Vulvar squamous cell carcinoma in women 80 years and older: Treatment, survival and impact of comorbidities.
Despite being a disease of mainly older women, little is known about the clinical management of older women with vulvar squamous cell carcinoma (VSCC). We evaluated their daily clinical management compared with younger women, and established the prevalence of comorbidities and its impact on overall survival (OS). All Dutch women diagnosed with VSCC from 2015 to 2020 (n = 2249) were selected from the Netherlands Cancer Registry. Women aged ≥80 years (n = 632, 28%) were defined as "older" patients, women <80 years were considered as "younger". Chi-square tests were performed to evaluate differences in treatment by age group and comorbidities. Differences in OS were evaluated using Kaplan-Meier Curves and log-rank test. The vast majority of both older (91%) and younger (99%) patients with FIGO IA VSCC received surgical treatment of the vulva. Older FIGO IB-IV VSCC patients were less likely to undergo groin surgery than younger patients (50% vs. 84%, p < 0.01). Performance of surgical treatment of the vulva and groin(s) was not associated with the number of comorbidities in older patients (p = 0.67 and p = 0.69). Older patients with ≥2 comorbidities did have poorer OS compared to women with one or no comorbidities (p < 0.01). The vast majority of older patients underwent vulvar/local surgery. Older patients less often received groin surgery compared to younger patients. The majority of older patients had at least one comorbidity, but this did not impact treatment choice. The poorer survival in older VSCC patients may therefore be due to death of competing risks instead of VSCC itself.


Structural basis for type VI secreted peptidoglycan DL-endopeptidase function, specificity and neutralization in Serratia marcescens.
Some Gram-negative bacteria target their competitors by exploiting the type VI secretion system to extrude toxic effector proteins. To prevent self-harm, these bacteria also produce highly specific immunity proteins that neutralize these antagonistic effectors. Here, the peptidoglycan endopeptidase specificity of two type VI secretion-system-associated effectors from Serratia marcescens is characterized. These small secreted proteins, Ssp1 and Ssp2, cleave between γ-D-glutamic acid and L-meso-diaminopimelic acid with different specificities. Ssp2 degrades the acceptor part of cross-linked tetratetrapeptides. Ssp1 displays greater promiscuity and cleaves monomeric tripeptides, tetrapeptides and pentapeptides and dimeric tetratetra and tetrapenta muropeptides on both the acceptor and donor strands. Functional assays confirm the identity of a catalytic cysteine in these endopeptidases and crystal structures provide information on the structure-activity relationships of Ssp1 and, by comparison, of related effectors. Functional assays also reveal that neutralization of these effectors by their cognate immunity proteins, which are called resistance-associated proteins (Raps), contributes an essential role to cell fitness. The structures of two immunity proteins, Rap1a and Rap2a, responsible for the neutralization of Ssp1 and Ssp2-like endopeptidases, respectively, revealed two distinct folds, with that of Rap1a not having previously been observed. The structure of the Ssp1-Rap1a complex revealed a tightly bound heteromeric assembly with two effector molecules flanking a Rap1a dimer. A highly effective steric block of the Ssp1 active site forms the basis of effector neutralization. Comparisons with Ssp2-Rap2a orthologues suggest that the specificity of these immunity proteins for neutralizing effectors is fold-dependent and that in cases where the fold is conserved sequence differences contribute to the specificity of effector-immunity protein interactions.


Umbilical Cord and Neonatal Transthyretin and Their Relationship to Growth and Nutrition in Preterm Infants.
Transthyretin (TTR), also known as prealbumin, has been suggested as an indicator of protein and nutritional status. The aim of this study was to examine the maternal and umbilical cord (UC) TTR in relation to intrauterine growth, and the serum TTR of preterm infants in relation to nutritional status and growth. After application of exclusion criteria, 49 preterm infants (mean gestational age and birth-weight 32.9±2.9 weeks and 1822±556 g) were included in the study. Transthyretin was sampled at birth and on days 14, 28, and at discharge with growth parameters and nutritional laboratory test results. Mean UC and maternal TTR were positively correlated (8.5±2.4 mg/dL and 20.4±7.0 mg/dL, r=0.31, P=0.07). Umbilical cord TTR was neither an index of maturity nor of intrauterine growth. Umbilical cord TTR was higher in females (9.4±2.6 versus 7.6±1.8 mg/dL, P=0.015). Maternal TTR was lower in twin pregnancies (16.8±4.9 versus 22.5±7.3 mg/dL, P=0.007). Although TTR levels gradually increased over time in correlation with post-menstrual and chronological ages (r=0.24, P=0.011 and r=0.40, P<0.001, respectively), there was no correlation to weight gain (r=0.10, P=0.41), nutritional status, protein intake, or nutritional laboratory test results. The only significant correlations were between TTR and glucose and triglycerides levels (r=0.51, P<0.001 for both). Although TTR levels increased over time, we could not demonstrate significant correlations between TTR and indices of the nutritional status in preterm infants at birth or during the neonatal course.


Pattern recognition analysis of 1H NMR spectra from perchloric acid extracts of human brain tumor biopsies.
Pattern recognition techniques (factor analysis and neural networks) were used to investigate and classify human brain tumors based on the 1H NMR spectra of chemically extracted biopsies (n = 118). After removing information from lactate (because of variable ischemia times), unsupervised learning suggested that the spectra separated naturally into two groups: meningiomas and other tumors. Principal component analysis reduced the dimensionality of the data. A back-propagation neural network using the first 30 principal components gave 85% correct classification of meningiomas and nonmeningiomas. Simplification by vector rotation gave vectors that could be assigned to various metabolites, making it possible to use or to reject their information for neural network classification. Using scores calculated from the four rotated vectors due to creatine and glutamine gave the best classification into meningiomas and nonmeningiomas (89% correct). Classification of gliomas (n = 47) gave 62% correct within one grade. Only inositol showed a significant correlation with glioma grade.


The Influence of Force Direction on the Fracture Pattern and Fracture Resistance of Canine Teeth in Dogs.
Biomechanical studies of the elongated canine tooth of animals are few, and thus our understanding of mechanical and physical properties of animal teeth is limited. The objective of the present study was to evaluate the influence of force direction on fracture resistance and fracture pattern of canine teeth in an ex vivo dog cadaver model. Forty-five extracted canine teeth from laboratory beagle dogs were standardized by hard tissue volume and randomly distributed among 3 force direction groups. The teeth were secured within a universal testing machine and a load was applied at different directions based on testing group. The maximum force to fracture and the fracture pattern classification were recorded for each tooth. After correcting for hard tissue cross-sectional area in a multivariate analysis, no significant difference in the amount of force required for fracture was apparent between the different force direction groups. However, the influence of force direction on fracture pattern was significant. The results of this study may allow the clinician to educate clients on possible causal force directions in clinically fractured teeth and, thus, help prevent any contributing behavior in the future.


The dual role of LSD1 and HDAC3 in STAT5-dependent transcription is determined by protein interactions, binding affinities, motifs and genomic positions.
STAT5 interacts with other factors to control transcription, and the mechanism of regulation is of interest as constitutive active STAT5 has been reported in malignancies. Here, LSD1 and HDAC3 were identified as novel STAT5a interacting partners in pro-B cells. Characterization of STAT5a, LSD1 and HDAC3 target genes by ChIP-seq and RNA-seq revealed gene subsets regulated by independent or combined action of the factors and LSD1/HDAC3 to play dual role in their activation or repression. Genes bound by STAT5a alone or in combination with weakly associated LSD1 or HDAC3 were enriched for the canonical STAT5a GAS motif, and such binding induced activation or repression. Strong STAT5 binding was seen more frequently in intergenic regions, which might function as distal enhancer elements. Groups of genes bound weaker by STAT5a and stronger by LSD1/HDAC3 showed an absence of the GAS motif, and were differentially regulated based on their genomic binding localization and binding affinities. These genes exhibited increased binding frequency in promoters, and in conjunction with the absence of GAS sites, the data indicate a requirement for stabilization by additional factors, which might recruit LSD1/HDAC3. Our study describes an interaction network of STAT5a/LSD1/HDAC3 and a dual function of LSD1/HDAC3 on STAT5-dependent transcription, defined by protein-protein interactions, genomic binding localization/affinity and motifs.


[Age-related changes in thyroxine regulation of the NADPH-dependent oxidative system in rat liver microsomes].
Age peculiarities of the thyroxin effect on oxidative microsome system are manifested at the level of different links of NADPH-dependent chain of electron transfer and are most pronounced relative to changes in the content of cytochrome P-450 and demethylase activity, which get considerably reduced with hyperthyrosis in the middle age. The aniline hydroxylase activity somehow increases with hyperthyrosis in young immature animals and is practically unchanged in adult and old ones. It is supposed that age peculiarities of the thyroid hormone action on the oxidation system in microsomes are determined to a consideralble extent by the level of androgens and depend on age changes in the reproductive function of the organism.


Attachment and therapeutic alliance in psychological therapy for people with recent onset psychosis who use cannabis.
We examine associations between client attachment style and therapeutic alliance in a 3-arm randomized controlled trial of brief motivational interviewing and cognitive-behavioural therapy compared with longer term motivational interviewing and cognitive-behavioural therapy or standard care alone. Client self-report measures of attachment style were completed at baseline, and both clients and therapists in the treatment arms of the trial completed alliance measures 1 month into therapy. We found that insecure-anxious attachment was positively associated with therapist-rated alliance, whereas clients with insecure-avoidant attachment were more likely to report poorer bond with therapist. There was no evidence that client attachment significantly predicted clinical or substance misuse outcomes either directly or indirectly via alliance. Nor evidence that the length of therapy offered interacted with attachment to predict alliance.


Structure of plant-associated microeukaryotes in roots and leaves of aquatic and terrestrial plants revealed by blocking peptide-nucleic acid (PNA) amplification.
Studies of plant-microbe interactions, including mutualistic, antagonistic, parasitic, or commensal microbes, have greatly benefited our understanding of ecosystem functioning. New molecular identification tools have increasingly revealed the association patterns between microorganisms and plants. Here, we integrated long-read PacBio single-molecule sequencing technology with a blocking protein-nucleic acid (PNA) approach to minimise plant amplicons in a survey of plant-eukaryotic microbe relationships in roots and leaves of different aquatic and terrestrial plants to determine patterns of organ, host, and habitat preferences. The PNA approach reduced the samples' relative amounts of plant reads and did not distort the fungal and other microeukaryotic composition. Our analyses revealed that the eukaryotic microbiomes associated with leaves and roots of aquatic plants exhibit a much larger proportion of non-fungal microorganisms than terrestrial plants, and leaf and root microbiomes are similar. Terrestrial plants had much stronger differentiation of leaf and root microbiomes and stronger partner specificity than aquatic plants.


Extended geographic distribution of several Indo-Pacific coral reef diseases.
Other than coral bleaching, few coral diseases or diseases of other reef organisms have been reported from Japan. This is the first report of lesions similar to Porites ulcerative white spots (PUWS), brown band disease (BrB), pigmentation response (PR), and crustose coralline white syndrome (CCWS) for this region. To assess the health status and disease prevalence, qualitative and quantitative surveys (3 belt transects of 100 m² each on each reef) were performed in March and September 2010 on 2 reefs of the Ginowan-Ooyama reef complex off Okinawa, and 2 protected reefs off Zamani Island, in the Kerama Islands 40 km west of Okinawa. Overall, mean (±SD) disease prevalence was higher in Ginowan-Ooyama (9.7 ± 7.9%) compared to Zamami (3.6 ± 4.6%). Porites lutea was most affected by PUWS at Ooyama (23.1 ± 10.4 vs. 4.5 ± 5.2%). White syndrome (WS) mostly affected Acropora cytherea (12. 5 ± 18.0%) in Zamami and Oxipora lacera (10.2 ± 10%) in Ooyama. Growth anomalies (GA) and BrB were only observed on A. cytherea (8.3 ± 6.2%) and A. nobilis (0.8%) at Zamami. Black band disease affected Pachyseris speciosa (6.0 ± 4.6%) in Ooyama only. Pigmentation responses (PR) were common in massive Porites in both localities (2.6 ± 1.9 and 5.6 ± 2.3% respectively). Crustose coralline white syndrome (CCWS) was observed in both localities. These results significantly expand the geographic distribution of PUWS, BrB, PR and CCWS in the Indo-Pacific, indicating that the northernmost coral reefs in the western Pacific are susceptible to a larger number of coral diseases than previously thought.


Does vowel harmony affect visual word recognition? Evidence from Finnish.
One of the most representative morpho-phonological features of Finnish is the existence of vowel harmony. Back vowels (a, o, and u) and front vowels (ä, ö, and y) cannot appear in the same monomorphemic word (e.g., PÖYTÄ [table] but not POYTÄ)-the vowels e and i are considered "neutral" and can accompany either front or back vowels (e.g., PELÄSTYÄ [get frightened]). Previous research has revealed that native speakers of Finnish use vowel harmony to help segment multilexeme compound words where each lexeme may differ in vowel harmony (e.g., työmaa = työ+maa [workplace]). In Experiments 1 and 2, we examined whether vowel harmony has an effect on the initial moments of monomorphemic word processing using the masked priming technique (lexical decision: Experiment 1; naming: Experiment 2). A target word (e.g., MÄNTY [pine]) could be preceded by a harmonious or disharmonious prime (mänty-MÄNTY vs. manty-MÄNTY; mönty-MÄNTY vs. monty-MÄNTY). As further controls, we also included a comparison with two harmonious conditions differing in the presence of a diacritical letter (mänty-MÄNTY vs. menty-MÄNTY) and a letter similarity comparison with disharmonious primes (manty-MÄNTY vs. monty-MÄNTY). To further examine whether vowel harmony has an effect at later phases of visual word processing, Experiment 3 compared the recognition of harmonious and disharmonious pseudowords in a single-presentation lexical-decision task (e.g., HÖPEÄ vs. HOPEÄ; baseword: HÄPEÄ [shame]). We found slower responses for harmonious than for disharmonious pseudowords. Taken together, these findings reveal that, while Finnish readers are sensitive to vowel harmony, this effect does not occur in the initial stages of processing. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


Physical behavior and function early after hip fracture surgery in patients receiving comprehensive geriatric care or orthopedic care--a randomized controlled trial.
This study is a part of the randomized controlled trial, the Trondheim Hip Fracture Trial, and it compared physical behavior and function during the first postoperative days for hip fracture patients managed with comprehensive geriatric care (CGC) with those managed with orthopedic care (OC). Treatment comprised CGC with particular focus on mobilization, or OC. A total of 397 hip fracture patients, age 70 years or older, home dwelling, and able to walk 10 m before the fracture, were included. Primary outcome was measurement of upright time (standing and walking) recorded for 24 hours the fourth day postsurgery by a body-worn accelerometer-based activity monitor. Secondary outcomes were number of upright events on Day 4, need for assistance in ambulation measured by the Cumulated Ambulation score on Days 1-3, and lower limb function measured by the Short Physical Performance Battery on Day 5 postsurgery. A total of 317 (CGC n = 175, OC n = 142) participants wore the activity monitor for a 24-hour period. CGC participants had significantly more upright time (mean 57.6 vs 45.1 min, p = .016), higher number of upright events (p = .005) and better Short Physical Performance Battery scores (p = .002), than the OC participants. Cumulated Ambulation score did not differ between groups (p = .234). When treated with CGC, compared with OC, older persons suffering a hip fracture spent more time in upright, had more upright events, and had better lower limb function early after surgery despite no difference in their need for assistance during ambulation.


Effects of scene content and layout on the perceived light direction in 3D spaces.
The lighting and furnishing of an interior space (i.e., the reflectance of its materials, the geometries of the furnishings, and their arrangement) determine the appearance of this space. Conversely, human observers infer lighting properties from the space's appearance. We conducted two psychophysical experiments to investigate how the perception of the light direction is influenced by a scene's objects and their layout using real scenes. In the first experiment, we confirmed that the shape of the objects in the scene and the scene layout influence the perceived light direction. In the second experiment, we systematically investigated how specific shape properties influenced the estimation of the light direction. The results showed that increasing the number of visible faces of an object, ultimately using globally spherical shapes in the scene, supported the veridicality of the estimated light direction. Furthermore, symmetric arrangements in the scene improved the estimation of the tilt direction. Thus, human perception of light should integrally consider materials, scene content, and layout.


The Efficacy and Safety of Regimens for Helicobacter pylori Eradication Treatment in China: A Systemic Review and Network Meta-Analysis.
With Helicobacter pylori's increasing antibiotic resistance, evidence of more effective treatments is lacking in China, where H. pylori prevalence is nearly 50%. Thus, we performed a network meta-analysis to compare therapeutic regimens. Data extracted from eligible randomized controlled trials from January 2000 to September 2021 were entered into a Bayesian hierarchical random-effects model to evaluate the efficacy and safety of H. pylori eradication regimens. This study included 101 trials involving 21,745 patients. Vonoprazan-bismuth-containing quadruple therapy (VBQT) ranked the highest [surfaces under cumulative ranking curve (SUCRA), 83.64%], followed by high-dose amoxicillin dual therapy (HDDT) [SUCRA, 79.70%, odds ratio (OR)=1.31, 95% credible interval (CrI) (0.36, 4.72)] and proton pump inhibitor-based bismuth-containing quadruple therapy (BQT) [SUCRA, 63.59%, OR=1.59, 95% CrI (0.48, 5.24)]. HDDT [OR=2.47, 95% CrI (1.51, 4.06)], BQT [OR=2.04, 95% CrI (1.69, 2.47)], concomitant quadruple nonbismuth therapy (CT) [OR=1.93, 95% CrI (1.19, 3.15)], and sequential therapy (ST) [OR=1.86, 95% CrI (1.50, 2.32)] had higher eradication rates than standard triple therapy (TT). ST (SUCRA, 82.52%) and VBQT (SUCRA, 83.89%) had the highest eradication rate before and after 2010 in the effectiveness ranking, respectively. Furthermore, the H. pylori eradication rate of patients receiving 14-day BQT treatment was higher than that of 10-day BQT regimen [OR=2.55, 95% CI (1.84, 3.53)] and 7-day BQT regimen [OR=3.64, 95% CI (2.64, 5.01)]. The TT regimen was not an optimal choice in China for H. pylori eradication; VBQT, HDDT, and BQT showed better efficacy. After 2010, there is a trend toward significance that VBQT provided a higher H. pylori eradication rate in China, but with only 1 randomized controlled trial. Thus, more supportive real-world data are needed to confirm its effectiveness.


Inhibition of HIV type 1 RNA dimerization by antisense DNA corresponding to the 17-nucleotide sequence downstream from the splice donor site of HIV type 1 RNA.
HIV-1 RNA dimerization involves at least two key regions, one located upstream from the splice donor (SD) site, and the other located downstream from the SD site. To determine the precise location and the mechanism of action of the downstream region, we constructed a model system using a synthetic HIV-1 RNA fragment (HXB2, 455-1146), which dimerized at relatively low salt concentrations (100 mM KCl, 1 mM MgCl2). We tested in this system antisense DNAs that are complementary to both the upstream and downstream regions of HIV-1 RNA for their possible inhibitory effects on dimerization. Antisense DNAs complementary to nucleotides 773-789 located downstream from the SD site effectively inhibited dimerization of HIV-1 RNA. These inhibitory antisense DNAs hybridized with the dimer form of HIV-1 RNA, and dissociated the dimer into monomers. However, antisense DNAs complementary to the region upstream from the SD site did not hybridize with the dimer, although they inhibited RNA dimerization and also dissociated the preformed dimer.


Size matters: insights from an allometric approach to evaluate control methods for invasive Australian Rhinella marina.
Invasive species are costly and difficult to control. In order to gain a mechanistic understanding of potential control measures, individual-based models uniquely parameterized to reflect the salient life-history characteristics of invasive species are useful. Using invasive Australian Rhinella marina as a case study, we constructed a cohort- and individual-based population simulation that incorporates growth and body size of terrestrial stages. We used this allometric approach to examine the efficacy of nontraditional control methods (i.e., tadpole alarm chemicals and native meat ants) that may have indirect effects on population dynamics mediated by effects on body size. We compared population estimates resulting from these control methods with traditional hand removal. We also conducted a sensitivity analysis to investigate the effect that model parameters, specifically those associated with growth and body size, had on adult population estimates. Incremental increases in hand removal of adults and juveniles caused nonlinear decreases in adult population estimates, suggesting less return with increased investment in hand-removal efforts. Applying tadpole alarm chemicals or meat ants decreased adult population estimates on the same level as removing 15-25% of adults and juveniles by hand. The combined application of tadpole alarm chemicals and meat ants resulted in approximately 80% decrease in adult abundance, the largest of any applied control method. In further support of the nontraditional control methods, which greatly affected the metamorph stage, our model was most sensitive to changes in metamorph survival, juvenile survival, metamorph growth rate, and adult survival. Our results highlight the use and insights that can be gained from individual-based models that incorporate growth and body size and the potential success that nontraditional control methods could have in controlling established, invasive Rhinella marina populations.


Syzygium cumini ameliorates insulin resistance and β-cell dysfunction via modulation of PPAR, dyslipidemia, oxidative stress, and TNF-α in type 2 diabetic rats.
Syzygium cumini (SC) is well known for its anti-diabetic potential, but the mechanism underlying its amelioration of type 2 diabetes is still elusive. Therefore, for the first time, we investigated whether SC aqueous seed extract (100, 200, or 400 mg/kg) exerts any beneficial effects on insulin resistance (IR), serum lipid profile, antioxidant status, and/or pancreatic β-cell damage in high-fat diet / streptozotocin-induced (HFD-STZ) diabetic rats. Wistar albino rats were fed with HFD (55% of calories as fat) during the experiment to induce IR and on the 10th day were injected with STZ (40 mg/kg, i.p.) to develop type 2 diabetes. Subsequently, after confirmation of hyperglycemia on the 14th day (fasting glucose level > 13.89 mM), diabetic rats were treated with SC for the next 21 days. Diabetic rats showed increased serum glucose, insulin, IR, TNF-α, dyslipidemia, and pancreatic thiobarbituric acid-reactive substances with a concomitant decrease in β-cell function and pancreatic superoxide dismutase, catalase, and glutathione peroxidase antioxidant enzyme activities. Microscopic examination of their pancreas revealed pathological changes in islets and β-cells. These alterations reverted to near-normal levels after treatment with SC at 400 mg/kg. Moreover, hepatic tissue demonstrated increased PPARγ and PPARα protein expressions. Thus, our study demonstrated the beneficial effect of SC seed extract on IR and β-cell dysfunction in HFD-STZ-induced type 2 diabetic rats.


Preferential Killing of Tetraploid Colon Cancer Cells by Targeting the Mitotic Kinase PLK1.
Chromosomal instability is a well-known factor in the progression of different types of cancer, including colorectal cancer. Chromosomal instability results in severely rearranged karyotypes and aneuploidy. Tetraploidy constitutes an intermediate phase during the polyploidy/aneuploidy cascade in oncogenesis, and tetraploid cells are particularly resistant to chemotherapy. Whether inhibition of the mitotic protein polo-like kinase 1 (PLK1) prevents the survival of tetraploid colon cancer cells is unknown. Diploid and tetraploid cells were transfected with siPLK1 or treated with PLK1 inhibitor Bi2536 in combination with spindle poison. Cell toxicity was assessed via crystal violet staining and clonogenic assay. Flow cytometry assessment analyzed numerous cell apoptotic parameters and cell cycle phases. Synergistic activity between Bi2536 and paclitaxel, vincristine or colchicine was calculated using the CompuSyn software. Inhibition or abrogation of PLK1 prevented the survival of colon cancer cells, specifically tetraploid cells. The cell death induced by PLK inhibition was due to mitotic slippage, followed by the activation of the intrinsic pathway of apoptosis. We further demonstrated that co-treatment of the tetraploid colon cancer cells with a PLK1 inhibitor and the microtubule polymerisation inhibitor vincristine or colchicine, but not the microtubule depolymerisation inhibitor paclitaxel, provoked a lethal synergistic effect. PLK1 inhibition together with microtubule-targeting chemicals, serve as a potent therapeutic strategy for targeting tetraploid cancer cells.


Obesity-driven inflammation and cancer risk: role of myeloid derived suppressor cells and alternately activated macrophages.
During carcinogenesis, tumors induce dysfunctional development of hematopoietic cells. Myeloid lineage cells, in the form of myeloid derived suppressor cells (MDSCs) and alternatively polarized M2 macrophages, influence almost all types of cancers by regulating diverse facets of immunosuppression, angiogenesis, cell proliferation, growth and metastasis. One-third of Americans are obese, and accumulating evidence suggests that obesity is a risk factor for various cancers. However, the relationship between these immune players and obesity are not well-described. In this review, we evaluate potential mechanisms through which different aspects of obesity, namely insulin resistance, increased estrogen, adiposity and low grade chronic inflammation from adipose tissue macrophages, may coalesce to promote MDSC induction and M2 macrophage polarization, thereby facilitating cancer development. Detailed understanding of the interplay between obesity and myeloid mediated immunosuppression may provide novel avenues for therapeutic targeting, with the goal to reduce the challenge obesity presents towards gains made in cancer outcomes.


[Carbon monoxide poisoning].
Carbon monoxide (CO) poisoning still represents a frequent and severe casualty in France. Aside from the well-known effect of CO on hemoglobin, the role of CO binding to other hemoproteins like myoglobin and cytochrome a3 has been more recently recognized. Moreover, in addition to these hypoxic injuries, the reoxygenation phase may itself induce toxic effects by a mechanism close to the ischemia-reperfusion phenomenon. Clinical manifestations include neurologic disturbances, cardiac arrhythmia, respiratory and circulatory failures which usually disappear with removal from toxic atmosphere and administration of oxygen. However, long term neurologic manifestations may occur and lead to important functional impairment and disability. Hyperbaric oxygen is actually the treatment of choice to avoid the occurrence of delayed sequelae. HBO is advocated in every patient who remains comatose on hospital admission, who has lost consciousness during toxic exposure or with persisting neurologic abnormalities. CO poisoned pregnant women should also undergo HBO.


Association of interleukin-10 polymorphisms with risk of irritable bowel syndrome: a meta-analysis.
To clarify the current understanding of the association between interleukin-10 (IL-10) polymorphisms and the risk of irritable bowel syndrome (IBS). We searched for studies in any language recorded in PubMed, Embase and Cochrane library before August 2013. The associations under allele contrast model, codominant model, dominant model, and recessive model were analyzed. The strengths of the association between IL-10 polymorphisms and IBS risk were estimated using odds ratios (OR) with 95% confidence interval (CI). Fixed effects model was used to pool the result if the test of heterogeneity was not significant, otherwise the random-effect model was selected. Eight case-control studies analyzing three single-nucleotide polymorphisms rs1800870 (-1082 A/G), rs1800871 (-819C/T), and rs1800872 (-592A/C) of the IL-10 gene, which involved 928 cases and 1363 controls, were eligible for our analysis. The results showed that rs1800870 polymorphisms were associated with a decreased risk of IBS (GG+GA vs AA: OR = 0.80, 95%CI: 0.66-0.96), (AA+GA vs GG: OR = 0.68, 95%CI: 0.52-0.90). Subgroup analysis revealed such association only existed in Caucasian ethnicity (AA+GA vs GG, OR = 0.70, 95%CI: 0.55-0.89). The rs1800872 polymorphisms were associated with an increased risk of IBS in Asian ethnicity (CC vs GG: OR = 1.29, 95%CI: 1.01-1.16). There were no associations between rs1800871 polymorphisms and the IBS risk. The results suggest that IL-10 rs1800870 confers susceptibility to the risk of IBS in Caucasian ethnicity, and the rs1800872 may associate with IBS risk in Asians. However, no significant associations are found between rs1800871 and IBS risk.


HIV-1 resistance patterns to integrase inhibitors in antiretroviral-experienced patients with virological failure on raltegravir-containing regimens.
Our aim was to study the in vivo viral genetic pathways for resistance to raltegravir, in antiretroviral-experienced patients with virological failure (VF) on raltegravir-containing regimens. We set up a prospective study including antiretroviral-experienced patients receiving raltegravir-based regimens. Integrase (IN) genotypic resistance analysis was performed at baseline. IN was also sequenced at follow-up points in the case of VF, i.e. plasma HIV-1 RNA>400 copies/mL at month 3 and/or >50 copies/mL at month 6. For phenotyping, the IN region was recombined with an IN-deleted HXB2-based HIV-1 backbone. A titrated amount of IN recombinant viruses was used for antiviral testing against raltegravir and elvitegravir. Among 51 patients, 11 (21.6%) had VF. Four different patterns of IN mutations were observed: (i) emergence of Q148H/R with secondary mutations (n=5 patients); (ii) emergence of N155H, then replaced by a pattern including Y143C/H/R (n=3); (iii) selection of S230N (n=1); and (iv) no evidence of selection of IN mutations (n=2). The median raltegravir and elvitegravir fold changes (FCs) were 244 (154-647) and 793 (339-892), respectively, for the Q148H/R pattern, while the median raltegravir and elvitegravir FCs were 21 (6-52) and 3 (2-3), respectively, with Y143C/H/R. The median plasma raltegravir Cmin was lower in patients with selection of the N155H mutation followed by Y143C/H/R compared with patients with Q148H/R and with patients without emerging mutations or without VF. Diverse genetic profiles can be associated with VF on raltegravir-containing regimens, including the dynamics of replacement of mutational profiles. Pharmacokinetic parameters could be involved in this genetic evolution.


Evaluation of right ventricular function using liver stiffness in patients with left ventricular assist device.
Although right ventricular failure (RVF) is a major concern after left ventricular assist device (LVAD) implantation, methodologies to evaluate RV function remain limited. Liver stiffness (LS), which is closely related to right-sided filling pressure and may indicate RVF severity, could be non-invasively and repeatedly assessed using transient elastography. Here we investigated the suitability of LS as a parameter of RV function in pre- and post-LVAD periods. The study included 55 patients with LVAD implantation as a bridge to transplantation between 2011 and 2015 whose LS was assessed using transient elastography. Seventeen patients presented with RVF, defined as requiring inotropic support for ≥30 days, nitric oxygen inhalation for ≥5 days, and/or mechanical RV support following LVAD implantation. Survival of patients with RVF was significantly worse compared with that of patients without RVF. Multivariate logistic regression analysis identified preoperative LS, LV diastolic dimension, RV stroke work index, and dilated phase of hypertrophic cardiomyopathy aetiology as significant risk factors; the combination of these parameters could improve predictive power of post-LVAD RVF with areas under the curve of 0.89. Furthermore, LS was significantly decreased by LV unloading and significantly correlated with right-sided filling pressure. In addition to dilated hypertrophic cardiomyopathy aetiology, reduced RV stroke work index and small LV dimension, we demonstrated that non-invasively measured LS was a predictor of post-LVAD RVF and can be used as a parameter for the evaluation and optimization of RV function in the perioperative period.


Ectopic expression of CXCL13, BAFF, APRIL and LT-β is associated with artery tertiary lymphoid organs in giant cell arteritis.
To investigate whether artery tertiary lymphoid organs (ATLOs) are present in giant cell arteritis (GCA) and that their formation is associated with the ectopic expression of constitutive lymphoid tissue-homing chemokines. Reverse transcriptase PCR, immunohistochemical and immunofluorescence analysis were used to determine the presence of ectopic ATLOs in GCA and the expression of chemokines/chemokine receptors and cytokines involved in lymphoneogenesis in the temporal artery samples obtained from 50 patients with GCA and 30 controls. The presence of lymphatic conduits, of follicular dendritic cells (FDCs) precursors and lymphoid tissue inducer cells was also investigated. Finally, expression of CXCL13, B cell activating factor (BAFF), a proliferation-inducing ligand (APRIL) and CCL21 by isolated myofibroblasts was evaluated before and after stimulation with Toll-like receptors (TLRs) agonists and cytokines. ATLOs were observed in the media layer of 60% of patients with GCA in close proximity to high endothelial venules and independently by the age of patients and the presence of atherosclerosis. ATLO formation was also accompanied by the expression of CXCL13, BAFF, a proliferation-inducing ligand (APRIL), lymphotoxin (LT)-β, interleukin (IL)-17 and IL-7, the presence of FDC precursors and of lymphoid conduits. Stimulation of myofibroblasts with TLR agonists and cytokines resulted in the upregulation of BAFF and CXCL13. ATLOs occur in the inflamed arteries of patients with GCA possibly representing the immune sites where immune responses towards unknown arterial wall-derived antigens may be organised.


Albendazole for the treatment of echinococcosis.
Twenty years after the first cases of echinococcal disease were treated with albendazole, it has become an important component in the overall management of both cystic and alveolar echinococcosis. This paper reviews some of the key steps and issues facing those who work in clinical research and who deal on a day-to-day basis with echinococcal disease. In many situations, chemotherapy alone is sufficient, but it is also used as an adjunct to surgery and to minimally invasive approaches to cyst management. While treatment may not be as effective as hoped, attempts to provide new regimens are progressing to increase cure rates further. There is now a greater understanding of the limitations of all approaches, and treatment guidelines as developed by the World Health Organization are now widely followed. As diagnostic tools are ever more widely available, the question as to who should be treated in endemic communities has to be answered.


Genome-wide association meta-analysis identifies risk loci for abdominal aortic aneurysm and highlights PCSK9 as a therapeutic target.
Abdominal aortic aneurysm (AAA) is a common disease with substantial heritability. In this study, we performed a genome-wide association meta-analysis from 14 discovery cohorts and uncovered 141 independent associations, including 97 previously unreported loci. A polygenic risk score derived from meta-analysis explained AAA risk beyond clinical risk factors. Genes at AAA risk loci indicate involvement of lipid metabolism, vascular development and remodeling, extracellular matrix dysregulation and inflammation as key mechanisms in AAA pathogenesis. These genes also indicate overlap between the development of AAA and other monogenic aortopathies, particularly via transforming growth factor β signaling. Motivated by the strong evidence for the role of lipid metabolism in AAA, we used Mendelian randomization to establish the central role of nonhigh-density lipoprotein cholesterol in AAA and identified the opportunity for repurposing of proprotein convertase, subtilisin/kexin-type 9 (PCSK9) inhibitors. This was supported by a study demonstrating that PCSK9 loss of function prevented the development of AAA in a preclinical mouse model.


The Association Between Female Smoking and Childhood Asthma Prevalence-A Study Based on Aggregative Data.
Aims: Socioeconomic and environmental factors influence childhood asthma prevalence across the world. In-depth epidemiological research is necessary to determine the association between asthma prevalence and socio-environmental conditions, and to develop public health strategies to protect the asthmatic children against the environmental precipitators. Our research was based on aggregative data and sought to compare the asthma prevalence between children of two different age-groups across the world and to identify the association among the key socio-environmental conditions with increased childhood asthma prevalence. Method: We included forty countries with available data on various socio-environmental conditions (2014-2015). Childhood asthma prevalence of two different age groups (6-7 and 13-14 years) were obtained from global asthma report 2014. Because of significant diversities, the selected countries were divided into two groups based on human developmental index (HDI), a well-recognized parameter to estimate the overall socioeconomic status of a country. Robust linear regression was conducted using childhood asthma prevalence as the dependent variable and female smoking prevalence, tertiary school enrollment (TSE), PM10 (particulate matter ≤10 μm in diameter) and gross domestic product (GDP) as predictors. Results: Asthma prevalence was not different between two age groups. Among all predictors, only female smoking prevalence (reflecting maternal smoking) was associated with asthma prevalence in the countries with lower socio-economic conditions (HDI), but not in the higher HDI group. The results were unchanged even after randomization. Conclusions: Childhood asthma prevalence did not change significantly with age. Female smoking may have a positive correlation with childhood asthma prevalence in lower HDI countries.


Review: Research progress on seasonal succession of phyllosphere microorganisms.
Phyllosphere microorganisms have recently attracted the attention of scientists studying plant microbiomes. The origin, diversity, functions, and interactions of phyllosphere microorganisms have been extensively explored. Many experiments have demonstrated seasonal cycles of phyllosphere microbes. However, a comprehensive comparison of these separate investigations to characterize seasonal trends in phyllosphere microbes of woody and herbaceous plants has not been conducted. In this review, we explored the dynamic changes of phyllosphere microorganisms in woody and non-woody plants with the passage of the season, sought to find the driving factors, summarized these texts, and thought about future research trends regarding the application of phyllosphere microorganisms in agricultural production. Seasonal trends in phyllosphere microorganisms of herbaceous and woody plants have similarities and differences, but extensive experimental validation is needed. Climate, insects, hosts, microbial interactions, and anthropogenic activities are the diverse factors that influence seasonal variation in phyllosphere microorganisms.


Crystallographic structural analysis of phosphoramidates as inhibitors and transition-state analogs of thermolysin.
The mode of binding to thermolysin of the unsubstituted phosphoramidate inhibitor N-phosphoryl-L-leucinamide (P-Leu-NH2) has been determined crystallographically and refined at high resolution (R = 17.9% to 0.16-nm resolution). The mode of binding of the naturally occurring thermolysin inhibitor phosphoramidon reported previously [Weaver, L. H., Kester, W. R. and Matthews, B. W. (1977) J. Mol. Biol. 114, 119-132] has also been confirmed by crystallographic refinement (R = 17.4% to 0.23-nm resolution). Phosphoramidon binds to the enzyme with a single oxygen of the phosphoramidate moiety as a zinc ligand. Together with three ligands to the metal from the protein the resultant complex has approximately tetrahedral geometry. However, in the case of P-Leu-NH2, two of the phosphoramidate oxygens interact with the zinc to form a complex that tends towards pentacoordinate. In this respect, P-Leu-NH2 appears to be a better transition-state analog than is phosphoramidon. In addition, the phosphorus-nitrogen bond length in P-Leu-NH2 is 0.18 nm, suggesting that the nitrogen is protonated whereas the same bond in phosphoramidon is much shorter (0.15 nm) suggesting that the nitrogen does not carry a charge. In phosphoramidon the distance from the phosphoramide nitrogen to Glu-143 is 0.39 nm whereas in P-Leu-NH2 this distance decreases to 0.34 nm. Taken together, these observations provide additional evidence in support of the participation of pentacoordinate intermediates in the mechanism of action of thermolysin [Holmes, M. A. and Matthews, B. W. (1981) Biochemistry 20, 6912-6920] and the role of Glu-143 in first promoting the attack of a water molecule on the carbonyl carbon of the scissile bond and subsequently acting as a 'proton shuttle' to transfer the proton to the leaving nitrogen [Monzingo, A. F. and Matthews, B. W. (1984) Biochemistry 23, 5724-5729; Hangauer, D. G., Monzingo, A. F. and Matthews, B. W. (1984) Biochemistry 23, 5730-5741].


[The peculiarity of the regeneration of the gingival mucosa after the operation of the tooth extraction].
The indices of the mitotic activity, the quantity of the double-nucleated cells and the dying nucleus coefficient in the basal and spinous layers of the rat multilayer flat epithelium after the extraction a tooth were studied. The experiments were carried out on 45 nonlinear white mature rats - males. After peeling the gingiva around the dental neck we extract three basal teeth. In the epithelial regenerates we counted amount of the mitotic figures (prophase, metaphase, anaphase, telophase) in the basal and spinous cells, double-nucleated cells in the spinous layer and the number of the dying nucleus (picnosis, karyolisis) among 5 000 cells. It was established that the tissue defect was filled up owing to the intensification of the mitotic activity in the germinative layer, namely, dew new cells generation. In spite of the rise the quantity of dying nucleus, the number of the dividing cells exceeds the number of the dying owns, what provides the reparation of the multilayer flat gingival epithelium in the region of the wound.


Suicidality among nonadherent patients living with HIV in Buenos Aires, Argentina: prevalence and correlates.
Of those in the general population hospitalized for suicidal ideation and suicide attempts in Argentina, many reattempt suicide and are readmitted. However, few studies in Argentina have examined suicidal ideation and suicide-related behaviors among people living with HIV (PLHIV) and none have examined these factors among nonadherent PLHIV, though the prevalence of suicidal ideation in this group may be higher than in the general population and also than in other groups of PLHIV. This study of PLHIV in Buenos Aires, Argentina, examined the correlates of suicidal ideation in nonadherent PLHIV. Nonadherent patients with HIV (N = 118) were recruited from two clinics providing outpatient healthcare services to PLHIV in Buenos Aires, Argentina. Participants completed assessments on demographic characteristics, depression and suicidality, stigma, and self-efficacy. Participants were HIV-infected men (51%) and women (49%) with a median age of 40 years (IQR = 11). About half had completed high school or more, two-thirds were employed, and had a mean monthly income of 4196.79 (SD = 3179.64) Argentine pesos (USD$221). Thirty-three (28% [95% CI 20.3, 37.3]) participants reported suicidal ideation in the past two weeks, and one-third (35.6% [27.1, 44.9]) reported lifetime suicidal ideation. In bivariate analyses, attending a public clinic, being female, younger, unemployed, and experiencing greater stigma and depression were associated with suicidal ideation. In multivariable logistic regression, stigma interacted with the number of years since HIV diagnosis to predict suicidal ideation. The impact of stigma on suicidal ideation decreased with time since HIV diagnosis, suggesting that suicidal ideation may arise following HIV diagnosis due to perception of HIV-related stigma. Interventions to reduce perceived stigma during the period following HIV diagnosis may reduce suicidal ideation in this population. Organizational initiatives that explore HIV stigma microagressions in the healthcare setting may be needed to optimize health outcomes.


Haemodilution tolerance in patients with mitral regurgitation.
Haemodynamic parameters and oxygen consumption were determined in 20 patients with mitral regurgitation before and after a 12 ml.kg-1 isovolaemic exchange of blood for 6% hydroxyethyl starch. During haemodilution, mean (SEM) haemoglobin concentration decreased from 13.0 (0.4) to 10.3 (0.4) g.dl-1 (p = 0.001). With cardiac filling pressures maintained at predilution levels, cardiac index increased from 1.84 (0.08) to 1.94 (0.08) l.min-1.m-2 (p = 0.025) while systemic vascular resistance decreased from 1556 (86) to 1425 (83) dyne.s.cm-5 (p = 0.002) and oxygen extraction increased from 31.7 (1.1) to 37.3 (1.4)% (p = 0.001) resulting in an unchanged oxygen consumption. The haemodynamic response to haemodilution was not affected by the patients' cardiac rhythm, i.e. whether it was sinus rhythm or atrial fibrillation. In conclusion, isovolaemic haemodilution to a haemoglobin of 10.3 g.dl-1 is well tolerated in patients with mitral regurgitation. Compensatory mechanisms include both an increase in cardiac index and an increase in oxygen extraction.


Gene expression profiles associated with advanced pancreatic cancer.
Few studies have addressed the expression profiles associated with progression of pancreatic cancer to advanced disease. Towards this end, we performed expression profiling of a series of normal pancreas, pancreatitis and cancer tissues representing early stage resected pancreatic cancers (stages pT2/T3), late stage unresectable cancers (stage pT4) and matched metastases to a variety of organ sites. Microarray data was analyzed using linear modeling of microarray data (LIMMA), and differentially expressed genes were subjected to Gene Set Enrichment Analysis (GSEA). While robust differences were found in primary cancers as compared to normal pancreatic tissues, no differences were found between primary cancers and metastases, whether using matched or unmatched samples. When resected pancreatic cancers were specifically compared to advanced pancreatic cancers, significant differences in gene expression were found associated with growth at the primary site. These differentially expressed genes were most prominent in gene classes that related to MAPK and Wnt pathway, metabolism, immune regulation, cell-cell and cell-matrix interactions within the infiltrating carcinoma. One candidate upregulated gene (MXI1) was validated as having increased expression in advanced stage (T4) carcinomas by real-time PCR (p<0.05) and immunolabeling (p<0.003). We conclude that in addition to the robust changes in expression that accompany pancreatic carcinogenesis additional specific changes occur in association with growth at the primary site. By contrast, metastatic spread is not accompanied by reproducible changes in gene expression. These findings add to our understanding of pancreatic cancer and offer new topics for investigation into the aggressive nature of this deadly tumor type.


Pulsed Electromagnetic Fields and Tissue Engineering of the Joints.
Bone and joint formation, maintenance, and regeneration are regulated by both chemical and physical signals. Among the physical signals there is an increasing realization of the role of pulsed electromagnetic fields (PEMF) in the treatment of nonunions of bone fractures. The discovery of the piezoelectric properties of bone by Fukada and Yasuda in 1953 in Japan established the foundation of this field. Pioneering research by Bassett and Brighton and their teams resulted in the approval by the Food and Drug Administration (FDA) of the use of PEMF in the treatment of fracture healing. Although PEMF has potential applications in joint regeneration in osteoarthritis (OA), this evolving field is still in its infancy and offers novel opportunities. We have systematically reviewed the literature on the influence of PEMF in joints, including articular cartilage, tendons, and ligaments, of publications from 2000 to 2016. PEMF stimulated chondrocyte proliferation, differentiation, and extracellular matrix synthesis by release of anabolic morphogens such as bone morphogenetic proteins and anti-inflammatory cytokines by adenosine receptors A2A and A3 in both in vitro and in vivo investigations. It is noteworthy that in clinical translational investigations a beneficial effect was observed on improving function in OA knees. However, additional systematic studies on the mechanisms of action of PEMF on joints and tissues therein, articular cartilage, tendons, and ligaments are required.


Circumpolar synchrony in big river bacterioplankton.
Natural bacterial communities are extremely diverse and highly dynamic, but evidence is mounting that the compositions of these communities follow predictable temporal patterns. We investigated these patterns with a 3-year, circumpolar study of bacterioplankton communities in the six largest rivers of the pan-arctic watershed (Ob', Yenisey, Lena, Kolyma, Yukon, and Mackenzie), five of which are among Earth's 25 largest rivers. Communities in the six rivers shifted synchronously over time, correlating with seasonal shifts in hydrology and biogeochemistry and clustering into three groups: winter/spring, spring freshet, and summer/fall. This synchrony indicates that hemisphere-scale variation in seasonal climate sets the pace of variation in microbial diversity. Moreover, these seasonal communities reassembled each year in all six rivers, suggesting a long-term, predictable succession in the composition of big river bacterioplankton communities.


[Secondary prevention of arterial hypertension in an organized population: methods of implementation, efficacy, prospects].
Five-year follow-up of an organized population of males between 35 and 54 years of age and medication of patients with arterial hypertension (AH) demonstrated possibilities of considerably reducing the incidence of cerebral insult (by 42.9%) and myocardial infarction (by 15.5%) and the respective mortality rates (by 56.1% and 23.8%), invalidism associated with cardiovascular diseases (by 36%), temporary disability because of AH (by 38.2%). The efficiency of treatment for AH increases considerably where medication is given on a regular basis. Possible approaches to improving the efficiency of secondary AH prevention within an organized population are discussed, as are possibilities of introducing preventive measures in routine work of the factory therapeutic service.


Adaptive Control of Subpopulations in Evolutionary Dynamic Optimization.
Multipopulation methods are highly effective in solving dynamic optimization problems. Three factors affect this significantly: 1) the exclusion mechanisms to avoid the convergence to the same peak by multiple subpopulations; 2) the resource allocation mechanism that assigns the computational resources to the subpopulations; and 3) the control mechanisms to adaptively adjust the number of subpopulations by considering the number of optima and available computational resources. In the existing exclusion mechanisms, when the distance (i.e., the distance between their best found positions) between two subpopulations becomes less than a predefined threshold, the inferior one will be removed/reinitialized. However, this leads to incapability of algorithms in covering peaks/optima that are closer than the threshold. Moreover, despite the importance of resource allocation due to the limited available computational resources between environmental changes, it has not been well studied in the literature. Finally, the number of subpopulations should be adapted to the number of optima. However, in most existing adaptive multipopulation methods, there is no predefined upper bound for generating subpopulations. Consequently, in problems with large numbers of peaks, they can generate too many subpopulations sharing limited computational resources. In this article, a multipopulation framework is proposed to address the aforementioned issues by using three adaptive approaches: 1) subpopulation generation; 2) double-layer exclusion; and 3) computational resource allocation. The experimental results demonstrate the superiority of the proposed framework over several peer approaches in solving various benchmark problems.


Tell me what you eat and I will tell you your sociotype: coping with diabesity.
The term sociotype has been introduced to describe the dynamic relationship of an individual with his/her social environment throughout life. The sociotype is a conceptual framework to highlight, in addition to bio-medical pathways, the psycho-social and environmental factors necessary to understand responses to life stresses and patient self-management for chronic illness. The sociotype interacts with genotype expression through mate selection and metabolic programming, and with the phenotype to determine adaptation throughout life from birth to old age. Following on the work of Antonovsky, Engel, and McEwen, and others in the life and social sciences, the sociotype details and expands the many factors generally included in the environmental influences on a person's life identified here as the domains of health, relationships, and environment. Physiological mediators for sociotypic influences include: adrenal steroids and the sympathetic nervous system (allostatic load), and oxytocin (social neuroscience). The biological pathways are multiple through nutrition (essential dietary-derived amino- and fatty acids for neurotransmitter synthesis, caloric restriction, and diet-gene interactions), epigenesis, and metabolic programming. Nutrition influences growth and development, fertility and longevity, and also determines susceptibility to non-communicable diseases such as cardiovascular disease and cancer, and particularly diabetes and obesity, through in-utero effects, the development of intestinal flora (microbiome), and chronic stress. Thus the sociotype and nutrition are reciprocally related in both health and disease.


Interactions of semiflexible filaments and molecular motors.
This paper summarizes the results of numerical simulations of the interaction of a pair of biofilaments mediated by a molecular motor. The filaments are modeled as flexible rods, and the results are applicable to microtubules, which are relatively stiff, as well as to much softer filaments, such as actin. The results provide insight into the effects of flexibility on cytoskeleton formation and the rheology of semiflexible filament networks. The simulations are based on a nonlinear elasticity equation. The results show that flexibility enhances the tendency of filaments to align. The enhancement in turn favors the formation of large-scale structures in multifilament systems. Simulations for soft filaments show that the action of the motor can result in the formation of multiple loops of the filaments as a result of buckling, which can affect the structure of a cross-linked network and thereby its rheology. The estimate for the minimal buckling length as a function of the motor speed, the viscosity of the solvent, and the bending stiffness of the filament is derived analytically.


[Arachidonic acid metabolites, leukotrienes--mediators of hypersensitivity and inflammation].
A problem of leukotrienes--metabolites of arachidonic acid is reviewed in immunological aspects. Their nomenclature is given; basic pathways of biosynthesis, transformation and mode of leukotriens participation in hypersensitivity and inflammatory reactions are considered. The possibility of application of leukotrienes antagonists and inhibitors of their formation for allergic diseases treatment is discussed.


Anti-apolipoprotein A-1 IgG predicts major cardiovascular events in patients with rheumatoid arthritis.
To determine whether anti-apolipoprotein A-1 (anti-Apo A-1) IgG are associated with major cardiovascular events in patients with rheumatoid arthritis (RA). We determined anti-Apo A-1 IgG levels and the concentrations of cytokines, oxidized low-density lipoprotein (LDL), and matrix metalloproteinase 1 (MMP-1) MMP-2, MMP-3, and MMP-9 in sera from 133 patients with RA who did not have cardiovascular disease at baseline, all of whom were longitudinally followed up over a median period of 9 years. A major cardiovascular event was defined as a fatal or nonfatal stroke or acute coronary syndrome. The proinflammatory effects of anti-Apo A-1 IgG were assessed on human macrophages in vitro. During followup, the overall incidence of major cardiovascular events was 15% (20 of 133 patients). At baseline, anti-Apo A-1 IgG positivity was 17% and was associated with a higher incidence of major cardiovascular events (adjusted hazard ratio 4.2, 95% confidence interval 1.5-12.1). Patients who experienced a subsequent major cardiovascular event had higher circulating levels of anti-Apo A-1 IgG at baseline compared with those who did not have a major cardiovascular event. Receiver operating curve analysis showed that anti-Apo A-1 IgG was the strongest of all tested biomarkers for the prediction of a subsequent major cardiovascular event, with an area under the curve value of 0.73 (P = 0.0008). At the predefined and previously validated cutoff levels, the specificity and sensitivity of anti-Apo A-1 IgG to predict major cardiovascular events were 50% and 90%, respectively. Anti-Apo A-1 IgG positivity was associated with higher median circulating levels of interleukin-8 (IL-8), oxidized LDL, and MMP-9 and higher proMMP-9 activity as assessed by zymography. On human macrophages, anti-Apo A-1 IgG induced a significant dose-dependent increase in IL-8 and MMP-9 levels and proMMP-9 activity. Anti-Apo A-1 IgG is an independent predictor of major cardiovascular events in RA, possibly by affecting vulnerability to atherosclerotic plaque.


Cells expressing FLT3/ITD mutations exhibit elevated repair errors generated through alternative NHEJ pathways: implications for genomic instability and therapy.
The internal tandem duplication (ITD) mutations of the FMS-like tyrosine kinase-3 (FLT3) receptor found in acute myeloid leukemia patients are associated with poor prognosis. Although DNA double-strand breaks (DSBs) are mainly repaired by the DNA-PK-dependent nonhomologous end-joining (NHEJ) pathway in normal mammalian cells, an alternative and less well-defined NHEJ pathway, characterized by microhomology at the repair junctions, play a role in the generation of deletions and translocations leading to cancer progression. Here we report that in FLT3/ITD-expressing cell lines and bone marrow mononuclear cells from FLT3/ITD knock-in mice, end-joining of DSBs occurs at microhomologous sequences resulting in a high frequency of DNA deletions. Strikingly, levels of Ku proteins, key components of the main NHEJ pathway, are decreased in FLT3/ITD(+) cell lines and murine FLT3/ITD bone marrow mononuclear cells. Concomitantly, levels of DNA ligase IIIα, a component of ALT NHEJ, are increased in FLT3/ITD-expressing cells. Cells treated with a FLT3 inhibitor demonstrate decreased DNA ligase IIIα and a reduction in DNA deletions, suggesting that FLT3 signaling regulates the pathways by which DSBs are repaired. Thus, therapy to inhibit FLT3/ITD signaling and/or DNA ligase IIIα may lead to repair that reduces repair errors and genomic instability.


Hard to handle: how lipid saturation affects the nuclear envelope.
The nuclear envelope is a unique subdomain of the endoplasmic reticulum (ER) that encapsulates the genome and mediates communication between the nucleus and the rest of the cell via nuclear pore complexes. A recent study by Romanauska and Köhler shows that balanced lipid unsaturation is critical for nuclear envelope and nuclear pore complex architecture and function.


A novel alternative to environmental monitoring to detect workers at risk for beryllium exposure-related health effects.
The purpose of this study was to describe a methodology for surveillance and monitoring of beryllium exposure using biological monitoring to complement environmental monitoring. Eighty-three Israeli dental technicians (mean age 41.6 ± 1.36 years) and 80 American nuclear machining workers (54.9 ± 1.21 years) were enrolled. Biological monitoring was carried out by analyzing particle size (laser technique) and shape (image analysis) in 131/163 (80.3%) induced sputum samples (Dipa Analyser, Donner Tech, Or Aquiva, Israel). Environmental monitoring was carried out only in the United States (Sioutas impactor, SKC, Inc., Eighty Four, Pa.). Pulmonary function testing performance and induced sputum retrieval were done by conventional methods. Sixty-three Israeli workers and 37 American workers were followed up for at least 2 years. Biological monitoring by induced sputum indicated that a >92% accumulation of <5 μm particles correlated significantly to a positive beryllium lymphocyte proliferation test result (OR 3.8, 95% CI 1.2-11.4, p = 0.015) among all participants. Environmental monitoring showed that beryllium particles were <1 μm, and this small fraction (0.1-1 μ) was significantly more highly accumulated in nuclear machining workers compared to dental technicians. The small fractions positively correlated with induced sputum macrophages (r = 0.21 p = 0.01) and negatively correlated with diffusion lung carbon monoxide single breath (DLCO-SB r = 0.180 p = 0.04) in all subjects. Years of exposure were positively correlated to the number of accumulated particles 2-3 μ in diameter (r = 0.2, p = 0.02) and negatively correlated to forced expiratory volume in one second/forced vital capacity findings (r = -0.18, p = 0.02). DLCO was decreased in both groups after two years of monitoring. Biological monitoring is more informative than environmental monitoring in the surveillance and monitoring of workers in beryllium industries. Induced sputum is a feasible and promising biomonitoring method that should be included in the surveillance of exposed workers.


Mutational analysis of Plasmodium falciparum dihydrofolate reductase and dihydropteroate synthase genes in the interior division of Sabah, Malaysia.
The sulphadoxine/pyrimethamine (SDX/PYR) combination had been chosen to treat uncomplicated falciparum malaria in Malaysia for more than 30 years. Non-silent mutations in dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) genes are responsible for the resistance to pyrimethamine and sulphadoxine, respectively. This study reports the mutational analysis of pfdhfr and pfdhps in single Plasmodium falciparum infection isolates from the interior division of Sabah, Malaysian Borneo. A total of 22 P. falciparum single infection isolates collected from two districts of the interior division of Sabah from February to November 2010 were recruited for the mutational study of pfdhfr and pfdhps. Both genes were amplified by nested PCR prior to DNA sequencing and mutational analysis. A total of three pfdhfr and four pfdhps alleles were identified. The most prevalent pfdhfr allele is ANRNL (86%) involving triple mutation at position 108(S to N), 59(C to R) and 164(I to L). In pfdhps, two novel alleles, SGTGA (73%) and AAKAA (5%) were identified. Alleles involving triple mutation in both pfdhfr (ANRNL) and pfdhps (SGTGA), which were absent in Sabah in a study conducted about 15 years ago, are now prevalent. High prevalence of mutations in SDX/PYR associated drug resistance genes are reported in this study. This mutational study of pfdhps and pfdhfr indicating that SDX/PYR should be discontinued in this region.


The influence of ionizing radiation on itraconazole in the solid state.
The aim of this study was to investigate the ionizing radiation effects, in the form of an electron beam, on itraconazole (ITR) in the solid phase. It was found that the ITR, under the influence of a standard 25 kGy dose of radiation used for the sterilization of drug substances, decomposed at 0.4%. Moreover, a gentle change of colour and a decrease in melting point does not exceed pharmacopoeial standards causing that ITR can be sterilized by radiation method. The use of high 400 kGy radiation doses resulted in a 6.5% decomposition of the ITR and eight radiodegradation products were found. However, with the exception of differential scanning calorimetry (DSC), the X-ray diffraction, Fourier transform infrared spectroscopy (FT-IR) and ultraviolet-visible (UV-vis) methods showed no changes in the form and the morphology of the crystals. The structures of all those compounds were investigated. It was confirmed that the ITR decomposition takes place by dehalogenation (one of Cl atom elimination), the oxidation in isobutyl residue (beside the triazole ring) and C-O bond rupture.


Neurological complications in thyroid surgery: a surgical point of view on laryngeal nerves.
THE CERVICAL BRANCHES OF THE VAGUS NERVE THAT ARE PERTINENT TO ENDOCRINE SURGERY ARE THE SUPERIOR AND THE INFERIOR LARYNGEAL NERVES: their anatomical course in the neck places them at risk during thyroid surgery. The external branch of the superior laryngeal nerve (EB) is at risk during thyroid surgery because of its close anatomical relationship with the superior thyroid vessels and the superior thyroid pole region. The rate of EB injury (which leads to the paralysis of the cricothyroid muscle) varies from 0 to 58%. The identification of the EB during surgery helps avoiding both an accidental transection and an excessive stretching. When the nerve is not identified, the ligation of superior thyroid artery branches close to the thyroid gland is suggested, as well as the abstention from an indiscriminate use of energy-based devices that might damage it. The inferior laryngeal nerve (RLN) runs in the tracheoesophageal groove toward the larynx, close to the posterior aspect of the thyroid. It is the main motor nerve of the intrinsic laryngeal muscles, and also provides sensory innervation to the larynx. Its injury finally causes the paralysis of the omolateral vocal cord and various sensory alterations: the symptoms range from mild to severe hoarseness, to acute airway obstruction, and swallowing impairment. Permanent lesions of the RNL occur from 0.3 to 7% of cases, according to different factors. The surgeon must be aware of the possible anatomical variations of the nerve, which should be actively searched for and identified. Visual control and gentle dissection of RLN are imperative. The use of intraoperative nerve monitoring has been safely applied but, at the moment, its impact in the incidence of RLN injuries has not been clarified. In conclusion, despite a thorough surgical technique and the use of intraoperative neuromonitoring, the incidence of neurological complications after thyroid surgery cannot be suppressed, but should be maintained in a low range.


Global conformational changes in allosteric proteins. A study of Escherichia coli cAMP receptor protein and muscle pyruvate kinase.
One of the basic features in allosteric regulation involves long range transduction of information. Based on crystallographic data on protein systems that are regulated by allosteric mechanisms, a global conformational change has always been observed. It is, therefore, important and useful to correlate the cooperativity of global structural change with the mode of binding of the regulatory ligand. Two systems were chosen for study, namely Escherichia coli cAMP receptor protein and muscle pyruvate kinase, which show negative and positive cooperativity in the binding of allosteric ligands, respectively. Quantitative titration of the global structural change, monitored by a high precision analytical gel chromatography technique, was conducted as a function of allosteric effector concentration. The results obtained for cAMP receptor protein show that the protein undergoes contraction upon binding of cAMP. The decreases in Stokes radius associated with complex formation are 0.1 +/- 0.1 and 0.7 +/- 0.1 A when one and two cAMP-binding sites are filled, respectively. The results for the pyruvate kinase system show a concerted structural change that quantitatively match the predicted behavior based on equilibrium constants derived from the analysis of steady state kinetic data by a two-state model. Hence, for these two systems, these results show that negative and positive cooperativity are correlated with sequential and concerted modes of structural change, respectively.


Immobilization of horseradish peroxidase in phospholipid-templated titania and its applications in phenolic compounds and dye removal.
In this study, horseradish peroxidase (HRP) was encapsulated in phospholipid-templated titania particles through the biomimetic titanification process and used for the treatment of wastewater polluted with phenolic compounds and dye. The encapsulated HRP exhibited improved thermal stability, a wide range of pH stability and high tolerance against inactivating agents. It was observed an increase in Km value for the encapsulated HRP (8.21 mM) when compared with its free counterpart. For practical applications in the removal of phenolic compounds and dye by the encapsulated HRP, the removal efficiency for phenol, 2-chlorophenol, Direct Black-38 were 92.99%, 87.97%, and 79.72%, respectively, in the first treatment cycle. Additionally, the encapsulated HRP showed better removal efficiency than free HRP and a moderately good capability of reutilization.


Expression of Escherichia coli F-18 type 1 fimbriae in the streptomycin-treated mouse large intestine.
Escherichia coli F-18, isolated from the feces of a healthy human, makes type 1 fimbriae and is an excellent colonizer of the streptomycin-treated mouse large intestine. Recently, it was shown that the inability to produce type 1 fimbriae had no effect on the ability of E. coli F-18 to colonize the streptomycin-treated mouse large intestine, suggesting the possibility that E. coli F-18 does not express type 1 fimbriae in vivo. However, we show here that E. coli F-18 does express type 1 fimbriae in mouse cecal mucus in vivo and, in fact, appears to express substantially more type 1 fimbriae in cecal mucus in vivo than in L broth in vitro.


[Case-control study on therapeutic effects between modified Weaver-Dunn surgery and clavicular hook plate fixation in the treatment of acromioclavicular joint dislocation].
To study therapeutic effects between hook plate fixation and modified Weaver-Dunn surgery for the treatment of acromioclavicular joint dislocation. Forty patients with fresh acromioclavicular joint dislocations of type III according to Rockwood classification were reviewed. All the patients were divided into two groups: hook plate fixation group and modified surgery group. There were 20 patients in hook plate fixation group, including 13 males and 7 females, with an average age of (37.45 +/- 14.29) years old; 12 patients had injuries in the left and 8 patients had injuries in the right; preoperative Constant-Murley score was 40.75 +/- 10.40. And there were 20 patients in modified surgery group,including 11 males and 9 females, with an average age of (41.65 +/- 14.83) years old; 11 patients had injuries in the left and 9 patients had injuries in the right; preoperative Constant-Murley score was 42.75 +/- 8.18. The Lazzcano standard, Constant-Murley score and imaging changes were used to evaluate shoulder joint function before and after surgery. All the patients were followed up,and the duration ranged from 7 to 32 months,with an average of 24 months. According to Lazzcano evaluation, 16 patients got an excellent result,3 good and 1 poor in modified surgery group with no re-dislocation, and 1 patient had pain more than middle degree; while in hook plate fixation group, 9 patients got an excellent result, 7 good and 4 poor, 1 patient had re-dislocation, and 3 patients got pain more than middle degree. The therapeutic effects of modified surgery group were better than those of hook plate fixation group. Constant-Murley scores:preoperative 42.75 +/- 8.18 vs 93.40 +/- 4.04 at the latest follow-up in modified surgery group; preoperative 40.75 +/- 10.40 vs postoperative 88.40 +/- 4.81 and 92.05 +/- 4.49 at the latest follow-up in hook plate fixation group. The postoperative scores all improved compared to preoperative scores in two groups. And there was no statistical difference of scores at the latest follow-up between two groups. The surgery of allograft tendon transplantation combined with anchor fixation to strengthen coracoclavicular ligament, as well as part transposition of acromiocoracoid ligament and resection at the distal part of clavicle may got safety fixation and less postoperative complications compared with hook plate internal fixation.


New microsatellite markers for the shallow coral Madracis auretenra from the Caribbean.
Coral reefs species represent one-third of all marine species described in the ocean. They are also responsible for providing habitat and support to different species. Recently, Caribbean coral reefs ecosystems have suffered an alarming decrease in their populations as a result of overexploitation. Madracis auretenra in particular, is a widespread shallow coral in marine protected areas (MPAs) of the Caribbean. Due to the important role of MPAs as a biodiversity conservation tool, this species can be used as a model to estimate its dispersion/migration among Caribbean reefs through the use of informative genetic markers (microsatellites) specifically designed for it. Seventeen new polymorphic microsatellites markers for M. auretenra were developed and tested in 330 samples from Colombia, Guatemala, Curacao and Barbados. The gene diversity (1-D) ranged from 0.482 to 0.903, while the evenness ranged from 0.456 to 0.884 after clone removal. The expected heterozygosity (He) ranged from 0.347 to 0.742, while the observed heterozygosity (Ho) ranged from 0.078 to 0.578. The specificity of our microsatellites shows the potential use of these markers in a-posteriori analysis to detect population structure at different spatial scales, where M. auretenra is reported.


Glutamatergic neuronal populations in the brainstem of the sea lamprey, Petromyzon marinus: an in situ hybridization and immunocytochemical study.
Glutamate is the major excitatory neurotransmitter in vertebrates, and glutamatergic cells probably represent a majority of neurons in the brain. Physiological studies have demonstrated a wide presence of excitatory (glutamatergic) neurons in lampreys. The present in situ hybridization study with probes for the lamprey vesicular glutamate transporter (VGLUT) provides an anatomical basis for the general distribution and precise localization of glutamatergic neurons in the sea lamprey brainstem. Most glutamatergic neurons were found within the periventricular gray layer throughout the brainstem, with the following regions being of particular interest: the optic tectum, torus semicircularis, isthmus, dorsal and medial nuclei of the octavolateral area, dorsal column nucleus, solitary tract nucleus, motoneurons, and reticular formation. The reticular population revealed a high degree of cellular heterogeneity including small, medium-sized, large, and giant glutamatergic neurons. We also combined glutamate immunohistochemistry with neuronal tract-tracing methods or γ-aminobutyric acid (GABA) immunohistochemistry to better characterize the glutamatergic populations. Injection of Neurobiotin into the spinal cord revealed that retrogradely labeled small and medium-sized cells of some reticulospinal-projecting groups were often glutamate-immunoreactive, mostly in the hindbrain. In contrast, the large and giant glutamatergic reticulospinal perikarya mostly lacked glutamate immunoreactivity. These results indicate that glutamate immunoreactivity did not reveal the entire set of glutamatergic populations. Some spinal-projecting octaval populations lacked both VGLUT and glutamate. As regards GABA and glutamate, their distribution was largely complementary, but colocalization of glutamate and GABA was observed in some small neurons, suggesting that glutamate immunohistochemistry might also detect non-glutamatergic cells or neurons that co-release both GABA and glutamate.


Antileukemic effect of interleukin-2-transduced murine bone marrow after autologous transplantation.
Myeloablative chemotherapy or radiation therapy supported by autologous stem cell transplantation (SCT) for the treatment of hematologic malignancies such as acute leukemia, lymphoma, and myeloma is associated with high rates of relapse. The reasons for this are 1) autologous transplantation lacks the in vivo graft-vs.-tumor (GVT) effect associated with allogeneic SCT, which is effective in controlling or eliminating residual malignant cells remaining in the body after high-dose therapy, and 2) contaminating malignant cells in the autologous graft are reinfused into the body. Some researchers have attempted to administer immunomodulatory cytokines to simulate a GVT effect, and although this has shown some efficacy, it has several disadvantages. These include high toxicity associated with systemic administration, a short in vivo half-life, and insufficient levels reaching the site of residual disease. As an alternative, we investigated whether delivery of the cytokine interleukin (IL)-2 to the bone marrow can exert an antileukemic effect while avoiding the problems associated with systemic administration. We describe the delivery of IL-2 to the bone marrow by transplantation of syngeneic bone marrow, retrovirally transduced with the gene for IL-2, into lethally irradiated mice. We were able to efficiently transduce murine bone marrow with the IL-2 gene without adversely affecting clonogenic output from hematopoietic progenitors, and we were able to achieve expression of the transgene in transplanted animals. However, IL-2 transduction inhibited hematopoietic reconstitution in lethally irradiated mice. Marrow transduced with high-titer, high-expressing IL-2 retrovirus failed to engraft, and a low-titer, low-expressing IL-2 retrovirus also demonstrated reduced engraftment, although engraftment was sufficient to support survival of transplanted mice. Long-term, low-level expression of the IL-2 transgene was detectable in these mice and was effective in exerting an antileukemic effect. Mice transplanted with control marrow and challenged with leukemic cells suffered 100% mortality within 70 days, whereas mice transplanted with IL-2-transduced marrow exhibited 50% survival over the 175-day duration of this study. The work shows that delivery of immunomodulatory cytokines to the bone marrow can be achieved by transplantation of genetically modified hematopoietic cells. Furthermore, low-level IL-2 expression can exert an antileukemic effect. These data suggest that this may be an effective immunotherapeutic strategy to reduce relapse after autologous transplantation, but the selection and expression of the cytokine must be carefully considered to minimize adverse effects on hematopoiesis.


[Clinical significance and fetal outcome in end-diastolic decreased flow in the umbilical artery and/or fetal aorta: analysis of 51 cases].
The AEDV in the umbilical artery or the foetal aorta is considered to be the most severe waveform abnormality. Using pulsed Doppler, we found such a waveform in 51 foetuses out of 954 high-risk pregnancies (33/51 in both vessels, 17/51 aorta only and 1/51 umbilical artery only). A reverse flow was registered in 24 foetuses. The outcome was compared with that of a control group (n = 72) showing normal Doppler findings. The following parameters were highly significant (p less than 0.001): Rate of Caesarean section owing to foetal distress (85.3% to 4.8%), of growth retardation (IUGR) (66.7% to 6.0%), of premature delivery (73.5% to 7.5%), of low postnatal pH- and Apgar score (73.5 to 12.1%), of admission to the neonatal intensive care unit (94.1% to 8.6%), of morbidity (35.3% to 2.3%) and of mortality (41.1% to 0%). We observed 17/51 intrauterine and 4/51 postnatal deaths. The rate of malformations was 35.3% with 4 cases of aneuploidy. Considering the malformations, the rate of corrected mortality was 23%. We found, that the association of an AEDV and the absence of severe IUGR is highly suspicious of malformation. We also observed, that congenital heart diseases (CHD) could lead to an AEDV too. An AEDV precedes a pathological cardiotocogram (CTG) with a latency of 0 to 35 days (mean 9.5 days). This latency is not predictable, but we think, that a reliable assessment of jeopardy is possible by analysing further vessels (Aa. arcuatae, A. renalis, A. carotis interna): 72.5% of the foetuses with AEDV had high indices in the carotid artery and 93.1% among these showed a pathological CTG pattern.(ABSTRACT TRUNCATED AT 250 WORDS)


Central lymph node characteristics predictive of outcome in patients with differentiated thyroid cancer.
The aim of our study was to determine central compartment lymph node (LN) characteristics predictive of outcomes in patients with differentiated thyroid cancer (DTC) and pathologically confirmed positive central LNs, in the absence of lateral neck disease or distant metastases at presentation. An institutional database of 3664 previously untreated patients with DTC operated between 1986 and 2010 was reviewed. Six hundred patients with central compartment nodal disease on histopathology were identified. Patient demographics, number of positive LNs, size of largest LN, and presence of extranodal spread (ENS) were recorded for each patient. Variables predictive of recurrence-free survival (RFS) were identified using the Kaplan-Meier method. Univariate analysis was carried out by the log-rank test and multivariable analysis was carried out using cox proportional hazard model. The median age of the cohort was 41 years (range 12-91 years). The median follow-up was 61 months (range 1-330 months). Neck recurrence occurred in 43 patients. Recurrence occurred in the central neck in 11 patients, lateral neck in 27 patients, and both compartments in five patients. Factors predictive of neck RFS on univariate analysis were higher T stage (p=0.007), increased number of positive LNs, increased LN diameter, and presence of ENS (p=0.001). Multivariable analysis of LN characteristics showed that the only statistically significant predictor of neck recurrence was the presence of ENS. Neck RFS at five years for patients with and without ENS was 84.7% and 94.5% respectively (p=0.001). The LN feature most predictive of neck recurrence appears to be the presence of ENS in the positive central neck.


Altering α-dystroglycan receptor affinity of LCMV pseudotyped lentivirus yields unique cell and tissue tropism.
The envelope glycoprotein of lymphocytic choriomeningitis virus (LCMV) can efficiently pseudotype lentiviral vectors. Some strains of LCMV exploit high affinity interactions with α-dystroglycan (α-DG) to bind to cell surfaces and subsequently fuse in low pH endosomes. LCMV strains with low α-DG affinity utilize an unknown receptor and display unique tissue tropisms. We pseudotyped non-primate feline immunodeficiency virus (FIV) vectors using LCMV derived glycoproteins with high or low affinity to α-DG and evaluated their properties in vitro and in vivo. We pseudotyped FIV with the LCMV WE54 strain envelope glycoprotein and also engineered a point mutation in the WE54 envelope glycoprotein (L260F) to diminish α-DG affinity and direct binding to alternate receptors. We hypothesized that this change would alter in vivo tissue tropism and enhance gene transfer to neonatal animals. In mice, hepatic α- and β-DG expression was greatest at the late gestational and neonatal time points. When displayed on the surface of the FIV lentivirus the WE54 L260F mutant glycoprotein bound weakly to immobilized α-DG. Additionally, LCMV WE54 pseudotyped FIV vector transduction was neutralized by pre-incubation with soluble α-DG, while the mutant glycoprotein pseudotyped vector was not. In vivo gene transfer in adult mice with either envelope yielded low transduction efficiencies in hepatocytes following intravenous delivery. In marked contrast, neonatal gene transfer with the LCMV envelopes, and notably with the FIV-L260F vector, conferred abundant liver and lower level cardiomyocyte transduction as detected by luciferase assays, bioluminescent imaging, and β-galactosidase staining. These results suggest that a developmentally regulated receptor for LCMV is expressed abundantly in neonatal mice. LCMV pseudotyped vectors may have applications for neonatal gene transfer. Armstrong 53b (Arm53b); baculovirus Autographa californica GP64 (GP64); charge-coupled device (CCD); dystroglycan (DG); feline immunodeficiency virus (FIV); glycoprotein precursor (GP-C); firefly luciferase (Luc); lymphocytic choriomeningitis virus (LCMV); nuclear targeted β-galactosidase (ntLacZ); optical density (OD); PBS/0.1% (w/v) Tween-20 (PBST); relative light units (RLU); Rous sarcoma virus (RSV); transducing units per milliliter (TU/ml); vesicular stomatitis virus (VSV-G); wheat germ agglutinin (WGA); 50% reduction in binding (C50).


Implications of apurinic/apyrimidinic endonuclease in reactive oxygen signaling response after cisplatin treatment of dorsal root ganglion neurons.
Peripheral neuropathy is one of the major side effects of the anticancer drug cisplatin. Although previous work suggests that this neuropathy correlates with formation of DNA adducts in sensory neurons, growing evidence suggests that cisplatin also increases the generation of reactive oxygen species (ROS), which could cause DNA damage. Apurinic/apyrimidinic endonuclease/redox factor-1 (Ape1/Ref-1) is a multifunctional protein involved in DNA base excision repair of oxidative DNA damage and in redox regulation of a number of transcription factors. Therefore, we asked whether altering Ape1 functions would influence cisplatin-induced neurotoxicity. Sensory neurons in culture were exposed to cisplatin for 24 hours and several end points of toxicity were measured, including production of ROS, cell death, apoptosis, and release of the immunoreactive calcitonin gene-related peptide (iCGRP). Reducing expression of Ape1 in neuronal cultures using small interfering RNA (siRNA) enhances cisplatin-induced cell killing, apoptosis, ROS generation, and cisplatin-induced reduction in iCGRP release. Overexpressing wild-type Ape1 attenuates all the toxic effects of cisplatin in cells containing normal endogenous levels of Ape1 and in cells with reduced Ape1 levels after Ape1siRNA treatment. Overexpressing the redox deficient/repair competent C65-Ape1 provides partial rescue, whereas the repair-deficient Ape1 (N226A + R177A) does not protect neurons from cisplatin toxicity. We also observe an increase in phosphorylation of p53 after a decrease in Ape1 levels in sensory neuronal cultures. These results strongly support the notion that Ape1 is a potential translational target such that protecting Ape1 levels and particularly its DNA repair function could reduce peripheral neuropathy in patients undergoing cisplatin treatment.


Injury patterns and circumstances associated with electric scooter collisions: a scoping review.
Electric scooters are personal mobility devices that have risen in popularity worldwide since 2017. Emerging reports suggest that both riders and other road users, such as pedestrians and cyclists, have been injured in electric scooter-associated incidents. We undertook a scoping review of the current literature to evaluate the injury patterns and circumstances of electric scooter-associated injuries. A scoping review of literature published from 2010 to 2020 was undertaken following accepted guidelines. Relevant articles were identified in Medline, Embase, SafetyLit and Transport Research International Documentation using terms related to electric scooters, injuries and incident circumstances. Supplemental searches were conducted to identify relevant grey literature (non-peer-reviewed reports). Twenty-eight peer-reviewed studies and nine grey literature records were included in the review. The current literature surrounding electric scooter-associated injuries mainly comprises retrospective case series reporting clinical variables. Factors relating to injury circumstances are inconsistently reported. Findings suggest that the head, upper extremities and lower extremities are particularly vulnerable in electric scooter falls or collisions, while injuries to the chest and abdomen are less common. Injury severity was inconsistently reported, but most reported injuries were minor. Low rates of helmet use among electric scooter users were noted in several studies. Electric scooters leave riders vulnerable to traumatic injuries of varying severity. Future work should prospectively collect standardised data that include information on the context of the injury event and key clinical variables. Research on interventions to prevent electric scooter injuries is also needed to address this growing area of concern.


H3K27 acetylation activated-COL6A1 promotes osteosarcoma lung metastasis by repressing STAT1 and activating pulmonary cancer-associated fibroblasts.
Background: Collagen type VI alpha 1 (COL6A1) has been found to be dysregulated in several human malignancies. However, the role of COL6A1 in osteosarcoma (OS) progression remains largely unclear. Here, we aimed to explore the clinical significance and biological involvement of COL6A1 in the OS cell migration and invasion. Material and Methods: We used immunohistochemistry, qRT-PCR and western blot to detect the expression of COL6A1 in 181 OS patient samples. Chromatin immunoprecipitation (ChIP) and PCR were carried out to verify the regulatory interaction of p300, c-Jun and COL6A1 promoter. The invasion and migration function of COL6A1 in OS was detected in vitro and in vivo. RNA sequence was performed to detect the downstream pathway of COL6A1, and then co-immunoprecipitation (co-IP), ubiquitination assays and rescue experiments were performed to determine the regulatory effect of COL6A1 and signal transducers and activators of transcription (STAT1). Exosomes derived from OS cell lines were assessed for the ability to promote cancer progression by co-cultured assay and exosomes tracing. Results: COL6A1 was commonly upregulated in OS tissues, especially in lung metastasis tissues, which was associated with a poor prognosis. c-Jun bound p300 increased the enrichment of H3K27ac at the promoter region of the COL6A1 gene, which resulted in the upregulation of COL6A1 in OS. Overexpression of COL6A1 promoted OS cell migration and invasion via interacting with SOCS5 to suppress STAT1 expression and activation in an ubiquitination and proteasomal degradation manner. Most interestingly, we found that exosomal COL6A1 derived from OS cells convert normal fibroblasts to cancer-associated fibroblasts (CAFs) by secreting pro-inflammatory cytokines, including IL-6 and IL-8. The activated CAFs could promote OS cell invasion and migration by mediating TGF-β/COL6A1 signaling pathway. Conclusion: Our data demonstrated that upregulation of COL6A1 activated by H3K27 acetylation promoted the cell migration and invasion by suppressing STAT1 pathway in OS cells. Moreover, COL6A1 can be packaged into OS cell-derived exosomes and activate CAFs to promote OS metastasis.


[The use of therapeutic play in the intensive care of a preschool child with virus-associated hemophagocytic syndrome].
Hospitalization is a stressful experience for children that increases their anxiety and fears, generates resistance and noncompliance, and, as a result, delays necessary treatments. Developing an age-appropriate intervention to reduce the hospitalization-related stress perceived by children is an important component of pediatric nursing. This case study used therapeutic play and drawing to care for a virus-associated hemophagocytic syndrome preschooler who stayed in our pediatric intensive care unit (PICU) between 11/13/2012 and 11/19/2012. Stressors faced by the patient included separation from primary caregiver, unfamiliarity with the medical environment and equipment, non-comprehension of the treatment and medication regimens, and loss of control. The patient displayed incorporative behaviors such as crying, screaming, refusing to be touched, and requesting parental accompaniment. Painting and picture books were used as developmentally appropriate interventions to understand the patient's feelings and to provide a means for him to project and release emotions. This strategy successfully assisted the child to overcome the perceived stress of hospitalization and to cooperate with healthcare providers on his treatment.


[Philippe Pinel (1745-1826) a tonsured cleric].
Philippe Pinel received an excellent education from the Fathers of the Christian Doctrine whose recently discovered library is here analyzed. New facts about his first teacher, Jean-Pierre Gorsse, indicate that he, too, was a student of the Doctrinaires and that a benefice requiring the tonsure passed to Pinel when Gorsse married in 1759.


Safety of anti-TNFalpha therapy in children with juvenile idiopathic arthritis.
Anti-TNFalpha agents are frequently used in the treatment of severe JIA. Etanercept, a fully human soluble recombinant tumour necrosis factor p75 receptor Fc fusion protein, has been registered for the treatment of polyarticular course JIA patients who fail to respond to or do not tolerate methotrexate (MTX). Infliximab, a chimeric human-mouse monoclonal antibody to TNFalpha, is expected to be registered soon for JIA and Crohn's disease (CD) in children. As in adults, both agents are effective in controlling inflammation and inhibiting the progression of joint destruction. Despite this good clinical efficacy, the physician must remain alert for potential side effects, especially after prolonged use. This review gives an overview of the reported adverse events.