Obstructive Sleep Apnea is Associated with an Increased Prevalence of Polycythemia in Patients with Chronic Obstructive Pulmonary Disease.
Chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA) are associated with polycythemia. However, there still remain unanswered questions about the relationship between overlap syndrome (OVS), where OSA and COPD coexist, and polycythemia. Here, we aimed to establish the prevalence of polycythemia in OVS patients and to explore the impact of OSA on polycythemia. Patients with COPD underwent overnight polysomnography (PSG), pulmonary function tests, echocardiography, and complete blood counts. All patients were ethnic Han Chinese and free of prolonged oral corticosteroid use, hematological system disease, severe systemic disease, and other sleep-disordered breathing. OVS was defined as COPD patients with an apnea-hypopnea index ≥15 events/h, and polycythemia was defined as an Hb >165 g/L in men and >160 g/L in women. Eight-hundred and eighty-six patients with COPD were included in the analysis. The prevalence of polycythemia was significantly higher in OVS patients than COPD-alone patients (6.4% vs 2.9%, p < 0.05). The prevalence of polycythemia increased with OSA severity (χ 2 = 7.885, p = 0.007), but not in GOLD grade 3-4 COPD patients (χ 2 = 0.190, p = 0.663). After adjusting for confounders, percentage of total sleep time with SaO2 <90% (TS90) remained independently associated with an increased odds of polycythemia (OR 1.030, 95% CI 1.015-1.046) and, with an increase in TS90, the hemoglobin increased, especially in GOLD grade 1-2 patients (p < 0.05). Patients with OVS have a higher prevalence of polycythemia than those with COPD alone, and TS90 is an independent factor for polycythemia, especially in GOLD1-2 COPD patients.


Evidence for a selective link between cooperation and individual recognition.
The ability to recognize others is a frequent assumption of models of the evolution of cooperation. At the same time, cooperative behavior has been proposed as a selective agent favoring the evolution of individual recognition abilities. Although theory predicts that recognition and cooperation may co-evolve, data linking recognition abilities and cooperative behavior with evidence of selection are elusive. Here, we provide evidence of a selective link between individual recognition and cooperation in the paper wasp Polistes fuscatus through a combination of clinal, common garden, and population genomics analyses. We identified latitudinal clines in both rates of cooperative nesting and color pattern diversity, consistent with a selective link between recognition and cooperation. In behavioral experiments, we replicated previous results demonstrating individual recognition in cooperative and phenotypically diverse P. fuscatus from New York. In contrast, wasps from a less cooperative and phenotypically uniform Louisiana population showed no evidence of individual recognition. In a common garden experiment, groups of wasps from northern populations formed more stable and individually biased associations, indicating that recognition facilitates group stability. The strength of recent positive selection on cognition-associated loci likely to mediate individual recognition is substantially greater in northern compared with southern P. fuscatus populations. Collectively, these data suggest that individual recognition and cooperative nesting behavior have co-evolved in P. fuscatus because recognition helps stabilize social groups. This work provides evidence of a specific cognitive phenotype under selection because of social interactions, supporting the idea that social behavior can be a key driver of cognitive evolution.


Improving Spatial Resolution and Selectivity of Transcorneal Electrical Stimulation by Temporal Interference Technology.
Transcorneal electrical stimulation (TES) used in a therapeutic device has been demonstrated significant neuroprotective effect for rescuing retinal function. However, the diffuse electric field induced by conventional TES devices reduced their spatial resolution and selectivity, limiting their capability of actively stimulating a severely diseased retina. A cutting-edge neuromodulation approach named temporal interference stimulation (TIS) was reported to induce electric fields focalizing on local neuronal targets. Despite the competent feasibility of application in retinal TIS, the interpretation of characteristics of spatial resolution and selectivity under TIS remains rudimentary. In this study, we conduct in silico investigations to understand the characteristics of spatial selectivity and resolution using a finite element model of a multi-layered eyeball and multiple electrode configuration. By simulating different metrics of electric potentials envelope modulated by TIS, our model supports the possibility of achieving mini-invasive and spatially selective electrical stimulation using retinal TIS. These simulations provide theoretical evidence on the basis of which sophisticated devices for improved spatial selectivity can be designed.Clinical Relevance- This study provides a theoretical basis for understanding how the design of electrode configuration impacts transcorneal TIS performance. This model can guide future development of transcorneal TIS configurations and stimulation strategies that may benefit patients with inherited retinal diseases.


RP-HPLC method for simultaneous estimation of tenofovir disoproxil fumarate, lamivudine, and efavirenz in combined tablet dosage form.
A simple, precise, accurate, and rapid reverse phase-high performance liquid chromatography (RP-HPLC) method with UV-Visible detector has been developed and subsequently validated for the simultaneous determination of tenofovir disoproxil fumarate (TDF), lamivudine (LAMI), and efavirenz (EFV) in their combined tablet dosage form. The separation was based on the use of a Kromasil C18 analytical column (150 × 4.6 mm, i.d., 5 μm). The mobile phase consisted of a mixture of 70 volumes of methanol and 30 volumes of 10 mM phosphate buffer (pH 5.0). The separation was carried out at 40°C temperature with a flow rate of 1 ml/min. Quantitation was achieved with UV detection at 254 nm, with linear calibration curves at concentration ranges of 1-6 μg/ml for TDF and LAMI and 2-12 μg/ml for EFV. The recoveries obtained were 99.46-101.36% for LAMI, 99.57-101.42% for TDF, and 99.96-100.87 for EFV. The method was validated according to International conference of harmonisation guidelines in terms of accuracy, precision, specificity, robustness, limits of detection and quantitation, and other aspects of analytical validation.


Argonaute HITS-CLIP decodes microRNA-mRNA interaction maps.
MicroRNAs (miRNAs) have critical roles in the regulation of gene expression; however, as miRNA activity requires base pairing with only 6-8 nucleotides of messenger RNA, predicting target mRNAs is a major challenge. Recently, high-throughput sequencing of RNAs isolated by crosslinking immunoprecipitation (HITS-CLIP) has identified functional protein-RNA interaction sites. Here we use HITS-CLIP to covalently crosslink native argonaute (Ago, also called Eif2c) protein-RNA complexes in mouse brain. This produced two simultaneous data sets-Ago-miRNA and Ago-mRNA binding sites-that were combined with bioinformatic analysis to identify interaction sites between miRNA and target mRNA. We validated genome-wide interaction maps for miR-124, and generated additional maps for the 20 most abundant miRNAs present in P13 mouse brain. Ago HITS-CLIP provides a general platform for exploring the specificity and range of miRNA action in vivo, and identifies precise sequences for targeting clinically relevant miRNA-mRNA interactions.


Cooperativity in long-range gene regulation by the lambda CI repressor.
Effective repression of cI transcription from PRM by the bacteriophage lambda CI repressor requires binding sites (OL) located 2.4 kb from the promoter. A CI tetramer bound to OL1.OL2 interacts with a tetramer bound near PRM (OR1.OR2), looping the intervening DNA. We previously proposed that in this CI octamer:DNA complex, the distant OL3 operator and the weak OR3 operator overlapping PRM are juxtaposed so that a CI dimer at OL3 can cooperate with a CI dimer binding to OR3. Here we show that OL3 is necessary for effective repression of PRM and that the repressor at OL3 appears to interact specifically with the repressor at OR3. The OL3-CI-OR3 interaction involves the same CI interface used for short-range dimer-dimer interactions and does not occur without the other four operators. The long-range interactions were incorporated into a physicochemical model, allowing estimation of the long-range interaction energies and showing the lysogenic state to be ideally poised for CI negative autoregulation. The results establish the lambda system as a powerful tool for examining long-range gene regulatory interactions in vivo.


Current uses of open phenol nerve block for adult acquired spasticity.
Forty-nine open phenol nerve injections were performed for acquired spasticity during a five-year period. The most common etiology of acquired spasticity was closed head injury (70%). Thirteen phenol injections to the musculocutaneous nerve were performed for excessive elbow flexion. The immediate results were absence of biceps and brachialis muscle activity, and an average gain of 43 degrees in extension. The effects of the nerve block subsided within six months. Nine nerve blocks were followed for more than one year. In two patients the upper extremities were almost normal. In the remaining seven the upper extremities were nonfunctional. Twenty-eight phenol injections to the posterior tibial nerve were performed for uncontrolled excessive plantar flexion and/or fixed equinus. The immediate result was cessation of gastrocnemius and soleus activity. Twenty-seven ankles attained a neutral position. The effects of the nerve block subsided within six months. Thirteen patients with 19 blocks were followed for more than eight months. Nine patients underwent lengthening of the Achilles tendon and six patients required orthotic devices for control of plantar flexion spasticity. In general, patients with acquired spasticity who require open phenol nerve blocks are unlikely to have normal functioning extremities when the effects of the nerve block have subsided.


Uptake and transepithelial transport of nerve growth factor in suckling rat ileum.
Nerve growth factor (NGF) is necessary for the development of sympathetic and some sensory neurons. Milk may be a source of NGF for suckling young, but sites of intestinal absorption of the protein have not been identified. To determine whether NGF is transported across the absorptive epithelium of suckling rat ileum, we assessed binding, uptake, and transport of 125I-NGF by light microscopy and EM autoradiography. Blood and tissue extracts were analyzed by biochemical and immunological methods to determine whether NGF was taken up structurally intact. NGF binding sites were identified on microvilli and apical invaginations of ileal absorptive cells in vitro. Injected into ileal loops in vivo, NGF radioactivity retained by fixation was evident after 20 min in apical regions of absorptive cells, in endocytic tubules (which mediate the uptake of membrane-bound ligands), in vesicles (which mediate nonspecific endocytosis), and in the supranuclear lysosomal vacuole. At 1 and 2 h, radiolabel in these compartments increased and silver grains were evident at the basal cell surface, and in cells, matrix, and vessels of the lamina propria. In blood and liver, radiolabeled molecules that were immunologically and electrophoretically indistinguishable from NGF and that co-eluted with NGF on gel filtration columns were detected, confirming that some NGF was transported across the epithelium structurally intact. Thus, absorptive cells of suckling rat ileum can take up NGF by both receptor-mediated and nonspecific endocytosis, and direct NGF either to the lysosome for degradation, or into a transepithelial transport pathway.


Managing insect and plant pathogen pests with organic and conventional pesticides in onions.
Onion thrips (Thrips tabaci Lindeman, Thysanoptera: Thripidae) is a significant insect pest of onions (Allium cepa L., Asparagales: Amaryllidaceae). In addition to feeding on onion foliage, they may spread plant pathogens. Currently, onion thrips and pathogens are managed as separate pests with insecticides and fungicides. It may be beneficial to manage these pests simultaneously as limiting onion thrips may reduce pathogen damage. We tested combinations of bio- and conventional pesticides in a season-long management program in Michigan onion fields. From 2020 to 2022, we counted onion thrips weekly and visually estimated plant foliage necrotic damage (%) in experimental plots each year. In 2020, we tested 6 treatment programs including: azadirachtin, spinosad, a copper-based fungicide, azadirachtin + copper-based fungicide, spinosad + copper-based fungicide, and untreated control. The thrips populations were not significantly reduced compared to the control, but necrotic damage was reduced significantly in spinosad-treated plots. In 2021, we tested a combination of 8 bio- and conventional pesticide programs. Compared to the control, the bioinsecticides did not reduce onion thrips populations, but the conventional pesticide programs reduced both onion thrips numbers and necrotic damage. In 2022, we tested only conventional insecticide programs but included 3 different action thresholds for initiation and applied them with or without a fungicide, for 8 treatments. All insecticide programs reduced onion thrips compared to the control, the action threshold did not impact thrips numbers significantly. Overall, the use of action thresholds can lead to fewer insecticide applications and a lower incidence of leaf damage.


Rapid Kinetics of Pistol Ribozyme: Insights into Limits to RNA Catalysis.
Pistol ribozyme (Psr) is a distinct class of small endonucleolytic ribozymes, which are important experimental systems for defining fundamental principles of RNA catalysis and designing valuable tools in biotechnology. High-resolution structures of Psr, extensive structure-function studies, and computation support a mechanism involving one or more catalytic guanosine nucleobases acting as a general base and divalent metal ion-bound water acting as an acid to catalyze RNA 2'-O-transphosphorylation. Yet, for a wide range of pH and metal ion concentrations, the rate of Psr catalysis is too fast to measure manually and the reaction steps that limit catalysis are not well understood. Here, we use stopped-flow fluorescence spectroscopy to evaluate Psr temperature dependence, solvent H/D isotope effects, and divalent metal ion affinity and specificity unconstrained by limitations due to fast kinetics. The results show that Psr catalysis is characterized by small apparent activation enthalpy and entropy changes and minimal transition state H/D fractionation, suggesting that one or more pre-equilibrium steps rather than chemistry is rate limiting. Quantitative analyses of divalent ion dependence confirm that metal aquo ion pKa correlates with higher rates of catalysis independent of differences in ion binding affinity. However, ambiguity regarding the rate-limiting step and similar correlation with related attributes such as ionic radius and hydration free energy complicate a definitive mechanistic interpretation. These new data provide a framework for further interrogation of Psr transition state stabilization and show how thermal instability, metal ion insolubility at optimal pH, and pre-equilibrium steps such as ion binding and folding limit the catalytic power of Psr suggesting potential strategies for further optimization.


Modeling the fluid dynamics in a human stomach to gain insight of food digestion.
During gastric digestion, food is disintegrated by a complex interaction of chemical and mechanical effects. Although the mechanisms of chemical digestion are usually characterized by using in vitro analysis, the difficulty in reproducing the stomach geometry and motility has prevented a good understanding of the local fluid dynamics of gastric contents. The goal of this study was to use computational fluid dynamics (CFD) to develop a 3-D model of the shape and motility pattern of the stomach wall during digestion, and use it to characterize the fluid dynamics of gastric contents of different viscosities. A geometrical model of an averaged-sized human stomach was created, and its motility was characterized by a series of antral-contraction waves of up to 80% relative occlusion. The flow field within the model (predicted using the software Fluent™) strongly depended on the viscosity of gastric contents. By increasing the viscosity, the formation of the 2 flow patterns commonly regarded as the main mechanisms driving digestion (i.e., the retropulsive jet-like motion and eddy structures) was significantly diminished, while a significant increase of the pressure field was predicted. These results were in good agreement with experimental data previously reported in the literature, and suggest that, contrary to the traditional idea of a rapid and complete homogenization of the meal, gastric contents associated with high viscous meals are poorly mixed. This study illustrates the capability of CFD to provide a unique insight into the fluid dynamics of the gastric contents, and points out its potential to develop a fundamental understanding and modeling of the mechanisms involved in the digestion process. This study illustrates the capability of computational fluid dynamic techniques to provide a unique insight into the dynamics of the gastric contents, pointing out its potential to develop a fundamental understanding and modeling of the human digestion process.


Preservation of pancreatic tissue morphology, viability and energy metabolism during extended cold storage in two-layer oxygenated University of Wisconsin/perfluorocarbon solution.
In contrast to the relative scarcity of donor kidneys and hearts, the potential supply of deceased donor pancreata is exceeding the demand. However, this organ surplus is not being fully realized because, in current transplantation practice, the duration of pancreas storage before transplantation is limited to 8-10 hours due to the extreme vulnerability of pancreatic tissue to anaerobic damage caused by preservation. To reduce cold ischemic injury in order to increase the utilization of donor pancreases in Israel for whole-organ and cell transplantation. We evaluated a novel two-layer preservation oxygenated cold storage method that uses perfluorocarbon to continuously supply oxygen to the pancreas during preservation in conventional University of Wisconsin solution. Pancreatic tissue morphology, viability and adenosine-triphosphate content were serially examined during preservation of the pig pancreas for 24 hours either by a two-layer or by conventional simple cold storage. Already after 12 hours of storage, the superiority of the two-layer method over the University of Wisconsin method was apparent. Starting at this time point and continuing throughout the 24 hours of preservation, the tissue architecture, mitochondrial integrity, cellular viability and ATP tissue concentration were improved in samples preserved in oxygenated UW/PFC as compared to controls stored in conventional UW solution alone. The UW/PFC two-layer preservation method allowed tissue ATP synthesis and amelioration of cold ischemic tissue damage during extended 24 hour pancreas preservation. This method could be implemented in clinical practice to maximize utilization of pancreata for whole-organ and islet transplantation as well as for pancreas sharing with remote centers.


Gender differences in home environments related to childhood obesity in Nanchang, China.
Childhood obesity is rapidly increasing in China, with rates doubling between 2000 and 2010. Several large, epidemiological studies have shown boys to be consistently more likely to be obese than girls. The aim of this study was to investigate gender differences in the home environment and parenting practices related to childhood obesity. A cross-sectional survey using a convenience sampling of 522 (86.1% response rate) primary caregivers of children ages 2-10 years was conducted in four locations in Nanchang, China, in the spring of 2013 using face-to-face, anonymous questionnaires. Boys were significantly (p<0.05) more likely than girls to watch more television (TV) per week, be allowed to have snacks/sweets or soft drinks without permission, and to have sugary drinks at snacks and meals. Girls were significantly more likely than boys to have parental encouragement and support for physical activity, participate in organized sports/group activities, and have fresh fruits accessible. Parents also believed that boys eat too much junk foods or their favorite foods if not controlled. Few differences were noted in the actual physical environment in the home, including access to sports equipment, junk food availability, and access to media. RESULTS indicate that parents tend to be more permissive with boys than girls, allowing them access to unhealthy foods and more TV time. These differences may contribute to the higher prevalence of obesity in boys in China.


Decreased Serum Levels of C-Terminal Agrin in Postmenopausal Women Following Resistance Training.
Elevated circulating C-terminal agrin fragment (CAF) is a marker of neuromuscular junction degradation and sarcopenia. This study sought to determine if resistance training (RT) impacted the serum levels of CAF in perimenopausal (PERI-M) and postmenopausal (POST-M) women. A total of 35 women, either PERI-M or POST-M, participated in 10 weeks of RT. Body composition, muscle strength, and serum estradiol and CAF were determined before and after the RT. The data were analyzed with two-way analysis of variance (p ≤ .05). Upper body and lower body strength was significantly increased, by 81% and 73% and 86% and 79% for the PERI-M and POST-M participants, respectively; however, there were no significant changes in body composition. Estradiol was significantly less for the POST-M participants at pretraining compared with the PERI-M participants. CAF moderately increased by 22% for the PERI-M participants in response to RT, whereas it significantly decreased by 49% for the POST-M participants. Ten weeks of RT reduced the circulating CAF in the POST-M women and might play a role in attenuating degenerative neuromuscular junction changes.


Letter perception emerges from unsupervised deep learning and recycling of natural image features.
The use of written symbols is a major achievement of human cultural evolution. However, how abstract letter representations might be learned from vision is still an unsolved problem 1,2 . Here, we present a large-scale computational model of letter recognition based on deep neural networks 3,4 , which develops a hierarchy of increasingly more complex internal representations in a completely unsupervised way by fitting a probabilistic, generative model to the visual input 5,6 . In line with the hypothesis that learning written symbols partially recycles pre-existing neuronal circuits for object recognition 7 , earlier processing levels in the model exploit domain-general visual features learned from natural images, while domain-specific features emerge in upstream neurons following exposure to printed letters. We show that these high-level representations can be easily mapped to letter identities even for noise-degraded images, producing accurate simulations of a broad range of empirical findings on letter perception in human observers. Our model shows that by reusing natural visual primitives, learning written symbols only requires limited, domain-specific tuning, supporting the hypothesis that their shape has been culturally selected to match the statistical structure of natural environments 8 .


Parent, family, and neighborhood effects on the development of child substance use and other psychopathology from preschool to the start of adulthood.
We examined the long-term effects of childhood familial and neighborhood risk on adolescent substance use and psychiatric symptomatology. This study used data from an ongoing 2-decade long study that recruited alcoholic and neighborhood control families through fathers' drunk-driving records and door-to-door canvassing in a four county area. The sample included 220 male, initially 3- to 5-year-old children of the participant families, who received in-home assessments at baseline and thereafter at 3-year intervals. Parental lifetime psychopathology and offspring symptomatology at ages 18-20 were assessed by semistructured diagnostic interviews. Census tract variables were used to indicate neighborhood characteristics. The isomorphic parental symptomatology predicted offspring psychopathology. For marijuana-use disorder, major depressive disorder, and nicotine dependence, the other parental comorbidities were also significant predictors. Neighborhood residential instability in childhood contributed to the development of late adolescent alcohol-use disorder, marijuana-use disorder, major depressive disorder, antisocial personality disorder, and nicotine-dependence symptomatology. Although lower family socioeconomic status in childhood contributed to more adolescent marijuana-use disorder, major depressive disorder, and nicotine-dependence symptoms, neighborhood socioeconomic status did not predict adolescent psychopathology. Longitudinal changes in neighborhood environments from early childhood to adolescence had significant effects on alcohol-use disorder, marijuana-use disorder, and major depressive disorder symptoms in late adolescence. A higher frequency of family mobility from early childhood to adolescence predicted more nicotine-dependence symptoms in late adolescence. Findings indicate that parental psychopathology, family socioeconomic status, and neighborhood residential instability are all important risk factors for the development of substance-use disorder and other comorbid psychopathology. Intervention programming might effectively use these early parental psychopathology indicators to identify risk and might target community activity to stabilize the social environment and provide youth services to counteract the effects of family transience.


[Cytological characteristics of the gonocytes in the course of their migration in early rat embryos].
The work was carried out in 23 rat embryos from 9,5 to the 11th day of development. In 9,5-day embryos the primary sex cells are localized in the mesenchyma of the allantois and in the intestinal entoderm. Later they migrate either with the blood flow or on the surface of cellular layers towards gonad germs which are reached by the 11th day of the intrauterine development. In the course of this process there occur structural and cytochemical changes in gonocyte nuclei. The nucleolus is replaced to the periphery of the nucleus, around it there appears a rim intensively stained with methylene green. Chromatin has a shape of thin threads. These changes of the nuclei seem to be associated with an increased synthesis of r-DNA and hence with the synthesis of substances having the role to prevent the somatic differentiation of primary sex cells in the course of migration.


Frequencies of genetic polymorphisms of TLR4 and CD14 and of HLA-DQ genotypes in children with celiac disease, type 1 diabetes mellitus, or both.
Besides the central role of the adaptive immune system, a disturbance of innate immunity is also involved in the pathogenesis of celiac disease (CD). Inasmuch as CD and type 1 diabetes mellitus (T1DM) frequently coexist because of a common genetic predisposition, our aim was to study the frequency of CD14 C-260T and TLR4 A+896G single nucleotide polymorphisms (SNPs) and the distribution of HLA-DQ genotypes in children affected by CD, T1DM, or both. TLR4 and CD14 SNPs were tested by polymerase chain reaction, followed by restriction fragment length polymorphism analysis in 80 children with T1DM, 100 children with CD, and 47 children with both CD and T1DM. Determination of HLA-DQ alleles was done by sequence-specific polymerase chain reaction. Frequencies were compared with those of healthy control children. The prevalence of the homozygous CD14 C-260TT genotype was significantly (P = 0.0081) lower in children with T1DM but not in those with CD and T1DM, compared with control children. No difference was found in the genotype and allele frequencies of TLR4 between the studied groups. In patients with T1DM, the frequency of the homozygous HLA-DQ8 genotype was significantly higher than in CD, whereas the frequency of homozygous or heterozygous HLA-DQ2 genotypes did not differ from that in control children. In patients with CD, both homozygous and heterozygous HLA-DQ2 genotypes were significantly more frequent than in the control and T1DM groups, and no elevation in the frequency of the HLA-DQ8 genotypes was observed. In patients with T1DM and those with CD and T1DM, the occurrence of HLA-DQ2/8 heterozygosity was significantly higher than in children with CD only and in control children. Our results suggest that in patients with T1DM, the CD14 C-260TT homozygous genotype increases the risk for the development of CD. The distribution of HLA-DQ genotype is different in children with CD and T1DM than in children with CD or T1DM only. Determination of the HLA-DQ genotype in children with T1DM may help in estimating the risk for the development of CD.


[Two doses of the paternal Tme gene do not compensate for the lethality of the Thp deletion in mice].
The hairpin-tail (Thp) deletion in chromosome 17 is lethal when inherited from the mother. Heterozygotes with this deletion, paternal in origin, are viable. The Thp maternal effect is related to a deficiency of Tme gene located in the Thp deleted region. Herein, the viability of mice with tertiary trisomy of chromosome 17Ts(17(16))43H with different doses of the paternal and maternal Tme alleles is analysed. It is demonstrated that the presence of an additional copy of the region with Tme in the female gamete entirely compensates Thp maternal lethality. We failed to compensate the absence of the Tme gene in the chromosome of maternal origin with a double dose of Tme derived from the father. Thus, evidence was obtained indicating that there are sharp differences between the activities of the paternal and maternal alleles of the Tme gene, due to chromosome imprinting.


Dual Inhibition of TNFR1 and IFNAR1 in Imiquimod-Induced Psoriasiform Skin Inflammation in Mice.
Psoriasis is a chronic inflammatory skin disease affecting 2-3% of the world population and is mainly characterized by epidermal hyperplasia, scaling, and erythema. A prominent role for TNF in the pathogenesis of psoriasis has been shown, and consequently various types of TNF antagonists such as etanercept and infliximab have been used successfully. Recently, increasing amounts of data suggest that type I IFNs are also crucial mediators of psoriasis. To investigate whether blocking their respective receptors would be useful, TNFR1- and IFNAR1-deficient mice were challenged with Aldara, which contains imiquimod, and is used as an experimental model to induce psoriasis-like skin lesions in mice. Both transgenic mice showed partial protection toward Aldara-induced inflammation compared with control groups. Additionally, TNFR1 knockout mice showed sustained type I IFN production in response to Aldara. Double knockout mice lacking both receptors showed superior protection to Aldara in comparison with the single knockout mice and displayed reduced levels of IL-12p40, IL-17F, and S100A8, indicating that the TNF and type I IFN pathways contribute significantly to inflammation upon treatment with Aldara. Our findings reveal that dual inhibition of TNFR1 and IFNAR1 may represent a potential novel strategic treatment of psoriasis.


Final 3-year Results of the Dasatinib Discontinuation Trial in Patients With Chronic Myeloid Leukemia Who Received Dasatinib as a Second-line Treatment.
We previously reported an interim analysis of the DADI (dasatinib discontinuation) trial. The results showed that 48% of patients with chronic myeloid leukemia in the chronic phase who maintained a deep molecular response (DMR) for ≥ 1 year could discontinue second- or subsequent-line dasatinib treatment safely at a median follow-up of 20 months. However, the results from longer follow-up periods would be much more useful from a clinical perspective. The DADI trial was a prospective, multicenter trial conducted in Japan. After confirming a stable DMR for ≥ 1 year, dasatinib treatment subsequent to imatinib or nilotinib was discontinued. After discontinuation, the loss of DMR (even of 1 point) was defined as stringent molecular relapse, thereby triggering therapy resumption. The predictive factors of treatment-free remission (TFR) were analyzed. The median follow-up period was 44.0 months (interquartile range, 40.5-48.0 months). The estimated overall TFR rate at 36 months was 44.4% (95% confidence interval, 32.0%-56.2%). Only 2 patients developed a molecular relapse after the 1-year cutoff point. The presence of imatinib resistance was a significant risk factor for molecular relapse. Moreover, high natural killer cell and low γδ+ T-cell and CD4+ regulatory T-cell (CD25+CD127low) counts before discontinuation correlated significantly with successful therapy discontinuation. These findings suggest that discontinuation of second- or subsequent-line dasatinib after a sustained DMR of ≥ 1 year is feasible, especially for patients with no history of imatinib resistance. In addition, the natural killer cell count was associated with the TFR.


Preconditioning of Mesenchymal Stem Cells with Electromagnetic Fields and Its Impact on Biological Responses and "Fate"-Potential Use in Therapeutic Applications.
Mesenchymal stem cells (MSCs) offer great potential for use in stem cell-based therapies due to their unique regenerative potential via reconstructive and paracrine capacities. These therapies offer new hope for patients suffering from conditions that have no cure. Currently, mesenchymal stem cells (from adipose tissues, bone marrow, and umbilical cords) are most interesting for application in those therapies. Nevertheless, the development of MSC-based medical products requires thorough research and standardization that maximizes the therapeutic effect while minimizing side effects. One of the interesting novel approaches to achieving this goal is combining MSC therapy with an electromagnetic field (EMF). Many studies have shown that EMF can enhance the regenerative properties of MSCs by influencing stem cell fate through modulating differentiation, proliferation, cell cycle regulation, metabolism, and cytokine and growth factor secretions. Combination therapy of EMF-MSCs is a promising perspective; however, it is important to select appropriate EMF parameters to obtain beneficial therapeutic effects. Therefore, understanding the mechanisms involved in the EMF impact on MSCs is crucial. In this study, we provide an overview of the effects of EMF on the biological response and "fate" of MSCs, paying attention to the gaps in research that remain unfilled and discuss the clinical application of this approach.


["Microbial air pollutants--methods for detection of endotoxins, mycotoxins and MVOC"].
In the context of microbial emissions from composting facilities the methods for the detection and identification of the groups of substances released, i.e. endotoxins, mycotoxins and Microbial Volatile Compounds (MVOC) are discussed. With the aid of an overview of the different methods employed for the investigation of the single groups of compounds the current state of the art in this field is presented. In conclusion the enormous research needs, especially with regard to the mycotoxins and MVOC, are pointed out.


Efficacy of a bismuth-based quadruple therapy regimen for Helicobacter pylori eradication in Saudi Arabia.
The treatment efficacy of Helicobacter pylori (H. pylori) has been decreasing over time due to resistance to multiple antimicrobial therapies. The most effective treatment regimen for Saudi Arabian patients infected with H. pylori is still unknown. We aimed to study the eradication rate of 10 days of quadruple therapy; bismuth subcitrate potassium 140 mg, metronidazole 125 mg, and tetracycline 125 mg for H. pylori infection in a Saudi population. This was a prospective, open-label, non-randomized controlled trial. Patients with H. pylori infection were diagnosed by upper gastrointestinal (GI) endoscopy and rapid urease test (RUT) or histology. Patients who tested positive were recruited. Eligible patients were prescribed a 10-day course of quadruple therapy and received three capsules 4 times daily for 10 days along with omeprazole 20 mg twice daily. H. pylori was considered eradicated if the urea breath test (UBT) was negative after 6 weeks of completing the treatment. Ninety-two patients with H. pylori infection were recruited. Three patients withdrew from the trial and another seven patients lost follow-up. We analyzed 82 patient's data as per-protocol analysis, of whom 66 (80%) were naive to H. pylori treatment. Four patients had failed previous treatment with the sequential regimen and 12 patients had treatment with clarithromycin-based triple therapy. The post-treatment UBT for H. pylori infection was negative by per-protocol analysis in 72/82 patients (87.8%), and 72/92 (78.3%) by intention-to-treat analysis. There was no correlation between previous treatment failure and treatment response to the bismuth-based quadruple therapy (P value = 0.28). Treatment with a bismuth-based quadruple therapy was effective in eradicating H. pylori infection in 78.3% of Saudi patients with an ITT analysis and in 87.8% as per-protocol analysis.


Castration therapy results in decreased Ku70 levels in prostate cancer.
Neoadjuvant castration improves response to radiotherapy of prostate cancer. Here, we determine whether castration therapy impairs nonhomologous end-joining (NHEJ) repair of DNA double-strand breaks (DSB) by downregulating Ku70 protein expression. Twenty patients with locally advanced prostate cancer were enrolled, and 6 to 12 needle core biopsy specimens were taken from the prostate of each patient before treatment. Bilateral orchidectomy was conducted in eight patients and 12 patients were treated with a GnRH agonist. After castration, two to four similar biopsies were obtained, and the levels of Ku70 and γ-H2AX foci were determined by immunofluorescence in verified cancer tissues. We observed that the androgen receptor binds directly to Ku70 in prostate tissue. We also found a reduction of the Ku70 protein levels in the cell nuclei in 12 of 14 patients (P < 0.001) after castration. The reduction in Ku70 expression correlated significantly with decreased serum prostate-specific antigen (PSA) levels after castration, suggesting that androgen receptor activity regulates Ku70 protein levels in prostate cancer tissue. Furthermore, a significant correlation between the reductions of Ku70 after castration versus changes induced of castration of γ-H2AX foci could be seen implicating a functional linkage of decreased Ku70 levels and impaired DNA repair. Castration therapy results in decreased levels of the Ku70 protein in prostate cancer cells. Because the Ku70 protein is essential for the NHEJ repair of DSBs and its downregulation impairs DNA repair, this offers a possible explanation for the increased radiosensitivity of prostate cancer cells following castration.


When opposites attract: a multi-sample demonstration of complementary person-team fit on extraversion.
This study assessed the nature of the person-team fit relationships for extraversion on members' attraction toward their teams. Unlike most studies of personality-based fit, which emphasize similarity, we predicted that complementary fit on extraversion (i.e., high individual-low team or low individual-high team levels) would result in greater attraction to the team. Data from two independent samples of intact project teams were analyzed, including 324 MBA students comprising 64 case analysis teams and 217 members of 26 manufacturing teams. Using polynomial regression analysis and three-dimensional surface plots, our results supported the predicted relationship. In addition, the data indicated that individuals who were more attracted to their teams were also better performers, as judged by their peers and supervisors.


Ancestral loss of short wave-sensitive cone visual pigment in lorisiform prosimians, contrasting with its strict conservation in other prosimians.
Mammals are basically dichromatic in color vision, possessing middle to long wave-sensitive (M/LWS) and the short wave-sensitive (SWS) cone opsins in the retina, whereas some nocturnal mammals lack functional SWS opsins. Prosimians, primitive primates consisting of three extant groups (Lorisiformes, Lemuriformes, and Tarsiiformes), include many nocturnal species. Among nocturnal prosimians, a species of lorisiforms, the greater galago (Otolemur crassicaudatus), is known to lack a functional SWS opsin gene, while lemuriforms and tarsiiforms appear to retain SWS opsins in the retina. It has not been established, however, whether the loss of SWS opsin is a universal phenomenon among lorisiforms and whether the functional SWS opsin genes of lemuriforms and tarsiiforms are under strict or relaxed selective constraint. To gain better insight into an association between nocturnality and loss of SWS function, we isolated and sequenced the SWS opsin genes from two species of lorisiforms, the slow loris (Nycticebus coucang; nocturnal) and the lesser galago (Galago senegalensis; nocturnal), and one species each of lemuriforms and tarsiiforms, the brown lemur (Eulemur fulvus; cathemeral) and the western tarsier ( Tarsius bancanus; nocturnal), respectively. Our sequence analysis revealed that (1) the SWS opsin gene was disrupted in the common ancestor of galagids and lorisids and (2) the rate of nonsynonymous nucleotide substitution has been kept significantly lower than that of synonymous substitution in tarsier and lemur, demonstrating the presence of strict selective constraint on the SWS opsin genes in tarsiiforms and lemuriforms.


Morphine, a potential antagonist of cisplatin cytotoxicity, inhibits cisplatin-induced apoptosis and suppression of tumor growth in nasopharyngeal carcinoma xenografts.
Morphine is an opioid analgesic drug often used for pain relief in cancer patients. However, there is growing evidence that morphine may modulate tumor growth, progression and metastasis. In this study, we evaluated whether morphine modulates cisplatin-induced apoptosis in human nasopharyngeal carcinoma CNE-2 cells and whether morphine affects the antitumor activity of cisplatin on tumor growth in human nasopharyngeal carcinoma CNE-2 xenografts in nude mice. We showed that a pretreatment with morphine (1 μg/ml) inhibited the sensitivity of CNE-2 cells to cisplatin by inhibiting cisplatin-induced CNE-2 cell apoptosis, decreasing caspase-3 activity and increasing the Bcl-2/Bax ratio. However, a high dose of morphine (1000 μg/ml) had the opposite effect. We also showed that at a low dose, morphine enhances chemoresistance in an in vivo nasopharyngeal carcinoma (NPC) model by inhibiting cisplatin-induced apoptosis and decreasing neovascularization. Taken together, our results indicate that a low dose of morphine may lead to chemoresistance of cisplatin in NPC models in vitro and in vivo by inhibiting cisplatin-induced apoptosis and decreasing neovascularization.


Early results of the use of tantalum femoral cones for revision total knee arthroplasty.
The optimum treatment method for large femoral bone defects during revision knee replacement has not been established. The purpose of the present study was to determine the initial results associated with the use of porous tantalum metaphyseal cones for the treatment of severe femoral bone loss at the time of revision total knee arthroplasty. Porous tantalum metaphyseal cones were implanted during twenty-four revision total knee replacements. The study group included thirteen women and eleven men with a mean age of sixty-four years at the time of the procedure. The indications for the revision procedure included aseptic loosening of the femoral component (eleven patients), second-stage reimplantation for the treatment of deep infection (seven patients), severe osteolysis around a well-fixed femoral component (three patients), periprosthetic femoral fracture (two patients), and severe knee instability (one patient). The patients were followed for an average of thirty-three months (range, twenty-four to fifty months). Overall, the average Knee Society clinical score improved from 55 points preoperatively to 81 points at the time of the latest follow-up. Radiographic evaluation was completed for twenty patients after a mean duration of follow-up of thirty-five months. All femoral cones appeared well fixed radiographically, with no evidence of complications related to the cone. At the time of short-term follow-up, the porous tantalum metaphyseal femoral cones effectively provided structural support for the femoral implants of a revision total knee arthroplasty in this series. The potential for long-term biologic fixation may provide durability for reconstructions. Long-term follow-up and comparison with alternative reconstructive techniques will be required to evaluate the true effectiveness of this implant.


The Influence of Tissue Ischemia Time on RNA Integrity and Patient-Derived Xenografts (PDX) Engraftment Rate in a Non-Small Cell Lung Cancer (NSCLC) Biobank.
Bio-repositories are invaluable resources to implement translational cancer research and clinical programs. They represent one of the most powerful tools for biomolecular studies of clinically annotated cohorts, but high quality samples are required to generate reliable molecular readouts and functional studies. The objective of our study was to define the impact of cancer tissue ischemia time on RNA and DNA quality, and for the generation of Patient-Derived Xenografts (PDXs). One-hundred thirty-five lung cancer specimens were selected among our Institutional BioBank samples. Associations between different warm (surgical) and cold (ex-vivo) ischemia time ranges and RNA quality or PDXs engraftment rates were assessed. RNA quality was determined by RNA integrity number (RINs) values. Fresh viable tissue fragments were implanted subcutaneously in NSG mice and serially transplanted. RNAs with a RIN>7 were detected in 51% of the sample (70/135), with values of RIN significantly lower (OR 0.08, P = 0.01) in samples preserved for more than 3 hours before cryopreservation. Higher quality DNA samples had a concomitant high RIN. Sixty-three primary tumors (41 adenocarcinoma) were implanted with an overall engraftment rate of 33%. Both prolonged warm (>2 hours) and ex-vivo ischemia time (>10 hours) were associated to a lower engraftment rate (OR 0.09 P = 0.01 and OR 0.04 P = 0.008, respectively). RNA quality and PDXs engraftment rate were adversely affected by prolonged ischemia times. Proper tissue collection and processing reduce failure rate. Overall, NSCLC BioBanking represents an innovative modality, which can be successfully executed in routine clinical settings, when stringent Standard Operating Procedures are adopted.


Assessing the experiences of intra-uterine device users in a long-term conflict setting: a qualitative study on the Thailand-Burma border.
In Burma, severe human rights violations, civil conflict, and the persecution of ethnic and linguistic minority populations has resulted in the displacement of millions of people, many of whom now reside as internally displaced populations (IDPs) in Eastern Burma or in Thailand as refugees or undocumented migrants. Use of the intra-uterine device (IUD), a non-user dependent and highly reliable method of long acting reversible contraception, has the potential to make a significant impact on reproductive health in this protracted conflict setting. This qualitative study aimed to understand Burmese women's experiences with and perceptions of the IUD and identify avenues for improving contraceptive service delivery along the Thailand-Burma border. In the summer of 2013, we conducted in-person in-depth open-ended interviews with 31 women who obtained IUDs from a clinic along the border. We conducted a content and thematic analysis of these data using both a priori (pre-determined) and emergent codes and inductive techniques. Women's experiences with the IUD are overwhelmingly positive and the experiences of friends and family impact use of the device. Financial considerations and access to reproductive health facilities also shape the use of the IUD in this region. The IUD is rare along the Thailand-Burma border and misinformation about this method of contraception is pervasive. Our findings suggest that this modality of contraception is culturally acceptable and may be able to address structural barriers to reproductive health services along the Thailand-Burma border. Ensuring that information provided by health care providers and among peer groups is evidence-based, a full range of contraceptive methods is available, and adoption of an IUD is affordable are priorities for expanding access to reproductive health services in this setting.


Should a lower quality organ go to the least sick patient? Model for end-stage liver disease score and donor risk index as predictors of early allograft dysfunction.
There is a global tendency to justify transplanting extended criteria organs (ECD; Donor Risk Index [DRI] ≥ 1.7) into recipients with a lower Model for End-Stage Liver Disease (MELD) score and to transplant standard criteria organs (DRI < 1.7) into recipients with a higher MELD scores. There is a lack of evidence in the current literature to justify this assumption. A review of our prospectively entered database for donation after brain death (DBD) liver transplantation (n = 310) between January 1, 2006, and September 30, 2010, was performed. DRI was dichotomized as <1.7 and ≥ 1.7. Recipients were divided into 3 strata, those with high (≥ 27), moderate (15-26), and low MELD (<15) scores. The recently validated definition of early allograft dysfunction (EAD) was used. We analyzed EAD and its relation with donor DRI and recipient MELD scores. The overall incidence of EAD was 24.5%. Mortality in the first 6 months in recipients with EAD was 20% compared with 3.4% for those without EAD (relative risk [RR], 5.56, 95% confidence interval [CI], 1.96-15.73; P < .001). Graft failure rate in the first 6 months in those with EAD was 27% compared with 5.8% for those without EAD (RR, 4.63; 95% CI, 2.02-10.6; P < .001). In patients with low MELD scores, a significantly increased rate of EAD (25%) was seen in patients transplanted with a high DRI liver compared with those transplanted with a low DRI liver (6.25%; P = .012). In moderate and high MELD recipients, there was no significant difference in the rate of EAD in patients transplanted with a high DRI liver (62%) compared with those transplanted with a low DRI liver (59%). These results suggest that contrary to common belief it is not justified to preferentially allocate organs with higher DRI to recipients with lower MELD scores.


Policy Complexities in Financing First Episode Psychosis Services: Implementation Realities from a Home Rule State.
Over the past decade, significant investments have been made in coordinated specialty care (CSC) models for first episode psychosis (FEP), with the goal of promoting recovery and preventing disability. CSC programs have proliferated as a result, but financing challenges imperil their growth and sustainability. In this commentary, the authors discuss (1) entrenched and emergent challenges in behavioral health policy of consequence for CSC financing; (2) implementation realities in the home rule context of Ohio, where significant variability exists across counties; and (3) recommendations to improve both care quality and access for individuals with FEP. The authors aim to provoke careful thought about policy interventions to bridge science-to-service gaps, and in this way, advance behavioral health equity.


Fabrication of microband glucose biosensors using a screen-printing water-based carbon ink and their application in serum analysis.
Microband glucose biosensors were fabricated by screen-printing a water-based carbon ink formulation containing cobalt phthalocyanine redox mediator and glucose oxidase (GOD) enzyme, then insulating and sectioning through the thick (20mum) film to expose a 3mm-long working electrode edge. The performance of these biosensors for glucose analysis was investigated at 25 degrees C. Voltammetry in glucose-containing buffer solutions established that an operating potential of +0.4V vs. Ag/AgCl was suitable for analysis under both stirring and quiescent conditions. The influence of pH on biosensor performance was established and an operational pH of 8.0 was selected. Steady-state responses were obtained under quiescent conditions, suggesting a mixed mechanism predominated by radial diffusion, indicative of microelectrode behaviour. Calibration studies obtained with these biosensors showed steady-state currents that were linearly dependent on glucose concentration from the limit of detection (0.27mM) up to 2.0mM, with a precision for replicate biosensors of 6.2-10.7%. When applied to the determination of glucose in human serum, the concentration compared favourably to that determined by a spectroscopic method. These results have demonstrated a simple means of fabricating biosensors for glucose measurement and determination in situations where low-current real-time monitoring under quiescent conditions would be desirable.


Is Intussusception a Middle-of-the-Night Emergency?
Intussusception is the most common abdominal emergency in pediatric patients aged 6 months to 3 years. There is often a delay in diagnosis, as the presentation can be confused for viral gastroenteritis. Given this scenario, we questioned the practice of performing emergency reductions in children during the night when minimal support staff are available. Pneumatic reduction is not a benign procedure, with the most significant risk being bowel perforation. We performed this analysis to determine whether it would be safe to delay reduction in these patients until normal working hours when more support staff are available. We performed a retrospective review of intussusceptions occurring between January 2010 and May 2015 at 2 tertiary care institutions. The medical record for each patient was evaluated for age at presentation, sex, time of presentation to clinician or the emergency department, and time to reduction. The outcomes of attempted reduction were documented, as well as time to surgery and surgical findings in applicable cases. A Wilcoxon rank test was used to compare the median time with nonsurgical intervention among those who did not undergo surgery to the median time to nonsurgical intervention among those who ultimately underwent surgery for reduction. Multivariable logistic regression was used to test the association between surgical intervention and time to nonsurgical reduction, adjusting for the age of patients. The median time to nonsurgical intervention was higher among patients who ultimately underwent surgery than among those who did not require surgery (17.9 vs 7.0 hours; P < 0.0001). The time to nonsurgical intervention was positively associated with a higher probability of surgical intervention (P = 0.002). Intussusception should continue to be considered an emergency, with nonsurgical reduction attempted promptly as standard of care.


Characterization of a CV-1 cell cycle. II. The role of cell-substrate attachment.
The availability of synchronous cultures of untransformed CV-I cells has allowed analysis of the role of cell-substrate attachment in cell cycle progression as well as the ability of serum and SV40 infection to override the requirement for cell-substrate attachment. Attachment to a solid substrate is required for progression through G1. Prevention of attachment results in cell cycle arrest 30 min after cytokinesis. Serum is required for attachment, but increasing the serum concentration from 2 to 20 % does not enhance cell attachment, nor obviate its need for cell cycle progression. SV40 infection does not overcome the requirement of serum for attachment nor the need of attachment for normal cycling.


Potentiality of proton nuclear magnetic resonance and multivariate calibration methods for the determination of dermatan sulfate contamination in heparin samples.
A 1H NMR method for the quantification of dermatan sulfate impurities in heparin industrial samples is proposed. The method is based on the analysis of 1H NMR spectral data by multivariate calibration. The 1H NMR spectra of heparin and dermatan sulfate standards showed characteristic profiles. Thus, differences in the methyl peaks of acetamido groups of heparin and dermatan sulfate were greatly advantageous for the analysis. Other hydrogens of the sugar ring were also relevant in this study. Thus, the determination of dermatan sulfate by multivariate calibration depended on all these differences. Partial least squares regression (PLS) was chosen as the calibration method. In addition, a data standardization procedure was developed in order that 1H NMR spectra registered with different instruments operating under different measurement conditions were comparable. The quantification of dermatan sulfate in the samples was satisfactory, with an overall prediction error of 6%.


Phenethyl isothiocyanate induces cytotoxicity and apoptosis of porcine kidney cells through Mitochondrial ROS-associated ERS pathway.
Glucosinolates (GLS) in cruciferous vegetables are anti-nutritional factors. Excessive or long-term intake of GLS-containing feed is harmful to animal health and may cause kidney damage. Phenethyl isothiocyanate (PEITC) is a GLS. In this study, we investigated the inhibitory effect of PEITC on a porcine kidney (PK-15) cell line and explored the mechanism of PEITC-induced apoptosis. We found that PEITC could affect cell viability and induce cell apoptosis after incubating cells for 24 h. High concentrations of PEITC can induce intracellular ROS accumulation, resulting in impaired mitochondrial function (decreased MMP, decreased ATP) and DNA damage (increased 8-OHdG), cytochrome c in mitochondria is released into the cytoplasm and activates mitochondrial pathway apoptosis-related proteins (Bcl-2 family and caspase-9, -3). Meanwhile, PEITC could induce intracellular Ca2+ accumulation, disrupt ER homeostasis, and activate the expression levels of three ER-resident transmembrane proteins orchestrating the UPR (PERK, IRE-1α and ATF6) and ER-related proteins (GRP78 and CHOP), thereby activating ERS-pathway apoptosis-related proteins (caspase-12, -7). Our results showed that low concentration (2.5 μM) of PEITC had no damaging effect on cells. In comparison, a high concentration (10 μM) of PEITC could induce cell damage in porcine kidney cells and induce apoptosis in PK-15 cells via the Mitochondrial ROS-associated ERS pathway.


Barriers and facilitators of meaningful patient participation at the collective level in healthcare organizations: A systematic review.
Collective patient participation, such as patient participation in policy making, has become increasingly important to achieve high-quality care. However, there is little knowledge on how to let patients participate in a meaningful manner at this level. The aim of this systematic literature review was to provide an overview of barriers, facilitators, and associated impact of collective patient participation. PubMed and EMBASE were searched until May 2023 for studies that evaluated collective patient participation. Study characteristics, methods for patient participation, barriers and facilitators, and impact (if measured) of patient participation were extracted from the articles. We included 59 articles. Identified barriers and facilitators of collective patient participation were grouped into five categories: (1) preconditions for patient participation, (2) strategy for patient participation, (3) preparation of patients and staff for patient participation, (4) support for patients and staff during patient participation, and (5) evaluation of patient participation. Impact of patient participation was reported in 34 included studies at three levels: quality of care and research, the team and organization, and the participants themselves. Only three studies reported quantitative outcomes. Interestingly, similar challenges were experienced during a period of twenty years, indicating that little progress has been made in structuring patient participation. Our overview of barriers and facilitators will therefore help to improve and structure collective patient participation.


Profile of patients triply infected with HIV and the hepatitis B and C viruses in the HAART era.
HIV-HCV-HBV-coinfected patients were assessed to characterize the viral interactions in the setting of HIV coinfection and in the HAART era. All positive anti-HCV antibody and HBs antigen-positive HIV-infected patients were identified at five HIV clinics. Antihepatitis delta (HDV) antibody, serum HIV RNA, HCV RNA, and HBV DNA quantification and genotype determinations were performed. Out of 67 patients identified 47 (70%) were receiving anti-HBV therapy. HCV RNA and HBV DNA were detectable in 52.5% and 37% of patients, respectively. All possible patterns were found, regardless of anti-HBV therapy. HDV coinfection was associated with undetectable HCV RNA [RR 9.52 (95% CI 1.85-49.01); p = 0.007]. Independent factors predicting undetectable HBV DNA lacked HBeAg [RR 13.94 (95% CI 3.05-63.72); p = 0.001] and use of anti-HBV therapy [RR 11.42 (95% CI 2.43-53.54); p = 0.002]. Replication and genotypes of HCV or HBV had no impact on the replication of the other virus. In conclusion, in this cohort of triple infection (HBV/HCV/HIV) various viral patterns were identified. Spontaneous HCV clearance was frequent, and it was independently associated with HDV coinfection. In the absence of HBV therapy, HBV most often actively replicates. HBV/HCV replication or genotypes were not related to the replication of the other virus.


Policy and sustainability issues.
The need for combined and integrated strategies to address iron deficiency is widely recognized, utilizing targeted supplementation, as well as food based strategies including both fortified and nonfortified foods. The challenge is not so much knowing "what" to do as is understanding "how" to implement effective and sustainable interventions. Because the causes of iron and other micronutrient deficiencies are complex, including inadequate food intake, unsanitary conditions and inadequate health services, the solutions may also be complex, requiring multisectoral and interdisciplinary approaches. Top-down strategies are unlikely to be effective and sustainable. Rather, the beneficiaries of the program at the community level must be able to understand malnutrition in simple terms, to envisage potential solutions and to become "demanders" of services. The experience in Thailand provides an example of a country-wide, community-based and participatory approach utilizing facilitators and motivators at the local level to implement and sustain interventions. The experience in Thailand indicates the potential for developing effective and sustainable interventions to address iron deficiency and other micronutrient problems as part of a broad, community-based effort.


Syntheses of rod-shaped fluorescent 1,3,2-benzodiazaboroles with phosphonium, and phosphane chalcogenide acceptor functions.
A series of 1,4-phenylenes X-C(6)H(4)-BDB with a 1,3,2-benzodiazaborolyl (BDB) and a phosphorus based end group [X = PPh(2) (2), P(O)Ph(2) (3), P(S)Ph(2) (4), P(Se)Ph(2) (5), P(AuCl)Ph(2) (6) and P(Me)Ph(2) (7)] as well as 2-(2')thienyl-1,3,2-benzodiazaboroles with a second end group X [X = PPh(2) (8), P(S)Ph(2) (9), P(Se)Ph(2) (10) and P(Me)Ph(2) (11)] in the 5' position were synthesised using established methodologies. Molecular structures of 2-9 and 11 were determined by X-ray diffraction. Compounds 3, 4, 6, 7, 9 and 11 show intense blue luminescence in cyclohexane, toluene, chloroform, dichloromethane and tetrahydrofuran with pronounced solvatochromism. Thereby Stokes shifts in the range of 8950-10,440 cm(-1) and quantum yields up to 0.70 were observed in dichloromethane solutions. In contrast to this, for the selenides 5 and 10 quantum yields are small (<0.1). The absorption maxima (298-340 nm) are well reproduced by TD-DFT computations (B3LYB/G-311G(d,p)) and arise from strong HOMO-LUMO transitions. With the exception of 5 and 10 the HOMOs of the molecules under study are mainly located on the benzodiazaborole group. In 5 and 10 the HOMOs are on the selenium atoms. The LUMOs of all new neutral molecules are mainly represented by the phenylene or thiophene bridge. In the phosphonium cations the LUMOs have additional contributions from the phosphonium unit.


Intravitreal ranibizumab for symptomatic drusenoid pigment epithelial detachment without choroidal neovascularization in age-related macular degeneration.
The aim of our study was to evaluate the functional and anatomic outcomes of intravitreal ranibizumab for the treatment of symptomatic drusenoid pigment epithelial detachment without choroidal neovascularization in age-related macular degeneration. This was a prospective, single-center, uncontrolled, interventional pilot study. Six consecutive eyes (six patients) with drusenoid pigment epithelial detachment with a visual acuity of 20/63 to 20/100 and no evidence of choroidal neovascularization in age-related macular degeneration participated. Patients were given at least one intravitreal ranibizumab injection and were followed for a mean of 66.67 ± 10.3 weeks. Main outcome measures included best-corrected visual acuity (BCVA) measured by Early Treatment Diabetic Retinopathy Study charts and optical coherence tomography, and central macular thickness measured by optical coherence tomography. The mean number of intravitreal ranibizumab injections was 3.0 at the end of follow-up. Regarding BCVA and optical coherence tomography, 33.3% of eyes gained between 19 and 21 letters of BCVA, with a median decrease in central macular thickness of 21 μm. There was a statistically significant difference between baseline and final BCVA (P = 0.046). There was a positive correlation between intraretinal fluid by optical coherence tomography and improved BCVA after intravitreal ranibizumab. Metamorphopsia disappeared completely after the first injection in all subjects, with no further recurrences. No patient developed choroidal neovascularization or atrophic changes. Intravitreal ranibizumab demonstrated anatomic and functional benefit in patients with symptomatic drusenoid pigment epithelial detachment without choroidal neovascularization in age-related macular degeneration. Further long-term, randomized, controlled trials should be performed to confirm our preliminary results.


A randomised trial of the effect of omega-3 polyunsaturated fatty acid supplements on the human intestinal microbiota.
Omega-3 polyunsaturated fatty acids (PUFAs) have anticolorectal cancer (CRC) activity. The intestinal microbiota has been implicated in colorectal carcinogenesis. Dietary omega-3 PUFAs alter the mouse intestinal microbiome compatible with antineoplastic activity. Therefore, we investigated the effect of omega-3 PUFA supplements on the faecal microbiome in middle-aged, healthy volunteers (n=22). A randomised, open-label, cross-over trial of 8 weeks' treatment with 4 g mixed eicosapentaenoic acid/docosahexaenoic acid in two formulations (soft-gel capsules and Smartfish drinks), separated by a 12-week 'washout' period. Faecal samples were collected at five time-points for microbiome analysis by 16S ribosomal RNA PCR and Illumina MiSeq sequencing. Red blood cell (RBC) fatty acid analysis was performed by liquid chromatography tandem mass spectrometry. Both omega-3 PUFA formulations induced similar changes in RBC fatty acid content, except that drinks were associated with a larger, and more prolonged, decrease in omega-6 PUFA arachidonic acid than the capsule intervention (p=0.02). There were no significant changes in α or β diversity, or phyla composition, associated with omega-3 PUFA supplementation. However, a reversible increased abundance of several genera, including Bifidobacterium, Roseburia and Lactobacillus was observed with one or both omega-3 PUFA interventions. Microbiome changes did not correlate with RBC omega-3 PUFA incorporation or development of omega-3 PUFA-induced diarrhoea. There were no treatment order effects. Omega-3 PUFA supplementation induces a reversible increase in several short-chain fatty acid-producing bacteria, independently of the method of administration. There is no simple relationship between the intestinal microbiome and systemic omega-3 PUFA exposure. ISRCTN18662143.


Objective measurement of quality of life changes after ACE Malone using the FICQOL survey.
There is little objective data demonstrating improved quality of life after a Malone antegrade continence enema (ACE) despite the dramatic subjective improvements seen by physicians and caretakers. We utilized the FICQOL survey, a reliable and valid instrument for measuring the impact of fecal incontinence and constipation on quality of life (FICQOL) of caregivers and children with spina bifida. Between 2002 and 2009, 23 families were evaluated prospectively before and after an ACE procedure. Items on the survey were compared with Wilcoxon rank sum or signed rank test. After an ACE Malone the mean number of bowel movements (BM) per day decreased along with a decrease in number of accidents per week from 3.9 to 0.3. There was no change in the time committed to bowel care. The percentage of patients taking oral laxatives decreased from 44% to 6%. Both parent and child were less often prevented from leaving the house and the caretakers' bother, anxiety and depression due to bowel care decreased. Although factors regarding the child's social issues and parent's employment improved, the changes were not statistically significant. Among patients with spina bifida and fecal incontinence who underwent the ACE procedure at our institution, a significant improvement in fecal incontinence and QOL scores was observed using a validated instrument, FICQOL. Without changing the amount of time necessary for bowel care, the ACE procedure decreases the families' worries and anxieties and allows them to leave home with the confidence that their child will not have leakage of stool.


[The multivariate analysis of clinico-laboratory data in stomatology].
The authors demonstrate the potentialities of multidimensional analysis methods: component, cluster, and discriminant as exemplified by clinico-laboratory examinations of 26 patients with medium-severe periodontitis and concomitant diseases. A two-stage modification of multidimensional grouping of biomedical objects is suggested. The first stage implies detection of the principal components and their estimation for each examinee. The second stage consists in realization of multidimensional grouping method according to G. S. Kil'dishev and Iu. I. Abolentsev in relation to individual component values. Different typologically homogeneous groups of patients with a specific microbiologic and biochemical status evidently requiring a differentiated approach to treatment may be singled out within the frames of a current classification of periodontal diseases basing on clinical and laboratory data.


Collective Computation in Animal Fission-Fusion Dynamics.
Recent work suggests that collective computation of social structure can minimize uncertainty about the social and physical environment, facilitating adaptation. We explore these ideas by studying how fission-fusion social structure arises in spider monkey (Ateles geoffroyi) groups, exploring whether monkeys use social knowledge to collectively compute subgroup size distributions adaptive for foraging in variable environments. We assess whether individual decisions to stay in or leave subgroups are conditioned on strategies based on the presence or absence of others. We search for this evidence in a time series of subgroup membership. We find that individuals have multiple strategies, suggesting that the social knowledge of different individuals is important. These stay-leave strategies provide microscopic inputs to a stochastic model of collective computation encoded in a family of circuits. Each circuit represents an hypothesis for how collectives combine strategies to make decisions, and how these produce various subgroup size distributions. By running these circuits forward in simulation we generate new subgroup size distributions and measure how well they match food abundance in the environment using transfer entropies. We find that spider monkeys decide to stay or go using information from multiple individuals and that they can collectively compute a distribution of subgroup size that makes efficient use of ephemeral sources of nutrition. We are able to artificially tune circuits with subgroup size distributions that are a better fit to the environment than the observed. This suggests that a combination of measurement error, constraint, and adaptive lag are diminishing the power of collective computation in this system. These results are relevant for a more general understanding of the emergence of ordered states in multi-scale social systems with adaptive properties-both natural and engineered.


Targeting dual tolerant regions of binding pocket: Discovery of novel morpholine-substituted diarylpyrimidines as potent HIV-1 NNRTIs with significantly improved water solubility.
To address the intractable issues of drug resistance and poor solubility, a novel series of morpholine-substituted diarylpyrimidines targeting the tolerant region I and tolerant region II of NNIBP were rationally designed by utilizing the available crystallography studies. The biological evaluation results showed that four most promising compounds (14e1, 14g1, 14g2 and 14j2) displayed excellent potency against WT HIV-1 strain with EC50 values ranging from 58 to 87 nM, being far more potent than NVP and comparable to ETV. Besides, some derivatives exhibited moderate activity in inhibiting the mutant HIV-1 strains. More encouragingly, 14d2 (RF = 0.4) possessed higher antiresistance profile than ETV (RF = 6.3) and K-5a2 (RF = 3.0) toward the double mutant strain F227L + V106A. The HIV-1 RT inhibition assay confirmed their binding target. The molecular docking studies were conducted and discussed in detail to rationalize the preliminary SARs. Further test indicated that morpholine could indeed promote the improvement of water solubility. Additionally, the in silico prediction of physicochemical properties and CYP enzymatic inhibitory ability were investigated to evaluate their drug-like features.


Circulating miR-199a-3p as a novel serum biomarker for colorectal cancer.
Serum microRNAs (miRNAs) have been shown to have potential for cancer diagnosis. The main objective of the present study was to identify a novel serum miRNA biomarker from patients with colorectal cancer (CRC). Microarray analysis of miRNA expression was performed using paired pre-operative and post-operative serum from 10 CRC patients. Expression of two miRNAs (let-7a and miR-199a-3p) was significantly decreased in the post-operative serum when compared to levels in the pre-operative serum (P=0.015 and 0.029, respectively). Quantitative real-time polymerase chain reaction (qRT-PCR) confirmed the decrease in the miRNAs in an extended number (n=30) of paired serum samples. Next, we examined the serum let-7a level in 32 non-cancer patients and 84 CRC patients but we found no significant difference (P=0.120). In contrast, miR199a-3p expression was significantly higher in the CRC patients than that in the non-cancer patients (P=0.016). Furthermore, clinical and pathological survey indicated that high expression of miR-199a-3p was significantly associated with deep wall invasion. Our data suggest that circulating miR-199a-3p could be a novel serum biomarker for CRC.


Detection of a branched alkyl molecule in the interstellar medium: iso-propyl cyanide.
The largest noncyclic molecules detected in the interstellar medium (ISM) are organic with a straight-chain carbon backbone. We report an interstellar detection of a branched alkyl molecule, iso-propyl cyanide (i-C3H7CN), with an abundance 0.4 times that of its straight-chain structural isomer. This detection suggests that branched carbon-chain molecules may be generally abundant in the ISM. Our astrochemical model indicates that both isomers are produced within or upon dust grain ice mantles through the addition of molecular radicals, albeit via differing reaction pathways. The production of iso-propyl cyanide appears to require the addition of a functional group to a nonterminal carbon in the chain. Its detection therefore bodes well for the presence in the ISM of amino acids, for which such side-chain structure is a key characteristic.


Mechanism of action of transmembrane activator and calcium modulator ligand interactor-Ig in murine systemic lupus erythematosus.
B cell-activating factor belonging to the TNF family (BAFF) blockade prevents the onset of disease in systemic lupus erythematosus (SLE)-prone NZB/NZW F(1) mice. To determine the mechanism of this effect, we administered a short course of TACI-Ig with and without six doses of CTLA4-Ig to 18- to 20-wk-old NZB/NZW F(1) mice and evaluated the effect on B and T cell subsets and on anti-dsDNA Ab-producing B cells. Even a brief exposure to TACI-Ig had a beneficial effect on murine SLE; CTLA4-Ig potentiated this effect. The combination of TACI-Ig and CTLA4-Ig resulted in a temporary decrease in serum IgG levels. However, after cessation of treatment, high titers of IgG anti-dsDNA Abs appeared in the serum and IgG Abs deposited in the kidneys. Despite the appearance of pathogenic autoantibodies, the onset of proteinuria was markedly delayed; this was associated with prolonged depletion of B cells past the T1 stage, a decrease in the size of the spleen and lymph nodes, and a decrease in the absolute number of activated and memory CD4(+) T cells. TACI-Ig treatment normalized serum levels of IgM that are markedly elevated in NZB/W F(1) mice; this appeared to be due to a prolonged effect on the ability of the splenic microenvironment to support short-lived IgM plasma cells. Finally, a short course of combination TACI-Ig and CTLA4-Ig prolonged life and even reversed proteinuria in aged NZB/W F(1) mice, suggesting that BAFF blockade may be an effective therapeutic strategy for active SLE.


Adenoid cystic carcinoma of the breast: molecular markers, treatment, and clinical outcome.
The objective of this study was to comprehensively characterize the clinical and biologic features of adenoid cystic carcinoma (ACC) and to assess the implications for management in a large cohort of patients. From a database of 50,000 patients, 28 were identified with ACC for which clinical follow-up and biologic information was available. The biologic features examined included estrogen receptor and progesterone receptor status, DNA ploidy, and S-phase fraction. Median follow-up was 83 months with a range of 29 to 144 months. Overall survival and disease free survival curves were drawn using Kaplan and Meier estimates and were compared by the log-rank test. All but one patient were postmenopausal with a median age at diagnosis of 66 years (range, 40-96 years). One patient had macroscopic metastatic disease at diagnosis. Median tumor size was 1.9 cm (range, 0.5-7.0 cm). Axillary lymph node dissection was performed in 23 patients. Only 1 patient (4%) had histologic positive lymph nodes (2 of 10), and no recurrence was detected for this patient. Forty-six percent were ER positive (median, 16 fmol/mg protein; range, 5-1017 fmol/mg), and 35% were PgR positive (median, 61 fmol/mg protein; range, 6-854 fmol/mg). S-phase fraction and DNA ploidy were assessable in 24 cases. Ninety percent of tumors had low S-phase (median, 3.3%; range, 0.1-34.2%), and 92% were diploid. Simple or modified radical mastectomy was performed in 22 patients, and 6 patients were treated by lumpectomy. Five of these six patients also received radiation therapy after lumpectomy. Despite the different surgical approaches, there were no local recurrences. The 5-year disease free survival rate was 100%, and the 5-year overall survival rate was 85% (95% confidence interval, 71.7-98.6%). Adenoid cystic carcinomas of the breast have very favorable biologic characteristics and, consistent with this, an excellent prognosis. Good local control can be achieved by lumpectomy with radiation or by simple mastectomy. Axillary lymph node dissection is not helpful in clinical management.


Effect of prophylactic brimonidine instillation on bleeding during strabismus surgery in adults.
To investigate the effects of preoperative brimonidine-purite 0.15% instillation on intraoperative bleeding and postoperative subconjunctival hemorrhage during strabismus surgery in adult patients. Randomized comparative interventional case series. One hundred and eighteen eyes of 90 consecutive adult patients were instilled with either a single drop of brimonidine-purite 0.15% (42 eyes), phenylephrine 1% (38 eyes), or sodium hyaluronate 0.1% (38 eyes) 15 minutes prior to strabismus surgery. Intraoperative bleeding and postoperative subconjunctival hemorrhage were graded on a scale of one to three. The scores were compared among the study groups. Scores of the intraoperative bleeding and the postoperative subconjunctival hemorrhage of the treatment groups were significantly less than that of the control group (P < .001). The scores of the brimonidine group were similar to those of the phenylephrine group (intraoperative bleeding score, P = .405; subconjunctival hemorrhage score, P = .722). Topical brimonidine administration before strabismus surgery may reduce intraoperative bleeding and postoperative subconjunctival hemorrhage in adult patients.


Intersession reproducibility of mass spectrometry profiles and its effect on accuracy of multivariate classification models.
The 'reproducibility' of mass spectrometry proteomic profiling has become an intensely controversial topic. The mere mention of concern over the 'reproducibility' of data generated from any particular platform can lead to the anxiety over the generalizability of its results and its role in the future of discovery proteomics. In this study, we examine the reproducibility of proteomic profiles generated by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) across multiple data-generation sessions. We analyze the problem in terms of the reproducibility of signals, reproducibility of discriminative features and reproducibility of multivariate classification models on profiles for serum samples from early lung cancer and healthy control subjects. Proteomic profiles in individual data-generation sessions experience within-session variability. We show that combining data from multiple sessions introduces additional (inter-session) noise. While additional noise can affect the discriminative analysis, we show that its average effect on profiles in our study is relatively small. Moreover, for the purposes of prediction on future (previously unseen) data, classifiers trained on multi-session data are able to adapt to inter-session noise and improve their classification accuracy.


[Multilevel model for global weight gain rate in the kangaroo-mother program in Bogotá].
Objectives To formulate a multilevel model for the longitudinal study of global weight gain rate in the Kangaroo-Mother Care Program. Methodology A multilevel model is used, taking time and some infant and mother variables in the first level. Measures associated with the global weight gain rate are considered for the second level. Results At 5 % significance, the intercept and the parameter associated to the time (days after birth) squared variable have a significant effect on the global rate of weight gain. The slope for the time variable is significant at the 6 % level. Also, under this model, we find that the gender delay in intrauterine growth of the infant, height and perimeter do not have a significant effect on the infant's global rate of weight gain. The weight in the various controls performed is significant at the 5 % level. There are differences between the two infant's gestational classifications (1: 26 to 40 weeks; 2: greater than 40 weeks), and between the infant's weight classifications of the categories two with one, and three with one (1: 2500 gm or more; 2: between 1500 and 2499 gm; 3: less than 1500 gm). Conclusion For each additional appointment, the average weight gain rate of the infant decreases. However, the infant keeps gaining weight, but not at the same rate as in the initial appointments.


[Identification of neurodegenerative diseases in administrative databases in France: A systematic review of the literature].
Given the health, social and economic burden of neurodegenerative diseases (ND), the development of epidemiologic studies is required. Administrative databases, such as the French national health insurance database (SNIIRAM) could represent an opportunity for researchers. ND could be presumed from drug reimbursement data, hospital stays or registration of a chronic condition. The aim of this study was to describe, in French administrative databases, algorithms used to identify Alzheimer's disease and associated disorders (ADAD), Parkinson's disease and associated disorders (PDAD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS). A systematic literature review was performed in Medline and gray literature through December 31th, 2015. French studies focusing on ADAD, PDAD, MS or ALS as a primary health outcome, conducted among one of the SNIIRAM data sources (outpatient reimbursements, chronic condition registration, hospital discharge) were included. Thirty-four studies were included (ADAD, n=18, PDAD, n=9, MS, n=4, ALS, n=3), leading to 36 algorithms. For each studied ND, there was an important variability in the algorithms, concerning (i) the type of criteria used (administrative database versus multi-source systems); (ii) the number of criteria used; (iii) the definition used for each criteria. The extent and level of drug exposure highly varied. Identification through hospitalizations showed variations in terms of type of stay (short stay, long-term stay, psychiatric ward…), extent of diagnosis codes used, diagnosis type (principal, related, associated diagnosis) and period used. A validation study was conducted for 2 out of 36 algorithms (PDAD), and criteria completeness was estimated for 3 algorithms (MS, ALS). Despite the increase in ND identification among French administrative databases, few algorithms have been validated. Validation studies should be encouraged.


Musculoskeletal Conditions in Persons Living with HIV/AIDS: A Scoping Review.
Globally 37.9 million people are living with HIV/AIDS, and with mortality rates declining, there is an increasing focus on comorbidities including musculoskeletal (MSK) disorders. Therefore, the aim of this scoping review was to generate and summarize an overview of the existing scientific literature dealing with MSK complaints in people living with HIV/AIDS (PLWHAs). This scoping review followed the five-stage methodological framework proposed by Arksey and O'Malley. We searched PubMed, EMBASE, CINAHL, and the Cochrane Library from inception to June 1, 2020. Two reviewers independently reviewed the articles for eligibility. A data extraction form was used to chart information such as author, year of publication, data source, sample size, country of origin, ethnicity, age, gender, antiretroviral therapy, MSK condition prevalence, and anatomical location. The search identified 10 522 articles. Of these, 27 studies were included after full-text screening for data extraction. Studies were conducted in thirteen different countries with diverse data sources such as outpatient clinic files, hospital records, primary care clinic files, and AIDS Service Organization files. PLWHAs have a variety of MSK conditions. Most studies reported spinal pain such as lower back or neck pain, but pain in the extremities and osteoarthritis (OA) were also represented. However, the frequencies of pain at various anatomical sites were highly variable. There is a lack of knowledge regarding MSK conditions in PLWHAs. Future studies designed to specifically study MSK complaints and disabilities are needed to gain a better picture of the impact of these conditions in PLWHAs and to inform prevention and treatment strategies globally in this often-underserved population.


[The Molecular Classification Of Blackfly (Diptera: Simuliidae) Species Which Pose a Problem in Nevşehir Part of Central Kızılırmak Basin].
This study was carried out to determine the molecular characterization of simuliid species which cause a problem in the part of Kızılırmak passes from Ürgüp and Gülşehir districts of Nevşehir. Between May and September 2011, totally 150 simuliid larvae were sampled. Morphological identifications of the collected larvae specimens were done before the molecular analyses. Genomic DNA extractions were utilized on 7 larvae specimens which were selected from morphologically identified samples and the sequence and phylogenetic analyses were performed after the amplification of the partial mitochondrial cytochrome oxidase subunit 1 (mt-COI) and ribosomal complete internal transcript spacer 2 and partial 28S (ITS-2/28S) gene regions. Eighty-five, 46 and 19 out of 150 morphologically examined specimens were identified as Simulium (S.) Wilhelmia sp., S. Wilhelmia lineatum and S. Wilhelmia balcanicum, respectively. Among the amplified samples with respect to mt-COI and ITS-2/28S gene regions, sequence analyses were performed on 3 and 2 isolates from S. Wilhelmia sp. and both S. lineatum and S. balcanicum. The isolates were found to be clustered together depending on the species for both gene regions phylogenetically and the sequence heterogeneity was found to be higher in S. lineatum. When comparing with the other species under the Wilhelmia subgenus, S. lineatum and S. balcanicum were determined to be more close to each other. Scientific data on the molecular characterization and phylogeny of blackfly species under the S. Wilhelima subgenus which pose a problem in the Central Kızılırmak Basin were provided with this study.


Three-component ruthenium-catalyzed remote C-H functionalization of 8-aminoquinoline amides.
Multicomponent reactions can efficiently construct complex molecular structures from simple precursors. Herein, a novel ruthenium-catalyzed three-component highly selective remote C-H functionalization of 8-aminoquinoline amides has been described. The reaction tolerates a wide range of functional groups, producing arylation/difluoroalkylation products of olefins with potential biological activity and pharmaceutical value. Radical scavenging and radical clock experiments show that a free radical process is involved and a H/D exchange experiment suggests that the reaction might involve ortho-C-H activation of the aromatic ring. A possible mechanism is proposed.


Candida arteritis in kidney transplant recipients: case report and review of the literature.
Multi-organ procurement is a risk factor for contamination of preservation fluid with intestinal flora including fungi (e.g., Candida). Transmission of fungal species to the graft vessel can cause mycotic arteritis. This is a very rare but life-threatening complication of renal transplantation. We present 2 cases of renal transplant recipients from the same multi-organ donor. Both recipients suffered from severe hemorrhages from renal graft anastomosis and renal artery pseudoaneurysm due to Candida albicans arteritis (CAA). The culture of the preservation fluid revealed growth of Escherichia coli, but neither preservation fluid nor multiple routine blood cultures performed before hemorrhagic complications revealed fungal growth (media non-selective for fungal growth were applied). The first recipient suffered from sudden severe hemorrhage in the area of graft anastomosis on day 10 post surgery (without any preceding clinical or radiological symptoms). This led to urgent surgery and graftectomy, which was complicated by cardio-respiratory arrest with resuscitation in the operating room; despite resuscitation, irreversible brain damage, and subsequent death occurred in the intensive care unit (ICU) 2 weeks later (on day 24 after transplantation). The second patient underwent urgent vascular surgery on day 22 (after transplantation), because of hemorrhage from a pseudoaneurysm of the graft artery. She required repeated vascular operations, extended antimicrobial and antifungal therapy, and ICU monitoring and, despite these interventions, she died on day 80 after transplantation as a result of Pseudomonas aeruginosa sepsis. Arteritis of the renal artery in both patients was caused by C. albicans. This was confirmed by histopathology: infiltration of renal artery with budding yeast forming pseudohyphae (Case 1), and the presence of C. albicans in the culture of the renal artery and surrounding tissue (Case 2). We conclude that organ preservation solution should be cultured with use of media selective for fungal growth. As soon as the positive culture is detected, appropriate measures protecting patients against CAA should be undertaken.


Frequency of extracardiac findings on "negative" CT coronary angiography studies.
To evaluate the prevalence and nature of extracardiac findings identified on computed tomography (CT) coronary angiography (CTCA) in patients with chest pain but without evidence of coronary artery disease (CAD). CTCA studies in patients referred to the hospital between January 2017 to February 2021 with chest pain and a suspected diagnosis of CAD were reviewed retrospectively for the presence of extracardiac findings. Consensus review of CTCA studies was performed by two experienced thoracic radiologists. The presence and severity of extracardiac findings, together with the likelihood that chest pain might be attributed to these, was recorded. Patient records were reviewed to ascertain the recording of extracardiac findings on initial CTCA reports and, where applicable, the nature of the follow-up. Extracardiac findings (n=210) were present in 110/180 patients (61%) with a mean of 1.9 findings per patient. Extracardiac findings were more prevalent in patients aged ≥65 years compared to those <65 years (p<0.001). At least one extracardiac finding with the potential to cause chest pain was present in 40 patients (22%): degenerative disc disease (n=23 [13%]) and hiatus hernia (n=6 [3.3%]) were the most common extracardiac findings. Only 37.6% (79) of all retrospectively identified findings had been initially reported and, of these, 12.7% (10) required further follow-up. Extracardiac findings are common in patients with no evidence of CAD on CTCA. The entire dataset should be evaluated for the presence of extracardiac findings that could explain chest pain symptoms on wide field of view reconstructions.


Why join groups? Lessons from parasite-manipulated Artemia.
Grouping behaviours (e.g. schooling, shoaling and swarming) are commonly explicated through adaptive hypotheses such as protection against predation, access to mates or improved foraging. However, the hypothesis that aggregation can result from manipulation by parasites to increase their transmission has never been demonstrated. We investigated this hypothesis using natural populations of two crustacean hosts (Artemia franciscana and Artemia parthenogenetica) infected with one cestode and two microsporidian parasites. We found that swarming propensity increased in cestode-infected hosts and that red colour intensity was higher in swarming compared with non-swarming infected hosts. These effects likely result in increased cestode transmission to its final avian host. Furthermore, we found that microsporidian-infected hosts had both increased swarming propensity and surfacing behaviour. Finally, we demonstrated using experimental infections that these concurrent manipulations result in increased spore transmission to new hosts. Hence, this study suggests that parasites can play a prominent role in host grouping behaviours.


B lymphocyte depletion by CD20 monoclonal antibody prevents diabetes in nonobese diabetic mice despite isotype-specific differences in Fc gamma R effector functions.
NOD mice deficient for B lymphocytes from birth fail to develop autoimmune or type 1 diabetes. To assess whether B cell depletion influences type 1 diabetes in mice with an intact immune system, NOD female mice representing early and late preclinical stages of disease were treated with mouse anti-mouse CD20 mAbs. Short-term CD20 mAb treatment in 5-wk-old NOD female mice reduced B cell numbers by approximately 95%, decreased subsequent insulitis, and prevented diabetes in >60% of littermates. In addition, CD20 mAb treatment of 15-wk-old NOD female mice significantly delayed, but did not prevent, diabetes onset. Protection from diabetes did not result from altered T cell numbers or subset distributions, or regulatory/suppressor T cell generation. Rather, impaired CD4+ and CD8+ T cell activation in the lymph nodes of B cell-depleted NOD mice may delay diabetes onset. B cell depletion was achieved despite reduced sensitivity of NOD mice to CD20 mAbs compared with C57BL/6 mice. Decreased B cell depletion resulted from deficient FcgammaRI binding of IgG2a/c CD20 mAbs and 60% reduced spleen monocyte numbers, which in combination reduced Ab-dependent cellular cytotoxicity. With high-dose CD20 mAb treatment (250 microg) in NOD mice, FcgammaRIII and FcgammaRIV compensated for inadequate FcgammaRI function and mediated B cell depletion. Thereby, NOD mice provide a model for human FcgammaR polymorphisms that reduce therapeutic mAb efficacy in vivo. Moreover, this study defines a new, clinically relevant approach whereby B cell depletion early in the course of disease development may prevent diabetes or delay progression of disease.