A subset of functional adaptation mutations alter propensity for α-helical conformation in the intrinsically disordered glucocorticoid receptor tau1core activation domain.
Adaptive mutations that alter protein functionality are enriched within intrinsically disordered protein regions (IDRs), thus conformational flexibility correlates with evolvability. Pre-structured motifs (PreSMos) with transient propensity for secondary structure conformation are believed to be important for IDR function. The glucocorticoid receptor tau1core transcriptional activation domain (GR tau1core) domain contains three α-helical PreSMos in physiological buffer conditions. Sixty change-of-function mutants affecting the intrinsically disordered 58-residue GR tau1core were studied using disorder prediction and molecular dynamics simulations. Change-of-function mutations were partitioned into seven clusters based on their effect on IDR predictions and gene activation activity. Some mutations selected from clusters characterized by mutations altering the IDR prediction score, altered the apparent stability of the α-helical form of one of the PreSMos in molecular dynamics simulations, suggesting PreSMo stabilization or destabilization as strategies for functional adaptation. Indeed all tested gain-of-function mutations affecting this PreSMo were associated with increased stability of the α-helical PreSMo conformation, suggesting that PreSMo stabilization may be the main mechanism by which adaptive mutations can increase the activity of this IDR type. Some mutations did not appear to affect PreSMo stability. Changes in PreSMo stability account for the effects of a subset of change-of-function mutants affecting the GR tau1core IDR. Long IDRs occur in about 50% of human proteins. They are poorly characterized despite much recent attention. Our results suggest the importance of a subtle balance between PreSMo stability and IDR activity, which may provide a novel target for future pharmaceutical intervention.


An examination of traffic-related traumatic injuries among children at a Level-1 pediatric trauma center, 2005-2014.
Traffic-related injuries are the leading fatal injury among children in the United States, but no published study compares the different types of traffic-related pediatric injuries to date. Thus, this study was aimed at examining the10-year trend of traffic-related injury among children at a pediatric hospital and to assess if there were differences in injury mechanism. All data were drawn from a Level-1 pediatric trauma center in North Texas in 2005-2014. Demographic characteristics, length of hospitalization, and patient type were included. Severity of injury outcome was assessed by injury severity score and fatality. The traffic-related injury mechanism included motor vehicle collision (MVC), motor-pedestrian collision (MPC), and motorcycle/moped collision (MMC). Description analyses and multinominal logistic regressions were applied to examine the factors associated with the type of motor-related injuries adjusting for covariates. All analyses were conducted by STATA version 14.0. A total of 3,742 traffic-related pediatric injuries were identified. The mean (SD) age was 6.4 (4.0) years; most patients were boys (59%) and Hispanic (40%). There was a waving trend of the number of traffic-related injuries over the 10-year period. Compared with MVC, demographic disparities exist with children experiencing an MPC injury. Hispanic and African American children were more likely to have an MPC but less likely to have a motorcycle/moped collision injury (relative risk [RR], 1.6; 95% confidence interval, 1.3-1.9; RR, 2.0; 95% confidence interval, 1.9-2.4, respectively). Children with an MPC injury had a more severe outcome than those with an MVC injury, but no difference was found in fatality. The MCC injuries did not significantly differ from MVC in injury severity. Although efforts have been made to prevent MVC-related pediatric injuries, the trend of MVCs was stable in the most recent years. The MPC-related injury continues to be a higher likelihood of severe pediatric trauma. Thus, continuing efforts and innovative intervention programs are still needed to prevent traffic-related pediatric injuries. Epidemiologic study, level III.


Drug-Loaded Acoustic Nanodroplet for Dual-Imaging Guided Highly Efficient Chemotherapy Against Nasopharyngeal Carcinoma.
Chemotherapy is an important approach to treating nasopharyngeal carcinoma (NPC). Unfortunately, the lack of selectivity, insufficient tumor accumulation, uneven tumor distribution and severe systemic toxicity lead to the unsatisfactory performance of these drugs. While a more precise drug delivery, on-demand drug release, and deep diffusion of drugs (homogeneous distribution of drugs in the tumor) could improve the application, they remain challenging. Chemotherapeutic drug-loaded acoustic nanodroplet with dual-imaging capacity is expected to solve these problems. Folate (Fa)-modified and doxorubicin (Dox)-loaded acoustic poly (lactic-co-glycolic acid) (PLGA), low intensity focused ultrasound (LIFU)-responsive perfluoropentane (PFP) and Fe3O4 nanoparticles (designated as Fa-Fe@P-PFP-Dox) were integrated by a double-emulsion method. After the synthesis, the LIFU-triggered acoustic droplet vaporization (ADV) effect, LIFU-triggered drug release, cell targeting capability, in vitro cell-killing effects, biodistribution, PA/MR dual imaging (PA: photoacoustic; MR: magnetic resonance), LIFU-augmented Dox distribution in tumors and chemotherapeutic efficacy of Fa-Fe@P-PFP-Dox were investigated. The distribution of these drug-loaded nanodroplets was clearly monitored via PA/MR dual imaging. Upon LIFU irradiation, PFP within the Fa-Fe@P-PFP-Dox nanodroplets underwent ADV, which led to the release of Dox and promoted the deep penetration of Dox in tumor tissue, eventually achieving highly efficient chemotherapy against NPC. As a result, LIFU-triggered chemotherapy exerted a highly efficient therapeutic effect with a tumor inhibition rate of 74.24 ± 7.95%. Fa-modified and drug-loaded acoustic nanodroplets have been successfully constructed for dual-imaging guided highly efficient chemotherapy against NPC. This novel tumor drug delivery method is expected to provide an efficient, visualized, and precise personalized treatment method for NPC patients with minimal side effects.


Case Report: α-Spectrin Mutation Associated with αLELY Polymorphism Responsible for Hereditary Pyropoikilocytosis.
Hereditary pyropoikilocytosis (HPP) is characterised by severe hemolytic anemia due to membrane instability. We report the case of a 13-day-old boy with neonatal jaundice and severe hemolytic anemia. A peripheral smear examination showed severe anisopoikylocytosis. DNA sequencing revealed compound double heterozygous for mutant α-spectrin SPTA1 (Arg28His) and homozygous αLELY polymorphism (low expression α-spectrin allele), compatible with diagnosis of HPP.The patient required a blood transfusion initially, but spontaneously improved after two years. Our case illustrates that, despite the presence of the allele αLELY in homozygous, the clinical phenotype is similar to cases with a mutation in SPTA1 associated with αLELY in trans.


Postnatal development of neurons expressing NADPH-diaphorase and parvalbumin in the parietal cortex of male and female rats.
Expression of the enzyme nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) and the calcium-binding protein parvalbumin was studied in the parietal cortex of male and female rats during postnatal development at 20, 60 and 90 days of age. First, localization of the activity of NADPH-d was combined with the immunohistochemical localization of parvalbumin to facilitate recognition of morphological details and distribution patterns of these two types of cortical neurons. Double staining of neurons for parvalbumin and NADPH-d was never found. Second, it was found that NADPH-d is a simple and proper marker for quantitative studies. Morphometric analysis revealed sexual dimorphism in the density of NADPH-d-positive neurons in 20 days-old prepubertal rats. Females showed higher amounts of NADPH-d-positive neurons than males. No sex-dependent differences were detected in 60 days-old pubertal and 90 days-old postpubertal rats. The present results suggest that sex differences in the number of NADPH-d-positive neurons in the rat parietal cortex may be related to epigenetic effects of gonadal hormones in the early prepubertal period of postnatal development.


Middle age serum sodium levels in the upper part of normal range and risk of heart failure.
With increasing prevalence of heart failure (HF) owing to the ageing population, identification of modifiable risk factors is important. In a mouse model, chronic hypohydration induced by lifelong water restriction promotes cardiac fibrosis. Hypohydration elevates serum sodium. Here, we evaluate the association of serum sodium at middle age as a measure of hydration habits with risk to develop HF. We analysed data from Atherosclerosis Risk in Communities study with middle age enrolment (45-66 years) and 25 years of follow-up. Participants without water balance dysregulation were selected: serum sodium within normal range (135-146 mmol/L), not diabetic, not obese and free of HF at baseline (N = 11 814). In time-to-event analysis, HF risk was increased by 39% if middle age serum sodium exceeded 143 mmol/L corresponding to 1% body weight water deficit [hazard ratio 1.39, 95% confidence interval (CI) 1.14-1.70]. In a retrospective case-control analysis performed on 70- to 90-year-old attendees of Visit 5 (N = 4961), serum sodium of 142.5-143 mmol/L was associated with 62% increase in odds of left ventricular hypertrophy (LVH) diagnosis [odds ratio (OR) 1.62, 95% CI 1.03-2.55]. Serum sodium above 143 mmol/L was associated with 107% increase in odds of LVH (OR 2.07, 95% CI 1.30-3.28) and 54% increase in odds of HF (OR 1.54, 95% CI 1.06-2.23). As a result, prevalence of HF and LVH was increased among 70- to 90-year-old participants with higher middle age serum sodium. Middle age serum sodium above 142 mmol is a risk factor for LVH and HF. Maintaining good hydration throughout life may slow down decline in cardiac function and decrease prevalence of HF.


Treatment Perspectives Based on Our Current Understanding of Concussion.
Sports-related concussion also referred to in the literature as mild traumatic brain injury remains a popular area of study for physicians, neurologists, neuropsychologists, neuroimaging, athletic trainers, and researchers across the other areas of brain sciences. Treatment for concussion is an emerging area of focus with investigators seeking to improve outcomes and protect patients from the deleterious short-term and long-term consequences which have been extensively studied and identified. Broadly, current treatment strategies for athletes recovering from concussion have remained largely unchanged since early 2000s. Knowledge of the complex pathophysiology surrounding injury should improve or advance our ability to identify processes which may serve as targets for therapeutic intervention. Clinicians working with athletes recovering from sports-related concussion should have an advanced understanding of the injury cascade and also be aware of the current efforts within the research to treat concussion. In addition, how clinicians use the word "treatment" should be carefully defined and promoted so the patient is aware of the level of intervention and what stage of recovery or healing is being affected by a specific intervention. The purpose of this review is to bring together efforts across disciplines of brain science into 1 platform where clinicians can assimilate this information before making best practices decisions regarding the treatment of patients and athletes under their care.


Immunoreactive glucagon responses to intravenous tolbutamide in chronic pancreatitis.
The effects of tolbutamide infusion (1 gm. over forty minutes) on plasma pancreatic glucagon-like immunoreactivity (PGLI), serum insulin, and blood glucose were studied in six patients with chronic pancreatitis and six matched controls.asal PGLI levels were significantly higher in the patients, despite higher fasting glucose concentrations. Tolbutamide infusion had no significant effect on mean PGLI levels in controls but was associated with significant elevation in pancreatitis patients, despite higher circulating glucose levels in the latter. The data suggest that chronic calcific pancreatitis patients hypersecrete immunoreactive glucagon, possibly from a nonpancreatic source and that this immunocreactive material may be stimulated by sulfonylureas.


Bridging a spinal cord defect using collagen filament.
A rat model of spinal cord defect was designed to evaluate the effect of collagen filament implant on nerve regeneration in the spinal cord defect. To bridge a spinal cord defect and restore the function in adult mammals. Resection of the spinal cord in mammals is always followed by motor paralysis and loss of voluntary function below the lesion. Partial success in bridging the ends of the spinal cord after complete resection was reported. However, restoration of function has not been reported in adult mammalian. Four thousand collagen filaments 5-mm-long were grafted to bridge a 5-mm defect of rat spinal cord. Controls had their spinal cord defect left ungrafted after resection. At 1-week intervals, animals were evaluated functionally. After 4 and 12 weeks, animals were evaluated histologically. After 12 weeks, animals were evaluated electrophysiologically. The severed spinal cord axons regenerated along the collagen filament implant crossing the proximal and distal spinal cord implant interfaces at 4 weeks after surgery. The rats with collagen filament grafts could walk, run, and climb with hind forelimb coordination at 12 weeks after surgery. Sensory-evoked potential waveform was found in the rats with collagen filament at 12 weeks after surgery. The collagen filaments support the axonal regeneration of the transected spinal cord and the restoration of function.


Early onset bilateral juvenile myasthenia gravis masquerading as simple congenital ptosis.
Myasthenia gravis is an autoimmune disorder affecting the neuromuscular junction. Ocular myasthenia gravis presents as ptosis with extraocular motility restriction and is prone to be misdiagnosed as third nerve palsy or congenital or aponeurotic ptosis. Juvenile ocular myasthenia gravis in very young children is difficult to diagnose and can be easily labeled as a case of congenital ptosis, the more so when the condition is bilateral. We present a case of a two-year-old child who presented with bilateral ptosis and was diagnosed as a case of simple congenital ptosis elsewhere with the advice to undergo tarsofrontalis sling surgery. The child was diagnosed with juvenile myasthenia gravis on thorough history, examination, and systemic evaluation and was started on anti-myasthenic treatment.


Empirically supported treatments in pediatric psychology: where is the diversity?
To examine the extent to which studies used to support empirically supported treatments for asthma, cancer, diabetes, and obesity address issues of cultural diversity. We chose original articles (71) of treatments used to support empirically supported treatments (ESTs) published as part of a special series on ESTs in the Journal of Pediatric Psychology. Trained coders reviewed each study to determine if the following were reported: race/ethnicity and socioeconomic status (SES) of the sample, moderating cultural variables, cultural assumptions or biases of the treatment, larger cultural issues, and measurement or procedure bias. Results revealed that few studies addressed cultural variables in any way. Only 27% of the studies reported the race or ethnicity and 18% reported the SES of research participants. Additionally, 6% discussed potential moderating cultural variables. The remaining variables were addressed in 7% or less of the studies. These data support the criticism that ESTs fail to address important issues of culture and call into question the external validity of ESTs to diverse populations. Future research should explicitly address cultural issues according to the nine recommendations described here.


Effect of a yearlong, moderate-intensity exercise intervention on the occurrence and severity of menopause symptoms in postmenopausal women.
To evaluate the effect of moderate-intensity exercise on the occurrence and severity of menopause symptoms. A yearlong, randomized, clinical trial, conducted in Seattle, WA, with 173 overweight, postmenopausal women not taking hormone therapy in the previous 6 months. The intervention was a moderate-intensity exercise intervention (n = 87) versus stretching control group (n = 86). Using logistic regression, odds ratios comparing exercise with controls were calculated at 3, 6, 9, and 12 months for menopause symptoms and their severity. There was a significant increase in hot flash severity and decreased risk of memory problems in exercisers versus controls over 12 months, although the numbers affected were small. No other significant changes in symptoms were observed. Exercise does not seem to decrease the risk of having menopause symptoms in overweight, postmenopausal women not taking hormone therapy and may increase the severity of some symptoms in a small number of women.


Method for measuring visual resolution at the retinal level.
To measure the intrinsic resolving capacity of the retinal and neural levels of vision, we devised a method that creates two lines with controllable contrast on the retina. The line separation can be varied at will, down to values below those achievable with conventional optical techniques. Implementation of the method with use of a He-Ne laser leads to a procedure that permits analysis of the performance of the human visual apparatus.


Optimizing biological therapy in Crohn's disease.
Anti-TNF therapy has revolutionized the treatment of inflammatory bowel diseases, including both Crohn's disease and ulcerative colitis. However, a significant proportion of patients does not respond to anti-TNF agents or lose response over time. Recently, therapeutic drug monitoring has gained a major role in identifying the mechanism and management of loss of response. The aim of this review article is to summarize the predictors of efficacy and outcomes, the different mechanisms of anti-TNF/biological failure in Crohn's disease and identify strategies to optimize biological treatment.


Optogenetic investigation of the variable neurovascular coupling along the interhemispheric circuits.
The interhemispheric circuit connecting the left and the right mammalian brain plays a key role in integration of signals from the left and the right side of the body. The information transfer is carried out by modulation of simultaneous excitation and inhibition. Hemodynamic studies of this circuit are inconsistent since little is known about neurovascular coupling of mixed excitatory and inhibitory signals. We investigated the variability in hemodynamic responses driven by the interhemispheric circuit during optogenetic and somatosensory activation. We observed differences in the neurovascular response based on the stimulation site - cell bodies versus distal projections. In half of the experiments, optogenetic stimulation of the cell bodies evoked a predominant post-synaptic inhibition in the other hemisphere, accompanied by metabolic oxygen consumption without coupled functional hyperemia. When the same transcallosal stimulation resulted in predominant post-synaptic excitation, the hemodynamic response was biphasic, consisting of metabolic dip followed by functional hyperemia. Optogenetic suppression of the postsynaptic excitation abolished the coupled functional hyperemia. In contrast, light stimulation at distal projections evoked consistently a metabolic response. Our findings suggest that functional hyperemia requires signals originating from the cell body and the hemodynamic response variability appears to reflect the balance between the post-synaptic excitation and inhibition.


When Sexual Identity and Sexual Behaviors Do Not Align: The Prevalence of Discordance and its Physical and Psychological Health Correlates.
Although scholarly work on the complexity of human sexuality has increasingly been a focus of scholarship, comparatively little research has focused on the phenomenon of mismatch, or discordance, between different aspects of sexuality. This study used secondary data of sexually active adults (N=116,950) from a statewide representative survey which included both a measure of sexual identity (i.e., identifying as "heterosexual", "bisexual", etc.) and a measure of sexual behaviors (i.e., indicating the sex of your sexual partners). Using these data, we examined the prevalence and correlates of sexual identity-behavior discordance (IBD), and also included data from bisexual-identified individuals. In support of our hypotheses, we found that sexual IBD was particularly prevalent among young-adult women. However, we did not find sex differences in the prevalence of IBD overall. Furthermore, individuals who were categorized as IBD also tended to report poorer physical health and psychological functioning than both heterosexual- and gay/lesbian-identified concordant individuals, as well as more negative behaviors typically associated with poor psychological functioning (i.e., binge drinking and suicidal ideation.) Our findings highlight the need for more sensitive instruments and measures assessing sexual orientation in both research and practice, as well as the need for continued study into the area of discordance, and particularly across other dimensions of sexuality (e.g., attraction).


Challenge of mimicking the influences of the cellular environment on RNA structure by PEG-induced macromolecular crowding.
There are large differences between the cellular environment and the conditions widely used to study RNA in vitro. SHAPE RNA structure probing in Escherichia coli cells has shown that the cellular environment stabilizes both long-range and local tertiary interactions in the adenine riboswitch aptamer domain. Synthetic crowding agents are widely used to understand the forces that stabilize RNA structure and in efforts to recapitulate the cellular environment under simplified experimental conditions. Here, we studied the structure and ligand binding ability of the adenine riboswitch in the presence of the macromolecular crowding agent, polyethylene glycol (PEG). Ethylene glycol and low-molecular mass PEGs destabilized RNA structure and caused the riboswitch to sample secondary structures different from those observed in simple buffered solutions or in cells. In the presence of larger PEGs, longer-range loop-loop interactions were more similar to those in cells than in buffer alone, consistent with prior work showing that larger PEGs stabilize compact RNA states. Ligand affinity was weakened by low-molecular mass PEGs but increased with high-molecular mass PEGs, indicating that PEG cosolvents exert complex chemical and steric effects on RNA structure. Regardless of polymer size, however, nucleotide-resolution structural characteristics observed in cells were not recapitulated in PEG solutions. Our results reveal that the cellular environment is difficult to recapitulate in vitro; mimicking the cellular state will likely require a combination of crowding agents and other chemical species.


Smokers' strategies across social grades to minimise the cost of smoking in a period with annual tax increases: evidence from a national survey in England.
To assess associations between smokers' strategies to minimise how much their smoking costs and cost of smoking among smokers across three social grades during a period of annual tax increases in England. Repeat cross-sectional. England, May 2012-December 2016. 16 967 adult smokers in 56 monthly surveys with nationally representative samples. Weighted generalised additive models assessed associations between four cost-minimising strategies (factory-made and roll-your-own (RYO) cigarette consumption levels, illicit and cross-border purchases) and cost of smoking (£/week). We adjusted for inflation rate, age, gender and secular and seasonal trends. Cost of smoking did not increase above the rate of inflation. Factory-made cigarette consumption decreased, while proportion of RYO and, to a much lesser extent, illicit and cross-border purchases increased. These trends were only evident in lowest social grade. Cost of smoking was 12.99% lower with consumption of 10 fewer factory-made cigarettes (95% CI -13.18 to -12.80) and 5.86% lower with consumption of 10 fewer RYO cigarettes (95% CI -5.66 to -6.06). Consumption levels accounted for 60% of variance in cost. Cross-border and illicit tobacco purchases were associated with 9.64% (95% CI -12.94 to -6.33) and 9.47% (95% CI -12.74 to -6.20) lower costs, respectively, but due to low prevalence, accounted for only 0.2% of variation. Associations were similar across social grades, although weaker for illicit and cross-border purchases and stronger for consumption in higher social grades compared with lower social grades. During a period of annual tax increases, the weekly cost of smoking did not increase above inflation. Cost-minimising strategies increased, especially among more disadvantaged smokers. Reducing cigarette consumption and switching to RYO tobacco explained a large part of cost variation, while use of illicit and cross-border purchasing played only a minor role.


Spectrum- and time-resolved endogenous multiphoton signals reveal quantitative differentiation of premalignant and malignant gastric mucosa.
Early identification of premalignant and malignant gastric mucosa is crucial to decrease the incidence and mortality of stomach cancer. Spectrum- and time-resolved multiphoton microscopy are capable of providing not only structural but also biochemical information at the subcellular level. Based on this multidimensional imaging technique, we performed a systematic investigation on fresh human tissue specimens at the typical stages of gastric carcinogenesis, including normal, chronic gastritis with erosion, chronic gastritis with intestinal metaplasia, and intestinal-type adenocarcinoma. The results demonstrate that this technique is available to characterize the three-dimensional subcellular morphological and biochemical properties of gastric mucosa and further provide quantitative indicators of different gastric disorders, by using endogenous contrast. With advances in multiphoton endoscopy, it has the potential to allow noninvasive, label-free, real-time histological and functional diagnosis of premalignant and malignant lesions of stomach in the future.


Impact of Arginine-Phosphate Interactions on the Reentrant Condensation of Disordered Proteins.
Re-entrant condensation results in the formation of a condensed protein regime between two critical ion concentrations. The process is driven by neutralization and inversion of the protein charge by oppositely charged ions. Re-entrant condensation of cationic proteins by the polyvalent anions, pyrophosphate and tripolyphosphate, has previously been observed, but not for citrate, which has similar charge and size compared to the polyphosphates. Therefore, besides electrostatic interactions, other specific interactions between the polyphosphate ions and proteins must contribute. Here, we show that additional attractive interactions between arginine and tripolyphosphate determine the re-entrant condensation and decondensation boundaries of the cationic, intrinsically disordered saliva protein, histatin 5. Furthermore, we show by small-angle X-ray scattering (SAXS) that polyvalent anions cause compaction of histatin 5, as would be expected based solely on electrostatic interactions. Hence, we conclude that arginine-phosphate-specific interactions not only regulate solution properties but also influence the conformational ensemble of histatin 5, which is shown to vary with the number of arginine residues. Together, the results presented here provide further insight into an organizational mechanism that can be used to tune protein interactions in solution of both naturally occurring and synthetic proteins.


Structural basis for potency differences between GDF8 and GDF11.
Growth/differentiation factor 8 (GDF8) and GDF11 are two highly similar members of the transforming growth factor β (TGFβ) family. While GDF8 has been recognized as a negative regulator of muscle growth and differentiation, there are conflicting studies on the function of GDF11 and whether GDF11 has beneficial effects on age-related dysfunction. To address whether GDF8 and GDF11 are functionally identical, we compared their signaling and structural properties. Here we show that, despite their high similarity, GDF11 is a more potent activator of SMAD2/3 and signals more effectively through the type I activin-like receptor kinase receptors ALK4/5/7 than GDF8. Resolution of the GDF11:FS288 complex, apo-GDF8, and apo-GDF11 crystal structures reveals unique properties of both ligands, specifically in the type I receptor binding site. Lastly, substitution of GDF11 residues into GDF8 confers enhanced activity to GDF8. These studies identify distinctive structural features of GDF11 that enhance its potency, relative to GDF8; however, the biological consequences of these differences remain to be determined.


TSH receptor interaction with the extracellular matrix: role on constitutive activity and sensitivity to hormonal stimulation.
Using immunocytochemistry, we have observed that the TSH receptor (TSHR) is concentrated at the leading edge of lamellipodia in both cultured human thyroid cells and in various transfected cells. This segregation of the receptor is due to its interaction with extracellular matrix (ECM) and specially with fibronectin. The TSHR, which interacts with the ECM, is known to undergo cleavage by a matrix metalloprotease. The homologous LH receptor, which does not interact with ECM, is not cleaved. The attachment to the ECM modifies the functional properties of the receptor: it increases adenylate cyclase stimulation by hormone, whereas PLC stimulation is not modified. Furthermore, the constitutive activity of the TSHR is only observed in attached cells, suggesting that it is dependent on TSHR interaction with the ECM. Thus, aside from its classical properties of hormone binding and signalization through G proteins, the TSHR is also involved in cell-matrix interactions, which modulate its functional properties.


Myc protein: partners and antagonists.
One of the first oncogenes identified from human tumors was c-myc, which is frequently activated in Burkitt's lymphomas due to chromosomal translocations. Subsequently, members of the myc oncogene family were found to be amplified in neuroblastoma and small-cell lung cancer. In normal cells, Myc activity has been shown to be both necessary and sufficient for resting cells to enter the cell cycle. Interestingly, it appears that Myc not only drives the cell cycle, but also induces cell death by apoptosis in certain situations. Myc contains a transcriptional activation domain and a basic helix-loop-helix-leucine zipper DNA-binding and dimerization domain. As a heterodimer with a structurally related protein, Max, Myc can bind DNA in a sequence-specific manner. These results suggest that the Myc/Max heterodimer functions as a transcriptional activator of genes that are critical for the regulation of cell growth.


QT prolongation in the STREAM Stage 1 Trial.
BACKGROUND: STREAM (Standardized Treatment Regimen of Anti-TB Drugs for Patients with MDR-TB) Stage 1 demonstrated non-inferior efficacy of a shortened regimen (the Short regimen) for rifampicin-resistant TB (RR-TB) compared to the contemporaneous WHO-recommended regimen. This regimen included moxifloxacin and clofazimine, known to cause QT prolongation, and severe prolongation was more common on the Short regimen. Here we investigate risk factors for QT prolongation with the Short regimen.METHODS: Data from patients prescribed the Short regimen (n = 282) were analysed to identify risk factors for severe QT prolongation (QT/QTcF ≥500 ms or ≥60 ms increase in QTcF from baseline).RESULTS: Of the 282 patients on the Short regimen, 94 (33.3%) developed severe QT prolongation: 31 QT/QTcF ≥500 ms; 92 experienced ≥60 ms QTcF increase from baseline. The median time to QT/QTcF ≥500 ms was 20 weeks (IQR 8-28), and the time to ≥60 ms increase from baseline was 18 weeks (IQR 8-28). Prolongation ≥500 ms was most frequent in patients from Mongolia (10/22, 45.5%) compared with 3.5-11.9% at other sites, P < 0.001. Higher baseline QTcF increased risk of prolongation to ≥500 ms (QTcF ≥400 ms: OR 5.99, 95% CI 2.04-17.62).CONCLUSION: One third of patients on the Short regimen developed severe QT prolongation. QT/QTcF ≥500 ms was more common in patients from Mongolia and in those with a higher baseline QTcF, which may have implications for implementation of treatment.


Humoral and cellular immunity in atopic eczema.
Parameters of humoral and cellular immunity were measured in thirty-five patients with atopic eczema. The mean serum IgE level was raised but levels of the other major immunoglobulin classes were normal. Ten per cent of patients failed to respond to tetanus immunization. All patients responded to S. typhi H antigen. Fourteen per cent of patients failed to mount delayed hypersensitivity reactions to a battery of three intradermal antigens. The phytohaemagglutinin-stimulated uptake of 3H thymidine by lymphocytes was normal in the presence of autologous or of fetal calf serum, as was the spontaneous lymphocyte uptake. T and B lymphocyte numbers in the peripheral blood were normal. These results are similar to those found in asthmatic patients and support the hypothesis that, in some patients, atopic eczema is associated with an immunodeficiency state.


Concentration of soluble and nonsoluble zinc-based impurities by unidirectional freezing: basis for a method of sludges treatment.
Heavy metals are known to be significant pollutants in sludges produced by wastewater treatment. A newtechnique to make the metallic contaminants migrate is to submit such sludges to a slow freezing in order to purify the frozen region and to concentrate impurities in the non-frozen zone. In this paper, we apply this method to model contaminated sludges consisting of clayey suspensions charged with a heavy metal (zinc). The effect of some physicochemical parameters (zinc and clay concentrations, pH) on the effectiveness of the method is experimentally investigated. The pH is the most relevant parameter and the highest purification rate (approximately 80%) is obtained for pH approximately 9.


Effects of propofol and midazolam on lipids, glucose, and plasma osmolality during and in the early postoperative period following coronary artery bypass graft surgery: a randomized trial.
It is not clear how levels of serum lipids and glucose and plasma osmolality change during propofol infusion in the pre- and postoperative period of coronary artery bypass graft surgery (CABG). This prospective, randomized, controlled trial evaluated changes in these parameters during propofol or midazolam infusion during and in the early postoperative period following surgery. Twenty patients undergoing CABG were randomized preoperatively into two groups: 10 patients received propofol (induction 1.5 mg/kg, maintenance 1.5 mg kg(-1) h(-1)) and 10 patients received midazolam (induction 0.5 mg/kg, maintenance 0.1 mg kg(-1) h(-1)). Both groups also received fentanyl (induction 20 mug/kg, maintenance 10 microg kg(-1)). Serum lipids, glucose, and plasma osmolality were measured preinduction, precardiopulmonary bypass, at the end of cardiopulmonary bypass, at the end of surgery, and 4 and 24 h postoperatively. In the propofol group, we observed a significant increase in triglycerides and very low-density lipoprotein levels 4 h postoperatively. In the midazolam group, we observed a significant decrease in low-density lipoprotein, cholesterol at the end of cardiopulmonary bypass, end of surgery, and 4 and 24 h postoperatively and significant increase in osmolality at the end of cardiovascular bypass. Changes in glucose levels did not differ significantly different between the two groups. In patients with normal serum lipids, glucose, and plasma osmolality undergoing CABG, propofol infusion for maintenance anesthesia is not associated with dangerous changes in serum lipids, glucose, and plasma osmolality compared with midazolam. A propofol infusion technique for maintenance of anesthesia for cardiac surgery where serum lipids and glucose may be of concern could be recommended as an alternative to midazolam.


Sustainability of pyrethroid-impregnated bednets for malaria control in Afghan communities.
Between 1992 and 1995 a series of studies was undertaken to assess the long-term suitability of pyrethroid-impregnated bednets (PIBs) for malaria control in Afghan refugee communities in two villages in North-West Frontier Province, Pakistan. During 1992, 86% of bednet owners volunteered to have their bednets re-impregnated, and a further 15% of families purchased nets at two-thirds of cost price. From 1992 onwards, 27% of the villagers returned to Afghanistan, and annual house spraying campaigns were introduced to protect those still resident but sleeping without bednets. Within 3 years, these campaigns, together with PIBs, reduced the annual incidence of malaria by 87%, from 597 to 78 cases per 1000 population. Nevertheless, 65% of resident families continued to re-impregnate their nets annually with permethrin. To assess whether PIBs were still being used and were still protective, in view of these reduced transmission rates, we carried out a case--control study in 1994 on febrile or otherwise symptomatic patients presenting at village health centres. Comparison of the slide-positivity rates of PIB users and those without bednets showed that regular usage reduced the odds of contracting falciparum and vivax malaria to 0.22 (95% confidence interval (CI): 0.09-0.55) and 0.31 (95% CI: 0.19-0.51), respectively. There was no evidence of a sex- or age-bias in bednet use or in protective effect. The results indicate that a community-based PIB programme is an appropriate malaria control measure in areas where management or security problems make traditional house-spraying campaigns impossible. A relevant finding for those involved in the monitoring of bednet distribution projects is that the local coverage of bednets and the local impact on malaria, even when introduced to remote areas, can be estimated very cheaply by health centre microscopists who simply catalogue blood film diagnoses according to patients' bednet use practices.


Patients with breast cancer may be at higher risk of colorectal neoplasia.
The risk of colorectal neoplasia in breast cancer survivors is unclear. This study aimed to determine the colonic adenoma detection rate (ADR) in patients with breast cancer. We conducted a retrospective study of patients with breast cancer who underwent a colonoscopy between 2000 and 2017. A control group (n=3295), comprising cancer-free patients undergoing their first screening colonoscopy, was used for comparison. Of 62,820 breast cancer patients, 3304 met the inclusion criteria. The mean age at the time of first colonoscopy was 59 years. ADR was 55%; 1803 patients had adenomas. High-grade dysplasia was evident in 28% of polyps and invasive adenocarcinoma was detected in 172 patients (5%). The median time from breast cancer diagnosis to adenoma detection was 3 years. The ADR was 21% in patients aged <40 years (n=63) and 39% in patients aged 40-50 years (n=314). The ADR was 26% in patients <50 years with a body mass index (BMI) lower than 30 kg/m2 or no family history of colorectal cancer. Multivariate logistic regression analysis revealed that the following independent factors were associated with a greater risk of colon adenoma: older age, higher BMI, family history of colorectal cancer, and personal history of breast cancer. In patients with breast cancer, the ADR was higher than the reported rates for the general population. Screening colonoscopy should be considered soon after breast cancer diagnosis in patients <50 years of age. Further prospective studies investigating our findings are warranted.


Venous bypass grafts versus arteriovenous loops as recipient vessels for microvascular anastomosis in lower extremity reconstructions: A matched-pair analysis.
Limb salvage in patients with peripheral vascular disease (PVD) and soft tissue defects often requires both a restoration of blood flow to the lower extremity and soft tissue coverage. Outcomes of free tissue transfer may be affected by vein grafts, which can be used for the placement of an autologous venous bypass or an arteriovenous (AV) loop leading to different hemodynamic situations. The purpose of this study was to investigate whether free flap anastomosis to a bypass or an AV loop can be performed with comparable results. We performed a matched-pair analysis of 22 patients with PVD undergoing free flap reconstructions of the lower extremity with end-to-side anastomosis to an autologous venous bypass (n = 11, 1 female and 10 male patients) or an AV loop (n = 11, 2 female and 9 male patients). Defects caused by trauma, infection, ulcer, or fasciotomy were reconstructed in each group with 5 muscle-based flaps, 3 parascapular flaps, 2 anterolateral thigh (ALT) flaps, and 1 conjoined latissimus dorsi and parascapular flap. Postoperative complications including thromboses, flap failures, wound complications, and hematomas were compared. Postoperative complication rates including 1 venous pedicle thrombosis (9%vs. 0%, P = 1.0), minor (18% vs. 9%, P = 1.0) and major wound complications (45% vs. 27%, P = .69) as well as hematomas (27% vs. 36%, P = 1.0) did not show relevant differences between the groups. Flap failures were absent in both groups. In patients with PVD, autologous venous bypass grafts may be used for end-to-side anastomoses of free flaps, with postoperative outcomes being comparable to AV loop reconstructions.


Interaction Between the Complement System and Infectious Agents - A Potential Mechanistic Link to Neurodegeneration and Dementia.
As part of the innate immune system, complement plays a critical role in the elimination of pathogens and mobilization of cellular immune responses. In the central nervous system (CNS), many complement proteins are locally produced and regulate nervous system development and physiological processes such as neural plasticity. However, aberrant complement activation has been implicated in neurodegeneration, including Alzheimer's disease. There is a growing list of pathogens that have been shown to interact with the complement system in the brain but the short- and long-term consequences of infection-induced complement activation for neuronal functioning are largely elusive. Available evidence suggests that the infection-induced complement activation could be protective or harmful, depending on the context. Here we summarize how various infectious agents, including bacteria (e.g., Streptococcus spp.), viruses (e.g., HIV and measles virus), fungi (e.g., Candida spp.), parasites (e.g., Toxoplasma gondii and Plasmodium spp.), and prion proteins activate and manipulate the complement system in the CNS. We also discuss the potential mechanisms by which the interaction between the infectious agents and the complement system can play a role in neurodegeneration and dementia.


Dual-energy X-ray absorptiometry for histologic bone sections.
In fundamental osteoporosis research precise and accurate assessment of the mineral quantity in histological bone sections is of particular importance when studying the local effects of implants releasing bone modulating agents. A potentially useful technique to estimate the bone mineral density (BMD) is dual-energy X-ray absorptiometry (DXA). A highly collimated (0.13 mm) Hologic 2000 with a line spacing and point resolution of 0.13 mm was used. The mineral content was measured in regions of 3.1 mm(2). A ceramic hydroxyapatite (CHA) phantom was developed as a reference standard. The phantom was made of a single-phase hydroxyapatite starting powder by compressing and sintering at 1000 degrees Celsius. The true density was 3.14 + or - 0.001 g/cm(3). The calcium/phosphorus ratio was close to the theoretical one of 1.67. The mean precision error expressed as the coefficient of variation (CV) of the mineral density (MD) measurements of the phantoms with thicknesses of 1, 2, and 3 mm was 0.2%. Embedded undecalcified alveolar bone sections of dogs (0.0015-1 mm in thickness) were scanned simultaneously with a phantom 1 mm in thickness. The precision error (CV) of the BMD measurements calculated by DXA for sections > or = 0.1 mm and with a BMD > or = 0.14 g/cm(2) was 0.81%. There was a linear relationship between the BMD calculated by DXA and the estimated BMD in the histological bone sections by means of the true density of the phantom. It is concluded that DXA using a standard CHA phantom is a precise and accurate method to measure MD changes as small as 1% in histological bone areas of 3.1 mm(2) provided that the loss or gain in BMD is > or = 0.14 g/cm(2).


Synthesis of HC-Toxin via Matteson Homologation and C-H Functionalization.
A new synthetic route toward host-specific HC-toxin was developed. The HC-toxin belongs to a group of cyclic, tetrapeptide histone deacetylase inhibitors containing the unusual amino acid Aeo. Key steps in the synthesis of this building block include the Matteson homologation to generate the stereogenic centers in the side chain and a C-H functionalization to connect the side chain to a protected alanine.


Physical skill training increases the number of surviving new cells in the adult hippocampus.
The dentate gyrus is a major site of plasticity in the adult brain, giving rise to thousands of new neurons every day, through the process of adult neurogenesis. Although the majority of these cells die within two weeks of their birth, they can be rescued from death by various forms of learning. Successful acquisition of select types of associative and spatial memories increases the number of these cells that survive. Here, we investigated the possibility that an entirely different form of learning, physical skill learning, could rescue new hippocampal cells from death. To test this possibility, rats were trained with a physically-demanding and technically-difficult version of a rotarod procedure. Acquisition of the physical skill greatly increased the number of new hippocampal cells that survived. The number of surviving cells positively correlated with performance on the task. Only animals that successfully mastered the task retained the cells that would have otherwise died. Animals that failed to learn, and those that did not learn well did not retain any more cells than those that were untrained. Importantly, acute voluntary exercise in activity wheels did not increase the number of surviving cells. These data suggest that acquisition of a physical skill can increase the number of surviving hippocampal cells. Moreover, learning an easier version of the task did not increase cell survival. These results are consistent with previous reports revealing that learning only rescues new neurons from death when acquisition is sufficiently difficult to achieve. Finally, complete hippocampal lesions did not disrupt acquisition of this physical skill. Therefore, physical skill training that does not depend on the hippocampus can effectively increase the number of surviving cells in the adult hippocampus, the vast majority of which become mature neurons.


[Acute hyperkalemia disclosing an intraperitoneal rupture of an amebic liver abscess. Value of preoperative peritoneal dialysis].
In a patient with shock and hyperkalemia , a peritoneal dialysis, started to treat an hyperkalemia , showed the presence of chocolate-like pus in the peritoneal cavity, and confirmed the intraperitoneal rupture of an amoebic liver abscess . Peritoneal dialysis led to the correction of the metabolic disorders and of the shock and restored the diuresis, ensuring favourable conditions to surgical intervention. Surgical drainage of the abscesses and ornidazole treatment led to complete recovery.


Health-related quality of life in patients who develop bronchiolitis obliterans syndrome following allo-SCT.
Bronchiolitis obliterans syndrome (BOS) remains an important complication following allo-SCT. The development of this condition portends a higher morbidity and mortality but the effect on heath-related quality of life (HRQL) is unknown. The aim of this study was to determine whether the development of BOS impacted HRQL compared with patients without BOS. This Institutional Review Board-approved prospective study analyzed 126 patients who underwent allo-SCT at our institution. Patients were administered three HRQL survey tools (SF-36, European Organization for Research and Treatment of Cancer QLQ-c30 and St George Respiratory Questionnaire (SGRQ)) before transplant and then again at 6 months, 1 year and 2 years after transplant. Patients were analyzed in three groups determined by highest chronic GVHD (cGVHD) severity and BOS status. Overall, our study group had improving HRQL after transplant when measured over time, measured by the SF-36 with stable HRQL, when measured by the SGRQ total score and QLQ-c30. Patients that developed BOS had significantly worse HRQL scores measured by the SGRQ and the SF-36 physical composite score. This difference was not explained by the severity of cGVHD that patients with BOS developed.


Assessment of the coronary venous system by using cardiac CT.
We aimed to investigate the coronary venous system and its variations by using dual source computed tomography (CT). Retrospective assessment was carried out on 339 patients who underwent coronary CT angiography using 128-slice dual source CT for suspected coronary artery disease. The examinations were performed according to routine imaging protocols used to evaluate coronary arteries. The coronary venous system was evaluated in each case using maximum intensity projection and volume rendering technique multiplanar reformation reconstructions. In each patient, the presence and calibration of normal anatomy, as well as the variations of the coronary sinus, middle cardiac vein, small cardiac vein, posterior cardiac vein, great cardiac vein, anterior interventricular vein, posterolateral vein, left marginal vein, and anterolateral vein were recorded. The coronary sinus, middle cardiac vein, great cardiac vein, and anterior interventricular vein were visualized in all of the patients. In all cases, one of the lateral or posterolateral veins of appropriate localization and diameter for cardiac resynchronization therapy was detected. The posterior cardiac vein was visualized in 87% of the cases, the left marginal vein in 87.9%, and the small cardiac vein in 20%. There was no significant difference in the diameters or visibilities of the coronary veins in terms of age. The coronary venous system and its tributaries may be examined in detail using CT angiography examination performed according to the routine coronary CT angiography protocol used for dual source CT. Dual source CT may be a valuable tool for evaluation of the coronary veins prior to invasive procedures that are directed at the coronary venous system.


The behavior of the P-value when the alternative hypothesis is true.
The P-value is a random variable derived from the distribution of the test statistic used to analyze a data set and to test a null hypothesis. Under the null hypothesis, the P-value based on a continuous test statistic has a uniform distribution over the interval [0, 1], regardless of the sample size of the experiment. In contrast, the distribution of the P-value under the alternative hypothesis is a function of both sample size and the true value or range of true values of the tested parameter. The characteristics, such as mean and percentiles, of the P-value distribution can give valuable insight into how the P-value behaves for a variety of parameter values and sample sizes. Potential applications of the P-value distribution under the alternative hypothesis to the design, analysis, and interpretation of results of clinical trials are considered.


[Calcimimetics--a new treatment for hyperparathyroidism?].
The common feature of both primary and secondary hyperparathyroidism despite differences in their etiopathogenesis is excess parathormone (PTH) secretion. Calcium sensing receptor (CaR) belongs to G-protein coupled receptors superfamily and plays central role in the regulation of PTH secretion. Mutations in receptor's gene lead to PTH suppression set-point shift into higher (familial benign hypocalciuric hypercalcemia) or lower Ca2+ levels (familial hypercalciuric hypocalcemia). Calcimimetics are a new class of drugs which increase the CaR response to agonist binding by allosteric conformation modification. First generation calcimimetics: NPS R-467 and NPS R-568 revealed their effectiveness in PTH suppression in experimental animal model. Short-term trials with NPS R-568 used in people with primary or secondary hyperparathyroidism confirmed significant PTH suppression. In further clinical trials a second generation calcimimetic: AMG 073 was used. AMG 073 intake was related to decrease of serum PTH and phosphorus concentrations and Ca x P product suppression with low number of hypocalcemia or other side effects. In the future calcimimetics could be an alternative to vitamin D active metabolites or analogs treatment and to surgical procedures.


Predicting potential small molecule-miRNA associations based on bounded nuclear norm regularization.
Mounting evidence has demonstrated the significance of taking microRNAs (miRNAs) as the target of small molecule (SM) drugs for disease treatment. Given the fact that exploring new SM-miRNA associations through biological experiments is extremely expensive, several computing models have been constructed to reveal the possible SM-miRNA associations. Here, we built a computing model of Bounded Nuclear Norm Regularization for SM-miRNA Associations prediction (BNNRSMMA). Specifically, we first constructed a heterogeneous SM-miRNA network utilizing miRNA similarity, SM similarity, confirmed SM-miRNA associations and defined a matrix to represent the heterogeneous network. Then, we constructed a model to complete this matrix by minimizing its nuclear norm. The Alternating Direction Method of Multipliers was adopted to minimize the nuclear norm and obtain predicted scores. The main innovation lies in two aspects. During completion, we limited all elements of the matrix within the interval of (0,1) to make sure they have practical significance. Besides, instead of strictly fitting all known elements, a regularization term was incorporated to tolerate the noise in integrated similarities. Furthermore, four kinds of cross-validations on two datasets and two types of case studies were performed to evaluate the predictive performance of BNNRSMMA. Finally, BNNRSMMA attained areas under the curve of 0.9822 (0.8433), 0.9793 (0.8852), 0.8253 (0.7350) and 0.9758 ± 0.0029 (0.8759 ± 0.0041) under global leave-one-out cross-validation (LOOCV), miRNA-fixed LOOCV, SM-fixed LOOCV and 5-fold cross-validation based on Dataset 1(Dataset 2), respectively. With regard to case studies, plenty of predicted associations have been verified by experimental literatures. All these results confirmed that BNNRSMMA is a reliable tool for inferring associations.


Effects of Neighborhood Density on Adult Word Repetition.
Presumable lexical competition has been found to result in higher perceptual accuracy for words with few versus many neighbors. Previous studies have typically only analyzed the lexical-semantic level, however. In order to also explore the possibility of phonological effects, a word repetition task was administered to 46 typical adults in which 80 stimuli differed only in neighborhood density. In contrast to previous studies, verbal responses were elicited in order to analyze productions holistically and segmentally at the phonological level. An additional error analysis examined differences in neighborhood density between target words and substitutions. Findings revealed that words with more neighbors facilitated recognition, and were more accurately repeated than those with fewer neighbors. When a target word was misperceived, its substitution tended to be higher in neighborhood density, unrelated to word frequency. In order to interpret these results, an account of lexical competition is re-visited with consideration of characteristics of the lexicon discovered using graph theory (Vitevitch, 2008).


Nucleophilic Nitration of Arynes by Sodium Nitrite and its Multicomponent Reaction Leading to Double-Functionalized Arenes.
An unusual nucleophilic nitration of arynes by NaNO2 in the presence of water has been developed, and the concept was further demonstrated to accomplish a double functionalization of arynes using a multicomponent reaction protocol to synthesize pharmaceutically important (2-nitrophenyl)methanol derivatives. Such substitution ortho to -NO2 is difficult by other means. The reaction conditions are mild and avoid the use of strong acids, expensive transition metal catalysts, and additives.


Treatment of non-Aspergillus moulds in immunocompromised patients, with amphotericin B lipid complex.
An assessment was made of the efficacy and renal safety of amphotericin B lipid complex (ABLC) in the treatment of patients with invasive fungal infections caused by moulds other than Aspergillus species, on the basis of a retrospective analysis of data from the Collaborative Exchange of Antifungal Research (CLEAR) database. Data from CLEAR for 64 patients with zygomycosis were published previously. The database was further queried and yielded results for 28 patients with fusariosis and 84 patients infected with other non-Aspergillus moulds. Of 26 patients with fusariosis whose results could be evaluated, 46% (n = 12) were cured or improved, and an additional 12% (n = 3) were stable. Of 79 patients infected with other non-Aspergillus moulds whose results could be evaluated, 61% (n = 48) were cured or improved, and an additional 15% (n = 12) were stable. In an area with little guidance for therapy, the CLEAR data indicate that ABLC can be an effective broad-spectrum treatment choice for several invasive and refractory non-Aspergillus mould infections.


Lignans from Carthamus tinctorius suppress tryptophan breakdown via indoleamine 2,3-dioxygenase.
Seed extracts of Carthamus tinctorius L. (Asteraceae), safflower, have been traditionally used to treat coronary disease, thrombotic disorders, and menstrual problems but also against cancer and depression. A possible effect of C. tinctorius compounds on tryptophan-degrading activity of enzyme indoleamine 2,3-dioxygenase (IDO) could explain many of its activities. To test for an effect of C. tinctorius extracts and isolated compounds on cytokine-induced IDO activity in immunocompetent cells in vitro methanol and ethylacetate seed extracts were prepared from cold pressed seed cakes of C. tinctorius and three lignan derivatives, trachelogenin, arctigenin and matairesinol were isolated. The influence on tryptophan breakdown was investigated in peripheral blood mononuclear cells (PBMCs). Effects were compared to neopterin production in the same cellular assay. Both seed extracts suppressed tryptophan breakdown in stimulated PBMC. The three structurally closely related isolates exerted differing suppressive activity on PBMC: arctigenin (IC50 26.5μM) and trachelogenin (IC50 of 57.4μM) showed higher activity than matairesinol (IC50 >200μM) to inhibit tryptophan breakdown. Effects on neopterin production were similar albeit generally less strong. Data show an immunosuppressive property of compounds which slows down IDO activity. The in vitro results support the view that some of the anti-inflammatory, anticancer and antidepressant properties of C. tinctorius lignans might relate to their suppressive influence on tryptophan breakdown.


Vascular endothelial growth factor (VEGF): can we use it as prognostic factor in endometrial cancer?
The aim of the study was to investigate if VEGF levels reflect the severity of endometrial cancer and the clinic relationship between microvasal density (MVD) and concentration of VEGF in tumor. The study was conducted on 22 patients affected by endometrial cancer who were submitted to total abdominal radical hysterectomy plus bilateral salpingo-ophorectomy. VEGF (pg/mL) and MVD values were measured on histologic specimens of endometrial cancer obtained during the surgical treatment. The means and standard deviations of estimated values were calculated and a statistical comparison was effected by student t test for not coupled data. Pearson correlation test was used to analyze the eventual correlation among VEGF and MVD values in overall patients. We have documented that VEGF expression and MVD change according to FIGO stage, lympho-vascular infiltration and lymph node involvement. Pearson correlation test shows a good linear positive correlation in overall patients between VEGF and MVD values. Results obtained show a possible use of VEGF as prognostic factor in endometrial cancer. Confirmation of these data may permit both to identify high-risk patients, who must be treated with a more aggressive treatment, and to use an angiogenic therapy in endometrial cancer.


[Presence of residues and pollutants in human milk].
The contamination of human milk by xenobiotics is a common problem worldwide which is affected by the geographical, climate-related, cultural and socioeconomic variations in each individual location. Public health policies have dealt with this situation by means of ongoing monitoring and restrictive legislation in order to reduce the damaging effects on the populations and the environment, objectivatable data however being recorded particularly in the developing countries. Overall and individual aspects of waste and contaminating oganochlorines, organophosphorates, antibiotics, polychlorate biphenyls, dioxins and furans, their content values, toxic effects studies and the maximum limits permitted under international legislation are highlighted.


Role of four-membered rings in C32 fullerene stability and mechanisms of generalized Stone-Wales transformation: a density functional theory investigation.
Density functional theory (DFT) methods have been applied to study C(32) fullerenes built from four-, five-, and six-membered rings. The relative energies of pure C(32) fullerenes have been evaluated to locate three most stable structures, 32:D(4d) with two squares, 1:D(3) without square and 5:C(s) with one square. Structural analysis reveals that there is a rearrangement pathway between the lowest energy classical isomer 1:D(3) and the lowest energy non-classical isomer 32:D(4d), and 5:C(s) behaves just as an intermediate between them. The kinetic processes of generalized Stone-Wales transformation (GSWT) with four-membered rings have been explored and two distinct reaction mechanisms are determined by all the transition states and intrinsic reaction coordinates with PBE1PBE/6-31G(d) approach for the first time. One mechanism is the concerted reaction with a rotating dimer closed to the cage surface and another is the stepwise reaction with a carbene-like sp(3) structure, whereas the latter is sorted into two paths based on four-membered ring vanishing before or after the formation of the carbene-like structure. It is indicated that there is no absolute preference for any mechanism, which depends on the adaptability of different reactants on the diverse mechanisms. Furthermore, it's found that the interconversion process with the participation of squares is more reactive than the rearrangement between C(60)_I(h) and C(60)_C(2v), implying some potential importance of non-classical small fullerenes in the fullerene isomerization.


Rapid and sensitive analysis of morphine in serum by reversed-phase high performance liquid chromatography with electrochemical detection.
A method is described for the determination of morphine in serum. Separation and quantitation are performed by reversed-phase high performance liquid chromatography with electrochemical detection. A sample size of 100 microL or less is required for detection of concentrations as low as 1 to 2 ng/mL. In trials with standard solutions, recovery was 75%. The between-run and within-run coefficients of variation were 7.3% (over the range of 5 to 200 ng/mL) and 9.1% (at 5 ng/mL), respectively.


Intrathecal humoral immunity to encephalitic RNA viruses.
The nervous system is the target for acute encephalitic viral infections, as well as a reservoir for persisting viruses. Intrathecal antibody (Ab) synthesis is well documented in humans afflicted by infections associated with neurological complications, as well as the demyelinating disease, multiple sclerosis. This review focuses on the origin, recruitment, maintenance, and biological relevance of Ab-secreting cells (ASC) found in the central nervous system (CNS) following experimental neurotropic RNA virus infections. We will summarize evidence for a highly dynamic, evolving humoral response characterized by temporal alterations in B cell subsets, proliferation, and differentiation. Overall local Ab plays a beneficial role via complement-independent control of virus replication, although cross or self-reactive Ab to CNS antigens may contribute to immune-mediated pathogenesis during some infections. Importantly, protective Ab exert anti-viral activity not only by direct neutralization, but also by binding to cell surface-expressed viral glycoproteins. Ab engagement of viral glycoproteins blocks budding and mediates intracellular signaling leading to restored homeostatic and innate functions. The sustained Ab production by local ASC, as well as chemokines and cytokines associated with ASC recruitment and retention, are highlighted as critical components of immune control.


Beyond the WHO classification of meningioma: using molecular diagnostics to guide management.
Meningioma are the most common primary brain tumour. Classically, meningioma are phenotypically grouped using the World Health Organisation (WHO) classification system. However, it is now understood that the WHO approach overfits tumours into three grades, resulting in similarly graded tumours displaying phenotypically distinct behaviour. There is a growing body of research investigating the molecular biology of these tumours, including genomic, transcriptomic, metabolomic, proteomic, and methylomic profiling. Such advancements in molecular profiling of meningioma are providing greater accuracy in prognostication of tumours. Furthermore, a clearer understanding of tumour molecular biology highlights potential targets for pharmacotherapies. Currently, the routine application of in-depth tumour molecular analysis is limited, however as it becomes more widely available it will likely result in improved patient care. This review seeks to explore the important developments in meningioma molecular biology, discussed in the context of their clinical importance.


Modern medical schools curricula: Necessary innovations and priorities for change.
Medical schools' curricula have expanded over the decades to incorporate important new medical breakthroughs and discoveries. Their current focus and overall structures remain, however, stubbornly captive of early 20th-century thinking, with changes having been undertaken in a piecemeal fashion. Indeed, since the notable Flexner reform in 1910, medical schools' study plans have suffered successive and typically always partial adjustments which have failed to keep up with scientific, technological and sociological change. This difficulty may be attributable to the well-known conservatism of medical schools, where updating study plans is a process that invariably encounters numerous barriers to change. These observations were afforded detailed attention some 15 years ago when de Oliveira wrote: 'it is now perfectly demonstrated that public medical schools have not been able to adapt their operation in depth and in due time to the new demands of teaching dictated by an explosive scientific and technological development'. Recent advances in communication and information technologies, as well as the introduction of new pedagogical techniques, have the potential to bring significant benefits to medical practice and healthcare systems, but these have not in the main become properly taught and utilized. The proposition that healthcare is evolving from reactive disease care to care that is predictive, preventive, personalized and participatory was initially regarded as highly speculative, yet systems approaches to biology and medicine are now beginning to provide experience of both health and disease at the molecular, cellular and organ levels. Medicine is a broad scientific field. In contrast to the 19th century, current medical 'sectarianism' is a positive by-product of rapid and gratifying medical progress, and the multiplicity of new models means that the lines of evidence legitimately bearing on practice and health policymaking are already highly diverse and likely to become ever more variegated over time. Put simply, most sound decisions, by definition, will be evidence-informed and not evidence-based, where divergence may be as informative as convergence. Here, the most enduring lesson of history is, perhaps, that clinical medicine is constantly rediscovering its humanistic core. Complexities create opportunities for innovation. In innovative environments, high-performing organizations are finding ways to create a culture that supports a diverse workforce preparing to deliver different models of care, with direct implications for excellence of patient experience and strong repercussions for medical education. The COVID-19 crisis saw major increases in the use of telemedicine, virtual office visits and other forms of online contact, and these are likely to increase considerably. This particular transformation will not be easy or comfortable to make. But reconfiguration of medical education seems inevitable, fuelled by online educational technology and the need to transform clinical training to more outpatient settings with promotion based on competency and person-centeredness, not simply time. As we prepare to enter 2024, this is an exciting time to be working in healthcare. We have more evidence than ever about how to provide high quality, person-centered care, and to keep patients safe. Shame on us if there is any hesitation about applying this knowledge to make the healthcare experience better for patients and providers. Embracing change and making continuous improvements are essential and urgent priorities for medicine and healthcare and, as we describe in the current article, will become more and more indispensably important in our rapidly changing world.


The role of aromatase inhibitors in breast cancer.
Aminoglutethimide (AG) has antitumor activity in disseminated breast cancer similar to that of surgical adrenalectomy. AG works by blocking conversion of aromatase enzymes necessary for conversion of androgens to estrogens. Tumor response in patients with disseminated disease has been approximately 30%, with a further 13% of patients achieving stabilization of disease. Age and previous systemic treatment did not influence response to AG, except that those who had not responded to previous endocrine responded less well to AG. Relief of bone pain occurred not only in patients whose bone metastases objectively responded but also in some patients whose disease progressed. Side effects, although significant initially, usually subsided within 3 weeks; the incidence of side effects may be related to the rate of acetylation of the drug by the liver. In randomized clinical trials, AG has been shown to be as effective as adrenalectomy and tamoxifen therapy. AG was not as well tolerated as tamoxifen, but it was more effective in patients with bone metastases.


Cancer Stem Cell and Hepatic Stellate Cells in Hepatocellular Carcinoma.
Hepatocellular carcinoma (HCC) is the most common liver cancer. It is highly lethal and has high recurrence. Death among HCC patients occur mainly due to tumor progression, recurrence, metastasis, and chemoresistance. Cancer stem cells (CSCs) are cell subpopulations within the tumor that promote invasion, recurrence, metastasis, and drug resistance. Hepatic stellate cells (HSCs) are important components of the tumor microenvironment (TME) responsible for primary secretory ECM proteins during liver injury and inflammation. These cells promote fibrogenesis, infiltrate the tumor stroma, and contribute to HCC development. Interactions between HSC and CSC and their microenvironment help promote carcinogenesis through different mechanisms. This review summarizes the roles of CSCs and HSCs in establishing the TME in primary liver tumors and describes their involvement in HCC chemoresistance.


Diffusion-weighted magnetic resonance sequence and CA125/CEA ratio can be used as add-on tools to ultrasound for the differentiation of ovarian from non-ovarian pelvic masses.
To provide a straightforward approach to the sequential use of ultrasound (US), magnetic resonance (MR) and serum biomarkers in order to differentiate the origin of pelvic masses, making the most efficient use of these diagnostic resources. This is a cross-sectional study with 159 patients (133 with ovarian and 26 with non-ovarian tumors) who underwent surgery/biopsy for an adnexal mass. Preoperative CA125 and CEA serum measurements were obtained and a pelvic/abdominal ultrasound was performed. Preoperative pelvic MR studies were performed for all patients. Morphological and advanced MR sequences were obtained. Using a recursive partitioning algorithm to predict tumor origin, we devised a roadmap to determine the probability of non-ovarian origin using only statistically significant US, laboratory and MR parameters. Upfront US classification as ovarian versus non-ovarian and CA125/CEA ratio were significantly associated with non-ovarian tumors. Signal diffusion (absent/low versus high) was the only MR parameter significantly associated with non-ovarian tumors. When upfront US designated a tumor as being of ovarian origin, further MR signal diffusion and CA125/CEA ratio were corrected nearly all US errors: patients with MR signal diffusion low/absent and those with signal high but CA125/CEA ratio ≥25 had an extremely low chance (<1%) of being of non-ovarian origin. However, for women whose ovarian tumors were incorrectly rendered as non-ovarian by upfront US, neither MR nor CA125/CEA ratio were able to determine tumor origin precisely. MR signal diffusion is an extremely useful MR parameter to help determine adnexal mass origin when US and laboratory findings are inconclusive.


Anti-Markovnikov Hydroamination of Unactivated Alkenes with Primary Alkyl Amines.
We report here a photocatalytic method for the intermolecular anti-Markovnikov hydroamination of unactivated olefins with primary alkyl amines to selectively furnish secondary amine products. These reactions proceed through aminium radical cation (ARC) intermediates and occur at room temperature under visible light irradiation in the presence of an iridium photocatalyst and an aryl thiol hydrogen atom donor. Despite the presence of excess olefin, high selectivities are observed for secondary over tertiary amine products, even though the secondary amines are established substrates for ARC-based olefin amination under similar conditions.


Role of nephrology pharmacists in the management of anemia in outpatient dialysis units: A Canadian model .
Hemodialysis patients frequently suffer from anemia. Proper utilization of therapies such as iron and erythropoiesis-stimulating agents (ESAs) is crucial to attain symptom management and established hemoglobin targets. The purpose of this study was to evaluate the clinical and financial impact of nephrology-trained pharmacists on anemia management in these patients. A retrospective study of outpatient hemodialysis patients observed between January 2010 and December 2011. In December 2010, pharmacists were tasked to manage anemia under a medical directive. Primary endpoints were compared across years using a mixed-effects model strategy. An unstructured random effects correlation matrix was utilized to capture patient-level variation in 2010 and 2011, separately. Of 202 patients identified, 163 contributed in both years, 57% were males, aged 65.18 ± 16.3 years. Hemoglobin levels were 10.95 ± 0.95 and 10.83 ± 0.94 g/dL in 2010 vs. 2011, respectively (p = 0.158), while the transfusion rate was 1.3% and 1.8%, respectively (p = 0.196). Ferritin levels of 273.5 ± 22 and 317.1 ± 12 ng/mL (p = 0.0019), iron saturation 0.30 ± 0.11 and 0.30 ± 0.05 (p = 0.838), and parenteral iron dose of 215.4 ± 100.2 and 317.1 ± 123.7 mg, respectively (p = 0.996), were identified. Finally, the average weekly ESA dose in 2010 was higher and trending up as compared to 2011 where it significantly trended down. The amount of intravenous erythropoietin alfa was 12,315.6 ± 76 vs. 11,364.1 ± 52 units/week, respectively (p = 0.0556) with expenditure of 2.8 million Canadian dollars in 2010 vs. 2.3 million Canadian dollars in 2011. The participation of a nephrology pharmacist resulted in favorable outcomes in dose optimization, decreased expenditure, and positive trends in therapeutic goal achievement.


Association of aldosterone and arginine vasopressin concentrations and clinical markers of hypoperfusion in neonatal foals.
Critically ill foals often present to veterinary hospitals with impaired organ perfusion which can be demonstrated by increased blood L-lactate concentrations. As a compensatory mechanism to low blood pressure and electrolyte abnormalities, aldosterone and arginine vasopressin (AVP) are released to restore organ perfusion and function. Several studies have investigated the ability of blood L-lactate concentrations to predict severity of disease and outcome in critically ill human patients, adult horses and foals. However, information on the aldosterone and AVP response to hypoperfusion and its association with L-lactate concentrations in neonatal foals is limited. To determine the association between clinical hypoperfusion and endocrine markers of reduced tissue perfusion in normo- and hypoperfused foals. Prospective, multicentre, cross-sectional observational study. Blood samples were collected on admission from 72 clinically hypoperfused, 110 normoperfused (73 hospitalised and 37 healthy) foals of ≤4 days of age. Foals were considered clinically hypoperfused if they had L-lactate concentrations ≥2.5 mmol/l and one of the 3 following findings: heart rate >120 beats/min, packed cell volume (PCV) >0.44 l/l or azotaemia (increased creatinine and blood urea nitrogen [BUN]). Blood concentrations of aldosterone and AVP were determined by radioimmunoassays. Aldosterone, AVP, creatinine and BUN concentrations and heart rate, PCV and blood osmolality were higher in clinically hypoperfused compared with normoperfused foals (P<0.05). Risk of hypoperfusion increased with the presence of hypothermic extremities (OR = 5.26) and with each one unit increase in albumin concentrations (OR = 3.5) (P<0.05). The proposed admission L-lactate cut-off value above which nonsurvival could be reliably predicted in hospitalised foals was 10.6 mmol/l with 82% of sensitivity and 74% of specificity. Hyperaldosteronaemia and hypervasopressinaemia as well as hypothermic extremities and increased albumin concentrations are potent predictors of hypoperfusion in hospitalised foals.


Endocrine precursor lesions and microadenomas of the duodenum and pancreas with and without MEN1: criteria, molecular concepts and clinical significance.
Proliferative changes in the neuroendocrine cells that precede neoplasia are of interest for the understanding of tumorigenesis and the early recognition of neuroendocrine tumors. This review focuses on precursor lesions of duodenal and pancreatic neuroendocrine tumors in multiple endocrine neoplasia type 1 (MEN1) and also discusses 2 new disease entities of pancreatic microadenomatosis. The gastrinomas observed in MEN1 are almost exclusively localized in the duodenum and are multicentric. It has been shown that, in contrast to sporadic duodenal gastrinomas, they are associated with hyperplastic gastrin cell lesions and tiny gastrin-producing microtumors less than 500 microm in diameter. In the pancreas, microadenomatosis (multiple tumors up to 5 mm in diameter) is a feature of MEN1. These microadenomas predominantly express glucagon and pancreatic polypeptide, but do not cause a hormonal syndrome. Approximately 50% of MEN1 minigastrinomas in the duodenum and almost all microadenomas in the pancreas show allelic deletion of the MEN1 gene and therefore may represent 'initial' neoplasms. In contrast, endocrine cell precursor lesions retain heterozygosity. Pancreatic microadenomatosis was also found unassociated with hereditary syndromes and 2 monohormonal types were identified: (1) glucagon-producing microadenomatosis and (2) insulin-producing microadenomatosis, both associated with macrotumors. Whether these types of microadenomatosis represent novel disease entities and how to diagnose and treat these patients remains to be clarified by further studies.


[Normative wideband absorbance measures in children: a cross-sectional study].
Objective: This study was to investigate the main characteristics and related factors of wideband absorbance (WBA) in children with normal hearing and to obtain age-specific reference range of WBA. Methods: 384 children between 0-12 years old (615 ears) who visited the Beijing Children's Hospital, Capital Medical University from October 2019 to February 2021 were enrolled, including 230 males (376 ears) and 154 females (239 ears), with totally 306 left ears and 309 right ears. Wideband tympanometry (WBT) was performed and normative WBA data were analyzed by SPSS 24.0 statistical software. Repeated measures and multivariate analysis of variance were applied to the data from 16 points at 1/3-octave frequencies (226, 324, 408, 500, 667, 841, 1 000, 1 297, 1 682, 2 000, 2 670, 3 364, 4 000, 5 339, 6 727 and 8 000 Hz) to evaluate the effects of frequency, age, external auditory canal pressures, gender and ear on WBA. Results: According to the WBT frequency-absorbance curve, the subjects were divided into seven groups: 1-month old group, 2-month old group, 3-month old group, 4-5 month old group, 6-24 month old group,>2-6 year old group and>6-12 year old group. The WBA of normal-hearing children underwent a series of developmental changes with age at both ambient pressure and tympanometric peak pressures. WBA results for 1-month group and 2-month old group exhibited a multipeaked pattern, with the peaks occurring around 2 000 and 4 897 Hz, and a notch around 3 886 Hz. WBA results for 3-month group and 4-5 month old group exhibited a single broad-peaked pattern, with the peak occurring between 2 000-4 757 Hz. The WBA of 1-month old group to 4-5 month old group decreased gradually at low frequency (226-408 Hz) and 6 727 Hz, and increased at middle to high frequency (2 670-4 000 Hz). The WBA of 6-24 month old group were significantly lower than that of 2-month old group to 4-5 month old group at all frequencies except 3 364 and 4 000 Hz. WBA results for 6-24 month old group,>2-6 year old group and>6-12 year old group exhibited a single-peaked pattern, and the peak frequency of WBA moved to the lower frequency successively. From 6-24 month old group to>6-12 year old group, the WBA gradually increased at low to middle frequencies (667-2 670 Hz) and 8 000 Hz, and decreased at middle to high frequencies (3 364-5 339 Hz). Among the 16 frequencies of all age groups, the difference between WBA under ambient pressure and tympanometric peak pressure were -0.09-0.06, and 43.75%-81.25% frequency points had statistically significant difference, which was mainly manifested in that WBA under ambient pressure were lower than that under tympanometric peak pressure at 226-1 682 Hz. There was no significant ear effect on all of the age groups. Similarly, there was no significant gender effect except for 3-month old group and 4-5 month old group. Conclusions: The WBA of normal-hearing children measured at ambient pressure and tympanometric peak pressure varied across the frequencies with age from 1 month to 12 years old, and different frequencies followed different change patterns (increase vs. decrease) in WBA. There was also significant external auditory canal pressures effect on all of the age groups. The establishment of age-specific reference range of WBA for 0-12 years old normal-hearing children in this study would be useful for clinical practice of determining normative data regarding WBT.


Resin bonding to sclerotic, noncarious, cervical lesions.
Noncarious, cervical, wedge-shaped, sclerotic lesions are commonly encountered in clinical practice. In such lesions, dentin has been pathologically altered, often resulting in partial or complete obliteration of the dentinal tubules. These lesions are known to respond to etching and bonding differently from normal dentin, leading to complications during clinical treatment. A search of the literature was performed to obtain background information on the most commonly cited etiologic factors, clinical diagnoses, and morphologic and chemical characterizations along with an extensive review of all potential obstacles to bonding the most recent adhesives to such a dentinal substrate. Recent progress in adaptive strategies to render dentin more receptive to resin bonding is emphasized in this article, and the major drawbacks of these strategies are discussed.


Homocysteine thiolactone and protein homocysteinylation: mechanistic studies with model peptides and proteins.
In vitro incubations were performed to show that homocysteine thiolactone could generate covalent adducts with model peptides and proteins. MS and MS/MS data suggest that the thiolactone reacts with the side-chain amino group of lysine residues as well as with the N-terminal amino group or C-terminal carboxy group. For larger peptides and proteins, the contribution from the in-amino groups of lysine residues should be predominant. These data could help explain the detrimental effects of elevated levels of homocysteine and homocysteine thiolactone.


Synovial hemangioma--a case report.
True synovial based hemangiomas are rare lesions and should be differentiated from mass lesions especially pigmented villonodular synovitis. A case of 4 years old male child, presenting with recurrent painful swelling, is described in the present article. The differential diagnosis is also discussed.


Surgical treatment of urethral diverticula in men.
Two 21-year-old men were treated for congenital diverticulum at the bulbous portion of the anterior urethra. One of the diverticula contained a stone. Acquired anterior urethral diverticulum with ventral displacement of the penile shaft following repair of hypospadias was treated in a 21-year-old man. Correction of the defect involved ventral paramedian vertical incision, excision of the diverticulum with closure at the urethra, and traction sutures for the ventral penile displacement.


The matrix-dependent 3D spheroid model of the migration of non-small cell lung cancer: a step towards a rapid automated screening.
In vitro 3D cell culture systems utilizing multicellular tumor spheroids (MCTS) are widely used in translational oncology, including for studying cell migration and in personalized therapy. However, early stages of cellular migration from MCTS and cross-talk between spheroids are overlooked, which was addressed in the current study. Here, we investigated cell migration from MCTS derived from human non-small cell lung cancer (NSCLC) cell line A549 cultured on different substrates, collagen gel or plastic, at different time points. We found that migration starts at 4-16 h time points after the seeding and its speed is substrate-dependent. We also demonstrated that co-culture of two NSCLC-derived MCTS on collagen gel, but not on plastic, facilitates cell migration compared with single MTCS. This finding should be considered when designing MCTS-based functional assays for personalized therapeutic approach and drug screenings. Overall, our work characterizes the in vitro 3D cell culture model resembling NSCLC cell migration from the clusters of CTCs into surgical wound, and describes microscopy-based tools and approaches for image data analysis with a potential for further automation. These tools and approaches also might be used to predict patterns of CTCs migration based on ex vivo analysis of patient biopsy in a 3D culture system.


MicroRNA miR-126-5p Enhances the Inflammatory Responses of Monocytes to Lipopolysaccharide Stimulation by Suppressing Cylindromatosis in Chronic HIV-1 Infection.
Persistent immune activation during chronic human immunodeficiency virus type 1 (HIV-1) infection facilitates immune dysfunction and thereby fuels disease progression. The translocation of bacterial derivatives into blood and the hyperinflammatory responsiveness of monocytes have been considered important causative factors for persistent immune activation. Whether microRNAs (miRNAs) are involved in regulating monocyte-mediated inflammatory responses during chronic HIV-1 infection remains elusive. In this study, we show that miR-126-5p functions as a positive regulator of monocyte-mediated inflammatory responses. Significantly increased miRNA miR-126-5p and decreased cylindromatosis (CYLD) were observed in primary monocytes from chronic HIV-1 patients. Inhibition of miR-126-5p in monocytes from chronic HIV-1 patients attenuated the responsiveness of these cells to lipopolysaccharide (LPS) stimulation. Gain-of-function assays confirmed that miR-126-5p could downregulate CYLD, which in turn caused an upregulation of phosphorylation of JNK protein (pJNK) and enhanced inflammatory responses of monocytes to LPS stimulation. Overall, miR-126-5p upregulates the responsiveness of monocytes to LPS stimulation in chronic HIV-1 infection, and the suppression of miR-126-5p and the promotion of CYLD expression in primary monocytes may represent a practical immune intervention strategy to contain persistent inflammation in chronic HIV-1 infection.IMPORTANCE Monocyte-mediated hyperinflammatory responses during chronic HIV-1 infection are important causative factors driving AIDS progression; however, the underlying mechanism has not been fully addressed. We demonstrated that miR-126-5p, one of the most upregulated miRNAs during chronic HIV-1 infection, could enhance the inflammatory responses of monocytes to LPS by suppressing the inhibitory protein CYLD and thereby unleashing the expression of pJNK in the LPS/Toll-like receptor 4/mitogen-activated protein kinase pathway. This observation reveals a new mechanism for HIV-1 pathogenesis, which could be targeted by immune intervention.


Clinical implications of macrolide resistance in community-acquired respiratory tract infections.
Laboratory surveillance data suggest that macrolide resistance among Streptococcus pneumoniae has increased dramatically over the past 15 years. This review examines the specifics of macrolide resistance and the clinical relevance of in vitro susceptibility testing in light of the pharmacokinetics and pharmacodynamics of azithromycin and clarithromycin. These drugs concentrate extensively within respiratory tissue and have other positive characteristics not reflected by in vitro susceptibility testing. In general, clarithromycin is the most potent macrolide and the one most likely to maintain clinical efficacy against the low-level resistance associated with most macrolide-resistant pneumococci in the USA. These findings suggest that susceptibility data may underestimate clinical utility and that clarithromycin still has a place in the empiric treatment of respiratory infections.


Nanomaterials-induced toxicity on cardiac myocytes and tissues, and emerging toxicity assessment techniques.
The extensive production and use of nanomaterials have resulted in the continuous release of nano-sized particles into the environment, and the health risks caused by exposure to these nanomaterials in the occupational population and the general population cannot be ignored. Studies have found that particle exposure is closely related to cardiovascular disease. In addition, there have been many reports that nanomaterials can enter the heart tissue, accumulate and then cause damage. Therefore, in the present article, literature related to nanomaterials-induced cardiotoxicity in recent years was collected from the PubMed database, and then organized and summarized to form a review. This article mainly discusses heart damage caused by nanomaterials from the following three aspects: Firstly, we summarize the research 8 carbon nanotubes, etc. Secondly, we discuss in depth the possible underlying mechanism of the damage to the heart caused by nanoparticles. Oxidative stress damage, mitochondrial damage, inflammation and apoptosis have been found to be key factors. Finally, we summarize the current research models used to evaluate the cardiotoxicity of nanomaterials, highlight reliable emerging technologies and in vitro models that have been used for toxicity evaluation of environmental pollutants in recent years, and indicate their application prospects.


Value-based focused global population health management.
In 2018, approximately 18 million people worldwide were diagnosed with cancer and are predicted to double by 2040. The global quality chasm in improving health care worldwide requires "systems thinking" as the key to success. Aligning the goal around person-centered care captures the total needs of care of a population and not just disease categories. The integration of the Institute of Medicine's (IOM) six aims of quality termed "value-based focused" and population health management (PHM) provides all health care leaders grappling with improving the health care of the populations a framework for the communities they serve. In this context, the question becomes finding solutions to providing high quality, compassionate and patient-centered health care delivery. Over the last two decades, three paradigms have emerged; the six aims of quality, outcome-focused population health, and the "Quadruple Aim". We have termed the intersection of these concepts as Value-based focused Population Health Management (VBPHM). This review applies VBPHM across the geographic county and community levels in the United States. Specifically, we examine VBPHM at the county or county-equivalents and community levels within the United States. Lastly, the potential role of Community-based Participatory Research and it is applicability to our framework is discussed. VBPHM can comparably be applied globally to improve population health, especially in preventing and treating cancer better.


Reliability and Validity of an Acromion Marker Cluster for Recording Scapula Posture at End Range Clavicle Protraction, Retraction, Elevation, and Depression.
Acromion marker cluster (AMC) methods have been shown to accurately track scapula motion during humeral elevation below 90°, however, their accuracy has not been assessed in shoulder girdle motion such as clavicle protraction, retraction, elevation, and depression independent of humeral movement. The aim of this study was to examine the reliability and validity of the AMC method to record scapula orientation at end range clavicle protraction, retraction, elevation, and depression. The right scapulae of 22 female and 20 male asymptomatic volunteers were assessed with an AMC and scapula locator (SL) method during end range clavicle protraction, retraction, elevation, and depression (without humeral elevation) using an 8-camera 3D movement registration system. Measurements recorded from the AMC and SL measures showed fair to excellent agreement (ICC 0.4-0.92). While the AMC method overestimated and underestimated scapular motion in some planes compared to the SL, root mean square error between methods were low for scapular internal/external rotation (2.3-3.7°), upward/downward rotation (4.5-6.6°), and anterior/posterior tilt (3.2-5.1°), across all conditions. The AMC method was shown to be a reliable and valid measurement of scapula orientation at end range clavicle movements independent of humeral movement.


Radical prostatectomy for low risk carcinoma of the prostate.
To review the role of radical prostatectomy in the management of patients with low risk carcinoma of the prostate. A summary of personal experience and pertinent literature is provided. In particular, information which permits conclusions on the efficacy and side effects of radical prostatectomy in this situation is considered. For patients with low risk carcinoma of the prostate who choose to undergo treatment with curative intent, radical prostatectomy is an excellent option. Removal of the prostate with negative surgical margins can be achieved with a high frequency. Patients are afforded these curity of an undetectable PSA postoperatively which helps eliminate some of the inherent concerns which go along with an untreated or inadequately treated tumor. Recent modifications in surgical approach, including laparoscopic and robotic-assisted surgery, have lessened even further the impact of surgery on quality of life. Some patients with low risk disease who undergo radical prostatectomy are over treated and cured of a cancer which may not have been a significant threat to life or health. However, the uncertainty of active surveillance leads many patients to pursue curative therapy and radical prostatectomy offers an extremely low risk of death from prostate cancer, even with long term follow-up. Erectile dysfunction remains a potential quality of life compromise for some patients but, otherwise, the overwhelming majority return to their preoperative status within a short time with minimal risk for quality of life compromise.