Modeling and regression analysis of semiochemical dose-response curves of insect antennal reception and behavior.
Dose-response curves of the effects of semiochemicals on neurophysiology and behavior are reported in many articles in insect chemical ecology. Most curves are shown in figures representing points connected by straight lines, in which the x-axis has order of magnitude increases in dosage vs. responses on the y-axis. The lack of regression curves indicates that the nature of the dose-response relationship is not well understood. Thus, a computer model was developed to simulate a flux of various numbers of pheromone molecules (10(3) to 5 × 10(6)) passing by 10(4) receptors distributed among 10(6) positions along an insect antenna. Each receptor was depolarized by at least one strike by a molecule, and subsequent strikes had no additional effect. The simulations showed that with an increase in pheromone release rate, the antennal response would increase in a convex fashion and not in a logarithmic relation as suggested previously. Non-linear regression showed that a family of kinetic formation functions fit the simulated data nearly perfectly (R(2) >0.999). This is reasonable because olfactory receptors have proteins that bind to the pheromone molecule and are expected to exhibit enzyme kinetics. Over 90 dose-response relationships reported in the literature of electroantennographic and behavioral bioassays in the laboratory and field were analyzed by the logarithmic and kinetic formation functions. This analysis showed that in 95% of the cases, the kinetic functions explained the relationships better than the logarithmic (mean of about 20% better). The kinetic curves become sigmoid when graphed on a log scale on the x-axis. Dose-catch relationships in the field are similar to dose-EAR (effective attraction radius, in which a spherical radius indicates the trapping effect of a lure) and the circular EARc in two dimensions used in mass trapping models. The use of kinetic formation functions for dose-response curves of attractants, and kinetic decay curves for inhibitors, will allow more accurate predictions of insect catch in monitoring and control programs.


The timing of male reproductive effort relative to female ovulation in a capital breeder.
1. In large herbivores, the timing of breeding is important for females to hit peak plant protein levels. For males, the timing of reproductive effort is important to maximize the number of females they can mate during autumn rut in competition with other males. The latter depends on when most females are ovulating, but also on how other males with a different competitive ability are timing use of their capital (fat); it may pay younger males to invest more heavily later when prime aged males are exhausted. 2. Based on estimates of body mass loss, we quantify how much timing (start, peak and end dates) of male reproductive effort during rutting varies depending on male age, density and climate as well as timing of female ovulation. 3. Ovulation in adult females was delayed by 5 days from low to high density, and ovulation was also more synchronous at high density. The starting date of decline in male body mass was only later in yearlings than among other age groups. However, at low density, peak and end dates of rut became increasingly earlier and close to peak female ovulation with increasing age up to 7 years of age. Prime-aged males matched peak effort closely with peak rate of prime-aged female ovulation, while younger males were delayed. This is consistent with the view that younger males have a better chance when the prime-aged males are becoming exhausted. 4. Apart from yearlings, male age groups were synchronized in both the starting, peak and end dates of mass decline at high density. Thus, this partly follows change in female ovulation patterns, but also suggests that competition among males decreased with increasing density due probably to lower intensity of sexual selection. The lowered sexual selection may be due not only to more synchronous female ovulation, but also increasingly female-biased sex ratios and a younger male age structure with increasing density. 5. The onset of rutting is somewhat independent of male age (apart from the youngest males), but the peak and end of rutting effort is dependent strongly upon age, density and peak female ovulation. Male rutting phenology is thus best interpreted as a compromise between hitting peak female ovulation and intensity of sexual selection.


Mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 in tumors.
Heterozygous hotspot mutations in isocitrate dehydrogenases (IDH) IDH1 or IDH2 are frequently observed in specific types of cartilaginous tumors, gliomas, and leukemias. Mutant IDH enzyme loses its normal activity to convert isocitrate into α-ketoglutarate (αKG) and instead acquires the ability to reduce αKG to D-2-hydroxyglutarate. Through direct competition with αKG, accumulation of the oncometabolite D-2-hydroxyglutarate in IDH mutated tumors results in inhibition of αKG-dependent dioxygenases involved in DNA and histone demethylation. Apart from epigenetic alterations, perturbations in the tricarboxylic acid cycle (depletion of intermediates) and activation of the intricately linked hypoxia signaling pathway are apparent in IDH mutated cells. As molecular details are being unraveled, the emerging concept is that IDH mutations result in tumor formation by epigenetic alterations that affect gene expression and result in inhibition of cellular differentiation. Activation of hypoxic stress signaling reprograms cellular energy metabolism and promotes anabolic processes and angiogenesis, thus, providing an advantage to promote neoplastic growth.


Problems in microstaging of melanoma vertical growth.
Review of the currently available data would indicate that the measurement of tumor thickness in millimeters, especially those greater than 1.5 mm in thickness, is the single most important prognostic variable, closely followed by sex and location of the tumor. On the other hand, in thinner tumors, the level of invasion takes precedence over tumor thickness, especially in the setting of the "thin level IV" tumor. The microstaging must therefore include measurements of both level and thickness (keeping in mind the problems involved in thickness measurements noted above), as well as notation of special features of prognostic value (mitotic index, ulceration, microsatellites, etc.). Only with such refinements and the continued study of parameters from large databases can the estimates of prognosis in patients with primary malignant melanoma be made sufficiently accurate to be useful in planning appropriate therapy.


Pediatric emergency medicine fellowships adopt a new application process.
The growth of the subspecialty of pediatric emergency medicine has created a subsequent growth in the demands of pediatric emergency medicine fellowship training. To facilitate the application process for both applicants and fellowship training programs, a uniform application and uniform deadlines have been adopted by the Pediatric Emergency Medicine Fellowship Director's Subcommittee. The Electronic Residency Application Service will provide online support necessary for the implementation of this new process. A description of the new process and a description of theoretical benefits from this change are described. Pediatric emergency medicine fellowship applicants should be encouraged to investigate resources describing the new application process.


Reorientation phenomena in imidazolium methyl sulfonate as probed by advanced solid-state NMR.
Evidence for reorientation of imidazolium rings in imidazolium methylsulfonate is demonstrated using solid-state NMR. This material is a model system for exciting new proton-conducting materials based on imidazole. Two advanced NMR methods, including 1H-13C and 1H-15N recoupled polarization transfer with dipolar sideband pattern analysis and analysis of the coalescence of 13C lineshapes are used to characterize the ring reorientation. The process is found to occur at temperatures well below the melting point of the salt, between 240 and 380 K, and is described by a single activation energy, of 38+/-5 kJ/mol. This material is considered as a model system for quantifying the ring reorientation process, which is often proposed to be the rate-limiting step in proton transport in imidazole-based proton conducting materials.


Discovery of LAH-1 as potent c-Met inhibitor for the treatment of non-small cell lung cancer.
ABSTRCTDysregulated HGF/c-Met pathway has been implicated in multiple human cancers and has become an attractive target for cancer intervention. Herein, we report the discovery of N-(3-fluoro-4-((2-(3-hydroxyazetidine-1-carboxamido)pyridin-4-yl)oxy)phenyl)-1-(4-fluorophenyl)-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (LAH-1), which demonstrated nanomolar MET kinase activity as well as desirable antiproliferative activity, especially against EBC-1 cells. Mechanism studies confirmed the effects of LAH-1 on modulation of HGF/c-Met pathway, induction of cell apoptosis, inhibition on colony formation as well as cell migration and invasion. In addition, LAH-1 also showed desirable in vitro ADME properties as well as acceptable in vivo PK parameters. The design, synthesis, and characterisation of LAH-1 are described herein.


Egocentric network composition and structure relative to violence victimization among a sample of college students.
ObjectiveTo use egocentric network analysis to understand how composition and structure of egonetworks relate to violence victimization among college students. Participants: 697 students from a large southeastern university completed online surveys. Methods: Hierarchical logistic regression analyses assessed the relationship between egocentric network variables and a history of violence victimization. Results: Being connected to others with a history of violence victimization increased a student's odds of indicating their own history of physical, emotional, and sexual violence victimization. Having less dense egonetworks was related to sexual violence victimization, while being connected to less people of the same gender was related to emotional violence victimization. Conclusion: The way college students' networks are composed and structured could help in understanding violence victimization in this population, and should be considered in prevention and reactionary efforts on campuses. These findings add to the current literature largely focused on individual-level risk factors related to violence.


Camera-based Cardiovascular Screening based on Heart Rate and Its Variability In Pre- and Post-Exercise Conditions.
Analysis of heart rate (HR) and heart rate variability (HRV) in pre- and post-exercise conditions can provide useful information about the health condition of cardiovascular system. Remote photoplethysmography (rPPG) that uses a contactless camera to measure vital signs from the human face might allow for ubiquitous applications in the fitness scenario. This paper benchmarks the accuracy of HR and HRV measured by ECG, PPG and rPPG, and investigates the difference of HR and HRV parameters between individuals with/without the exercise habit in pre- and post-exercise phases. We built a fitness benchmark consisting of 14 healthy subjects to perform running exercise on a treadmill, with video and reference data recorded simultaneously. The results show that rPPG has a similar performance as PPG in both the estimation of HR and HRV. The HRV parameters (Mean IBI, SDNN, LF, VLF, and SD2) of rPPG/PPG show good agreements with the ECG reference. Subjects with a regular exercise habit show lower resting HR and smaller values of HRV parameters in pre-exercise phase, fewer changes in HR and HRV at the same exercise intensity, and faster HR recovery after exercising, as compared with those without an exercise habit. The preliminary results suggest that rPPG is a promising surrogate of PPG for screening HR and HRV before and after exercise, to indicate the performance of cardiac training.


Automatic GAN-based MRI volume synthesis from US volumes: a proof of concept investigation.
Usually, a baseline image, either through magnetic resonance imaging (MRI) or computed tomography (CT), is captured as a reference before medical procedures such as respiratory interventions like Thoracentesis. In these procedures, ultrasound (US) imaging is often employed for guiding needle placement during Thoracentesis or providing image guidance in MISS procedures within the thoracic region. Following the procedure, a post-procedure image is acquired to monitor and evaluate the patient's progress. Currently, there are no real-time guidance and tracking capabilities that allow a surgeon to perform their procedure using the familiarity of the reference imaging modality. In this work, we propose a real-time volumetric indirect registration using a deep learning approach where the fusion of multi-imaging modalities will allow for guidance and tracking of surgical procedures using US while displaying the resultant changes in a clinically friendly reference imaging modality (MRI). The deep learning method employs a series of generative adversarial networks (GANs), specifically CycleGAN, to conduct an unsupervised image-to-image translation. This process produces spatially aligned US and MRI volumes corresponding to their respective input volumes (MRI and US) of the thoracic spine anatomical region. In this preliminary proof-of-concept study, the focus was on the T9 vertebrae. A clinical expert performs anatomical validation of randomly selected real and generated volumes of the T9 thoracic vertebrae and gives a score of 0 (conclusive anatomical structures present) or 1 (inconclusive anatomical structures present) to each volume to check if the volumes are anatomically accurate. The Dice and Overlap metrics show how accurate the shape of T9 is when compared to real volumes and how consistent the shape of T9 is when compared to other generated volumes. The average Dice, Overlap and Accuracy to clearly label all the anatomical structures of the T9 vertebrae are approximately 80% across the board.


The afterglow of carbon dots shining in inorganic matrices.
Carbon dots (CDs) are a new type of quasi-spherical and zero-dimension carbon nanomaterial with a diameter less than 10 nm. They exhibit a broad absorption spanning from the ultraviolet (UV) to visible light regions and inspire growing interests due to their excellent performance. In recent years, it was identified that the CDs embedded in various inorganic matrices (IMs) can effectively activate afterglow emission by suppressing the nonradiative transitions of molecules and protecting the triplet excitons of CDs, which hold broad application prospects. Herein, recent advances in CDs@IMs are reviewed in detail, and the interaction and luminescence mechanisms between CDs and IMs are also summarized. We highlight the synthetic strategies of constructing composites and the roles of IMs in facilitating the applications of CDs in diverse areas. Finally, some directions and challenges of future research in this field are proposed.


Revisiting the comparative phylogeography of unglaciated eastern North America: 15 years of patterns and progress.
In a landmark comparative phylogeographic study, "Comparative phylogeography of unglaciated eastern North America," Soltis et al. (Molecular Ecology, 2006, 15, 4261) identified geographic discontinuities in genetic variation shared across taxa occupying unglaciated eastern North America and proposed several common biogeographical discontinuities related to past climate fluctuations and geographic barriers. Since 2006, researchers have published many phylogeographical studies and achieved many advances in genotyping and analytical techniques; however, it is unknown how this work has changed our understanding of the factors shaping the phylogeography of eastern North American taxa. We analyzed 184 phylogeographical studies of eastern North American taxa published between 2007 and 2019 to evaluate: (1) the taxonomic focus of studies and whether a previously detected taxonomic bias towards studies focused on vertebrates has changed over time, (2) the extent to which studies have adopted genotyping technologies that improve the resolution of genetic groups (i.e., NGS DNA sequencing) and analytical approaches that facilitate hypothesis-testing (i.e., divergence time estimation and niche modeling), and (3) whether new studies support the hypothesized biogeographic discontinuities proposed by Soltis et al. (Molecular Ecology, 2006, 15, 4261) or instead support new, previously undetected discontinuities. We observed little change in taxonomic focus over time, with studies still biased toward vertebrates. Although many technological and analytical advances became available during the period, uptake was slow and they were employed in only a small proportion of studies. We found variable support for previously identified discontinuities and identified one new recurrent discontinuity. However, the limited resolution and taxonomic breadth of many studies hindered our ability to clarify the most important climatological or geographical factors affecting taxa in the region. Broadening the taxonomic focus to include more non-vertebrate taxa, employing technologies that improve genetic resolution, and using analytical approaches that improve hypothesis testing are necessary to strengthen our inference of the forces shaping the phylogeography of eastern North America.


Lower extremity deep venous thrombosis: evaluation with ferumoxytol-enhanced MR imaging and dual-contrast mechanism--preliminary experience.
Institutional review board approval and informed consent were obtained for this HIPAA-compliant study, whose purpose was to prospectively evaluate the use of a dual-contrast mechanism in conjunction with an iron oxide blood pool contrast agent, ferumoxytol, to depict deep venous thrombosis (DVT). Nine patients with lower extremity DVT detected with duplex ultrasonography (US) were imaged with magnetic resonance (MR) imaging and ferumoxytol. Three techniques, including precontrast two-dimensional time-of-flight (TOF) imaging, ferumoxytol-enhanced bright-blood imaging, and ferumoxytol-enhanced dark-blood imaging, were applied. Image quality for precontrast and ferumoxytol-enhanced images was analyzed by using a four-point scale. Thrombus was depicted as a filling defect within the blood pool on bright-blood images and as bright tissue that appeared highly contrasted against a dark background on dark-blood images. Image quality of ferumoxytol-enhanced images was uniformly superior to that of precontrast TOF images (P = .007). Compared with precontrast TOF images, ferumoxytol-enhanced bright-blood images had higher contrast-to-noise ratios (CNRs) between thrombus and blood (P = .051), whereas ferumoxytol-enhanced dark-blood images showed significantly higher CNRs between thrombus and surrounding muscle (P = .008). Ferumoxytol-enhanced MR imaging can depict DVT with a dual-contrast mechanism and show the extent of thrombus.


The importance of sediment and submerged aquatic vegetation as potential habitats for persistent strains of enterococci in a subtropical watershed.
Recent evidence of extended survival of fecal indicator bacteria in sediments and submerged aquatic vegetation (SAV) has raised concerns about using indicator bacteria to reliably detect fecal contamination. We monitored enterococci densities and population structure in water, sediment and SAV simultaneously at sites across a subtropical watershed (Tampa Bay, FL, USA) over one year to determine the extent to which each matrix serves as a potential reservoir of enterococci. SAV harbored significantly higher mean densities of enterococci than sediments, which harbored higher densities than water. Mean enterococci densities were also greater at sites located further upstream in the watershed. The population structure assessed by BOX-PCR genotyping was relatively dissimilar in each sample, although some similarities among samples suggested grouping by location. Strain diversity ranged from very high to negligible, with lowest overall diversity in lake samples taken during the summer. Several strains were highly abundant and cosmopolitan (found across sites, seasons, and matrices) and were identified by 16S rRNA gene sequencing as the Enterococcus species casseliflavus, faecalis, faecium, hirae, and mundtii. The proportional dominance of certain strains suggests the existence of persistent and possibly naturalized indicator bacteria populations that are not directly related to pollution events.


Total Wrist Replacement Outcomes in the Asian Pacific Population - A Single-Centre Result.
Background: Total wrist replacement (TWR) is rarely done in the Asia-Pacific region. The aim of this study is to report the surgical outcomes and experience of TWR in patients with advanced arthritis. Methods: This is a retrospective review of all TWR patients in the Department of Orthopaedics and Traumatology, Prince of Wales Hospital, Hong Kong, which is a university tertiary centre, from January 2004 to March 2023. Recorded demographic parameters include gender, age upon surgery, pathology, types of implants and follow-up period. The surgical outcome parameters include range of motion, grip strength, wrist function assessment, radiological and clinical complications and any related secondary operations. Postoperative X-ray and clinical notes were reviewed. All wrist function assessments were performed by specialised occupational therapists according to protocol. Results: The study included a total of 12 wrists of 10 patients, all Chinese-Asian, with a mean age of 61.4 years at surgery. Larsen grade V arthritis constituted 50% and grade IV 16.7% of the patients, amongst which 33% had volar subluxation. The mean follow-up period was 97.4 months (21-205 months). The mean grip strength was 64.2% of the unaffected side. The mean postoperative Disabilities of Arm, Shoulder and Hand (DASH) score was 41.12% and patient-rated wrist/hand evaluation (PRWE) score 18.0. Complication incidence was 16.67% for loosening, 8.3% for metallosis and 8.3% for infection. One patient required conversion to total wrist arthrodesis due to metallosis. No patient suffered from dislocation, periprosthetic fracture and infection. Conclusions: TWR is an effective and safe alternative to total wrist arthrodesis with comparable outcomes. Our series outcomes are satisfactory and in line with literature. With meticulous soft tissue release and balancing, volar subluxation can also be corrected and may not be a contraindication. Level of Evidence: Level IV (Therapeutic).


Neuroreceptor imaging of stress and mood disorders.
Techniques such as positron emission tomography and single photon emission computed tomography allow for the imaging of neurotransmitter receptors and transporters in the brain. These tools have been used to investigate serotonergic, dopaminergic, and opioidergic function in healthy subjects as well as in patients with major depressive disorder, bipolar disorder, and other mood disorders. Pharmacologic challenges, such as amphetamine challenge, and physiologic stressors, such as pain challenge, have been used to further examine the function of these neurotransmitter systems. Neuroimaging of patient populations before and after medication treatment may be useful to understand changes in neurotransmission that accompany disease remission. As new radiotracers with higher selectivity for the various receptors and transporters are developed, imaging techniques may provide new insights into the pathophysiology of mood disorders, leading to improved diagnosis and treatment.


Synchronous multisensory stimulation blurs self-other boundaries.
In a study that builds on recent cognitive neuroscience research on body perception and social psychology research on social relations, we tested the hypothesis that synchronous multisensory stimulation leads to self-other merging. We brushed the cheek of each study participant as he or she watched a stranger's cheek being brushed in the same way, either in synchrony or in asynchrony. We found that this multisensory procedure had an effect on participants' body perception as well as social perception. Study participants exposed to synchronous stimulation showed more merging of self and the other than participants exposed to asynchronous stimulation. The degree of self-other merging was determined by measuring participants' body sensations and their perception of face resemblance, as well as participants' judgment of the inner state of the other, closeness felt toward the other, and conformity behavior. The results of this study show how multisensory integration can affect social perception and create a sense of self-other similarity.


Contribution of Monocarboxylate Transporter 6 to the Pharmacokinetics and Pharmacodynamics of Bumetanide in Mice.
Bumetanide, a sulfamyl loop diuretic, is used for the treatment of edema in association with congestive heart failure. Being a polar, anionic compound at physiologic pH, bumetanide uptake and efflux into different tissues is largely transporter-mediated. Of note, organic anion transporters (SLC22A) have been extensively studied in terms of their importance in transporting bumetanide to its primary site of action in the kidney. The contribution of one of the less-studied bumetanide transporters, monocarboxylate transporter 6 (MCT6; SLC16A5), to bumetanide pharmacokinetics (PK) and pharmacodynamics (PD) has yet to be characterized. The affinity of bumetanide for murine Mct6 was evaluated using Mct6-transfected Xenopus laevis oocytes. Furthermore, bumetanide was intravenously and orally administered to wild-type mice (Mct6+/+) and homozygous Mct6 knockout mice (Mct6-/-) to elucidate the contribution of Mct6 to bumetanide PK/PD in vivo. We demonstrated that murine Mct6 transports bumetanide at a similar affinity compared with human MCT6 (78 and 84 μM, respectively, at pH 7.4). After bumetanide administration, there were no significant differences in plasma PK. Additionally, diuresis was significantly decreased by ∼55% after intravenous bumetanide administration in Mct6-/- mice. Kidney cortex concentrations of bumetanide were decreased, suggesting decreased Mct6-mediated bumetanide transport to its site of action in the kidney. Overall, these results suggest that Mct6 does not play a major role in the plasma PK of bumetanide in mice; however, it significantly contributes to bumetanide's pharmacodynamics due to changes in kidney concentrations. SIGNIFICANCE STATEMENT: Previous evidence suggested that MCT6 transports bumetanide in vitro; however, no studies to date have evaluated the in vivo contribution of this transporter. In vitro studies indicated that mouse and human MCT6 transport bumetanide with similar affinities. Using Mct6 knockout mice, we demonstrated that murine Mct6 does not play a major role in the plasma pharmacokinetics of bumetanide; however, the pharmacodynamic effect of diuresis was attenuated in the knockout mice, likely because of the decreased bumetanide concentrations in the kidney.


Statins--is there potential for uncovering new benefits (or detriments)?
Despite over 20 years of clinical use and 15 years of clinical trial data, we still do not have a complete understanding of the mechanisms of action or full utility of statins as a class of drugs. The possibility of their use as a treatment for prevention of peri-operative morbidity and mortality is one of the newest indications being explored for this class of drugs. Issues regarding drug dosing and timing may rely on being able to elucidate and separate potential pleiotropic actions from lipid-lowering actions to identify the optimal benefit of these drugs in the peri-operative setting. Careful consideration of these two actions need to be considered in the design of adequately powered clinical trials to test the potential utility and safety of using statins in the peri-operative setting.


Effects of cadmium exposure during pregnancy on genome-wide DNA methylation and the CREB/CREM pathway in the testes of male offspring rats.
This experimental study explored the multigenerational and transgenerational effects of cadmium (Cd) exposure during pregnancy on the testicular tissue and spermatogenesis of male offspring rats. CdCl2 at different doses (0, 0.5, 1, 2 mg/kg/day) were dispensed to pregnant SD rats, thus producing generation F1. Adult females in F1 (PND 56) were mated with untreated fertile males so as to produce generation F2. Likewise, adult females in F2 were mated to produce generation F3. Damages to testicular tissue were observed in all the three generations, with serum testosterone (T) increased in F2 and F3. Notably, the genome-wide DNA methylation level in the testicular tissue of F1 was altered, as was the expression of F1-F3 methyltransferases. In addition, the expression of Creb/Crem pathway, a pathway critical for the metamorphosis from postmeiotic round spermatocytes to spermatozoa, was also remarkably altered in the three generations. In concludion, prenatal Cd exposure might bring multigenerational and transgenerational toxic effects to testes via genome-wide DNA methylation and the regulation of CREB/CREM pathway.


Paradoxical effects of phenobarbital on mouse hepatocarcinogenesis.
Phenobarbital was the first tumor promoter for rodent liver to be associated with the 2-stage or initiation-promotion concept of carcinogenesis. In rats and mice preinitiated with genotoxic carcinogens, phenobarbital administration increases the number of hepatocellular tumors by approximately 5-fold despite its nongenotoxicity. However, in mice phenobarbital occasionally exhibits strong inhibitory effects on hepatocarcinogenesis initiated with the potent carcinogen diethylnitrosamine. Both positive and negative effects of phenobarbital on hepatocytic proliferation and apoptosis, which are mechanistically involved in the promotion stage of hepatocarcinogenesis, have been described. These complex outcomes of phenobarbital treatment and their effects on hepatocarcinogenesis in mice raise serious issues regarding extrapolation of experimental data from laboratory animals to human risk assessment. Recent work suggests that the paradoxical actions of phenobarbital on hepatocarcinogenesis can be understood by consideration of qualitative diversity in initiated lesions and differential responses to promotion stimulus.


Round and Oval Window Anatomic Variability: Its Implication for the Vibroplasty Technique.
The objective of this study is to evaluate the anatomical variability of round and oval window regions and its relationship with their closest structures, to determine its implication on the fitting and stabilization of the middle ear implant Vibrant Soundbridge. Variations of the anatomy of round and oval window regions were assessed in a total of 85 human dissected temporal bones. Afterward, we evaluated the adaptation and subsequent stabilization of the floating mass transducer (FMT) of the Vibrant Soundbridge in 67 cases in round window (RW) and in 22 cases in oval window (OW), and the influence that the variability of the different anatomical features examined had on this stabilization. We also assessed access and surgeon's view of the RW niche through the facial recess approach. Stabilization of the FMT in the RW was achieved in 53 (79%) of the 67 cases; we found that the less favorable anatomical conditions for stabilization were: membrane smaller than 1.5 mm, presence of a high jugular bulb and a narrow or very narrow RW niche. Frequently, two or more of these conditions happened simultaneously. In seven cases (22%) access to the RW through facial recess approach did not allow positioning the FMT in place. OW stabilization succeeded in 18 (82%) of the 22 cases. Round and oval window vibroplasty are difficult surgical techniques. To place the FMT directly on the OW may be easier as we do not have to drill the niche. In both regions there are some anatomical conditions that hinder fitting the FMT and even make it impossible. Once fitted, the main problem is to achieve good stabilization of the device.


Peripheral muscle training in patients with chronic obstructive pulmonary disease: novel approaches and recent advances.
Pulmonary rehabilitation is one of the most effective non-pharmacological management options for individuals with chronic obstructive pulmonary disease (COPD). Exercise training is the cornerstone of pulmonary rehabilitation, however considerable variability exists regarding the way it is delivered across the world. It is widely accepted that efforts should be made to tailor specific therapeutic approaches to individuals' needs. This applies as much to respiratory medicine as it does to respiratory rehabilitation. Areas covered: This narrative review examines the emerging literature evaluating advancements of exercise training modalities targeting peripheral muscle function in people with COPD. It aims to highlight practical considerations regarding the delivery key evidence regarding clinical effectiveness, as well as highlight some of the and evaluation of their effectiveness to inform clinical practice. Expert commentary: Although novel therapies may offer advantages over more 'traditional' training methods under specific circumstances, challenges regarding the potential impact upon clinical rehabilitation, the identification of the best candidates for such therapy and access to equipment may pose realistic barriers to their more widespread clinical implementation. Future directions regarding the ways in which these barriers could be overcome will be discussed, including identification of the key research priorities to optimize evidence-based practice in this area.


Complicated grief in older adults: a randomized controlled trial of complicated grief group therapy.
This study compared the efficacy of complicated grief therapy (CGT; Shear, K. [2003]. Complicated grief: A guidebook for therapists [Liberty Version]. New York State Office of Mental Heath; Shear, K., Frank, E., Houck, P. R., & Reynolds, C. F. 3rd [2005]. Treatment of complicated grief: A randomized controlled trial. The Journal of the American Medical Association, 293, 2601-2608) administered as group therapy (CGGT) with standard group therapy (treatment as usual [TAU]) in older adults presenting with complicated grief (CG). The design was a 2×4, prospective, randomized controlled clinical trial. The independent variable was group type, with 1 group receiving experimental methods based on the work of Shear et al. (Shear, K., Frank, E., Houck, P. R., & Reynolds, C. F. 3rd. [2005]. Treatment of complicated grief: a randomized controlled trial. The Journal of the American Medical Association, 293, 2601-2608), CGGT versus. TAU. The dependent variable was treatment response. CGGT participants demonstrated higher treatment response than TAU participants. Although participants in both groups showed improvement in CG measures, CGGT participants realized significantly greater improvement. More importantly, when CG was measured on Prolonged Grief Disorder Scale, nearly half of CGGT participants realized clinically significant improvement. All CGGT completers had Brief Grief Questionnaire scores upon follow-up that, had they scored at that level at pretest, would have disqualified them for study enrollment. The high level of clinical significance suggests that CGGT participants were effectively treated for CG. This study offers evidence that CGGT holds promise for treatment of CG in older adults and merits inquiry in other populations.


Beetroot and Sodium Nitrate Ameliorate Cardiometabolic Changes in Diet-Induced Obese Hypertensive Rats.
Dietary intake of beetroot by humans reduces blood pressure but whether this is caused by nitrate or betanin is not well-defined; neither are effects on other signs of metabolic syndrome. Rats fed a high-carbohydrate, high-fat diet (H) for 16 weeks developed abdominal obesity, hypertension, altered cardiovascular and liver structure and function, and impaired glucose tolerance compared to rats fed a corn starch diet (C). H rats treated with ∼16 mg/kg/day of nitrate either from beetroot juice (H+B) or sodium nitrate (H+N) for the last 8 weeks reduced systolic blood pressure by ∼25 mmHg, improved cardiac structure and function, plasma lipid profile and plasma markers of liver function, reduced inflammatory cell infiltration in heart and liver and decreased left ventricular fibrosis. In the left ventricle, H rats increased mRNA expression of connective tissue growth factor (CTGF), monocyte chemoattractant protein 1 (MCP-1), matrix metalloproteinase-2 (MMP-2), and adenosine monophosphate-activated protein kinase-alpha (AMPK-α) and decreased mRNA expression of peroxisome proliferator-activated receptor-alpha (PPAR-α); both beetroot and sodium nitrate diet-fed rats decreased CTGF threefold, MCP-1, and MMP-2 twofold, and doubled PPAR-α mRNA expression in left ventricular tissue. The similar functional and molecular responses to beetroot and sodium nitrate indicate that the nitrate content of beetroot reduced inflammation and improved cardiovascular, liver, and metabolic function in rats with metabolic syndrome, rather than betanin.


Investigation of Camphor Effects on Fusarium graminearum and F. culmorum at Different Molecular Levels.
Fusarium graminearum and F. culmorum are phytopathogens, which cause destructive diseases in cereals. Epidemics of these phytopathogens are caused by mycotoxin contamination and the reduction of crop quality. In this study, the alteration due to in vitro camphor treatment on F. culmorum 9F and F. graminearum H11 isolates was investigated in terms of epigenetic, cellular, and transcription levels. Camphor with different concentrations (0.2, 0.4, 0.8, 1, 2, and 4 µg/µL) was applied to potato dextrose agar (PDA) growth media. The minimum inhibitory concentration (MIC) and the half maximal inhibitory concentration (IC50) were calculated as 2 and 1 µg/µL, respectively. hog1, mst20, CAT, POD, mgv1, stuA, and tri5 genes, which are related to various cellular processes and pathogenesis, were examined by qPCR assay. qPCR analysis showed that camphor treatment leads to the downregulation of tri5 expression but the upregulation of the remaining genes. Apoptosis and oxidative stress were confirmed via acridine orange/ethidium bromide (AO/EB) and dichlorofluorescin diacetate (DCF-DA) staining, respectively. Moreover, coupled restriction enzyme digestion-random amplification (CRED-RA) assay, used for DNA methylation analysis, was carried out to evaluate epigenetic alterations. The decrease in genomic template stability (GTS) values, which resulted due to the alterations in random amplified polymorphic DNA (RAPD) profiles caused by camphor treatment, were detected as 97.60% in F. culmorum 9F and 66.27% in F. graminearum H-11. The outer and inner methylated cytosine profiles are determined by CRED-RA assay as type I⁻IV epigenetic alterations. The outcomes indicated that camphor could lead to alterations at several molecular levels of F. graminearum and F. culmorum.


Genetic analysis of multiple sclerosis.
The increased recurrence risk within families indicates a role for genetic factors in the etiology of multiple sclerosis. Genes may influence susceptibility to the development of multiple sclerosis and the subsequent course of the disease. To date, associations have only been demonstrated consistently with class II major histocompatibility complex (MHC) alleles. The relatively low yield from additional candidate gene studies is only modestly advanced by several whole-genome linkage analyses, and by the first in a series of planned whole-genome linkage disequilibrium screens for allelic associations. The aims of linkage and association are to narrow the search for chromosomal regions encoding genes for multiple sclerosis and, with information from the human gene project, suggest new positional candidates. In time, it is expected that these genes will include some that confer susceptibility to the general process of autoimmunity, others that are specific for multiple sclerosis in all populations, some that act only in defined ethic groups, and those that determine particular phenotypes or shape the clinical course. These genetic analyses are predicated on the assumption that multiple sclerosis is one disease; a major part of future studies will be to resolve the question of disease heterogeneity in multiple sclerosis. When eventually in place, the potential of this genetic knowledge for improved understanding of the pathogenesis of multiple sclerosis and designing novel treatments is considerable.


Medical evaluation of the patient with liver disease prior to surgery.
Patients with liver disease have increased morbidity and mortality following general anesthesia and surgery when compared with the general population. The increase in mortality appears to be directly related to the severity of hepatic parenchymal cell failure and to the magnitude and duration of the surgical procedure. The importance of preoperative detection of subclinical liver disease by use of a variety of blood tests has been emphasized. However, with the exception of hepatitis B and non-A non-B hepatitis, a precise diagnosis of the exact cause of liver disease is usually less important to the anesthesiologist than is a full characterization of the severity of hepatic dysfunction. Recognition and understanding of the central metabolic role played by the liver in maintaining carbohydrate, fat, and protein homeostasis can help in predicting and managing abnormalities which may complicate the preoperative, interoperative, and postoperative periods. Liver failure after anesthesia and surgery is treated by the same management principles used for liver failure with acute hepatitis. The incidence of postoperative renal failure may be increased in patients who have severe hyperbilirubinemia and its occurrence should be differentiated from the hepatorenal syndrome. It should be understood that complications of portal hypertension may develop in the absence of overt hepatic parenchymal cell failure and that liver failure may occur without gross evidence of portal hypertension. Either situation must be recognized and treated as far in advance of surgery as possible. In general, elective surgery in the patient with liver disease should be delayed until consequences of hepatic parenchymal cell dysfunction and portal hypertension are optimally corrected.


Uveitis: a sight-threatening disease which can impact all systems.
Uveitis describes a group of conditions characterised by intraocular inflammation. The term uveitis technically describes inflammation of the uvea which comprises the iris, ciliary body and choroid, however now encompasses inflammation of adjacent intraocular structures such as the retina, vitreous and optic nerve. Uveitis is a significant cause of blindness worldwide, but its impact is generally underappreciated due to a lack of awareness and understanding of the condition among the public and most non-ophthalmic healthcare professionals. In this review, we provide an introduction to uveitis for the non-specialist, outlining the clinical presentations that should raise the suspicion of the disease, the signs that should be looked for and a framework in which to understand the condition. We show how a logical approach to classifying uveitis by aetiology and anatomical focus of disease provides the basis for treatment strategies (drug and route of administration) and clinical presentation and prognosis. We also show why understanding uveitis is helpful to clinicians working in almost every speciality due to the wide-ranging associations with systemic disease.


Naphthalimides as anti-cancer agents: synthesis and biological activity.
Naphthalimides are a class of compounds with high antitumor activity upon a variety of murine and human tumor cells. These compounds bind to DNA by intercalation of the chromophore and two of them, mitonafide and amonafide, were used in clinical trials. The therapeutic properties of these lead drugs were improved by designing bisintercalating agents. One of these, elinafide, showed intense in vitro and in vivo activity and is currently being used in clinical trials against solid tumors. In this paper, the history of elinafide is described.


The status of research in ambulatory pediatrics.
To investigate the status of clinical research in ambulatory pediatrics and to characterize those environments that produce the most research activities and receive funding for research, a questionnaire survey was undertaken of all ambulatory pediatrics programs in the United States and Canada (N = 143). Our response rate was 68%. We found that divisions of ambulatory pediatrics that conduct clinical research have more faculty with formal research training, faculty with more time devoted to research endeavors, a designated research coordinator, research funding, and regular research seminars. Divisions of ambulatory pediatrics that have funding for research have more faculty with formal research training, fellows, a designated research coordinator, and regular research seminars. Funding for research is a more influential factor in producing clinical research than the number of faculty members in the division. The most frequently mentioned barrier to doing research was lack of time. Divisions of ambulatory pediatrics must continue to stress formal research training, faculty time set aside for research, and skills in grant writing if they hope to compete for academic recognition in the years ahead.


Estimating the effect of zidovudine on Kaposi's sarcoma from observational data using a rank preserving structural failure-time model.
Researchers commonly express scepticism about using observational data to estimate the effect of a treatment on an outcome the treatment is intended to affect. In this paper, we consider using data from the Multicenter AIDS Cohort Study (MACS) to determine whether zidovudine prevents the development of Kaposi's sarcoma among HIV-positive gay men. Several methodologic issues common to observational data characterized the study: information on potentially important confounders was missing at some study visits; investigators did not always know the time of changes in treatment level, nor the value of confounders at that time, and the censoring process depended strongly on time-varying covariates related to outcome. We describe application to our data of Robins' paradigm for defining, modelling and estimating the effect of a time-varying treatment and show how to modify his approach to deal with the methodologic issues we have mentioned. Further, we demonstrate that relative risk regression is less well equipped to deal with these issues. We compare our results to the findings from randomized trials, and conclude that observational studies may sometimes be useful in evaluating the effect of treatment on an intended outcome.


Occurrence of backward bifurcation and prediction of disease transmission with imperfect lockdown: A case study on COVID-19.
The outbreak of COVID-19 caused by SARS-CoV-2 is spreading rapidly around the world, which is causing a major public health concerns. The outbreaks started in India on March 2, 2020. As of April 30, 2020, 34,864 confirmed cases and 1154 deaths are reported in India and more than 30,90,445 confirmed cases and 2,17,769 deaths are reported worldwide. Mathematical models may help to explore the transmission dynamics, prediction and control of COVID-19 in the absence of an appropriate medication or vaccine. In this study, we consider a mathematical model on COVID-19 transmission with the imperfect lockdown effect. The basic reproduction number, R 0, is calculated using the next generation matrix method. The system has a disease-free equilibrium (DFE) which is locally asymptotically stable whenever R 0 < 1. Moreover, the model exhibits the backward bifurcation phenomenon, where the stable DFE coexists with a stable endemic equilibrium when R 0 < 1. The epidemiological implications of this phenomenon is that the classical epidemiological requirement of making R 0 less than unity is only a necessary, but not sufficient for effectively controlling the spread of COVID-19 outbreak. It is observed that the system undergoes backward bifurcation which is a new observation for COVID-19 disease transmission model. We also noticed that under the perfect lockdown scenario, there is no possibility of having backward bifurcation. Using Lyapunov function theory and LaSalle Invariance Principle, the DFE is shown globally asymptotically stable for perfect lockdown model. We have calibrated our proposed model parameters to fit daily data from India, Mexico, South Africa and Argentina. We have provided a short-term prediction for India, Mexico, South Africa and Argentina of future cases of COVID-19. We calculate the basic reproduction number from the estimated parameters. We further assess the impact of lockdown during the outbreak. Furthermore, we find that effective lockdown is very necessary to reduce the burden of diseases.


Identification of a 5-hydroxytryptamine (5-HT2) receptor on guinea pig small intestinal crypt cells.
Radioligand labeling of [3H]ketanserin was examined in suspensions of dispersed guinea pig small intestinal mucosal cells prepared by modification of the EDTA-chelation method described by M. M. Weiser (J. Biol. Chem. 248: 2536-2541, 1973). Preferential incorporation of [3H]thymidine was used to confirm that suspensions were enriched in crypt cells. At 25 degrees C, binding of [3H]ketanserin to dispersed enterocytes was rapid, maximal by 5 min, saturable (dissociation constant = 1.5 nM), 65 +/- 5% specific, stable, and reversible. The maximal number of binding sites per cell was 92,000 (range 86,000-105,500). Binding was temperature dependent, with maximal binding at 37 degrees C, and was inhibited by 5-hydroxytryptamine (5-HT) (half-maximal inhibition of [3H]ketanserin binding observed in response to 1 microM 5-HT) and ketanserin (half-maximal inhibition of [3H]ketanserin binding observed in response to 1 nM ketanserin) but not by the 5-HT1P antagonist N-acetyl-5-hydroxytryptophyl 5-hydroxytryptophan amide (5-HTP-DP) or the 5-HT3 antagonist 3-tropanyl-indole-3-carboxylate methiodide (ICS-205-930). The second messenger system coupled to the putative mucosal 5-HT2 receptor was examined. 5-HT stimulated a concentration-dependent production of inositol 1,4,5-trisphosphate (IP3) in the dispersed enterocytes. This was maximal at 1 min and was inhibited in a concentration-dependent manner by ketanserin. 5-HTP-DP and ICS-205-930 had no effect on 5-HT-stimulated production of IP3. These data provide evidence for the existence of a mucosal 5-HT2 receptor located on guinea pig small intestinal crypt cells.


Micro-Net: A unified model for segmentation of various objects in microscopy images.
Object segmentation and structure localization are important steps in automated image analysis pipelines for microscopy images. We present a convolution neural network (CNN) based deep learning architecture for segmentation of objects in microscopy images. The proposed network can be used to segment cells, nuclei and glands in fluorescence microscopy and histology images after slight tuning of input parameters. The network trains at multiple resolutions of the input image, connects the intermediate layers for better localization and context and generates the output using multi-resolution deconvolution filters. The extra convolutional layers which bypass the max-pooling operation allow the network to train for variable input intensities and object size and make it robust to noisy data. We compare our results on publicly available data sets and show that the proposed network outperforms recent deep learning algorithms.


Modelling effects of nonbreeders on population growth estimates.
Adult individuals that do not breed in a given year occur in a wide range of natural populations. However, such nonbreeders are often ignored in theoretical and empirical population studies, limiting our knowledge of how nonbreeders affect realized and estimated population dynamics and potentially impeding projection of deterministic and stochastic population growth rates. We present and analyse a general modelling framework for systems where breeders and nonbreeders differ in key demographic rates, incorporating different forms of nonbreeding, different life histories and frequency-dependent effects of nonbreeders on demographic rates of breeders. Comparisons of estimates of deterministic population growth rate, λ, and demographic variance, σd2, from models with and without distinct nonbreeder classes show that models that do not explicitly incorporate nonbreeders give upwardly biased estimates of σd2, particularly when the equilibrium ratio of nonbreeders to breeders, Nnb∗/Nb∗, is high. Estimates of λ from empirical observations of breeders only are substantially inflated when individuals frequently re-enter the breeding population after periods of nonbreeding. Sensitivity analyses of diverse parameterizations of our model framework, with and without negative frequency-dependent effects of nonbreeders on breeder demographic rates, show how changes in demographic rates of breeders vs. nonbreeders differentially affect λ. In particular, λ is most sensitive to nonbreeder parameters in long-lived species, when Nnb∗/Nb∗>0, and when individuals are unlikely to breed at several consecutive time steps. Our results demonstrate that failing to account for nonbreeders in population studies can obscure low population growth rates that should cause management concern. Quantifying the size and demography of the nonbreeding section of populations and modelling appropriate demographic structuring is therefore essential to evaluate nonbreeders' influence on deterministic and stochastic population dynamics.


Using holistic interpretive synthesis to create practice-relevant guidance for person-centred fundamental care delivered by nurses.
Nursing policy and healthcare reform are focusing on two, interconnected areas: person-centred care and fundamental care. Each initiative emphasises a positive nurse-patient relationship. For these initiatives to work, nurses require guidance for how they can best develop and maintain relationships with their patients in practice. Although empirical evidence on the nurse-patient relationship is increasing, findings derived from this research are not readily or easily transferable to the complexities and diversities of nursing practice. This study describes a novel methodological approach, called holistic interpretive synthesis (HIS), for interpreting empirical research findings to create practice-relevant recommendations for nurses. Using HIS, umbrella review findings on the nurse-patient relationship are interpreted through the lens of the Fundamentals of Care Framework. The recommendations for the nurse-patient relationship created through this approach can be used by nurses to establish, maintain and evaluate therapeutic relationships with patients to deliver person-centred fundamental care. Future research should evaluate the validity and impact of these recommendations and test the feasibility of using HIS for other areas of nursing practice and further refine the approach.


Natural horizontal transfer of a naphthalene dioxygenase gene between bacteria native to a coal tar-contaminated field site.
Horizontal transfer of genes responsible for pollutant biodegradation may play a key role in the evolution of bacterial populations and the adaptation of microbial communities to environmental contaminants. However, field evidence for horizontal gene transfer between microorganisms has traditionally been very difficult to obtain. In this study, the sequences of the 16S rRNA and naphthalene dioxygenase iron-sulfur protein (nahAc) genes of nine naphthalene-degrading bacteria isolated from a coal tar waste-contaminated site, as well as a naphthalene-degrading bacterium from a contaminated site in Washington state and two archetypal naphthalene-degrading strains, were compared. Seven strains from the study site had a single nahAc allele, whereas the 16S rRNA gene sequences of the strains differed by as much as 7.9%. No nahAc alleles from the site were identical to those of the archetypal strains, although the predominant allele was closely related to that of Pseudomonas putida NCIB 9816-4, isolated in the British Isles. However, one site-derived nahAc allele was identical to that of the Washington state strain. Lack of phylogenetic congruence of the nahAc and 16S rRNA genes indicates that relatively recent in situ horizontal transfer of the nahAc gene has occurred, possibly as a direct or indirect consequence of pollutant contamination. Alkaline lysis plasmid preparations and pulsed-field gel electrophoresis have revealed the presence of plasmids ranging in size from 70 to 88 kb in all site isolates. Southern hybridizations with a 407-bp nahAc probe have suggested that the nahAc gene is plasmid borne in all the site isolates but one, a strain isolated from subsurface sediment 400 m upstream from the source of the other site isolates. In this strain and in the naphthalene-degrading strain from Washington state, nahAc appears to be chromosomally located. In addition, one site isolate may carry nahAc on both chromosome and plasmid. Within the group of bacteria with identical nahAc sequences the Southern hybridizations showed that the gene was distributed between plasmids of different sizes and a chromosome. This suggests that plasmid modification after transfer may have been effected by transposons. Horizontal transfer of catabolic genes may play a significant role in the acclimation of microbial communities to pollutants.


The human B cell response to IL-13 is dependent on cellular phenotype as well as mode of activation.
Normal mature quiescent human B lymphocytes, isolated as a function of buoyant density, require activation for up-regulation of IL-13R constituents. Cell activation through a combination of surface Ig and CD40 receptor ligation leads to the most substantial message production for IL-13Ralpha1. Functional consequences of this receptor variation, in initially quiescent cells, includes demonstrable effects on cellular proliferation in response to ligand exposure. Variations in the method of surface activation, with particular emphasis on the CD40 receptor, reveals that immobilized CD40 ligand may be sufficient, in and of itself, to up-regulate IL-13Ralpha1, which may bear significance for B-lymphocyte bystander proliferation. Regulation of the IL-13Ralpha1 protein and message also differs as a function of cellular phenotype. Although values are greater in memory than naive B cells, as they are initially isolated from extirpated tonsils, variations in the magnitude of message and protein, as a function of surface stimulation, are more substantial in the naive subset. The magnitude of variation in message production in naive cells is associated with a more vigorous proliferative response to IL-13 than seen in memory lymphocytes. The cellular response to IL-13, as a function of activation and phenotype, is the converse of that demonstrated for IL-2. Evaluation of proliferation, receptor message, ligand binding protein production, and the response to putatively synergistic cytokines reveals that IL-2 is the predominant lymphokine utilized by memory cells. This is in contradistinction to IL-13, which along with IL-4, are the predominant moieties for naive lymphocytes.


Impact of wearing a service vest on three-dimensional truncal motion in dogs.
To develop a 3-D kinematic model to measure truncal motion in dogs and assess changes in truncal motion in dogs when wearing each of 2 service vests. 5 adult mixed-breed dogs. 27 reflective markers were placed on the pelvis, trunk, and scapula of each dog. Six infrared cameras were placed around a treadmill to track the location of the markers within a calibrated space. Dogs were recorded during walking and trotting on the treadmill. Local and global coordinate systems were established, and a segmental rigid-body model of the trunk was created. Dogs were then recorded while wearing a custom vest and an adjustable vest during walking and trotting on the treadmill. Range of motion of the trunk when dogs were and were not wearing vests was compared by repeated-measures ANOVA. An anatomic coordinate system was established by use of markers located at T1, T13, and the xiphoid process. Range of motion of the trunk during a gait cycle did not differ significantly regardless of the day of the test for both walking and trotting gaits. Trunk motion of dogs when walking and trotting was significantly reduced when dogs were wearing a vest, compared with trunk motion when not wearing a vest. A 3-D kinematic model for measuring truncal rotation was developed. Results indicated measurable differences in the gait of dogs when wearing each of the 2 service vests, compared with the gait when not wearing a vest.


On the C-statistics for evaluating overall adequacy of risk prediction procedures with censored survival data.
For modern evidence-based medicine, a well thought-out risk scoring system for predicting the occurrence of a clinical event plays an important role in selecting prevention and treatment strategies. Such an index system is often established based on the subject's 'baseline' genetic or clinical markers via a working parametric or semi-parametric model. To evaluate the adequacy of such a system, C-statistics are routinely used in the medical literature to quantify the capacity of the estimated risk score in discriminating among subjects with different event times. The C-statistic provides a global assessment of a fitted survival model for the continuous event time rather than focussing on the prediction of bit-year survival for a fixed time. When the event time is possibly censored, however, the population parameters corresponding to the commonly used C-statistics may depend on the study-specific censoring distribution. In this article, we present a simple C-statistic without this shortcoming. The new procedure consistently estimates a conventional concordance measure which is free of censoring. We provide a large sample approximation to the distribution of this estimator for making inferences about the concordance measure. Results from numerical studies suggest that the new procedure performs well in finite sample.


Trends and weekly and seasonal cycles in the rate of errors in the clinical management of hospitalized patients.
Studies on the rate of adverse events in hospitalized patients seldom examine temporal patterns. This study presents evidence of both weekly and annual cycles. The study is based on a large and diverse data set, with nearly 5 yrs of data from a voluntary staff-incident reporting system of a large public health care provider in rural southeastern Australia. The data of 63 health care facilities were included, ranging from large non-metropolitan hospitals to small community and aged health care facilities. Poisson regression incorporating an observation-driven autoregressive effect using the GLARMA framework was used to explain daily error counts with respect to long-term trend and weekly and annual effects, with procedural volume as an offset. The annual pattern was modeled using a first-order sinusoidal effect. The rate of errors reported demonstrated an increasing annual trend of 13.4% (95% confidence interval [CI] 10.6% to 16.3%); however, this trend was only significant for errors of minor or no harm to the patient. A strong "weekend effect" was observed. The incident rate ratio for the weekend versus weekdays was 2.74 (95% CI 2.55 to 2.93). The weekly pattern was consistent for incidents of all levels of severity, but it was more pronounced for less severe incidents. There was an annual cycle in the rate of incidents, the number of incidents peaking in October, on the 282 nd day of the year (spring in Australia), with an incident rate ratio 1.09 (95% CI 1.05 to 1.14) compared to the annual mean. There was no so-called "killing season" or "July effect," as the peak in incident rate was not related to the commencement of work by new medical school graduates. The major finding of this study is the rate of adverse events is greater on weekends and during spring. The annual pattern appears to be unrelated to the commencement of new graduates and potentially results from seasonal variation in the case mix of patients or the health of the medical workforce that alters health care performance. These mechanisms will need to be elucidated with further research.


Is there a role for parenteral nutrition or hydration at the end of life?
This review aims to update healthcare providers on the role of parenteral nutrition/hydration in terminal patients and highlight recent research. Cachexia is felt to be refractory to treatment at the last stages of life. The majority of terminally ill patients will derive no benefit from parenteral nutrition with some exceptions including patients with a good functional status and a nonfunctional gastrointestinal tract or a slow growing tumor.Dehydration can potentially be reversible in patients at the end of life. However, recent research examining parenteral hydration reveals no clear clinical benefits on symptom burden or survival for terminally ill cancer patients with the exception of possibly reversing the complication of delirium. Hydration and nutrition are essential for the maintenance of life. In patients at the end of life, artificial hydration and nutrition pose clinical, ethical, and logistical dilemmas. No strong evidence exists supporting the use of parenteral hydration/nutrition for the majority of terminally ill patients; however, a subset of patients may derive some benefit. Uncertainty about determining prognosis, psychosocial factors, and perceptions of perceived benefits results in artificial nutrition/hydration being initiated in terminally ill patients. Discontinuation of artificial support can result in distress for patients, family members, and healthcare providers.


High-Resolution 4D Preclinical Single-Photon Emission Computed Tomography/X-ray Computed Tomography Imaging of Technetium Transport within a Heterogeneous Porous Media.
A dynamic 99mTc tracer experiment was performed to investigate the capabilities of combined preclinical single photon emission computed tomography (SPECT) and X-ray computed tomography (CT) for investigating transport in a heterogeneous porous medium. The experiment was conducted by continuously injecting a 99mTc solution into a column packed with eight layers (i.e., soil, silica gel, and 0.2-4 mm glass beads). Within the imaging results it was possible to correlate observed features with objects as small as 2 mm for the SPECT and 0.2 mm for the CT. Time-lapse SPECT imaging results illustrated both local and global nonuniform transport phenomena and the high-resolution CT data were found to be useful for interpreting the cause of variations in the 99mTc concentration associated with structural features within the materials, such as macropores. The results of this study demonstrate SPECT/CT as a novel tool for 4D (i.e., transient three-dimensional) noninvasive imaging of fate and transport processes in porous media. Despite its small scale, an experiment with such high resolution data allows us to better understand the pore scale transport which can then be used to inform larger scale studies.


Nonoperative management of the ruptured spleen: a revalidation of criteria.
Our goal was to revalidate this institution's original criteria for safe nonoperative management of splenic injury. This was a prospective series between October 1991 and December 1995 entering all patients with splenic injury to a modified algorithm. Patients were taken to the operating room if hemodynamically unstable (systolic blood pressure less than 90 mm Hg; pulse greater than 110 beats per minute) after 2 liters of fluid resuscitation, positive abdominal examination findings, American Association for the Surgery of Trauma Organ Injury Scale Grade IV or V injuries by computed tomographic scan (unless younger than 15 years old), or associated severe head injuries (unless younger than 15 years old), or age greater than 55. The remainder of the patients were closely observed. One hundred seventy-three patients were entered-six were excluded by death before operating room salvage, and one was excluded because of operation for a ruptured thoracic aorta. Therefore 166 patients were reviewed. Seventy splenectomies and 18 splenorrhaphies were performed, and 78 patients were treated nonoperatively (58% splenic salvage). Two failures occurred in the nonoperative group: a 16-year-old with a grade IV hilar injury was operated on on the eighth day after injury because of a continually falling hematocrit, and a 25-year-old with unresolved tachycardia was operated on at 6 hours (97% success rate). The patients in the operative group had a greater severity of injury as determined by mean Injury Severity Score of 32, 18 deaths, a mean transfusion requirement of 14 units of blood compared with mean injury severity score of 21, two deaths from brain injury, and no transfusions given in 58 of the 78 nonoperative cases. Prospectively applied, these guidelines allow the safe nonoperative management of patients with blunt splenic injury.


Assessing planning and set-shifting abilities in autism: are experimenter-administered and computerised versions of tasks equivalent?
Across studies, analysis of performance on classic measures of executive functioning (EF) among individuals with autism spectrum disorder (ASD) suggests that people with this disorder may be impaired only when tasks are experimenter-administered, but not when the same tasks are computer-administered. This would imply that the underlying cause of apparent executive dysfunction in ASD is a diminished ability to engage with another person/comprehend what another person expects, rather than a diminution of the control processes that typically underpin EF task performance. However, this suggestion is limited because, to our knowledge, no study has directly compared the equivalence of computer-administered and standard experimenter-administered versions of EF tasks that have been presented in counterbalanced order among a common sample of individuals with ASD. In the current study, 21 children with ASD and 22 age- and intelligence quotient (IQ)-matched comparison participants completed, in counterbalanced order, computerised and manual versions of both a planning task and a cognitive flexibility/set-shifting task. Contrary to expectation, results indicated that participants with ASD were equally impaired in terms of the key dependent variable on standard and computerised versions of both tasks. Practically, these results suggest that computer-administered and experimenter-administered versions of planning and set-shifting tasks are equivalent among individuals with ASD and can be used interchangeably in studies of EF among this population. Theoretically, these results challenge the notion that poor performance on EF tasks among school-aged children with ASD is only the result of a limited ability to engage with a human experimenter/comprehend socially presented rules.


[Immunotherapy of tumors expressing IGF-I].
Recently we demonstrated that rat glioma cells when transfected with a vector encoding antisense IGF-I c-DNA lost tumorigenicity and induced a tumor specific immune response involving CD8+ lymphocytes. Here we showed, using immunostaining flow cytometry analysis, that the transfected cell lines, rat C-6 glioma and rat LF hepatoma, expressed an increase level of MHC-class I, and even the amount of MHC-I was found to be higher in the transfected hepatoma, than in the transfected glioma cells. This increased expression of MHC-I could contribute to the final immune recognition of tumour immunogenicity.


Post-traumatic stress disorder symptoms and PrEP intentions among Black American young adults at high-risk for HIV.
Black Americans bear the greatest burden of HIV, accounting for 43% of new diagnoses. Yet Black Americans also evidence the lowest utilization rates of Pre-Exposure Prophylaxis (PrEP), a highly effective biomedical strategy for preventing HIV infection. Predictors of PrEP acceptance vary; however, little is known about psychological distress, such as post-traumatic stress disorder (PTSD) symptoms, as a predictor. In this cross-sectional study, n = 195 Black Americans, evidencing behaviors found in the research literature to heighten risk for contracting HIV (e.g. sex work, injection drug use) ages 18-29, 55% cisgender women, 39.5% cisgender men, 3% transgender/non-binary, completed audio-computer-assisted self-interviews. Bivariate analyses indicated significant positive associations between PTSD symptoms and PrEP acceptance and self-confidence. In multinomial logistic regression analyses, after controlling for Perceived HIV Risk, participants had a higher likelihood of responding they 'probably would' take PrEP (as opposed to 'definitely would not' take PrEP) if they reported higher levels of PTSD symptoms. Post-hoc analyses revealed a curvilinear relationship between PTSD symptoms and PrEP acceptance with those reporting the highest level of PTSD in the sample having slightly lower PrEP acceptance than those reporting moderately high levels of PTSD. Findings are discussed in the context of the negative impacts of high levels of PTSD and potential positive adaptations subsequent to moderate levels of PTSD that could be relevant to advances in HIV prevention efforts.


Oxidative stability of docosahexaenoic acid-containing oils in the form of phospholipids, triacylglycerols, and ethyl esters.
The peroxidative stability of docosahexaenoic acid (DHA)-containing oils (DHA at 10.7 mol% of the total fatty acids), in the form of phospholipids (PL), triacylglycerols (TG), and ethyl esters (EE) with the same constituent fatty acids, was investigated in the dark at 25 degrees C in a bulk phase, and compared with that of control palm oil (supplemented with 20% soybean oil). The oxygen absorption of the DHA-containing oil was significantly lower in the form of PL than in the form of TG and EE during a 10-week oxidation, and the oxygen absorption of PL was almost equivalent to that of the control oil. A gas chromatographic analysis showed that 90% of initial DHA was retained in the form of PL after the 10-week oxidation, while TG and EE respectively more rapidly decayed with the loss of 97% and 64% of DHA. Tocopherol in the form of TG and EE had also completely decayed after the oxidation, while 37% of the initial tocopherol remained in the form of PL. The peroxide and carbonyl values of TG and EE showed large increases after the oxidation, but no such increase was observed for PL. These results show that DHA-containing oil in the form of PL was more resistant to the oxidative degradation of DHA than that in the form of TG and EE in a bulk phase.


Phenylthioacetate: a useful substrate for the histochemical and colorimetric detection of cholinesterase.
Cholinesterase from frozen sections of honey bee (Apis mellifera, L.) brain hydrolyzes phenylthioacetate and acetylthiocholine to give virtually identical patterns of enzyme distribution with and without the use of paraoxon. In addition, phenylthioacetate is an economical substrate for in vitro and in vivo studies of cholinesterase. Phenylthioacetate offers the advantages of being easily synthesized and lipoid soluble, and appears to penetrate membranes easily.


Influence of microwave power on the preparation of NiO nanoflakes for enhanced magnetic and supercapacitor applications.
Nanoflake-structured NiO were synthesized by a microwave assisted method without the use of additives. The cubic phase of NiO nanoparticles with increasing crystalline nature for higher microwave power is ascertained by X-ray diffraction studies. Previous reports revealed that hexagonally structured β-Ni(OH)2 was completely transferred into the cubic phase of NiO around 350 °C, confirmed by using thermal analysis (TG/DTA). In our present work, the size and morphology of nanoparticles are ascertained from transmission electron microscopy (TEM) analysis. Flake-like morphology with uniform size, shape and less agglomerated structure formation is obtained for 900 and 600 W of microwave power used for the synthesis of NiO samples. The effect of microwave power used for the synthesis of NiO nanoflakes was analyzed by studying the magnetic and electrochemical behavior of NiO nanoflakes. Room temperature magnetic measurements revealed the small ferromagnetic nature of NiO nanoparticles. It was observed that the samples synthesized at higher microwave power exhibited divergence behavior below 300 K in FC and ZFC measurements, which results superparamagnetic behavior. An enhanced supercapacitor performance with higher specific capacitance values was determined for NiO nanoflake samples synthesized at (25)600 W and 900 W of microwave power.


Hantavirus illness in humans: review and update.
Hantavirus is a rodent-borne pathogen that has been well characterized since the 1950s in Asia and Northern Europe. The classic hantaviral illnesses hemorrhagic fever with renal syndrome and nephropathia epidemica are indistinguishable from the hantaviral pulmonary syndrome (HPS) in early symptoms and laboratory data, but HPS goes on to produce the adult respiratory distress syndrome (ARDS) and usually spares the kidney. HPS is the first hantaviral disease reported in humans in the Western Hemisphere and has a tenfold higher mortality than its Eurasian counterparts. The predominant serogroup causing the Four Corners epidemic of the summer of 1993 is the Sin Nombre virus, previously called the Muerto Canyon virus. It is a unique virus but shares some genetic similarity to the nonpathogenic Prospect Hill serogroup, which has been found in North American rodents for decades. Several new serotypes that also cause HPS are now appearing. This paper will review the three hantaviral diseases with emphasis on HPS, its diagnosis, treatment, and prevention.


Targeting the proviral host kinase, FAK, limits influenza a virus pathogenesis and NFkB-regulated pro-inflammatory responses.
Influenza A virus (IAV) infections result in ∼500,000 global deaths annually. Host kinases link multiple signaling pathways at various stages of infection and are attractive therapeutic target. Focal adhesion kinase (FAK), a non-receptor tyrosine kinase, regulates several cellular processes including NFkB and antiviral responses. We investigated how FAK kinase activity regulates IAV pathogenesis. Using a severe infection model, we infected IAV-susceptible DBA/2 J mice with a lethal dose of H1N1 IAV. We observed reduced viral load and pro-inflammatory cytokines, delayed mortality, and increased survival in FAK inhibitor (Y15) treated mice. In vitro IAV-induced NFkB-promoter activity was reduced by Y15 or a dominant negative kinase-dead FAK mutant (FAK-KD) independently of the viral immune modulator, NS1. Finally, we observed reduced IAV-induced nuclear localization of NFkB in FAK-KD expressing cells. Our data suggest a novel mechanism where IAV hijacks FAK to promote viral replication and limit its ability to contribute to innate immune responses.


Conserved Pro-Glu (PE) and Pro-Pro-Glu (PPE) protein domains target LipY lipases of pathogenic mycobacteria to the cell surface via the ESX-5 pathway.
The type VII secretion system ESX-5 is a major pathway for export of PE and PPE proteins in pathogenic mycobacteria. These mycobacteria-specific protein families are characterized by conserved N-terminal domains of 100 and 180 amino acids, which contain the proline-glutamic acid (PE) and proline-proline-glutamic acid (PPE) motifs after which they are named. Here we investigated secretion of the triacylglycerol lipase LipY, which in fast-growing mycobacteria contains a signal sequence, but in slow-growing species appears to have replaced the signal peptide with a PE or PPE domain. Selected LipY homologues were expressed in wild-type Mycobacterium marinum and its corresponding ESX-5 mutant, and localization of the proteins was investigated by immunoblotting and electron microscopy. Our study shows that Mycobacterium tuberculosis PE-LipY (LipY(tub)) and M. marinum PPE-LipY (LipY(mar)) are both secreted to the bacterial surface in an ESX-5-dependent fashion. After transport, the PE/PPE domains are removed by proteolytic cleavage. In contrast, Mycobacterium gilvum LipY, which has a signal sequence, is not transported to the cell surface. Furthermore, we show that LipY(tub) and LipY(mar) require their respective PE and PPE domains for ESX-5-dependent secretion. The role of the PE domain in ESX-5 secretion was confirmed in a whole cell lipase assay, in which wild-type bacteria expressing full-length LipY(tub), but not LipY(tub) lacking its PE domain, were shown to hydrolyze extracellular lipids. In conclusion, both PE and PPE domains contain a signal required for secretion of LipY by the ESX-5 system, and these domains are proteolytically removed upon translocation.


Effect of Theiler's murine encephalomyelitis virus and cytokines on cultured oligodendrocytes and astrocytes.
The pathogenesis of Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease is still controversial. Our hypothesis is that primary infection of oligodendrocytes (OLGs) is not a crucial event in the pathogenesis of demyelination in this model. In fact, it has been proposed that myelin may be destroyed, as an innocent bystander, following an antiviral delayed-type hypersensitivity (DTH) response. This hypothesis would not need widespread oligodendroglial infection, because virus present in other cells would be sufficient to trigger a DTH response. The present study demonstrates that cultured OLGs and astrocytes from susceptible strains of mice (SJL and DBA) and immortalized OLGs can be infected with TMEV in vitro. Infection of OLGs, however, is at very low levels and does not result in overt cytolytic effect. In contrast, infection of immortalized OLGs is very efficient and results in clear cytolysis. Because an important characteristic of DTH responses is the liberation of potentially injurious cytokines into adjacent tissues, we also examined the effects of mouse recombinant tumor necrosis factor-alpha (TNF-alpha), interleukin-1 alpha (IL-1 alpha), and interferon-gamma (IFN-gamma) on cultured OLGs and immortalized OLGs. We found that TNF-alpha caused immortalized OLG cytotoxicity in a time- and dose-dependent manner. In contrast, no cytotoxicity was observed on primary OLGs with any of the above cytokines. To determine whether functional effects could be demonstrated on primary OLGs by either virus or cytokines, we measured mRNA expression of different myelin proteins in primary and immortalized OLGs exposed to virus or TNF-alpha. Neither the BeAn strain or the GDVII strain of TMEV interfered with myelin protein mRNA expression in primary OLGs, whereas GDVII virus dramatically reduced myelin OLG glycoprotein (MOG) mRNA in immortalized OLGs. Interestingly, although even high concentrations of TNF-alpha (10,000 U/ml) did not produce primary OLG cytotoxicity, they resulted in a significant reduction in mRNA for both myelin basic protein (MBP) and MOG in these cells. TNF-alpha (at 500 U/ml) also specifically reduced MOG mRNA in immortalized OLGs. Because immortalized OLGs are considered to be arrested at an early stage of maturation, our results suggest that immature OLGs are susceptible to both virus- and cytokine-dependent cytotoxicity, whereas mature OLGs are resistant to cytolysis by either TMEV or cytokines. TNF-alpha, however, is capable of reducing mRNA expression of myelin proteins in primary OLGs; therefore, it may participate in the induction of demyelination, as suggested by the DTH-mediated hypothesis.


Cytokine-induced proliferation and immunoglobulin production of human B lymphocytes triggered through their CD40 antigen.
Human resting B lymphocytes enter a state of sustained proliferation when incubated with both mouse fibroblastic L cells stably expressing Fc gamma RII/CDw32 and anti-CD40 antibodies. We have explored the effects of 11 recombinant human cytokines (CKs) on induced cell proliferation and immunoglobulin (Ig) production. Interleukin 4 (IL-4) was the only CK able to enhance anti-CD40-induced B cell multiplication as measured by enumeration of viable cells, and interferon gamma (IFN-gamma) further stimulated this induced proliferation. IL-4 enhanced the production of IgM and IgG by B cells and induced them to produce IgE. Combinations of IL-4 and IL-2 resulted in the production of large amounts of IgM and IgA. Interestingly, IFN-gamma did not inhibit the production of IgE by cells stimulated with anti-CD40 and IL-4. None of the tested CK combinations resulted in the production of large quantities of IgG. Therefore, this new culture system represents a unique model to study isotype regulation in highly purified human B lymphocytes, in addition to allowing the generation of long-term factor-dependent human B cell lines.


Elevated CO2 enrichment induces a differential biomass response in a mixed species temperate forest plantation.
In a free-air carbon dioxide (CO(2)) enrichment study (BangorFACE), Alnus glutinosa, Betula pendula and Fagus sylvatica were planted in areas of one-, two- and three-species mixtures (n = 4). The trees were exposed to ambient or elevated CO(2) (580 μmol mol(-1)) for 4 yr, and aboveground growth characteristics were measured. In monoculture, the mean effect of CO(2) enrichment on aboveground woody biomass was + 29, + 22 and + 16% for A. glutinosa, F. sylvatica and B. pendula, respectively. When the same species were grown in polyculture, the response to CO(2) switched to + 10, + 7 and 0% for A. glutinosa, B. pendula and F. sylvatica, respectively. In ambient atmosphere, our species grown in polyculture increased aboveground woody biomass from 12.9 ± 1.4 to 18.9 ± 1.0 kg m(-2), whereas, in an elevated CO(2) atmosphere, aboveground woody biomass increased from 15.2 ± 0.6 to 20.2 ± 0.6 kg m(-2). The overyielding effect of polyculture was smaller (+ 7%) in elevated CO(2) than in an ambient atmosphere (+ 18%). Our results show that the aboveground response to elevated CO(2) is affected significantly by intra- and interspecific competition, and that the elevated CO(2) response may be reduced in forest communities comprising tree species with contrasting functional traits.


Comparison of the microhemagglutination assay for antibodies to Treponema pallidum and the automated fluorescent treponemal antibody-absorption test.
The qualitative microhemagglutination assay for detection of antibodies to Treponema pallidum and the automated fluorescent treponemal antibody-absorption tests were directly compared as confirmatory tests for syphilis. They were compared on 2,790 specimens from patients of New York City Social Hygiene Clinics. Overall agreement between the two assay methods was 89.6%. Only 1.5% of the total specimens tested were reactive by the automated fluorescent treponemal antibody-absorption test, and nonreactive by the microhemagglutination assay. The majority of specimens which disagreed were reactive only by the microhemagglutination assay. These comprised 8.9% of the total specimens tested. When such specimens were further tested by the manual fluorescent treponemal antibody-absorption test, 63% were also reactive in that test, and 16.7% gave borderline reactions. Fifty-four per cent of those reactive specimens were from patients suspected of being in a latent stage of syphilis, 10% from patients suspected of being in other stages, and 36% from patients not suspected of having syphilis. Because of the increased sensitivity of the microhemagglutination assay, its use is recommended instead of the automated fluorescent test. However, the manual fluorescent test should be performed when the result of the microhemagglutination assay is completely inconsistent with the clinician's impression.


[The green tea, a good choice for cardiovascular disease prevention?].
Tea (Camellia sinensis) has been used for centuries as a medical drink. Around two-thirds of the world's population drink tea. It is originated from southern China and entensive cultivated in Asia and in central African countries. Tea can be grouped into three main types, black, oolong, and green tea. Green tea is not fermented and is a major beverage consumed in Asian countries. Green tea is produced from freshly harvest leaves of the tea plant and they contain water, proteins, carbohydrates, minerals, vitamins and polyphenols of the flavonoid type. The major flavonoids in green tea are catechins which constitute about one third of its total dry weight. The major catechin present is epigallocatechin gallate (>50%). New data have increased the interest in green tea or its catechins and its role in treatment of cardiovascular disease (CHD) risk factors. The aim of the present paper is to review some studies that have found a relationship between green tea and CHD risk factors. From some of them it can be summarized that of green tea and its catechins consumptions (i) decrease body weight by interfering within the sympathoadrenal system and fatty acid synthesis, (ii) decrease cholesterol absorption and plasma levels, (iii) have strong free radical-scavenging activity inhibiting LDL oxidation, (iv) reduce the adhesion molecule expression, (v) have antitrombotic activities by inhibiting platelet aggregation and (vi) decrease systolic and diastolic blood pressures. The positive effects found suggest that a daily intake of 7 cups of green tea (3.5 g catechins) is a good choose for CHD prevention; however, it is still necessary more studies to check the action of the green tea and its catechins in humans in order to recommended its use in the general population or only in target subjects.


Upconversion nanocomposites for photo-based cancer theranostics.
Lanthanide ion doped upconversion nanoparticles (UCNPs) are known to be able to convert long-wavelength excitation light (usually 980 nm) into high-energy ultraviolet (UV) or visible emissions, and they have attracted significant attention because of their distinct photochemical properties including sharp emission bands, low autofluorescence, high tissue penetration depth, inertness to ambient interference and minimal photodamage to tissues. Until now, UCNPs have shown great potential in various realms including bioimaging, biosensing and biomedical applications. Especially in recent years, UCNP based nanocomposites have been found to be promising tools for multi-modal imaging and low-invasive photo-based therapy of tumors. In this review, we summarize the recent achievement and progress of UCNP based multifunctional nanoplatforms for bioimaging and cancer phototheranostics, including photodynamic therapy (PDT) and photothermal therapy (PTT). Furthermore, some emerging trends, future directions as well as challenges in this rapidly growing field are discussed.


Dithiocarbamate pesticides affect glutamate transport in brain synaptic vesicles.
Dithiocarbamate compounds are widely used agricultural fungicides that display low acute toxicity in mammals and that may become neurotoxic after prolonged exposure. Mancozeb, among other dithiocarbamates tested, proved to be the most potent (Ki= 0.27 microM) at noncompetitively inhibiting the in vitro ATP-dependent uptake of [3H]glutamate in rat cortical vesicles. Furthermore, mancozeb partially (20%) inhibited the ATP-dependent uptake of [14C]methylamine, used as an index for the vesicular transmembrane proton gradient (DeltapH), and evoked its efflux from organelles previously incubated with the 3H-labeled marker. Meanwhile, the vesicular uptake of 36chloride- anions whose concentrations regulate the transmembrane potential gradient (DeltapsiSV) was not impaired. The dithiocarbamate effects on the vesicular transport of [3H]glutamate thus appeared to involve mainly the DeltapH gradient rather than the potential gradient. Dithiocarbamate metabolites, the potent neurotoxin carbon disulfide included, did not affect the uptake process, thus implying the relevance for inhibition of the persistence, if any, of parent compounds in the brain. The present novel and potent in vitro interferences of selected dithiocarbamate pesticides with the vesicular transport of glutamate, if representative of in vivo alterations, may play some role in the probably complex origin of dithiocarbamate neurotoxicity.


The effect of subchronic fluoxetine treatment on learning and memory in adolescent rats.
Selective serotonin re-uptake inhibitors are increasingly used for the treatment of adolescents with behavioural disorders. However, the effect of this class of drugs during this sensitive period of brain development has not been extensively investigated. In this study we examine the effect of subchronic treatment with the selective serotonin re-uptake inhibitor, fluoxetine (10 mg/kg/day, i.p.) throughout adolescence (postnatal day 28-60) on learning and memory in the rat. Learning and memory were assessed at two time points: during adolescence, while the animals were being treated with fluoxetine and in young adulthood, 40 days after the termination of fluoxetine treatment. Fluoxetine treated rats were compared to a saline injected control group with respect to spatial navigation in the water maze, object recognition and object-in-place recognition memory. Additionally open field behaviour was examined. In adolescent rats fluoxetine treatment impaired water-maze probe trial performance and object recognition at intertrial intervals of 15 and 60 min, while leaving object-in-place recognition memory unaffected. In the open field the fluoxetine treated animals displayed reduced exploratory activity and higher levels of anxiety. Training the animals to a new platform position in young adulthood showed that the rats that had been treated with fluoxetine during adolescence were significantly slower to acquire this new spatial information. Adolescent fluoxetine treatment had no effect on cell proliferation in dorsal dentate gyrus and subgranular zone in young adulthood. This calls for further studies examining the long-term effects of this class of antidepressants on adolescent brain development and behaviour.


Brain Disposition of cis-para-Methyl-4-Methylaminorex (cis-4,4'-DMAR) and Its Potential Metabolites after Acute and Chronic Treatment in Rats: Correlation with Central Behavioral Effects.
para-Methyl-4-methylaminorex (4,4'-DMAR) is a phenethylamine derivative with psychostimulant activity whose abuse has been associated with several deaths and a wide range of adverse effects. We recently validated a high-performance liquid chromatography-tandem mass spectrometry method to measure the compound's concentrations in plasma, and we applied it to describe the pharmacokinetic properties of 4,4'-DMAR after a single dose in rats. In this study, we investigated the brain disposition and metabolism of cis-4,4'-DMAR after intraperitoneal injection as well as its central behavioral effects. Locomotor activity increased after a single injection of 10 mg/kg, peaking at 2 hours and disappearing at 5 hours; in these conditions, brain absorption was very rapid, (tmax = 30-60 minutes) and large (brain-to-plasma ratio = 24); the half-life was approximately 50 minutes. After 14 daily doses, the compound's effect on locomotor activity was greater (approximately 20% compared with the effect after the first dose), but not for pharmacokinetic reasons. Using high-resolution mass spectrometry, we also identified four metabolites of cis-4,4'-DMAR in the plasma and brain of treated rats. Semiquantitative analysis indicated low brain permeability and very low brain concentrations, suggesting that these metabolites do not contribute to central behavioral effects; however, the metabolite originating from oxidation of the para-methyl group (M2) persisted in the plasma longer and at higher concentrations than the parent molecule and could be used to evaluate drug intake in human consumers. Finally, we describe the rewarding effect of cis-4,4'-DMAR in the conditioning place preference test, suggesting a high risk of addiction in humans.


The effect of varied oxygen supply and of food intake on water movement in surviving liver tissue.
Water movement in liver slices has been measured in the presence of varied oxygen supply and during the progress of gastrointestinal digestion. Maximum water intake occurs both with anoxia and with exposure to oxygen when animals have received no food during 20 to 24 hours. It diminishes almost immediately after the ingestion of food and is least after 8 to 10 hours when digestion is nearly complete. These changes coincide with the passage of amino acids from the gastrointestinal tract to the liver by way of the blood. Movement of water into the liver cells is favorable to the entrance of dissolved substances and when it is greatest with approaching anoxia the movement promotes the diffusion of oxygen into the cells.


Key Components of Human Myofibre Denervation and Neuromuscular Junction Stability are Modulated by Age and Exercise.
The decline in muscle mass and function with age is partly caused by a loss of muscle fibres through denervation. The purpose of this study was to investigate the potential of exercise to influence molecular targets involved in neuromuscular junction (NMJ) stability in healthy elderly individuals. Participants from two studies (one group of 12 young and 12 elderly females and another group of 25 elderly males) performed a unilateral bout of resistance exercise. Muscle biopsies were collected at 4.5 h and up to 7 days post exercise for tissue analysis and cell culture. Molecular targets related to denervation and NMJ stability were analysed by immunohistochemistry and real-time reverse transcription polymerase chain reaction. In addition to a greater presence of denervated fibres, the muscle samples and cultured myotubes from the elderly individuals displayed altered gene expression levels of acetylcholine receptor (AChR) subunits. A single bout of exercise induced general changes in AChR subunit gene expression within the biopsy sampling timeframe, suggesting a sustained plasticity of the NMJ in elderly individuals. These data support the role of exercise in maintaining NMJ stability, even in elderly inactive individuals. Furthermore, the cell culture findings suggest that the transcriptional capacity of satellite cells for AChR subunit genes is negatively affected by ageing.