Antidepressant-like effects in various mice strains in the tail suspension test.
Several studies have reported rodent strain differences in the response to antidepressants in animal models of depression. The aim of the present study was to investigate the potential contribution of genetic factors to antidepressant response in an animal model of depression: the tail suspension test (TST). For this study four mice strains (Swiss and NMRI, two outbred strains and DBA/2 and C57BL/6J Rj, two inbred strains) were submitted to the TST after acute administration of five antidepressants: the tricyclic antidepressants (TCAs) imipramine and desipramine, the selective serotonin (5-HT) reuptake inhibitors (SSRIs) paroxetine and citalopram and the dopamine reuptake inhibitor bupropion. The C57BL/6J Rj strain had a longer baseline immobility time in comparison to the other strains. All antidepressants studied in this work decreased immobility time in the Swiss and C57BL/6J Rj strains. However, the Swiss strain displayed greater sensitivity to citalopram (from 2mg/kg) and C57BL/6J Rj to paroxetine (from 0.5mg/kg). This latter presented a greater size-effect with citalopram than with other strains and reached more than 60% from 8mg/kg. Moreover the size-effect of desipramine, paroxetine and bupropion in Swiss mice was greater than in the other strains in the TST. The NMRI and DBA/2 mice only responded to 5-HT reuptake inhibitors, both selective (paroxetine, citalopram) or non-selective (imipramine). The NMRI strain was more sensitive to imipramine and presented a size-effect (43% at 8mg/kg) superior to those of other strains. DBA/2 strain was more sensitive to citalopram than paroxetine and imipramine. Our results suggest that response to an antidepressant treatment is under control of genetic factors and that the strain of mouse is an important parameter to consider.


Regulation of B cell fates by BCR signaling components.
Recent results obtained in mice harboring cytoplasmic mutations of Igalpha and/or Igbeta have reinforced the concept that the strength of BCR signaling is important for ensuring appropriate developmental outcomes as well as antigen-specific responses. To establish the optimal signaling intensity and duration, the BCR utilizes positive and negative regulatory molecules. Studies are beginning to reveal how these molecules maintain immunological homeostasis and tolerance.


Mechanical thrombectomy of massive pulmonary embolism using an Arrow-Trerotola percutaneous thrombolytic device.
Mechanical thrombectomy of a large central thrombus in massive pulmonary embolism is a new option for the treatment of this serious condition. The special mechanical devices designed to fragmentize a blood clot include the Arrow-Trerotola percutaneous thrombolytic device (PTD), the use of which in the pulmonary arteries has not yet been reported. The case of massive embolism into the left pulmonary artery with subsequent collapse is to demonstrate the immediately clinically successful treatment using the PTD. Our initial experience with the PTD shows that its use is a safe and quick procedure.


Histone modifications associated with somatic hypermutation.
A number of modified histones, including acetylated H3 and H4 and phosphorylated H2AX (gammaH2AX), are associated with V(D)J recombination and class switch recombination (CSR). In contrast, little is known concerning the chromatin modifications associated with somatic hypermutation (SHM) in vivo. Here, we report that several modifications--including histone acetylation and H3-lysine 4 methylation--fail to demarcate an actively hypermutating immunoglobulin (Ig) locus or to correlate spatially with SHM within Ig loci. Furthermore, no obvious association between SHM and gammaH2AX could be detected. Instead, we find that the phosphorylated form of histone H2B (H2B(Ser14P)) correlates tightly with SHM and CSR. Phosphorylation of H2B within Ig variable and switch regions requires AID and may be mediated by the histone kinase Mst1. These findings indicate that SHM and CSR trigger distinct DNA damage responses and identify a novel histone modification pattern for SHM consisting of H2B(Ser14P) in the absence of gammaH2AX.


The 20S as a stand-alone proteasome in cells can degrade the ubiquitin tag.
The proteasome, the primary protease for ubiquitin-dependent proteolysis in eukaryotes, is usually found as a mixture of 30S, 26S, and 20S complexes. These complexes have common catalytic sites, which makes it challenging to determine their distinctive roles in intracellular proteolysis. Here, we chemically synthesize a panel of homogenous ubiquitinated proteins, and use them to compare 20S and 26S proteasomes with respect to substrate selection and peptide-product generation. We show that 20S proteasomes can degrade the ubiquitin tag along with the conjugated substrate. Ubiquitin remnants on branched peptide products identified by LC-MS/MS, and flexibility in the 20S gate observed by cryo-EM, reflect the ability of the 20S proteasome to proteolyze an isopeptide-linked ubiquitin-conjugate. Peptidomics identifies proteasome-trapped ubiquitin-derived peptides and peptides of potential 20S substrates in Hi20S cells, hypoxic cells, and human failing-heart. Moreover, elevated levels of 20S proteasomes appear to contribute to cell survival under stress associated with damaged proteins.


DNA probe modified with 3-iron bis(dicarbollide) for electrochemical determination of DNA sequence of Avian Influenza Virus H5N1.
In this work, we report on oligonucleotide probes bearing metallacarborane [3-iron bis(dicarbollide)] redox label, deposited on gold electrode for electrochemical determination of DNA sequence derived from Avian Influenza Virus (AIV), type H5N1. The oligonucleotide probes containing 5'-terminal NH2 group were covalently attached to the electrode, via NHS/EDC coupling to 3-mercaptopropionic acid SAM, previously deposited on the surface of gold. The changes in redox activity of Fe(III) centre of the metallacarborane complex before and after hybridization process was used as analytical signal. The signals generated upon hybridization with targets such as complementary or non-complementary 20-mer ssDNA or various PCR products consisting of 180-190 bp (dsDNA) were recorded by Osteryoung square-wave voltammetry (OSWV). The developed system was very sensitive towards targets containing sequence complementary to the probe with the detection limit estimated as 0.03 fM (S/N=3.0) and 0.08 fM (S/N=3.0) for 20-mer ssDNA and for dsDNA (PCR product), respectively. The non-complementary targets generated very weak responses. Furthermore, the proposed genosensor was suitable for discrimination of PCR products with different location of the complementarity region.


Role of sulfhydryl groups in the binding of vasoactive intestinal peptide to its receptor on murine lymphocytes.
The effect of sulfhydryl-containing compounds on the specific binding of the neuropeptide vasoactive intestinal peptide (VIP) to murine lymphocytes was studied. Both 2-mercaptoethanol (2ME) and dithiothreitol (DTT) inhibited VIP-binding to lymphocytes at millimolar concentrations. A sulfhydryl-containing analogue of VIP, [Cys2]VIP, was synthesized. This compound competed for the binding of [125I]VIP about 150,000 x more effectively than 2ME, but was approximately 100 x less effective than VIP itself. Both VIP and [Cys2]VIP increased intracellular cyclic AMP and inhibited the proliferative response of lymphocyte cultures to concanavalin A (ConA), but the molar potency of [Cys2]VIP on these lymphocyte activities was approximately 100 x less than that of VIP. The effects of VIP and [Cys2]VIP on intracellular cyclic AMP and ConA-stimulated proliferation were competed for by the VIP receptor antagonist [4Cl-D-Phe6,Leu17]VIP. Replacement of serine2 with L-cysteine disrupts the ability of VIP to occupy and activate lymphocyte VIP receptors. This may reflect a role of serine2 in hydrogen-bond formation during ligand-receptor interactions, or a functional role of sulfhydryl-containing residues of the VIP receptor in maintaining the integrity of the binding site of the VIP receptor on lymphocytes.


Complex I (reduced nicotinamide-adenine dinucleotide-coenzyme Q reductase) deficiency in two patients with probable Leigh syndrome.
Two infants who had clinical and radiographic findings consistent with Leigh syndrome were found to have deficiency of complex I (reduced nicotinamide-adenine dinucleotide--coenzyme Q reductase) activity. Significant abnormalities were found on computed tomographic scans and magnetic resonance images of the brain. Lactate and pyruvate concentrations in blood and cerebrospinal fluid were elevated, and muscle biopsy specimens showed abnormal mitochondria. These data indicate that Leigh syndrome, as well as MELAS syndrome (mitochondrial encephalopathy, myopathy, lactic acidosis, and stroke-like episodes) may result from complex I deficiency.


Both antigen optimization and lysosomal targeting are required for enhanced anti-tumour protective immunity in a human papillomavirus E7-expressing animal tumour model.
DNA immunization is a new approach for cancer immune therapy. In this study, we constructed human papillomavirus (HPV) 16 E7 expression vector cassettes and then compared the abilities of these constructs to induce antitumour protection. Lysosome-targeted E7 antigens, and to a lesser degree signal sequence-conjugated and transmembrane region sequence-conjugated E7 antigens in a DNA form, displayed tumour protection significantly higher than wild-type E7 antigens. This enhanced tumour protection was mediated by CD8+ cytotoxic T lymphocytes (CTL), as determined by in vivo T-cell depletion and in vitro interferon-gamma (IFN-gamma) production. Subsequent co-injection with interleukin-12-expressing cDNA showed insignificantly enhanced antitumour protection. However, E7 codon optimization plus lysosomal targeting resulted in a dramatic enhancement in antitumour protection both prophylactically and therapeutically through augmentation of the E7-specific CTL population, compared to either one of them alone. However, wild-type or codonoptimized E7 antigens without intracellular targeting displayed no protection against tumour challenge. Thus, these data suggest that antigen codon optimization plus lysosomal targeting strategy could be important in crafting more efficacious E7 DNA vaccines for tumour protection.


Genotype and anesthetic determine mate choice in Drosophila melanogaster.
Genetic differences that influence mating preferences were studied in genetically defined lines of Drosophila melanogaster. Initial results suggested substantial differences between two types of females with respect to the types of male preferred as mates, but further experimentation showed that the mating patterns were conditional on the mode of anesthesia (CO2 versus ether). In a statistical test of independence, the major determinant of mating choice in these experiments was due to an interaction effect between genotypes and mode of anesthesia. The observations might be explained by the differential sensitivity of male genotypes to ether. Etherization at emergence has lasting effects on mating behavior; it alters not only the latency and frequency of mating 4 days later, but also the pattern of matings observed.


Interaction between angiotensin II, osteoprotegerin, and peroxisome proliferator-activated receptor-gamma in abdominal aortic aneurysm.
Osteoprotegerin (OPG) has been associated with abdominal aortic aneurysm (AAA) expansion. Angiotensin II (AngII) receptor blockade has been shown to reduce OPG expression in human AAA tissue. Interaction between vascular AngII and OPG was further examined using cell culture and the AngII-infused ApoE(-/-) mouse AAA model. The ability of peroxisome proliferator-activated receptor-gamma (PPARgamma) activation to target OPG as potential therapy for AAA was also investigated. Human aortic smooth muscle cells (AoSMC) exposed to AngII exhibited dose-dependent increase in the production OPG. A 3-fold increase in suprarenal aortic concentration of OPG was observed in AngII-infused ApoE(-/-) mice. AngII type 1 receptor expression in human AAA tissue, and AoSMC in vitro, was stimulated up 4-fold in the presence of OPG. This effect in AoSMC was counteracted in the presence of the PPARgamma ligand, pioglitazone. Addition of PPARgamma ligand to cultured human AAA explant reduced OPG secretion by 60% and tissue concentration of OPG and metalloproteinase 9 by 2- and 3-fold, respectively. Administration of pioglitazone to AngII-infused ApoE(-/-) mice significantly reduced aortic concentrations of OPG and metalloproteinase 9. These data support an interaction between AngII and OPG in aneurysm formation. Activation of PPARgamma may have a role in treatment of AAA.


Characteristics of the Ontario Neurodegenerative Disease Research Initiative cohort.
Understanding synergies between neurodegenerative and cerebrovascular pathologies that modify dementia presentation represents an important knowledge gap. This multi-site, longitudinal, observational cohort study recruited participants across prevalent neurodegenerative diseases and cerebrovascular disease and assessed participants comprehensively across modalities. We describe univariate and multivariate baseline features of the cohort and summarize recruitment, data collection, and curation processes. We enrolled 520 participants across five neurodegenerative and cerebrovascular diseases. Median age was 69 years, median Montreal Cognitive Assessment score was 25, median independence in activities of daily living was 100% for basic and 93% for instrumental activities. Spousal study partners predominated; participants were often male, White, and more educated. Milder disease stages predominated, yet cohorts reflect clinical presentation. Data will be shared with the global scientific community. Within-disease and disease-agnostic approaches are expected to identify markers of severity, progression, and therapy targets. Sampling characteristics also provide guidance for future study design.


Numerical exploration of slip effects on second-grade fluid motion over a porous revolving disk with heat and mass transfer.
Revolving-disk systems are employed in various industrial settings including turbine engineering, chemical and food processing industries and others. The current article scrutinizes a second-grade fluid motion generated by an infinite porous disk having partial slip character. Heat transfer induced by heating of the disk surface and by viscous and ohmic heating effects is modeled and analyzed under thermal slip condition. Accompanying mass transfer process with thermophoretic diffusion is also formulated. A self-similar system is obtained akin to the case of no-slip case discussed in a previously published study. The adoption of velocity slip assumption induces non-linearity in the boundary conditions in velocity components. Computational procedure embedded in MATLAB bvp4c platform is opted to simulate the system for full range of slip parameters. In contrast to a previously published work pertaining to the no-slip case, present numerical methodology gives accurate results for wide ranges of Prandtl number and elasticity parameter. Boundary layer formations above the disk are examined under various controlling parameters. A comparative assessment of slip and no-slip cases is presented through both graphical illustrations and tabulated results for the resisting torque, the Nusselt number and the Sherwood number. Current numerical findings match very well with the existing homotopy solutions for the no-slip case. The presence of a wall slip mechanism leads to a clear suppression of all the velocity components. Furthermore, an augmentation in the thermal/concentration slip coefficient significantly reduces the thermal/solutal penetration depth. Additionally, we observe a noticeable increase in the driving torque as the elasticity parameter enhances. The slip action of the surface is also predicted to raise the torque required by the disk.


Capturing the patient's experience: using qualitative methods to develop a measure of patient-reported symptom burden: an example from ovarian cancer.
Experts in patient-reported outcome (PRO) measurement emphasize the importance of including patient input in the development of PRO measures. Although best methods for acquiring this input are not yet identified, patient input early in instrument development ensures that instrument content captures information most important and relevant to patients in understandable terms. The M. D. Anderson Symptom Inventory (MDASI) is a reliable valid PRO instrument for assessing cancer symptom burden. We report a qualitative (open-ended, in-depth) interviewing method that can be used to incorporate patient input into PRO symptom measure development, with our experience in constructing an MDASI module for ovarian cancer (MDASI-OC) as a model. Fourteen patients with ovarian cancer (OC) described symptoms experienced at the time of the study, at diagnosis, and during prior treatments. Researchers and clinicians used content analysis of interview transcripts to identify symptoms in patient language. Symptoms were ranked on the basis of the number of patients mentioning them and by clinician assessment of relevance. Forty-two symptoms were mentioned. Eight OC-specific items will be added to the 13 core symptom items and six interference items of the MDASI in a test version of the MDASI-OC on the basis of the number of patients mentioning them and clinician assessment of importance. The test version is undergoing psychometric evaluation. The qualitative interviewing process, used to develop the test MDASI-OC, systematically captures common symptoms important to patients with OC. This methodology incorporates the patient experience recommended by experts in PRO instrument development.


Toll-like receptor expression profile of stem/progenitor cells from human exfoliated deciduous teeth.
Stem/progenitor cells from human exfoliated deciduous teeth (SHED) show remarkable pluripotent, regenerative, and immunological capacities. During in vivo regenerative processes, there could be the presence of SHED in the surrounding inflammatory microenvironment, through toll-like receptors (TLRs). The aim of this paper was to present a characteristic TLR expression profile on SHED for the first time. Cells were harvested from extracted primary teeth (n = 10), anti-STRO-1 immunomagnetically sorted and cultivated, through colony-forming units (CFUs). SHED were examined for mesenchymal stem/progenitor cell traits, including the expression of clusters of differentiation (CDs) 14, 34, 45, 73, 90, 105, and 146, and their multilineage differentiation aptitude. TLRs 1-10 expression was investigated for SHED in uninflamed and inflamed (25 ng/mL IL-1β, 103 U/mL IFN-γ, 50 ng/mL TNF-α, and 3 × 103 U/mL IFN-α; SHED-i) microenvironmental conditions. SHED were negative for CDs 14, 34, and 45, but were positive for CDs 73, 90, 105, and 146, and demonstrated characteristic multilineage differentiation. In an uninflamed microenvironment, SHED expressed TLRs 1, 2, 3, 4, 6, 8, 9, and 10. The inflammatory microenvironment downregulated TLR7 significantly on gene level and upregulated TLR8 on gene and protein levels (p < .05; Wilcoxon signed-rank test). There appears to be a unique TLR expression profile on SHED, which could modulate their immunological and regenerative abilities in oral tissue engineering approaches.


Structural insights into the tropomodulin assembly at the pointed ends of actin filaments.
Tropomodulins are a family of important regulators of actin dynamics at the pointed ends of actin filaments. Four isoforms of tropomodulin, Tmod1-Tmod4, are expressed in vertebrates. Binding of tropomodulin to the pointed end is dependent on tropomyosin, an actin binding protein that itself is represented in mammals by up to 40 isoforms. The understanding of the regulatory role of the tropomodulin/tropomyosin molecular diversity has been limited due to the lack of a three-dimensional structure of the tropomodulin/tropomyosin complex. In this study, we mapped tropomyosin residues interacting with two tropomyosin-binding sites of tropomodulin and generated a three-dimensional model of the tropomodulin/tropomyosin complex for each of these sites. The models were refined by molecular dynamics simulations and validated via building a self-consistent three-dimensional model of tropomodulin assembly at the pointed end. The model of the pointed-end Tmod assembly offers new insights in how Tmod binding ensures tight control over the pointed end dynamics.


Validating a self-report screen for ADHD in early adulthood using childhood parent and teacher ratings.
This article evaluates the diagnostic utility of a self-report screening tool for adults based on Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV) ADHD criteria. Children with speech/language (S/L) impairment and typically developing controls had ADHD symptoms rated by parents and teachers at ages 5 and 12. At age 19, participants completed the Adult Attention Problems Scale (AAPS), an 18-item screen. Receiver operative characteristic curve analyses were used to assess the efficiency of this instrument in screening for ADHD. The AAPS had moderate sensitivity and high specificity, but only for adults without a history of communication disorders. The AAPS provides clinicians with the only self-report scales for ADHD in adulthood, validated with childhood ADHD symptoms assessed by multiple raters. However, scale characteristics were poor for the S/L-impaired cohort. Given the overlap between language impairment and ADHD, adult ADHD measures validated in S/L-impaired samples are needed.


Nanospheres for DNA separation chips.
We report here a technology to carry out separations of a wide range of DNA fragments with high speed and high resolution. The approach uses a nanoparticle medium, core-shell type nanospheres, in conjunction with a pressurization technique during microchip electrophoresis. DNA fragments up to 15 kilobase pairs (kbp) were successfully analyzed within 100 s without observing any saturation in migration rates. DNA fragments migrate in the medium while maintaining their characteristic molecular structure. To guarantee effective DNA loading and electrofocusing in the nanosphere solution, we developed a double pressurization technique. Optimal pressure conditions and concentrations of packed nanospheres are critical to achieve improved DNA separations.


Experimental Investigation on Minimum Frame Rate Requirements of High-Speed Videoendoscopy for Clinical Voice Assessment.
This study investigated the impact of high-speed videoendoscopy (HSV) frame rates on the assessment of nine clinically-relevant vocal-fold vibratory features. Fourteen adult patients with voice disorder and 14 adult normal controls were recorded using monochromatic rigid HSV at a rate of 16000 frames per second (fps) and spatial resolution of 639×639 pixels. The 16000-fps data were downsampled to 16 other rate denominations. Using paired comparisons design, nine common clinical vibratory features were visually compared between the downsampled and the original images. Three raters reported the thresholds at which: (1) a detectable difference between the two videos was first noticed, and (2) differences between the two videos would result in a change of clinical rating. Results indicated that glottal edge, mucosal wave magnitude and extent, aperiodicity, contact and loss of contact of the vocal folds were the vibratory features most sensitive to frame rate. Of these vibratory features, the glottal edge was selected for further analysis, due to its higher rating reliability, universal prevalence and consistent definition. Rates of 8000 fps were found to be free from visually-perceivable feature degradation, and for rates of 5333 fps, degradation was minimal. For rates of 4000 fps and higher, clinical assessments of glottal edge were not affected. Rates of 2000 fps changed the clinical ratings in over 16% of the samples, which could lead to inaccurate functional assessment.


Mechanism of activation for transcription factor PhoB suggested by different modes of dimerization in the inactive and active states.
Response regulators (RRs), which undergo phosphorylation/dephosphorylation at aspartate residues, are highly prevalent in bacterial signal transduction. RRs typically contain an N-terminal receiver domain that regulates the activities of a C-terminal DNA binding domain in a phosphorylation-dependent manner. We present crystallography and solution NMR data for the receiver domain of Escherichia coli PhoB which show distinct 2-fold symmetric dimers in the inactive and active states. These structures, together with the previously determined structure of the C-terminal domain of PhoB bound to DNA, define the conformation of the active transcription factor and provide a model for the mechanism of activation in the OmpR/PhoB subfamily, the largest group of RRs. In the active state, the receiver domains dimerize with 2-fold rotational symmetry using their alpha4-beta5-alpha5 faces, while the effector domains bind to DNA direct repeats with tandem symmetry, implying a loss of intramolecular interactions.


Terpene compound drug as medical expulsive therapy for ureterolithiasis: a meta-analysis.
The aim of this study is to investigate the efficacy of terpene compound drug (pinene, camphene, borneol, anethole, fenchone and cineol in olive oil) in facilitating spontaneous passage of ureteral calculi through meta-analysis of randomized controlled trials (RCT). Systematic literature search on MEDLINE, EMBASE, OVID, Science Direct, Proquest, Google scholar, Cochrane Library databases and reference list of related literatures were done without language restriction. RCTs on ureterolithiasis medical expulsive therapy (MET) that compare terpene compound drug versus placebo/control group or alpha-blockers were identified. Articles retrieved were critically appraised by two independent reviewers according to Cochrane Collaboration recommendations. Data from included studies were extracted for calculation of risk ratio (RR) and 95 % confidence interval (CI). Effect estimates were pooled using Mantel-Haenszel method with random effect model. Inter-study heterogeneity and publication bias were assessed. The PRISMA guidelines for meta-analysis reporting were followed. Five RCTs (total of 344 subjects) of adequate methodological quality were included. Pooled effect estimates from homogenous studies showed that compared to placebo/control group, patients treated with terpene compound drug had significantly better ureteral calculi spontaneous expulsion rate (pooled RR: 1.34; 95 % CI 1.12, 1.61). Subgroup analysis of studies that compare terpene compound drug with alpha-blockers showed no significant difference (pooled RR: 0.79; 95 % CI 0.59, 1.06), while significant inter-study heterogeneity was noted. Only minor gastrointestinal adverse effect was reported on terpene compound drug use. The results suggest that terpene compound drug as MET is effective in augmenting spontaneous passage of ureterolithiasis. High quality large-scale RCTs comparing alpha-blockers and terpene compound drug are warranted to make a more definitive conclusion.


Lichen Sclerosus Comorbidities and Complications from a National Sample of Patients Treated with Urethroplasty.
We characterize comorbidities and inpatient complications of patients with lichen sclerosus who underwent urethroplasty from a large national patient data source. We queried the Nationwide Inpatient Sample for patients who underwent urethroplasty between 2000 and 2010. We compared demographics, comorbidities, complications, length of hospital stay and hospital charges for patients with and without the diagnosis of lichen sclerosus. An estimated 13,700 urethroplasties were performed in the United States during the study period. Patients with lichen sclerosus comprised an estimated 3.8% of the urethroplasty population. The majority of patients with urethral stricture with lichen sclerosus were Caucasian (84%) and older, with 63% age 45 or older. Chronic hypertension, diabetes mellitus, rheumatoid arthritis/collagen vascular disease and obesity were associated with increased odds of having a lichen sclerosus diagnosis. The central East Coast (7.2%) and the Pacific Northwest (6.3%) had the highest percentage of patients treated with urethroplasty with lichen sclerosus. Patients with lichen sclerosus had longer hospital stays than those without lichen sclerosus (3.5 vs 2.6 days, p <0.0001). Patients with lichen sclerosus had more complications and hospital charges than those without lichen sclerosus but these differences did not reach statistical significance. A higher percentage of patients with lichen sclerosus had comorbidities, increased complications and longer hospital stays compared to patients treated with urethroplasty without lichen sclerosus. Our findings demonstrate the increased complexity that providers face when treating men with lichen sclerosus related urethral stricture disease.


In vivo and ex vivo regulation of breast cancer resistant protein (Bcrp) by peroxisome proliferator-activated receptor alpha (Pparα) at the blood-brain barrier.
Breast cancer resistance protein (Bcrp/Abcg2) localized at the blood-brain barrier (BBB) limits permeability into the brain of many xenobiotics, including pharmacological agents. Peroxisome proliferator-activated receptor α (Pparα), a ligand-activated transcription factor, primarily involved in lipid metabolism, has been shown to regulate the functional expression of Bcrp in human cerebral microvascular endothelial cells (hCMEC/D3). The aim of this study was to investigate ex vivo and in vivo, the regulation of Bcrp by Pparα in an intact BBB. Ex vivo quantitative real-time PCR and immunoblot analyses showed significant up-regulation of Abcg2/Bcrp mRNA and protein levels in CD-1 mouse brain capillaries incubated with clofibrate, a Pparα ligand. Fluorescence-based transport assays in CD-1 and C57BL/6 brain capillaries showed that exposure to clofibrate significantly increased Bcrp transport activity. This increase was not observed in capillaries isolated from Pparα knockout mice. In vivo, we found: i) significant Bcrp protein up-regulation in clofibrate-dosed CD-1 and C57BL/6 capillary lysates, but no effect in Pparα knockout capillary lysates, and ii) significantly increased Bcrp transport activity in capillaries isolated from clofibrate-treated mice. These results demonstrate an increase in Bcrp functional expression by Pparα in brain capillaries, and suggest that Pparα is another nuclear receptor that can contribute to the regulation of membrane efflux transporters and drug permeability at the BBB. We propose the involvement of the following pathways in clofibrate-mediated induction of the drug transporter Abcg2/Bcrp mRNA, protein expression and function by the nuclear receptor Pparα, in mouse brain capillary endothelial cells. Upon activation with clofibrate (Pparα, ligand), Pparα complex translocates from the cytoplasm into the nucleus and further recruits coactivators and transcription machinery which induce the transcription of Abcg2 gene and ultimately results in upregulation of Bcrp protein expression and function. These findings have significant implications since Bcrp is known to play an important role at the BBB in preventing the permeability of several xenobiotics and drugs into the brain.


Measuring health-related quality of life in elementary and secondary school students using the Chinese version of the EQ-5D-Y in rural China.
To measure health-related quality of life (HRQOL) of elementary and secondary school students in rural China using the simplified Chinese version of the EQ-5D-Y. Both the samples of students were from a school-based cohort study in a county located in southwestern China. The students self-completed the EQ-5D-Y. Feasibility was evaluated according to the percentages of missing values. Known group validity was assessed by comparing the frequency of reporting EQ-5D-Y problems between groups known to differ in health status. A total of 1728 elementary students and 2116 secondary students were included in the analysis. Their respective mean age was 8.7 (range: 7-15) years and 14.8 (range: 11-18) years, with girls being 45.1 and 50.1%, respectively. The missing values in both samples were quite low. Elementary students were less likely to have problems on'having pain or discomfort' and 'feeling worried, sad or unhappy' dimensions, but more likely to report problems on the dimensions related to physical functioning. Gender difference in HRQOL was only detected for secondary students in terms of 'doing usual activities', 'having pain or discomfort,' and 'feeling worried, sad or unhappy' (P < 0.05 for all). The significant differences in HRQOL were not observed for the other characteristics. It appears that the EQ-5D-Y is feasible and valid instrument in school-aged children and adolescents in rural China; but it suffers from similar disadvantages to those found in other general populations. The HRQOL distributions measured by the EQ-5D-Y were also provided.


Preoperative doxorubicin instillation in recurrent superficial bladder cancer.
Further recurrence of superficial bladder cancer after transurethral resection is frequent in patients who have already experienced recurrence. In an attempt to prevent or delay further recurrences in such patients, the effect of preoperative doxorubicin instillation was investigated. A total of 51 patients with recurrent superficial bladder cancer were randomized to receive either TUR alone or TUR with preoperative doxorubicin instillation. Doxorubicin was administered twice a week for 3 weeks before TUR surgery. An objective response (CR + PR) of the tumors was observed at operation in 12 of 25 (48%) evaluable doxorubicin-treated patients. Chemical cystitis was seen in 32% of the patients. Further recurrence after TUR was observed in 13 of 25 (52%) patients in the doxorubicin group, as against 15 of 23 (65%) evaluable patients in the control group. The mean disease-free interval was significantly longer (11.8 as against 7.1 months) in the doxorubicin group. These preliminary results suggest that preoperative doxorubicin instillation might be effective for prolongation of the disease-free interval in patients with recurrent bladder cancer.


The impact of globalisation on the distribution of Echinococcus multilocularis.
In the past three decades, Echinococcus multilocularis, the cause of human alveolar echinococcosis, has been reported in several new countries both in definitive hosts (canids) as well as in people. Unless treated, infection with this cestode in people is fatal. In previously endemic countries throughout the Northern Hemisphere, geographic ranges and human and animal prevalence levels seem to be increasing. Anthropogenic influences, including increased globalisation of animals and animal products, and altered human/animal interfaces are thought to play a vital role in the global emergence of this pathogenic cestode. Molecular epidemiological techniques are a useful tool for detecting and tracing introductions, and differentiating these from range expansions.


A Bayes-optimal sequence-structure theory that unifies protein sequence-structure recognition and alignment.
A rigorous Bayesian analysis is presented that unifies protein sequence-structure alignment and recognition. Given a sequence, explicit formulae are derived to select (1) its globally most probable core structure from a structure library; (2) its globally most probable alignment to a given core structure; (3) its most probable joint core structure and alignment chosen globally across the entire library; and (4) its most probable individual segments, secondary structure, and super-secondary structures across the entire library. The computations involved are NP-hard in the general case (3D-3D). Fast exact recursions for the restricted sequence singleton-only (1D-3D) case are given. Conclusions include: (a) the most probable joint core structure and alignment is not necessarily the most probable alignment of the most probable core structure, but rather maximizes the product of core and alignment probabilities; (b) use of a sequence-independent linear or affine gap penalty may result in the highest-probability threading not having the lowest score; (c) selecting the most probable core structure from the library (core structure selection or fold recognition only) involves comparing probabilities summed over all possible alignments of the sequence to the core, and not comparing individual optimal (or near-optimal) sequence-structure alignments; and (d) assuming uninformative priors, core structure selection is equivalent to comparing the ratio of two global means.


Antioxidant therapy for recurrent pancreatitis: placebo-controlled trial.
Oxidant stress has been proposed as the initiating pathogenetic mechanism in pancreatitis, hence micronutrient antioxidant therapy has been assessed in patients with recurrent attacks and/or constant pancreatic pain. In a 20-week double-blind double-dummy crossover trial active treatment was given as two types of tablets providing daily doses of 600 micrograms organic selenium, 9000 IU beta carotene, 0.54 g vitamin C, 270 IU vitamin E and 2 g methionine. Of 28 patients enrolled, 20 adhered to the full protocol (idiopathic chronic 8, alcoholic chronic 7, idiopathic acute 5). Six patients had an attack whilst on placebo but none whilst on active treatment (P = 0.032). Analysis of visual analogue scoresheets to compare background pain in the 10-week period before entry and during each phase of the trial, using a 10-cm scale for each of 11 best descriptors, endorsed the beneficial effect of active treatment (placebo v baseline, P = 0.073; active v baseline, P less than 0.001; active v placebo, P = 0.049). The same trend emerged from analysis of pain-score diaries by conventional and time series methods. Micronutrient antioxidant therapy thus offers a new approach to the treatment of recurrent (non-gallstone) pancreatitis and/or pancreatic pain.


Eye movements reveal no immediate "WOW" ("which one's weird") effect in autism spectrum disorder.
Autism spectrum disorder (ASD) and typically developed (TD) adult participants viewed pairs of scenes for a simple "spot the difference" (STD) and a complex "which one's weird" (WOW) task. There were no group differences in the STD task. In the WOW task, the ASD group took longer to respond manually and to begin fixating the target "weird" region. Additionally, as indexed by the first-fixation duration into the target region, the ASD group failed to "pick up" immediately on what was "weird". The findings are discussed with reference to the complex information processing theory of ASD (Minshew & Goldstein, 1998 ).


Promotion of growth by elevated carbon dioxide is coordinated through a flexible transcriptional network in Arabidopsis.
Although gibberellins (GAs) promote many developmental responses in plants, little is known about how the hormone interacts with environmental signals at the molecular level for regulating plant growth. Recently, we have demonstrated that inhibition of growth by the GA biosynthesis inhibitor paclobutrazol (PAC) at ambient [CO₂] (350 µmol CO₂ mol(-1)) is reverted by elevated [CO₂] (750 μmol CO₂ mol(-1)). Our finding points to an important role of elevated [CO₂] as a signal allowing higher growth rates of low-GA plants. GA promotes plant growth via a complex transcriptional network that integrates multiple signaling pathways. Herein, we discuss how elevated [CO₂] stimulates biomass accumulation in a GA-independent manner by regulating the expression of growth-related genes.


Mechanisms of disease: genetics of rheumatoid arthritis--ethnic differences in disease-associated genes.
Large studies on the genetics of common rheumatic diseases, such as rheumatoid arthritis and systemic lupus erythematosus, have identified multiple polymorphisms related to disease susceptibility, including peptidylarginine deiminase 4 (PADI4) and protein tyrosine phosphatase N22 (PTPN22). Some of the identified genes are associated with multiple autoimmune disorders, and some seem to have unique associations with particular disease entities. Although the molecules encoded by these genes have a primary role in the molecular pathways of autoimmunity, genetic variations and contribution to disease susceptibility seem to vary between ethnic groups. In this Review, we report the findings on genes associated with rheumatoid arthritis and focus on the differences in the frequency of polymorphisms between various ethnic groups.


A Prospective Randomized Trial Comparing Restorelle Y Mesh and Flat Mesh for Laparoscopic and Robotic-Assisted Laparoscopic Sacrocolpopexy.
The primary objective of this study was to compare case and mesh placement times between Restorelle Y mesh and flat mesh. The secondary objective was to compare subjective and objective outcomes between the 2 mesh configurations. This is a randomized trial of women undergoing laparoscopic (LSC) or robotic (RSC) sacrocolpopexy for posthysterectomy vaginal prolapse. Subjects were predetermined to undergo either an LSC or RSC and randomized to Y mesh or flat mesh. Case and mesh placement times were defined as incision time to time of closure and time from mesh introduced into the abdomen to placement of the last sacral stitch, respectively. All subjects underwent Pelvic Organ Prolapse Quantification System examination and completed the 20-item Pelvic Floor Disability Index preoperatively, at 6, 12, and 24 months. Sixty-two patients were enrolled, and 59 patients were implanted with mesh: 30 with Y mesh (17 LSC, 13 RSC) and 29 with flat mesh (18 LSC, 11 RSC). There were no differences in patient characteristics between mesh groups. Mean case and mesh placement times for all subjects were 204.4 ± 48 and 46.1 ± 13.5 minutes, respectively, with no differences between the groups. At 6 months, 20-item Pelvic Floor Disability Index scores improved significantly for all subjects with no differences by mesh type. Three subjects (5.5%) reported vaginal bulge symptoms, and no subjects were retreated for prolapse or were found to have recurrent prolapse on examination. There were also no mesh erosions. Case and mesh placement times do not differ in patients undergoing LSC or RSC with either Restorelle Y mesh or flat mesh. At 6 months, subjective and objective successes were 94% and 100%, respectively.


High-dose intravenous immunoglobulins reduce nerve macrophage infiltration and the severity of bortezomib-induced peripheral neurotoxicity in rats.
Chemotherapy-induced peripheral neurotoxicity (CIPN) is a severe adverse effect in patients receiving antitumor agents, and no effective treatment is available. Although the mechanisms responsible for the development of CIPN are poorly understood, recent findings make neuroinflammation an attractive target to be investigated, particularly when neuropathic pain is a prominent feature such as after bortezomib administration. The aim of our study was to evaluate the effect of intravenous immunoglobulins (IVIg) delivery in chronic CIPN. The related neuro-immune aspects were investigated in a well-characterized rat model of bortezomib-induced peripheral neurotoxicity (BIPN). After determination of a suitable schedule based on a preliminary pharmacokinetic pilot study, female Wistar rats were treated with IVIg 1 g/kg every 2 weeks. IVIg treatment was started at the beginning of bortezomib administration ("preventive" schedule), or once BIPN was already ensued after 4 weeks of treatment ("therapeutic" schedule). Neurophysiological and behavioral studies were performed to assess the extent of painful peripheral neurotoxicity induced by bortezomib, and these functional assessments were completed by pathologic examination of peripheral nerves and intraepidermal nerve fiber quantification (IENF). The role of the innate immune response in BIPN was investigated by immunochemistry characterization of macrophage infiltration in peripheral nerves. Both schedules of IVIg administration were able to significantly reduce bortezomib-induced heat and mechanical allodynia. Although these changes were not evidenced at the neurophysiological examination of peripheral nerves, they behavioral effects were paralleled in the animals treated with the preventive schedule by reduced axonopathy in peripheral nerves and significant protection from loss of IENF. Moreover, IVIg administration was very effective in reducing infiltration in peripheral nerves of macrophages with the M1, pro-inflammatory phenotype. Our results suggest a prominent role of neuroinflammation in BIPN and that IVIg might be considered as a possible safe and effective therapeutic option preventing M1 macrophage infiltration. However, since neuropathic pain is frequent also in other CIPN types, it also indicates the need for further investigation in other forms of CIPN.


Long-term growth hormone treatment in children with renal hypophosphatemic rickets: effects on growth, mineral metabolism, and bone density.
To evaluate the effects of treatment with recombinant human growth hormone (rhGH) on growth, mineral metabolism, and bone density in children with renal hypophosphatemic rickets (RHR). Long-term rhGH treatment combined with conventional therapy with 1,25-dihydroxyvitamin D3 plus inorganic phosphate salts. Endocrine unit, department of pediatrics, university hospital. Twelve patients (5 boys; age range 4.6 to 12.5 years, median 7.0 years) were subdivided into two groups of six patients on the basis of the median of height z score (-2.41) and the median bone age/statural age (BA/SA) ratio (1.23). Group A included patients with a severe degree of short stature (height z score -3.4 +/- 0.5) (mean +/- SD) and altered BA/SA ratio (1.26 +/- 0.08); group B included patients with a lesser degree of short stature (height z score -2.1 +/- 0.6, p < 0.001 vs group A) and more normal BA/SA ratio (1.04 +/- 0.15, p < 0.01 vs group A). Group A received rhGH treatment (0.6 IU/kg per week subcutaneously) combined with conventional therapy; group B received conventional therapy alone. Height, growth velocity, predicted adult height, serum values of calcium, phosphate, bone alkaline phosphatase isoenzyme, osteocalcin, propeptides of type I and type III procollagen, intact parathyroid hormone, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and urinary calcium/urinary creatinine ratio and tubular maximum for phosphate reabsorption normalized to the glomerular filtration rate (TmP/GFR), as well as radial bone density, were measured at baseline and for 3 years. Height z score, growth velocity z score, predicted adult height, serum values of phosphate, bone alkaline phosphatase isoenzyme, osteocalcin, propeptides of type I and type III procollagen, intact parathyroid hormone 1,25-dihydroxyvitamin D, and TmP/GFR, as well as radial bone density, improved significantly only in group A. Serum calcium and 25-hydroxyvitamin D, and urinary calcium/urinary creatinine ratio did not change in either group. Long-term rhGH administration may benefit growth, phosphate retention, and bone density in patients with RHR, without evidence of side effects.


No differences in subjective knee function between surgical techniques of anterior cruciate ligament reconstruction at 2-year follow-up: a cohort study from the Swedish National Knee Ligament Register.
The purpose of this study was to investigate how different techniques of single-bundle anterior cruciate ligament (ACL) reconstruction affect subjective knee function via the Knee injury and Osteoarthritis Outcome Score (KOOS) evaluation 2 years after surgery. It was hypothesized that the surgical techniques of single-bundle ACL reconstruction would result in equivalent results with respect to subjective knee function 2 years after surgery. This cohort study was based on data from the Swedish National Knee Ligament Register during the 10-year period of 1 January 2005 through 31 December 2014. Patients who underwent primary single-bundle ACL reconstruction with hamstrings tendon autograft were included. Details on surgical technique were collected using a web-based questionnaire comprised of essential AARSC items, including utilization of accessory medial portal drilling, anatomic tunnel placement, and visualization of insertion sites and landmarks. A repeated measures ANOVA and an additional linear mixed model analysis were used to investigate the effect of surgical technique on the KOOS4 from the pre-operative period to 2-year follow-up. A total of 13,636 patients who had undergone single-bundle ACL reconstruction comprised the study group for this analysis. A repeated measures ANOVA determined that mean subjective knee function differed between the pre-operative time period and at 2-year follow-up (p < 0.001). No differences were found with respect to the interaction between KOOS4 and surgical technique or gender. Additionally, the linear mixed model adjusted for age at reconstruction, gender, and concomitant injuries showed no difference between surgical techniques in KOOS4 improvement from baseline to 2-year follow-up. However, KOOS4 improved significantly in patients for all surgical techniques of single-bundle ACL reconstruction (p < 0.001); the largest improvement was seen between the pre-operative time period and at 1-year follow-up. Surgical techniques of primary single-bundle ACL reconstruction did not demonstrate differences in the improvement in baseline subjective knee function as measured with the KOOS4 during the first 2 years after surgery. However, subjective knee function improved from pre-operative baseline to 2-year follow-up independently of surgical technique.


The value of immunohistochemistry in increasing diagnostic precision of undifferentiated tumours by the surgical pathologist.
The availability of polyclonal and monoclonal antibodies allows immunohistochemical staining (immunofluorescence and immunoperoxidase) procedures to be used by the surgical pathologist, so as to obtain a definite diagnosis in cases where light microscopic examination of tissue sections from biopsy and surgical specimens in inconclusive. Four cases of undifferentiated tumours are described in which only a differential diagnosis could be obtained using light microscopy but a definite diagnosis was achieved when additional information was provided by immunohistochemistry. A scheme is presented for the use of immunohistochemistry to increase diagnostic precision in assessing tumours.


Pallidal neuronal discharge in Huntington's disease: support for selective loss of striatal cells originating the indirect pathway.
Chorea is the predominant motor manifestation in the early symptomatic phase of adult onset Huntington's disease (HD). Pathologically, this stage is marked by differential loss of striatal neurons contributing to the indirect pathway. This pattern of neuronal loss predicts decreased neuronal firing rates in GPi and increased firing rates in GPe, the opposite of the changes in firing rate known to occur in Parkinson's disease (PD). We present single-unit discharge characteristics (33 neurons) observed in an awake patient with HD (41 CAG repeats) undergoing microelectrode guided surgery for pallidal deep brain stimulation. Pallidal single-unit activity at "rest" and during voluntary movement was discriminated off line by principal component analysis and evaluated with respect to discharge rate, bursting, and oscillatory activity in the 0-200 Hz range. 24 GPi and 9 GPe units were studied, and compared with 132 GPi and 50 GPe units from 14 patients with PD. The mean (+/-SEM) spontaneous discharge rate for HD was 58+/-4 for GPi and 73+/-5 for GPe. This contrasted with discharge rates in PD of 95+/-2 for GPi and 57+/-3 for GPe. HD GPi units showed more bursting than PD GPi units but much less oscillatory activity in the 2-35 Hz frequency range at rest. These findings are consistent with selective early loss of striatal cells originating the indirect pathway.


Application of heart-cutting two-dimensional liquid chromatography-mass spectrometry to the characterization of highly polar impurities in calcium gluconate injection.
The separation and characterization of small polar impurities in polar drugs such as calcium gluconate products are always challenging, due to their poor retention on traditional reversed phase (RP) columns. Although ion-pair reversed-phase liquid chromatography (IPRP-LC) and hydrophilic interaction liquid chromatography (HILIC) are commonly used methods for polar compound analysis, both methods have some drawbacks. For example, IPRP-LC is incompatible with mass spectrometry (MS) due to the presence of non-volatile salts in its mobile phase and HILIC has limited sensitivity due to the poor solubility of polar drugs in the organic-rich sample diluents used in HILIC separations. In order to characterize the highly polar impurities in calcium gluconate injections, a heart-cutting two-dimensional liquid chromatography (2D-LC) method coupled with quadrupole time-of-flight mass spectrometry (Q-TOF/MS) was developed in this study. An IPRP-LC method in the first dimension (1D) provided the selectivity for the separation of polar analytes, using a 100% aqueous mobile phase containing phosphate buffer and ion-pair reagent. Heart cuts of target peaks were collected with sample loops and transferred to the second dimension (2D) HILIC column using an organic-rich mobile phase. In order to solve the mobile phase mismatch problem between the two dimensions, a make-up flow module was introduced in the 2D-LC system to dilute the 1D-water-rich fractions with acetonitrile before entering the sample loops. By optimizing the loop size and dilution factor, good retention and peak shape of the highly polar impurities were obtained on the 2D-HILIC column, and the ion suppression effect for MS detection from the ion-pair reagent and non-volatile salt in the 1D-effluent was minimized. A total of five impurities were identified through fragmentation studies by Q-TOF/MS analysis and their fragmentation pathways were proposed. Four of them were further confirmed by reference substances. This study not only provided useful information for quality control of calcium gluconate injections, but also provided an alternative method for polar impurity characterization in pharmaceuticals.


Prevalence and characteristics of cervical human papillomavirus genotypes and cervical lesions among 58630 women from Guangzhou, China.
To assess the prevalence and characteristics of human papillomavirus (HPV) genotypes and its associated cervical lesions in Guangzhou, China, which may be useful for adjusting area-specific cervical cancer prevention and control strategies. A total of 58630 women were enrolled. Cervical specimens were collected for HPV DNA testing and/or cervical cytology. Patients with visible cervical lesions or abnormal screening results underwent further cervical biopsies. The overall HPV positive rate was 14.07%. The top five genotypes in Guangzhou were HPV 52 (3.06%), HPV 16 (2.28%), HPV 58 (1.80%), HPV 51 (1.32%), and HPV 39 (1.15%). The prevalence of overall HPV and vaccine-targeted HPV genotypes showed a significantly decreasing trend from 2016 to 2019 (P < 0.05). While, the infection rate of HPV 35 increased significantly during this time (P = 0.015). The age-specific prevalence of any HPV genotypes showed a bimodal curve, which peaked firstly among the < 20 y age group, and then peaked secondly among the > 59 y age group. Among HPV-positive women, the proportions of HSIL and cervical cancer increased significantly with age (P < 0.05). Among > 59 y age group, 9.35% HPV-positive cases were diagnosed as cervical cancer. HPV 16/18 was the most common cause of cervical cancer. While, the percentage of non-HPV 16/18 infection among cervical cancer patients increased over time, from 15.21% in 2015 to 26.32% in 2019 (P = 0.010). Besides that, the prevalence of non-HPV 16/18 genotypes among cervical cancer patients significantly increased with age, which peaked at the > 59 y age group (P = 0.014). Although the prevalence of any HPV and vaccine-targeted HPV genotypes decreased significantly with time, it is still important to follow the HPV genotypes and their associated cancer risk after the large-scale popularization of HPV vaccine. And age should be taken into consideration in screening strategies and risk-based management of cervical cancer in Guangzhou.


Relationship between body condition score and ultrasound measurement of backfat thickness in multiparous Holstein dairy cows at different production phases.
The validity of the body condition score (BCS) for evaluating subcutaneous fat has been questioned because of its subjectivity. With the advent of ultrasonography, backfat thickness (BFT) can be objectively measured and used to assess the energy status of dairy cows in conjunction with BCS. Determine the relationship between BCS and ultrasound measurements of BFT throughout the lactation cycle. Cows (n = 1123) were selected randomly and classified according to their lactation stage into four different groups. BCS was determined using a 5-point scale and BFT measurements were obtained using a 5-MHz linear transducer. The correlation coefficient (r) for the relationship between BCS and BFT varied according to the stage of lactation. There was a high correlation (r = 0.96-0.98) and relationship (r(2) = 0.92-0.96) between BCS and BFT. The highest correlation was found at BFT values of 10-35 mm and BCS of 2-4.5 units. BCS is a practical tool for evaluating body condition; furthermore, it may be as valid as BFT for the estimation of subcutaneous fat in Holstein dairy cows over time.


ROS-responsive nanomodulators downregulate IFITM3 expression and eliminate ROS for Alzheimer's disease combination treatment.
Neuronal damage caused by β-amyloid (Aβ) aggregates and excess reactive oxygen species (ROS) is a crucial pathogenic event in Alzheimer's disease (AD). However, current Aβ-targeting RNA interference (RNAi) treatments have shown limited therapeutic efficacy due to ineffective intracerebral siRNA delivery and overlooked crosstalk between excess ROS and Aβ aggregates in the brain. Herein, a ROS-responsive nanomodulator (NM/CM) was developed for the combinational treatment of RNAi and ROS elimination for AD. NM/CM was coated with 4T1 cell membranes, which endowed NM/CM with the capability to cross blood-brain barrier (BBB). After being internalized by neural cells, NM/CM releases curcumin (Cur) and siIFITM3 spontaneously into the cytoplasm. The released Cur can eliminate ROS, protecting neurons from oxidative damage and reducing the production of Aβ induced by ROS-related neuroinflammation. The released siIFITM3 can downregulate the expression of interferon-induced transmembrane protein 3 (IFITM3), thereby reducing the abnormal Aβ production mediated by IFITM3. As a result, NM/CM remarkably alleviated ROS- and Aβ aggregate-induced neurotoxicity in vitro, showing significant neuroprotective effects. This work demonstrates the potential of NM/CM in the development of novel and effective AD combination therapies.


Rewiring AMPK and mitochondrial retrograde signaling for metabolic control of aging and histone acetylation in respiratory-defective cells.
Abnormal respiratory metabolism plays a role in numerous human disorders. We find that regulation of overall histone acetylation is perturbed in respiratory-incompetent (ρ(0)) yeast. Because histone acetylation is highly sensitive to acetyl-coenzyme A (acetyl-CoA) availability, we sought interventions that suppress this ρ(0) phenotype through reprogramming metabolism. Nutritional intervention studies led to the discovery that genetic coactivation of the mitochondrion-to-nucleus retrograde (RTG) response and the AMPK (Snf1) pathway prevents abnormal histone deacetylation in ρ(0) cells. Metabolic profiling of signaling mutants uncovered links between chromatin-dependent phenotypes of ρ(0) cells and metabolism of ATP, acetyl-CoA, glutathione, branched-chain amino acids, and the storage carbohydrate trehalose. Importantly, RTG/AMPK activation reprograms energy metabolism to increase the supply of acetyl-CoA to lysine acetyltransferases and extend the chronological lifespan of ρ(0) cells. Our results strengthen the framework for rational design of nutrient supplementation schemes and drug-discovery initiatives aimed at mimicking the therapeutic benefits of dietary interventions.


Differential functions of PKC-delta and PKC-zeta in cisplatin response of normal and transformed thyroid cells.
We investigated the effects of cisplatin (cisPt) in normal PC Cl3 and in transformed and tumourigenic PC E1Araf cells. cisPt cytotoxicity was higher in PC Cl3 than in PC E1Araf cells. In both cell lines, cisPt provoked the ERK1/2 phosphorylation; this was unaltered by Gö6976, a conventional PKC inhibitor, whilst it was blocked by low doses (0.1 microM) or high doses (10 microM) of GF109203X, an inhibitor of all PKC isozymes, in PC Cl3 and in PC E1Araf cells, respectively. In PC E1Araf, the cisPt-provoked ERK phosphorylation was also blocked by the use of a myristoylated PKC-zeta pseudosubstrate peptide. Conversely, in PC Cl3 the cisPt-provoked ERK phosphorylation was blocked by the use of rottlerin, a PKC-delta inhibitor. Results show that cisPt activates both PKC (the -delta and the -zeta isozymes in PC Cl3 and in PC E1Araf cells, respectively) and ERK in association with prolonged survival of thyroid cell lines.


Pediatric gastrointestinal diseases: are drugs the answer?
Owing to the lack of large randomized controlled studies, which would produce level 1 evidence, to guide management of gastrointestinal disorders in children, data are often extrapolated from adult studies to aid in treatment strategies. However, there are unique aspects to the management of children and adolescents with these chronic diseases, including issues of growth, side effects, long-term outcomes and psychosocial factors that might not be considered in adult trials. There is a major need for increased research in this population. In the future, a better understanding of the pathophysiologic mechanisms of these diseases should guide the development of rational novel therapies with better safety profiles for children with gastrointestinal disorders.


Evaluation of a Text Messaging-Based Human Papillomavirus Vaccination Intervention for Young Sexual Minority Men: Results from a Pilot Randomized Controlled Trial.
Men who have sex with men (MSM) are at high risk for human papillomavirus (HPV) infection and HPV-related anal cancer. Although a safe and effective vaccine is available to prevent HPV infection, HPV vaccine uptake among young MSM remains low. This pilot randomized controlled trial tested the acceptability, feasibility, and preliminary efficacy of a text messaging-based HPV vaccination intervention for young sexual minority men. In 2018, unvaccinated sexual minority men aged 18-25 years were recruited from Chicago to participate in a 9 month sexual health program called txt2protect. Participants (N = 150) were randomized to the intervention or control condition. Intervention condition messages focused primarily on HPV vaccination, with only a brief mention of other sexual health practices (e.g., condom use and HIV testing), while control condition messages focused on a variety of sexual health practices with only a brief mention of HPV vaccination. Participants received daily text messages for the first 3 weeks and monthly text messages for the remaining ~8 months of the trial. Participants completed surveys at baseline and 3 week and 9 month follow-ups. Participants reported high satisfaction with the intervention. Although trial retention was high (with over 88% completing the 9 month survey), the study fell short of meeting its recruitment goal. HPV vaccine series initiation was significantly higher among intervention participants (19.4%) compared to control participants (6.6%), odds ratio = 3.43, 95% confidence interval: 1.17, 10.08. Findings suggest that txt2protect is an acceptable and potentially promising intervention for increasing HPV vaccine initiation among young sexual minority men. NCT02994108.


New optimum solutions of nonlinear fractional acoustic wave equations via optimal homotopy asymptotic method-2 (OHAM-2).
The second iteration of the optimal homotopy asymptotic technique (OHAM-2) has been protracted to fractional order partial differential equations in this work for the first time (FPDEs). Without any transformation, the suggested approach can be used to solve fractional-order nonlinear Zakharov-Kuznetsov equations. The Caputo notion of the fractional-order derivative, whose values fall within the closed interval [0, 1], has been taken into consideration. The method's appeal is that it provides an approximate solution after just one iteration. The suggested method's numerical findings have been contrasted with those of the variational iteration method, residual power series method, and perturbation iteration method. Through tables and graphs, the proposed method's effectiveness and dependability are demonstrated.


Secreted phospholipase A2-induced neurotoxicity and epileptic seizures after intracerebral administration: an unexplained heterogeneity as emphasized with paradoxin and crotoxin.
After intracerebral injection, some toxic secreted phospholipases A2 (sPLA2) can induce epileptic seizures which bases are currently ill known. We undertook the detailed study of the central neurotoxicity of paradoxin (PDX), an analog of taipoxin, in rodents. Since literature strongly suggests a high variability in the sPLA2 epileptogenic properties, we compared, in an acute model, PDX with crotoxin (CTX), known to induce seizures and that may bind to similar neuronal receptors. Related toxic enzymes (ammodytoxin A, ATX A, and CTX subunit CB) and the non neurotoxic sPLA2 from pancreas and PLA2 analog ammodytin L (AML) were also tested. Despite being highly neurotoxic, PDX did not induce either convulsions or long-lasting seizure fits. The results obtained with the other enzymes showed that toxic sPLA2s can effectively be differentiated based on two criteria: the presence of cortically recorded epileptic paroxysmal discharges (E) and convulsions (C). We thus propose to classify the toxic sPLA2s into different groups depending on their epileptogenic properties: E-C-(PDX), E+C+ (CTX, CB), and E-C+ (ATX A). The non toxic AML and pancreatic enzyme were E-C-. Moreover, the results obtained with AML, and preliminarily with chemically inhibited CB, suggested that phospholipid hydrolysis is important to trigger seizures and convulsions. However, PDX and CTX that possess highly different epileptogenic properties exerted comparable, although slightly different, catalytic activities. Similarly, histological evaluations of the brain of PDX and CTX-treated rats (H&E staining, GFAP immunodetection, hsp70 and c-fos mRNA detection) did not provide satisfactory clues to explain these large differences. Further studies are strongly required.


Changes in intrahepatic gene expression profiles from chronic hepatitis to hepatocellular carcinoma in patients with hepatitis C virus infection.
DNA microarray technology has enabled genome-wide analysis of gene transcript levels, which has yielded insight into the molecular nature of hepatitis C virus infection. However, little insight into the molecular nature of the early to advanced stages of chronic liver disease has as yet been obtained. We compared the gene expression profiles of liver biopsy specimens from 14 patients at different stages of chronic hepatitis C. We also evaluated the liver tissue of hepatocellular carcinoma and its surrounding region obtained surgically in seven patients with hepatitis C virus infection. Of 21 073 genes, 582 genes showed significant changes in expression levels across the disease group. Twenty-eight samples from six disease groups clustered according to the histological classification except for 4 samples. A heat map produced by hierarchical clustering revealed nine clusters where gene expression profiles were changed in abundance. Among 44 genes which changed twofold or more in transcript abundance, transcripts from chronic hepatitis tended to be upregulated, and gradually downregulated according to disease progression toward hepatocellular carcinoma in five of nine clusters. In chronic hepatitis, transcripts relating to metabolism and immune response were upregulated, while in hepatocellular carcinoma, transcripts associated with cell cycle, growth, proliferation, apoptosis and signaling pathway were upregulated. Disease progression in hepatitis C virus-infected patients appeared to be associated with changes in gene expression profiles in the liver consistent with plausible functional categories, although we should confirm these findings using larger samples.


Quantification of HFV-integrated DNA in human cells by Alu-LTR real-time PCR.
Integration is described as a key step in viral replication of all retroviruses. A sensitive and quantitative measure of an integrated molecule is a good way to examine the importance of the integration step and to evaluate efficiency of retroviral vectors for gene transfer or anti-integrase drugs. Here, we report a sensitive and quantitative real-time polymerase chain reaction (PCR) technique to measure integrated viral DNA in human cells during a foamy virus (HFV) infection. This technique is based on two steps of PCR. The first round amplifies Alu-LTR (long terminal repeat) sequences resulting from viral integration. The second round of PCR is performed to quantify these events of integration. Quantification is monitored by the comparison of the amplification curve of the sample against a standard scale constituted of viral DNA from chronically infected cells. Sensitivity of this technique allows us to detect as few as 25 copies of HFV-integrated DNA in 50,000 cells.


The histology and ultrastructure of the salivary glands of Neopanorpa longiprocessa (Mecoptera: Panorpidae).
The salivary glands of Panorpidae usually exhibit distinct sexual dimorphism and are closely related to the nuptial feeding behavior. In this study, the salivary glands of Neopanorpa longiprocessa were investigated using light microscopy and transmission electron microscopy. The salivary glands are tubular labial glands and consist of a scoop-shaped salivary pump, a common salivary duct, and a pair of salivary tubes. The male and female salivary glands are remarkably different in the bifurcation position of the common salivary duct and the length and shape of the secretory tubes. Compared with the simple female salivary glands, the male's are more developed as their paired elongated salivary tubes can be divided into two parts, the glabrate anterior tube and the posterior tube with many secretory tubules. The ultrastructural study shows that the male salivary tubes have strong secretory function. The existence of different secretion granules indicates that there are some chemical reactions or mixing occurring in the lumen. Based on the ultrastructural characteristics, the functions of the different regions of the salivary tube have been speculated. The relationship between the salivary glands and nuptial feeding behavior of N. longiprocessa has been briefly discussed based on the structure of the salivary glands.


Kinematics of lateral tongue-pushing movement in coordination with masticatory jaw movement: An anteroposterior projection videofluorographic study.
During the mastication of solid food, the tongue pushes the bolus laterally to place it onto occlusal surfaces as the jaw is opened. This movement is referred to as tongue-pushing (TP). TP has an important role in efficient chewing, but its kinematic mechanisms remain unclear. The present study quantified the kinematics of TP and its coordination with masticatory jaw movements. Videofluorography (VFG) in anteroposterior projection was recorded while 14 healthy young adults ate 6 g each of cookies and meat. Small lead markers were glued to the tongue surface (left, right, and anterior) and buccal tooth surfaces (upper molars and lower canines). The position of the tongue and lower canine markers relative to the upper occlusal plane was quantified with Cartesian coordinates, using the right upper molar as the origin. Jaw motion during chewing was divided into TP and Non-TP cycles, based on the lateral movement of the food and tongue markers. The side of the jaw that compressed food particles was defined as the working side, while the other side was termed the balancing side. Horizontal and vertical displacements of tongue and jaw markers were compared between TP and Non-TP cycles, as well as between food types. The mediolateral displacement of all tongue markers was significantly larger in TP than in Non-TP cycles. Vertical displacement was also significantly greater in TP than in Non-TP cycles for the anterior and working side tongue markers. TP cycles occurred more frequently with meat-chewing than with cookie-chewing. TP is accomplished by rotation and lateral movements of the tongue surface on the working side and the anterior tongue blade, along with medial movement on the balancing side. These movements produce lateral shift and rotation of the tongue surface toward the working side in concert with jaw opening. Designing exercises to improve the strength of the lateral motion and rotation of the tongue body may be useful for individuals with impaired tongue function for eating and swallowing.


High concentrations of free kinins and kinin system components in abdominal transudate of a patient with nephrotic syndrome.
High levels of bradykinin (60--80 ng/ml) were found in abdominal transudate from a patient with nephrotic syndrome caused by chronic glomerulonephritis. The abdominal transudate contained neutral kininogenase and its precursor, identified with plasma kallikrein and prekallikrein, respectively, as well as both forms of kininogen, the low-molecular-weight form predominating. The abdominal transudate was characterized also by very low kininase activity and low levels of alpha 1-antitrypsin (0.46 g/l) and alpha 2-macroglobulin. Large amounts of very low density lipoproteins were present in the transudate. Despite the difference in total protein content between the abdominal transudate and the patient's serum (4.3 g/l and 48 g/l, respectively) their protein fraction composition was similar. The data obtained suggest that bradykinin is important in maintenance of long-lasting blood vessel hyperpermeability, which, in turn, is a driving force in the pathogenesis of refractory nephrotic edema.


Prominent forehead hematomas ("goose-eggs") as an initial manifestation of hemophilia.
Prominent forehead hematomas, "goose-eggs," may suggest an underlying disorder of coagulation. We reviewed records of 324 children with hemophilia and confirmed that a goose-egg was the presenting feature leading to a diagnosis of hemophilia in 14 of them. Primary care providers should be aware of this unique presentation of hemophilia.


Isolation and characterization of Bacillus cereus-like bacteria from faecal samples from greenhouse workers who are using Bacillus thuringiensis-based insecticides.
Since the discovery of the insecticidal activity of Bacillus thuringiensis at the beginning of the twentieth century, this bacterium has been used increasingly against various insect pests. In spite of the extensive use of B. thuringiensis, only sporadic clinical case reports have been published. In recent years, the close relationship between B. thuringiensis and the human pathogen Bacillus cereus has been confirmed. In practice, only the insecticidal activity of B. thuringiensis distinguishes the two species. However, both species are composed of thousands of isolates with varying potential for causing adverse effects in humans. The aim of this study was to employ molecular biology methods for assessment of occupational exposure to B. thuringiensis-based biopesticides by determination of specific genetic information including plasmid profiles and random amplified polymorphic DNA (RAPD). Faecal samples from 12 persons, working in Danish greenhouses, were collected for microbial analysis. Seven persons were using B. thuringiensis-based insecticides, whereas five persons were employed at greenhouses that did not use B. thuringiensis. The bacteria were isolated on B. cereus-specific solid substrate, and colonies were further identified using the polymerase chain reaction (PCR). The PCR method was used for the identification of the enterotoxin genes HblA and BceT. The expression of enterotoxins was detected with two commercial serological kits. Primers specific for 16S-23S spacer region were used to identify the bacteria as members of the B. cereus group. Several primers towards insecticidal genes have been used in order to further characterize the isolates as subspecies of B. thuringiensis. Two faecal samples from the B. thuringiensis-exposed greenhouse workers were positive for B. cereus-like bacteria. One isolate displayed intracellular crystalline inclusions characteristic of B. thuringiensis, production of and genes for B. cereus enterotoxins and it was PCR-positive for an insecticidal toxin primer set. RAPD profiles of the faecal isolate were identical to that of strains isolated from a commercial product. The methods applied have verified that the faecal isolate was identical to the B. thuringiensis isolate found in the biopesticide used. This is the first reported case of isolation of a bacterial biopesticide from human faeces. The biopesticide was shown to harbour and express enterotoxin genes. However, there is no evidence that this caused any adverse effects to the person from whom these bacteria were isolated.


Complete nucleotide sequence of Cherry leaf roll virus (CLRV), a subgroup C nepovirus.
The complete nucleotide sequence of both genomic (+)ss RNAs of a rhubarb isolate of Cherry leaf roll virus (CLRV) was determined. The larger RNA1 is 7918 nucleotides and the shorter RNA2 6360 nucleotides in size, each genome component comprising a single open reading frame (ORF). The RNA1-encoded polyprotein (P1) is 2112 amino acids long (235.6 kDa) containing domains characteristic for a proteinase-cofactor (PCo), nucleotide-binding helicase (Hel), genome-linked protein (VPg), proteinase (Pro), and an RNA-dependent RNA polymerase (Pol). The RNA2-encoded polyprotein (P2) has a molecular mass of 174.9 kDa (1589 aa) encoding the putative movement protein (MP) and the coat protein (CP) of CLRV. The genome region upstream of the MP has a coding capacity of 77 kDa, however processing of P2 by the putative virus-encoded proteinase and protein-function encoded by this region is unknown. Furthermore, it could be demonstrated that the 5'-termini including the N-terminal region (208 aa) of P1 and P2 of the rhubarb isolate of CLRV are nearly identical among the two genome segments. The taxonomic position of CLRV as member of the genus Nepovirus was confirmed by phylogenetic analyses employing the amino acid sequences of the conserved Pro-Pol region of RNA1, the complete P2, and the CP. However, clustering of Nepovirus-species according to allocated subgroups was inconsistent and depended on the compared genome fragment.


New pre-pandemic influenza vaccines: an egg- and adjuvant-independent human adenoviral vector strategy induces long-lasting protective immune responses in mice.
Highly pathogenic avian H5N1 influenza viruses that are currently circulating in southeast Asia may acquire the potential to cause the next influenza pandemic. A number of alternate approaches are being pursued to generate cross-protective, dose-sparing, safe, and effective vaccines, as traditional vaccine approaches, i.e., embryonated egg-grown, are not immunogenic. We developed a replication-incompetent adenoviral vector-based, adjuvant- and egg-independent pandemic influenza vaccine strategy as a potential alternative to conventional egg-derived vaccines. In this paper, we address suboptimal dose and longevity of vaccine-induced protective immunity and demonstrate that a vaccine dose as little as 1 x 10(6) plaque-forming unit (PFU) is sufficient to induce protective immune responses against a highly pathogenic H5N1 virus. Furthermore, the vaccine-induced humoral and cellular immune responses and protective immunity persisted at least for a year.


Strongylus vulgaris (Looss, 1900) in horses in Italy: is it still a problem?
A post-mortem survey was carried out on 46 Sardinian horses to evaluate the presence of Strongylus vulgaris and associated pathology. Horses were from local farms and had been treated with broad-spectrum anthelmintics at least 3 times a year. Examination of the cranial mesenteric arterial system (CMAS) showed parasite-induced lesions in all horses. S. vulgaris larvae were found in 39% of examined arteries, while their detection rate in coprocultures was 4%. Histology, carried out on 26 horses, showed mainly chronic and chronic-active lesions. Histometry showed a significant increase in thickness of the arterial wall, in particular of the intima tunic and adventitia tunic of the ileocolic artery and its colic branch. MCV, MCHC and alpha2, beta and gamma globulins were increased in horses with S. vulgaris larvae in the arteries, while the albumin/globulin ratio was decreased. Horses that were positive on faecal examination showed decreased values for RBC, PCV and the albumin/globulin ratio. Although several studies have shown a dramatic decrease of S. vulgaris infection worldwide, our data show that this parasite continues to exert its pathogenic role, even when its detection rate is quite low within the strongyle population infecting horses.


Etiology of Phytophthora drechsleri and P. nicotianae (=P. parasitica) Diseases Affecting Floriculture Crops.
Phytophthora nicotianae and P. drechsleri isolates (n = 413) recovered from eight floricultural hosts at 11 different production sites were described according to compatibility type, resistance to mefenoxam, and amplified fragment length polymorphism (AFLP) profiles. Sample sizes ranged from 2 to 120. In all cases, isolates recovered from a single facility had the same compatibility type and resistance to mefenoxam. AFLP analysis indicated that six clonal lineages of P. nicotianae and two clonal lineages of P. drechsleri were responsible for the 11 epidemics and that isolates recovered from the same facility were identical. A single clone of P. nicotianae was recovered from snapdragons at two field production sites in the southeastern United States receiving seedlings from the same source. This clone persisted at one site from 2000 to 2001. Another clone was recovered from verbena at three separate greenhouse facilities where one facility was supplying verbena to the other two. These results suggest that asexual reproduction of these pathogens plays an important role in epidemics and spread may occur between distant facilities via movement of plants.


Role of formative assessment in predicting academic success among GP registrars: a retrospective longitudinal study.
The James Cook University General Practice Training (JCU GPT) programme's internal formative exams were compared with the Royal Australian College of General Practitioners (RACGP) pre-entry exams to determine ability to predict final performance in the RACGP fellowship exams. A retrospective longitudinal study. General Practice (GP) trainees enrolled between 2016 and 2019 at a Registered Training Organisation in regional Queensland, Australia. 376 GP trainees enrolled in the training programme. The pre-entry exams were Multiple-Mini Interviews (MMI), Situational Judgement Test (SJT) and Candidate Assessment and Applied Knowledge Test. The internal formative exams comprised multiple choice questions (MCQ1 and MCQ2), short answer questions, clinical skills and clinical reasoning. The college exams were Applied Knowledge Test (AKT), Key Feature Problems (KFP) and Objective Structured Clinical Examination (OSCE). Correlations (r), coefficients of determination (R2) and OR were used as parameters for estimating strength of relationship and precision of predictive accuracy. SJT and MMI were moderately (r=0.13 to 0.31) and MCQ1 and MCQ2 highly (r=0.37 to 0.53) correlated with all college exams (p<0.05 to p<0.01), with R2 ranging from 0.070 to 0.376. MCQ1 was predictive of failure in all college exams (AKT: OR=2.32, KFP: OR=3.99; OSCE: OR=3.46); while MCQ2 predicted failure in AKT (OR=2.83) and KFP (OR=3.15). We conclude that the internal MCQ formative exams predict performance in the RACGP fellowship exams. We propose that our formative assessment tools could be used as academic markers for early identification of potentially struggling trainees.


Implementation of vaccine programs in Ecuador.
The experience in Ecuador with various immunization strategies between 1971 and 1984 and their impact on immunization coverage and morbidity due to vaccine-preventable diseases are described. A national campaign of social mobilization was undertaken in 1986, raising coverage levels substantially.


Liponeurocytoma: Systematic Review of a Rare Entity.
Liponeurocytoma is a rare benign tumor of the central nervous system, which develops mainly in adult patients within the posterior fossa. The World Health Organization has categorized this entity in its last classification of 2016 as a benign grade II tumor. Histopathologic characteristics contain neuronal and variable astrocytic differentiation with foci of lipomatous distinction. Only a few case reports and case series have been reported and the knowledge of this tumor is limited. General treatment guidelines do not exist. The aim of this study was to analyze the literature to create treatment guidelines. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines were followed to search existing online databases between January 1, 1978 and May 15, 2018. A systematic review of the literature found 73 patients (40 female, 33 male) with liponeurocytoma, in 59 of whom (80.8%) the disease occurred in the posterior fossa. The Ki-67/MIB-1 proliferation index was described in 58 patients, showing a mean value of 3.73% ± 4.01%. Follow-up was performed in 49 patients, with a median length of 52.02 ± 50.52 months, showing tumor recurrence in 14 patients (28.57%). Tumor recurrence was observed in only 1 patient (1/12, 8.33%) after adjuvant radiotherapy, whereas tumor recurrence was seen in 13/29 patients (44.83%) who did not receive adjuvant radiotherapy. Liponeurocytomas are rare benign tumors, occurring mainly in the cerebellum. The therapy of choice is surgery. Postoperative radiotherapy seems to decrease the risk of tumor recurrence and should be offered to the patient.


Curcumin encapsulation in functional PLGA nanoparticles: A promising strategy for cancer therapies.
Nanoparticles have emerged as promising drug delivery systems for the treatment of several diseases. Novel cancer therapies have exploited these particles as alternative adjuvant therapies to overcome the traditional limitations of radio and chemotherapy. Curcumin is a natural bioactive compound found in turmeric, that has been reported to show anticancer activity against several types of tumors. Despite some biological limitations regarding its absorption in the human body, curcumin encapsulation in poly(lactic-co-glycolic acid) (PLGA), a non-toxic, biodegradable and biocompatible polymer, represents an effective strategy to deliver a drug to a tumor site. Furthermore, PLGA nanoparticles can be engineered with targeting moieties to reach specific cancer cells, thus enhancing the antitumor effects of curcumin. We herein aim to bring an up-to-date summary of the recently developed strategies for curcumin delivery to different types of cancer cells through encapsulation in PLGA nanoparticles, correlating their effects with those of curcumin on the biological capabilities acquired by cancer cells (cancer hallmarks). We discuss the targeting strategies proposed for advanced curcumin delivery and the respective improvements achieved for each cancer cell analyzed, in addition to exploring the encapsulation techniques employed. The conjugation of correct encapsulation techniques with tumor-oriented targeting design can result in curcumin-loaded PLGA nanoparticles that can successfully integrate the elaborate network of development of alternative cancer treatments along with traditional ones. Finally, the current challenges and future demands to launch these nanoparticles in oncology are comprehensively examined.


Dopamine-mediated behavior produced by the enkephalin analogue FK 33-824.
Intraperitoneal injection of FK 33-824 produced apomorphine-like stereotyped behavior in rats. Antagonism of this stereotypy by naloxone and neuroleptics suggests that FK 33-824 can activate opiate and dopamine receptors in the brain. Because increased dopaminergic neuronal activity is thought to be involved in schizophrenia and dopamine-mediated stereotypy has been used as an animal model for this illness, these results are consistent with an involvement of endogenous opiate-like peptides in schizophrenia. This involvement provides a possible mechanism for the reported improvement in schizophrenic psychosis produced by naloxone.


Serum organophosphate flame retardants and plasticizers in Chinese females of childbearing age: Association with serum reproductive and thyroid hormones.
Organophosphate flame retardants (OPFRs) are extensively used as flame retardants and plasticizers, but their endocrine disrupting potentials have raised concerns. However, the impacts of OPFR exposures on reproductive and thyroid hormones in females remains unclear. In this study, serum concentrations of OPFRs were investigated, and levels of reproductive and thyroid hormones, including follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, anti-Müllerian hormone, prolactin (PRL), testosterone (T), and thyroid stimulating hormone, were analyzed in childbearing-age females undergoing in-vitro fertilization treatment from Tianjin, a coastal city in China (n = 319). Tris (2-chloroethyl) phosphate (TCEP) was the predominant OPFR, with a median concentration of 0.33 ng/mL and a detection frequency of 96.6%. In the whole population, tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) and tris(2-chloroisopropyl) phosphate (TCIPP) were positively associated with T (p < 0.05), while triethyl phosphate (TEP) was negatively associated with LH (p < 0.05) and LH/FSH (p < 0.01). Particularly, TCIPP was negatively associated with PRL in the younger subgroup (age≤30, p < 0.05). Moreover, TCIPP was negatively associated with diagnostic antral follicle counting (AFC) in the mediation analysis by a dominating direct effect (p < 0.01). In conclusion, serum levels of OPFRs were significantly associated with reproductive and thyroid hormone levels and a risk of decreased ovarian reserve in childbearing-age females, with age and body mass index being significant influencing factors.


What credentials are required for robotic-assisted surgery in reconstructive and functional urology?
The increasing popularity of robotic assisted surgery (RAS) as it is implemented in to sub specialities poses many challenges to ensuring standards in quality and safety. The area of Reconstructive and Functional Urology (RFU) has a wide range and largely complex heterogeneous procedures. In recent years RFU has started to incorporate RAS as the primary method to undertake these procedures due to improved vision, dexterity, and access to deep cavities. To ensure patient safety majority of institutions maintain minimal requirements to operate using RAS however across specialities and institutions these greatly vary. A narrative review of all the relevant papers known to the author was conducted. Specific challenges facing RFU is the inability to rely on case numbers as a surrogate means to measure competency as well the ongoing consideration of how to differentiate between surgeons with robotic training and those with the clinical experience specific to RFU. This review explores current models of training and credentialling and assess how it can be adapted to suggest a standardised guideline for RFU to ensure the highest standards of patient care.


Hexavalent chromium induces apoptosis in human liver (HepG2) cells via redox imbalance.
Hexavalent chromium, Cr(VI), is an environmental toxicant and is associated with hepatotoxicity. However, very little is known about the intracellular antioxidant defense mechanism against Cr(VI)-induced cytotoxicity in hepatocytes. In the present study, we cultured human liver (HepG2) cells in the absence or presence of Cr(VI) and determined its effect on cellular oxidative stress, mitochondrial damage, apoptosis and the expression of the transcription factor Nrf2 and the Nrf2-dependent antioxidant enzymes. Cr(VI) intoxication at a dose of 0, 3.125, 6.25, 12.5, 25, or 50 μM for 24 h exhibited a dose dependent cytotoxic effects in hepatocytes. Besides, Cr(VI) induced oxidative stress and subsequent mitochondrial damage. Cr(VI) also induced caspase 3-dependent apoptosis in HepG2 cells. In addition, Cr(VI) induced the translocation of Nrf2 into the nucleus and up-regulated the expression of Nrf2-dependent antioxidant enzymes, including SOD2, GCLC, and HO1. Our present experimental data support the notion that Cr(VI) caused mitochondrial damage, apoptosis, oxidative stress, and subsequently lead to a strong induction of HO1, GCLC and SOD2 via the Nrf-2 signaling pathway in hepatocytes.


A class of novel nitronyl nitroxide labeling basic and acidic amino acids: synthesis, application for preparing ESR optionally labeling peptides, and bioactivity investigations.
Aimed at optional ESR label 2-(4'-hydroxyl)phenyl-4,4,5,5-tetramethylimidazoline-3-oxide-1-oxyl was introduced into the guanido of L-Arg-OH, the omega-amino group of L-Lys-OH with methylcarboxyl as a linker, and into the beta-carboxyl of L-Asp-OH and the gamma-carboxyl of L-Glu-OH with ethylamino as a linker. It was explored that the synthetic 30 novel ESR labeling amino acid derivatives were stable enough to the reaction conditions of peptide synthesis. Their incorporation led to 12 novel ESR optionally labeling PAK, RGDS, RGDV, and ECG. A series of NO related chemical tests, the in vitro and in vivo assays of these peptides confirmed that this strategy was practical.


Proteolytic mechanisms in amyloid-beta metabolism: therapeutic implications for Alzheimer's disease.
The accumulation of the amyloid-beta peptide, the main constituent of the "amyloid plaque", is widely considered to be the key pathological event in Alzheimer's disease. Amyloid-beta is produced from the amyloid precursor protein through the action of the proteases beta-secretase and gamma-secretase. Alternative cleavage of amyloid precursor protein by the enzyme alpha-secretase precludes amyloid-beta production. In addition, several proteases are involved in the degradation of amyloid-beta. This review focuses on the proteolytic mechanisms of amyloid-beta metabolism. An increasingly detailed understanding of proteolysis in both amyloid-beta deposition and clearance has identified some of these proteases as potential therapeutic targets for Alzheimer's disease. A more complex knowledge of these proteases takes us one step closer to developing "disease-modifying" therapies, but these advances also emphasize that significant challenges must be overcome before clinically effective drugs to treat Alzheimer's disease become a reality.


Aesthetic sports as high-risk contexts for eating disorders--young elite dancers and gymnasts perspectives.
This is the first study developed in Portugal which investigates specific characteristics of dance and gymnastics environments that make them high-risk contexts for the development of eating disorders. Four focus groups were conducted with thirteen ballet students from a professional dance school and nine gymnasts from a gymnastics club (aged 12 to 17 years old), which were subjected to an inductive-deductive analysis procedure. Specific risk and protective factors were identified. Among their respective sources of influence, teachers and coaches are those who exert a stronger influence upon young athletes. We also explored some themes related to the influence of peers, parents, and environmental characteristics, which could have an important role on the development or prevention of disordered eating.


Sustainable UNiversity Life (SUN) study: protocol for a prospective cohort study of modifiable risk and prognostic factors for mental health problems and musculoskeletal pain among university students.
Mental health problems and musculoskeletal pain are common health problems among young adults including students. Little is known about the aetiology and prognosis of these problems in university students. We aim to determine the role of personal, sociodemographic, academic and environmental factors for risk and prognosis of symptoms of depression, anxiety and stress as well as musculoskeletal pain in university students. The constructs that will be studied are based on the biopsychosocial model and psychopathology associated with disabling pain. This model acknowledges illness to consist of interrelated mechanisms categorised into biological, psychological, environmental and social cues. This cohort study aims to recruit around 5000 Swedish full-time students. Data will be collected using five online surveys during one academic year. A subgroup (n=1851) of the cohort, recruited before the COVID-19 pandemic, receive weekly text messages with three short questions assessing mood, worry and pain, sent through the web-based platform SMS-track . Statistical analyses will include Kaplan-Meier estimates, Cox regression analyses, multinomial logistic regression analyses and generalised estimating equations. We will assess effect measure modification when relevant and conduct sensitivity analyses to assess the impact of lost to follow-up. Due to opportunity and timing of the study, with relevance to the outbreak of the COVID-19 pandemic, this study further aims to address mental health problems, musculoskeletal pain and lifestyle in university students before and during the pandemic. The Sustainable UNiversity Life study was approved by the Swedish ethics authority (2019-03276; 2020-01449). Results will be disseminated through peer-reviewed research papers, reports, research conferences, student theses and stakeholder communications. NCT04465435.