated B cell depletion are currently unknown.


Selective transfection of microglia in the brain using an antibody-based non-viral vector.
There are currently few approaches to transiently manipulate the expression of specific proteins in microglia of the brain. An antibody directed against an extracellular epitope of scavenger receptor class B, type I (SR-BI) was found to be selectively taken up by these cells in the brain. Other antibodies tested were not internalised by microglia. A vector was produced by linking the SR-BI antibody to polyethyleneimine and binding a DNA plasmid encoding green fluorescent protein. Infusions of this vector into the hippocampus produced a widespread transfection of cells, more than 80% of which were immunoreactive for microglial/macrophage markers. Transfection was not detected in cells expressing markers for astrocytes or neurons. Reporter gene expression was most prominent near the infusion site but was seen in tissue up to 4mm away. DNA bound to polyethyleneimine alone or to a vector containing a different antibody did not produce transfection in the brain. Single injections of the vector containing the SR-BI antibody into the brain also resulted in transfection of microglia, albeit with lower efficiency. Vector modifications to promote lysis of endosomes or entry of DNA into the nucleus did not increase efficiency. The findings clearly demonstrate the capacity of the SR-BI antibody to selectively target brain microglia. This approach offers considerable potential to deliver DNA and other molecules capable of modifying the function of these cells in vivo.


Detection of ROS Induced Proteomic Signatures by Mass Spectrometry.
Reversible and irreversible post-translational modifications (PTMs) induced by endogenously generated reactive oxygen species (ROS) in regulatory enzymes and proteins plays an essential role in cellular signaling. Almost all cellular processes including metabolism, transcription, translation and degradation have been identified as containing redox regulated proteins. Specific redox modifications of key amino acids generated by ROS offers a dynamic and versatile means to rapidly alter the activity or functional structure of proteins in response to biochemical, environmental, genetic and pathological perturbations. How the proteome responds to these stimuli is of critical importance in oxidant physiology, as it can regulate the cell stress response by reversible and irreversible PTMs, affecting protein activity and protein-protein interactions. Due to the highly labile nature of many ROS species, applying redox proteomics can provide a signature footprint of the ROS species generated. Ideally redox proteomic approaches would allow; (1) the identification of the specific PTM, (2) identification of the amino acid residue that is modified and (3) the percentage of the protein containing the PTM. New developments in MS offer the opportunity of a more sensitive targeted proteomic approach and retrospective data analysis. Subsequent bioinformatics analysis can provide an insight into the biochemical and physiological pathways or cell signaling cascades that are affected by ROS generation. This mini-review will detail current redox proteomic approaches to identify and quantify ROS induced PTMs and the subsequent effects on cellular signaling.


Intentions to use contraceptives in Pakistan: implications for behavior change campaigns.
Since 1990-91, traditional method use has increased at a faster rate in Pakistan than modern method use. The importance of hormonal methods or the IUD has diminished and that of traditional methods has increased in the method mix. There is a need to identify factors motivating and deterring the adoption of specific family planning methods among married men and women in Pakistan. In addition to social and demographic characteristics of respondents, a representative household survey collected information on psychological correlates of family planning behavior from 1,788 non-pregnant wives and 1,805 husbands with not-pregnant wives. Males and females were from separate households. Principal components analysis was conducted to identify the underlying constructs that were important for each gender. Multinomial logistic regression analysis was conducted to determine the correlates of male and female intentions to use contraceptive methods. Amongst women, the perception that her in-laws support family planning use was the strongest determinant of her intentions to use contraceptive methods. A woman's belief in the importance of spacing children and her perception that a choice of methods and facilities with competent staff were available were also powerful drivers of her intentions to use contraceptive methods. The strongest obstacle to a woman's forming an intention to use contraceptive methods was her belief that family planning decisions were made by the husband and fertility was determined by God's will. Fears that family planning would harm a woman's womb lowered a woman's intentions to use methods requiring procedures, such as the IUD and female sterilization.The perception that a responsible, caring, husband uses family planning to improve the standard of living of his family and to protect his wife's health was the most important determinant of a man's intention to use condoms. A husband's lack of self-efficacy in being able to discuss family planning with his wife was the strongest driver of the intention to use withdrawal. A man's fear that contraceptives would make a woman sterile and harm her womb lowered his intention to use modern contraceptive methods. These findings highlight the importance of having secondary target audiences such as mothers-in-law and husbands in family planning behavior change campaigns implemented in Pakistan. Campaigns that stress the importance of child spacing are likely to have an impact. Client perceptions of the quality of care are important determinants of intentions to use contraceptive methods in Pakistan. Client concerns that the IUD and sterilization procedures might harm a woman's womb and cause sterility should be addressed. The findings suggest that there is a need to assess the actual quality of service delivery in Pakistan.


Systematic gene deletions evidences that laccases are involved in several stages of wood degradation in the filamentous fungus Podospora anserina.
Transformation of plant biomass into biofuels may supply environmentally friendly alternative biological sources of energy. Laccases are supposed to be involved in the lysis of lignin, a prerequisite step for efficient breakdown of cellulose into fermentable sugars. The role in development and plant biomass degradation of the nine canonical laccases belonging to three different subfamilies and one related multicopper oxidase of the Ascomycota fungus Podospora anserina was investigated by targeted gene deletion. The 10 genes were inactivated singly, and multiple mutants were constructed by genetic crosses. lac6(Δ), lac8(Δ) and mco(Δ) mutants were significantly reduced in their ability to grow on lignin-containing materials, but also on cellulose and plastic. Furthermore, lac8(Δ), lac7(Δ), mco(Δ) and lac6(Δ) mutants were defective towards resistance to phenolic substrates and H2 O2 , which may also impact lignocellulose breakdown. Double and multiple mutants were generally more affected than single mutants, evidencing redundancy of function among laccases. Our study provides the first genetic evidences that laccases are major actors of wood utilization in a fungus and that they have multiple roles during this process apart from participation in lignin lysis.


Methods for reducing the serum requirement for growth in vitro of nontransformed diploid fibroblasts.
The amount of serum protein required for clonal growth of normal diploid human and chicken fibroblasts has been reduced more than 90% by development of improved synthetic media and culture conditions. The following has contributed significantly to the reduction: (1) replacement of specific serum proteins with defined small molecular nutrients; (2) precise quantitative balance of all defined nutrients for optimal growth of single cells of each type under consideration; (3) modification of the culture substrate; (4) improvement of the cell harvesting technique. By combining these improvements, optimal growth of human fibroblasts (fetal lung, newborn foreskin, amniotic fluid) and chicken embryo fibroblasts occurs in synthetic media supplemented with 500 microgram/ml dialyzed fetal bovine serum protein [equivalent to 1% (v/v) whole serum]. The human fibroblasts form large colonies at a suboptimum rate at 25 microgram/ml dialyzed serum protein [equivalent to 0.05% (v/v) whole serum] and several divisions can be obtained in the complete absence of serum protein. Human and chicken fibroblasts differ both in their quantitative requirements for defined nutrients, and in the type and number of incompletely characterized serum components that they continue to require under the improved growth conditions. The improved systems provide a sensitive assay for the remaining undefined growth-promoting components of serum and other biological extracts.


Perspectives on Low-Temperature Electrolysis and Potential for Renewable Hydrogen at Scale.
Hydrogen is an important part of any discussion on sustainability and reduction in emissions across major energy sectors. In addition to being a feedstock and process gas for many industrial processes, hydrogen is emerging as a fuel alternative for transportation applications. Renewable sources of hydrogen are therefore required to increase in capacity. Low-temperature electrolysis of water is currently the most mature method for carbon-free hydrogen generation and is reaching relevant scales to impact the energy landscape. However, costs still need to be reduced to be economical with traditional hydrogen sources. Operating cost reductions are enabled by the recent availability of low-cost sources of renewable energy, and the potential exists for a large reduction in capital cost withmaterial and manufacturing optimization. This article focuses on the current status and development needs by component for the low-temperature electrolysis options.


Simple and rapid data-reduction method with pixel-level spatial frequency of shift-rotation method.
Absolute testing methods are commonly employed in surface metrology to calibrate the reference surface deviation and obtain the absolute deviation of the surface under test. A simple and reliable data-reduction method of absolute shift-rotation method with rotational and translational measurements is presented here, which relies on the decomposition of the surface deviation into rotationally asymmetric and symmetric components. The rotationally asymmetric surface deviation can be simply obtained by classical N-position averaging method. After that, the two-dimensional problem of estimating the other rotationally symmetric surface deviation can be simplified to a one-dimensional problem, and it can be directly calculated out with pixel-level spatial frequency based on several measurements of different translations in one same direction. Since that no orthogonal polynomials fitting, such as Zernike polynomials, is required in the calculation, the data reduction of the method is simple and rapid. Experimental absolute results of spherical surfaces are given.


Simple Approach to Reducing Particle Trapping Voltage in Insulator-Based Dielectrophoretic Systems.
Insulator-based dielectrophoresis (iDEP) is a microfluidic technique used for particle analysis in a wide array of applications. Significant efforts are dedicated to improve iDEP systems by reducing voltage requirements. This study assesses how the performance of an iDEP system, in terms of particle trapping, depends on the number of insulating obstacles longitudinally present in the microchannel. In analogy with Kirchhoff's loop rule, iDEP systems were analyzed as a series combination of electrical resistances, where the equivalent resistance of the post array is composed by a number of individual resistors (columns of insulating posts). It was predicted by the COMSOL model, and later confirmed by experimental results, that reducing the number of columns of insulating posts significantly affects the electric field distribution, decreasing the required voltage to dielectrophoretically trap particles within the post array. As an application, it was demonstrated that decreasing the number of columns in the post array allows for the dielectrophoretic trapping of nanometer-scale particles at voltages well below those reported in previous similar iDEP systems. These findings illustrate how the iDEP channel configuration can be customized for specific applications.


Genetic risk of progression to type 2 diabetes and response to intensive lifestyle or metformin in prediabetic women with and without a history of gestational diabetes mellitus.
OBJECTIVE The Diabetes Prevention Program (DPP) trial investigated rates of progression to diabetes among adults with prediabetes randomized to treatment with placebo, metformin, or intensive lifestyle intervention. Among women in the DPP, diabetes risk reduction with metformin was greater in women with prior gestational diabetes mellitus (GDM) compared with women without GDM but with one or more previous live births. RESEARCH DESIGN AND METHODS We asked if genetic variability could account for these differences by comparing β-cell function and genetic risk scores (GRS), calculated from 34 diabetes-associated loci, between women with and without histories of GDM. RESULTS β-Cell function was reduced in women with GDM. The GRS was positively associated with a history of GDM; however, the GRS did not predict progression to diabetes or modulate response to intervention. CONCLUSIONS These data suggest that a diabetes-associated GRS is associated with development of GDM and may characterize women at risk for development of diabetes due to β-cell dysfunction.


Bis-cyclometalated iridium complexes with electronically modified aryl isocyanide ancillary ligands.
In this work we report a study on the effect of systematic ancillary ligand modifications on electrochemical and photophysical properties of cationic biscyclometalated bis(arylisocyanide)iridium(iii) complexes. Nine new Ir(iii) complexes were synthesized using three different cyclometalating (C^N) ligands (2,4-difluorophenylpyridine (F2ppy), 2-benzothienylpyridine (btp), and 2-phenylbenzothiazole (bt)) with three aryl isocyanide ancillary ligands (2,4-dimethoxyphenyl isocyanide (CNArOMe), 3,5-bis(trifluoromethyl)phenyl isocyanide (CNArCF3) and 4-nitrophenyl isocyanide (CNArNO2)). Systematic modifications of ancillary ligands with electron-donating or electron-withdrawing groups have a very minor influence on the positions of the absorption and emission bands, suggesting that aryl isocyanide ancillary ligands minimally perturb the primarily ligand-centered emissive states, but still can control the dynamics of the excited state. Replacing electron-donating groups with electron-withdrawing group influences kr and/or knr, resulting in changes in the lifetimes and quantum yields. In addition, we reveal that electronic structures can be substantially altered by incorporating electron-donating or electron-withdrawing groups on the aryl isocyanide ancillary ligand, with different magnitudes of the perturbation depending on the cyclometalating C^N ligand. Particularly, the formally IrIV/IrIII oxidation couple can be perturbed by over 200 mV when electron-donating substituents are replaced with electron-withdrawing groups.


[Recurrence of acute gastroduodenal ulcer bleedings].
Multifactor analysis of 818 cases of acute gastroduodenal ulcer bleedings (clinical and laboratory examination, gastroscopy, morphological studies) was carried out, 97 of these patients had recurrence of bleeding. It is demonstrated that recurrence of gastroduodenal ulcer bleeding is cause by progressed ischemic necrosis in periulcerous zone in condition of local hypoperfusion as a result of systemic hemodynamic disorders due to acute blood loss syndrome and chronic ischemia dueto ulcerous process. Systemic hemostatic therapy, antisecretory drugs, methods of endoscopic hemostasis don't guarantee absence of bleeding recurrence. Prognosis of the recurrence must be based on assessment of significant clinical and gastroscopic data. Dynamical determination of pO2 in periulcerous zone is an additional prognostic criterion. Recurrence of gastroduodenal ulcer bleeding increases general and postoperative lethality 2 times as minimum. Active surgical policy based on prognosis of bleeding recurrence probability permitted us to reduce total lethality in acute gastroduodenal ulcer bleedings to 6.2%, postoperative lethality to 8.5%.


Improvement of type 2 diabetes mellitus after gastric cancer surgery: short-term outcome analysis after gastrectomy.
To evaluate the effect of gastrectomy on diabetes control in patients with type 2 diabetes mellitus and early gastric cancer. Data from 64 patients with early gastric cancer and type 2 diabetes mellitus were prospectively collected. All patients underwent curative gastrectomy (36 subtotal gastrectomy with gastroduodenostomy, 16 subtotal gastrectomy with gastrojejunostomy, 12 total gastrectomy) and their physical and laboratory data were evaluated before and 3, 6 and 12 mo after surgery. Fasting blood glucose (FBS), HbA1c, insulin, C-peptide, and homeostasis model assessment-estimated insulin resistance were significantly improved 3 mo after surgery, regardless of operation type, and the significant improvement in all measured values, except HbA1c, was sustained up to 12 mo postoperatively. Approximately 3.1% of patients stopped diabetes medication and had HbA1c < 6.0% and FBS < 126 mg/dL. 54.7% of patients decreased their medication, and had reduced FBS or HbA1c. In multivariate analysis, good diabetic control was not associated with operation type, but was associated with diabetes duration. Diabetes improved in more than 50% of patients during the first year after gastric cancer surgery. The degree of diabetes control was related to diabetes duration.


What Predictability for Animal Models of Peripheral Vestibular Disorders?
The different clinical entities grouped under the term peripheral vestibulopathies (PVs) or peripheral vestibular disorders (PVDs) are distinguished mainly based on their symptoms/clinical expression. Today, there are very few commonly accepted functional and biological biomarkers that can confirm or refute whether a vestibular disorder belongs to a precise classification. Consequently, there is currently a severe lack of reliable and commonly accepted clinical endpoints, either to precisely follow the course of the vertigo syndrome of vestibular origin or to assess the benefits of therapeutic approaches, whether they are pharmacological or re-educational. Animal models of PV are a good means to identify biomarkers that could subsequently be exploited in human clinical practice. The question of their predictability is therefore crucial. Ten years ago, we had already raised this question. We revisit this concept today in order to take into account the animal models of peripheral vestibular pathology that have emerged over the last decade, and the new technological approaches available for the behavioral assessment of vestibular syndrome in animals and its progression over time. The questions we address in this review are the following: are animal models of PV predictive of the different types and stages of vestibular pathologies, and if so, to what extent? Are the benefits of the pharmacological or reeducational therapeutic approaches achieved on these different models of PV (in particular the effects of attenuation of the acute vertigo, or acceleration of central compensation) predictive of those expected in the vertiginous patient, and if so, to what extent?


[Adrenergic and cholinergic innervation of the prostate in laboratory animals].
The prostate innervation has been studied in 50 white rats, 12 rabbits, 12 guinea pigs, 6 cats and 6 dogs. Together with the impregnation techniques, Karnovsky-Roots method has been applied, for revealing cholinergic components, and the incubation method in 2% solution of glyoxylic acid, for revealing adrenergic nervous structures. Density of adrenergic and cholinergic nervous plexuses has been estimated by means of the planimetric point method. The prostate of the laboratory animals possesses well manifested adrenergic and cholinergic nervous plexuses. The organ's alveolus and ducts are covered with adrenergic and cholinergic fibers, however, the relative density of the cholinergic plexuses is less than that of the adrenergic ones. The guinea pig prostate is the most richly supplied with the adrenergic nervous plexuses, and the rabbit prostate--with the cholinergic nervous plexuses.


Enhanced efficacy and reduced side effects of diazepam by kava combination.
The long term use of antiepileptic drugs possesses many unwanted effects; thus, new safe combinations are urgently mandated. Hence, the present study aimed to investigate the anticonvulsant effect of kava alone or in combination with a synthetic anticonvulsant drug, diazepam (DZ). To this end, female Wistar rats were divided into two subsets, each comprising 6 groups as follows: group (i) received 1% Tween 80 p.o. and served as control, while groups (ii) and (iii) received kava at two dose levels (100 and 200 mg/kg, p.o.). The remaining three groups received (iv) DZ alone (10 mg/kg p.o.) or kava in combination with DZ (v) (5 mg/kg, p.o.) or (vi) (10 mg/kg, p.o.). Results of the present study revealed that kava increased the maximal electroshock seizure threshold (MEST) and enhanced the anticonvulsant effect of diazepam following both acute and chronic treatment. Moreover, neither kava nor its combination with DZ impaired motor co-ordination either acutely or chronically. Furthermore, kava ameliorated both the reduction in locomotor activity as well as changes in liver function tests induced by chronic administration of DZ. Moreover, no elevation was shown in the creatinine concentration vs. control group following chronic administration of kava or DZ either alone or in combination with kava. In conclusion, the present study suggests the possibility of combining a low dose DZ with kava to reduce harmful effects and might be recommended for clinical use in patients chronically treated with this synthetic anticonvulsant drug.


Environmental risk factors associated with H5N1 HPAI in Ramsar wetlands of Europe.
The objective of this study was to identify environmental characteristics of European Ramsar wetlands, which are natural habitats for waterbirds, that could have contributed as risk factors for H5N1 HPAI (highly pathogenic avian influenza) in water birds (2006-2009). Ramsar wetlands in which H5N1 outbreaks were reported were considered infected (positive), and a case-control study was conducted using a logistic regression model in order to identify environmental risk factors associated with disease. Forestry (odds ratio, OR = 6.90) and important area for water birds with mixosaline water (OR = 6.31), as well as distance to the nearest positive wetland (OR = 0.66), which was included into the model to adjust for spatial dependence, were associated with status of the wetlands. The model was used to estimate the risk for H5N1 HPAI on each European Ramsar wetland. Results will help to identify wetlands at high risk for H5N1 HPAI infection, wetlands that could be selectively targeted as part of a surveillance program aimed at early detection and prevention of future H5N1 HPAI epidemics.


[Mesenchymoma of the mediastinum].
A case of multicomponent mesenchymoma of the mediastinum with a malignancy of its connective tissue component and recurrence 6 months after its removal is described. Protracted benign course of the tumour with subsequent development of a spindle cell sarcoma confirm the possibility of the malignancy of one of the tumour components.


Serotonin noradrenaline reuptake inhibitors: A new generation of treatment for anxiety disorders.
A variety of agents are currently used to treat the different anxiety disorders. Benzodiazepines, such as diazepam, are still preferred by some for the treatment of acute anxiety, with the advantage of a rapid onset of action, but they are less suitable for long-term treatment due to their potential for memory disturbances, sleepiness, lethargy, physical dependence and withdrawal. Compounds acting on monoamine neurotransmission are more suitable in the treatment of long-term or chronic anxiety disorders. Tricyclic antidepressants, such as imipramine, and monoamine oxidase inhibitors have been shown to be effective anxiolytics, but their side effects and safety concerns have limited their use. The probable role of disturbed serotonergic neurotransmission in anxiety is widely accepted and is the theoretical basis for the use of serotonergic agents such as the 5-HT1A receptor partial agonist, buspirone, and the selective serotonin reuptake inhibitors (SSRI), such as sertraline and paroxetine, which have largely replaced the earlier antidepressants. There is clear evidence for decreased serotonergic function in anxiety as well as in depression. Studies of patients with anxiety disorders show reduced levels of serotonin in cerebrospinal fluid (CSF) as well as reduced serotonin transporter binding. The role of noradrenaline in the control of anxiety is less well understood, although there is considerable evidence to suggest that a disturbance of noradrenergic neurotransmission may also contribute to the symptoms of anxiety. Noradrenaline modulates the activity of brain regions such as the amygdala which are associated with anxiety. In addition, anxiety states are associated with increases in the metabolite of noradrenaline, 3-methoxy-4-hydrophenylglycol (MHPG), and hypersecretion of noradrenaline in plasma and CSF. It appears likely that modulation of both serotonin and noradrenaline systems by dual-reuptake inhibitors may prove to be an advantage in the treatment of anxiety disorders. The serotonin-noradrenaline reuptake inhibitors (SNRI), venlafaxine, milnacipran and duloxetine are efficacious in relieving anxiety symptoms within depression, and some have proven efficacy in certain anxiety disorders. Initial studies suggest that dual acting agents may have an advantage over selective reuptake inhibitors in certain anxiety disorders, such as post-traumatic stress disorder (PTSD), and in patients with comorbid anxiety and depression.