Manifold Alignment Aware Ants: A Markovian Process for Manifold Extraction.
The presence of manifolds is a common assumption in many applications, including astronomy and computer vision. For instance, in astronomy, low-dimensional stellar structures, such as streams, shells, and globular clusters, can be found in the neighborhood of big galaxies such as the Milky Way. Since these structures are often buried in very large data sets, an algorithm, which can not only recover the manifold but also remove the background noise (or outliers), is highly desirable. While other works try to recover manifolds either by pushing all points toward manifolds or by downsampling from dense regions, aiming to solve one of the problems, they generally fail to suppress the noise on manifolds and remove background noise simultaneously. Inspired by the collective behavior of biological ants in food-seeking process, we propose a new algorithm that employs several random walkers equipped with a local alignment measure to detect and denoise manifolds. During the walking process, the agents release pheromone on data points, which reinforces future movements. Over time the pheromone concentrates on the manifolds, while it fades in the background noise due to an evaporation procedure. We use the Markov chain (MC) framework to provide a theoretical analysis of the convergence of the algorithm and its performance. Moreover, an empirical analysis, based on synthetic and real-world data sets, is provided to demonstrate its applicability in different areas, such as improving the performance of t-distributed stochastic neighbor embedding (t-SNE) and spectral clustering using the underlying MC formulas, recovering astronomical low-dimensional structures, and improving the performance of the fast Parzen window density estimator.


Relationships among stress measures, risk factors, and inflammatory biomarkers in law enforcement officers.
Law enforcement officers suffer higher morbidity and mortality rates from all causes than the general population. Cardiovascular disease (CVD) accounts for a significant portion of the excess illness, with a reported prevalence as high as 1.7 times that of the general population. To determine which occupational hazards cause this increased risk and morbidity, it is imperative to study law enforcement officers before they retire. The long-range goal of our research is to reduce the incidence of CVD-related illness and death among aging law enforcement officers. The purpose of the present study was to measure pro- and anti-atherogenic inflammatory markers in blood samples from law enforcement officers (n = 71) and determine what types of occupation-related stress correlate with differences in these markers. For each outcome variable of interest, we developed separate regression models. Two groups of potential predictors were examined for inclusion in the models. Selected measures of stress were examined for inclusion in the models, in addition to general covariates, such as gender, ethnicity, years in law enforcement, and body mass index. Our results revealed statistically significant relationships between several physiologic variables and measures of stress.


Zoospore chemotaxis of mangrove thraustochytrids from Hong Kong.
Zoospores of mangrove isolates of Schizochytrium mangrovei KF6, KF7, KF12 (three strains), Thraustochytrium striatum KF9 and Ulkenia sp. KF13 were examined for their chemotactic responses to amino acids, carbohydrates, ethanol, and leaf extracts using a capillary root model. Most leaf extracts of mangrove plants and a marsh grass tested were shown to induce moderate chemotactic responses in zoospores of both S. mangrovei KF6 and Ulkenia sp. KF13. Of the remaining amino acids and carbohydrates evaluated, glutamic acid and pectin induced strong attraction in zoospores of S. mangrovei KF6 and Ulkenia sp. KF13, suggesting these are the major components in leaves which may be responsible for the chemotactic response of thraustochytrid zoospores in nature. Zoospores of T. striatum KF9, in general, showed a weak chemotactic response to all the tested compounds and extracts except cellulose, which elicited a moderate response. The ecological significance of the data presented is discussed.


Digital subtraction angiography versus real-time fluoroscopy for detection of intravascular penetration prior to epidural steroid injections: meta-analysis of prospective studies.
Neurological injury is a rare but devastating complication of epidural steroid injections (ESIs) generally thought to arise from neurovascular compromise. The use of real-time fluoroscopy (RTF) with contrast media is the most common preventative measure taken to avoid intravascular penetration. In 2002, it was proposed that digital subtraction angiography (DSA) might be more useful than RTF. Since then, several prospective studies have advocated for its use. As DSA is not currently a "gold standard," a meta-analysis was performed to compare the efficacy of DSA versus RTF for detection of intravascular penetration during ESI. Meta-analysis of prospective observational studies. A targeted Pubmed search was conducted, yielding 49 reports and 4 manuscripts, which were analyzed using Review Manager Software (Rev Man 5.2). Inclusion/exclusion criteria: peer-reviewed prospective reports comparing the sensitivity of DSA to RTF in the same individuals without change in needle position between comparative imaging. Pooled estimate of odds ratios with 95% confidence interval using a random effect model was applied. There were a total of 188 intravascular events from 1,290 ESIs performed. RTF was able to detect 148 events with DSA detecting an additional 40 events missed by RTF. No major neurological complications were reported. DSA had a statistically significant favorable odds ratio over RTF for detection of intravascular penetration during ESI (OR = 1.32 [1.05 - 1.67]; P = 0.02). Although the major methodological aspects of each study assessed in this meta-analysis were quite similar, there were small differences in needle gauge and the selection of secondary outcome measures. Despite attempts to minimize it, concern for operator bias also exists. DSA had a 32% improvement (OR = 1.32) for detection of intravascular penetration with ESI when compared to RTF. Although this supports advocacy for use of DSA, it also suggests that there is a greater than 30% "missed-events" rate for detection of vascular penetration when using RTF for ESI, which does not correlate with the generally reported cumulative rates of complications (1%). This discrepancy suggests that factors other than vascular events also play a role in complications. Nonetheless, given the evidence, we advocate for the increased use of DSA over RTF for transformational ESIs.


Optimizing the acceptability, effectiveness and costs of immunization programs: the Quebec experience.
In Canada, publicly funded immunization programs are a provincial/territorial responsibility. In the province of Quebec, much effort has been devoted to optimize the acceptability, effectiveness and cost-effectiveness of publicly funded immunization programs for children during the last 20 years. The aim of this article is to describe how programs are planned, implemented and evaluated and to identify key factors that contribute to the success of this enterprise. A comprehensive framework was developed for the evaluation of new vaccines and new programs in a societal perspective. It is used by the Quebec Immunization Committee to prepare reports proposing options with their costs and consequences for the public health authority. When a decision is made, the implementation of the new program is carefully planned. Surveys and consultations with stakeholders are systematically conducted to identify potential obstacles. A fraction of the budget is always reserved for program evaluation and monitoring. At the present time, the recommended immunization schedule targets 15 different diseases and only 20 injections are offered up to 15 years of age. Vaccine uptake rate is high and, although a reduced number of doses are recommended for several vaccines, program effectiveness is highly satisfactory, as shown for hepatitis B, meningococcal and pneumococcal diseases.


Low-Dose Dextromethorphan for the Treatment of Fibromyalgia Pain: Results from a Longitudinal, Single-Blind, Placebo-Controlled Pilot Trial.
Fibromyalgia (FM) is a debilitating chronic pain condition with few treatment options. Central sensitization and neuroinflammation have been forwarded as models of FM pathophysiology, both of which indicate dextromethorphan (DXM) as a potential treatment. DXM is an NMDA-receptor antagonist and microglial modulator with anti-neuroinflammatory properties at low doses. It is available for clinical use but has not been tested as a treatment for FM at low dosages. This study evaluated the effectiveness of DXM in treating FM-associated symptoms. In a single-blind, placebo-controlled trial, 14 women meeting the 2010 American College of Rheumatology criteria for FM received a placebo for five weeks, followed by 20 mg DXM for ten weeks, while providing daily symptom reports on a 0-100 scale. Pain and physical activity were the primary and secondary outcomes, respectively. Daily symptom ratings during the last four weeks of placebo were contrasted with ratings during the last four weeks of the active treatment using generalized estimating equations (GEE). DXM was well tolerated, and treatment adherence was high. Baseline pain was reduced by at least 20% in six participants. Self-reported daily pain and physical activity in the entire cohort were not significantly different between the placebo and DXM conditions, and the primary hypotheses were not supported. Exploratory analyses using the entire placebo and DXM data showed that pain was significantly lower in the DXM condition than in the placebo condition (b=-9.933, p=0.013). A strong clinical effect of DXM was not observed at the 20mg/day dosage.


Effect of Wetting Transition during Multiphase Displacement in Porous Media.
The effects of wettability on multiphase displacement in porous media have been studied extensively in the past, and the contact angle is identified as an important factor influencing the displacement patterns. At the same time, it has been found that the effective contact angle can vary drastically in a time-dependent manner on rough surfaces due to the Cassie-Wenzel wetting transition. In this study, we develop a theoretical model at the pore scale describing the apparent contact angle on a rough interface as a function of time. The theory is then incorporated into the lattice Boltzmann method for simulation of multiphase displacement in disordered porous media. A dimensionless time ratio, Dy, describing the relative speed of the wetting transition and pore invasion is defined. We show that the displacement patterns can be significantly influenced by Dy, where more trapped defending ganglia are observed at large Dy values, leading to lower displacement efficiency. We investigate the mobilization of trapped ganglia through identifying different mobilization dynamics during displacement, including translation, coalescence, and fragmentation. Agreement is observed between the mobilization statistics and the total pressure gradient across a wide range of Dy values. Understanding the effect of the wetting transition during multiphase displacement in porous media is of importance for applications such as carbon geosequestration and oil recovery, especially for porous media where solid surface roughness cannot be neglected.


Apolipoprotein/lipid interactions: studies with synthetic polypeptides.
The understanding of complex interactions which occur in the serum lipoproteins has been greatly aided by using peptide synthesis to obtain fragments of the apolipoproteins which are unobtainable by other means. The results from lipid-binding studies with these synthetic materials have generally supported the amphipathic helical hypothesis of Segrest et al. for the interaction of phospholipid with the apolipoprotein. However, CD results from these same experiments suggest that the amphipathic helices may not be as large as originally proposed. The contribution of other protein structural features, e.g. beta-sheets and beta-turns, to lipid binding has not been systematically investigated. The importance of hydrophobicity to lipid-protein interaction is strongly supported by the experimental data. Indeed, there is preliminary evidence that the hydrophobic residues positioned beneath the paired acidic and basic residues on the amphipathic helix are extremely critical to the interaction with phospholipid. The role of charged residues in binding is less clear and needs further investigation. The importance of the structural features previously mentioned can be elucidated through the synthesis of appropriately substituted peptides. However, the final proof of the protein structural features involved in protein-lipid interaction must await x-ray diffraction analysis and detailed NMR measurements. As more peptides are synthesized and studied, the authors feel that the complexities of lipid transport and metabolism will be better understood. The surface properties of peptide fragments of the apoproteins are presently being investigated and could lead to important findings on the exchange of apoproteins between lipoprotein classes. The interactions of synthetic peptides with the enzymes which control lipid synthesis and degradation have increased the understanding of protein-protein and protein-lipid interactions which control these important processes. The ability of a synthetic peptide to accelerate lipolysis in an apoC-II deficient lipoprotein offers the potential for treating these patients with synthetic material to reduce their hypertriglyceridemia. The ability to model the amphipathic helix opens new vistas for the study of the role of hydrophobicity, peptide length, helix potential, and charged residues in lipid binding. The observation of Pownall et al. and Yokayama et al. that phospholipid-cholesterol complexes of these model peptides can serve as substrates for LCAT suggests several exciting avenues for further study of cholesterol metabolism and transport. As these studies increase knowledge of lipid transport, the potential exists to intervene therapeutically with potent synthetic lipid-binding peptides to reduce serum cholesterol or to remove cholesterol from arterial lesions.


[From alcoholism to the alcoholic patient (author's transl)].
When we consider alcoholism and the alcoholic patient--the phenomenon and the human being--we usually think in out-of-date terms. The criterion for excessive consumption of alcohol has been modified by our changed pattern of life, and what would once have been regarded as modest over-drinking--in a large, closely-knit family in a rural community--and tolerated and accepted as such, is no longer compatible with the demands of our technological age, with its small family units often in cramped conditions in big cities and living a life which demands precision and dexterity at all times, an acuteness of both mental and physical faculties--whether at home, in a factory or behind the wheel of a car. And it is these very qualities which the alcoholic has lost. Doctors, therefore, must be able to detect excessive consumption of alcohol before the dire stages of days gone by are reached and, supported by psychiatrists and the use of drugs where necessary, the doctor can provide the patient with a security and identity all too often lacking in the alcoholic patient, and thus help him to break away from his dependence on alcohol.


Smoking increases the risk of panic: findings from a prospective community study.
We examined prospectively determined bidirectional associations between smoking and panic and other anxiety disorders and their temporal ordering of onset in a representative community sample of adolescents and young adults. Baseline and 4-year follow-up data were used from the Early Developmental Stages of Psychopathology Study, a prospective longitudinal study of adolescents and young adults in Munich, Germany. We assessed smoking (occasional and regular), nicotine dependence, panic attacks, panic disorder, other anxiety disorders, and other mental disorders using the Munich-Composite International Diagnostic Interview. At baseline, panic attacks and panic disorder were strongly associated with occasional and regular smoking and nicotine dependence (odds ratio [OR] range, 3.0-28.0). In the prospective analyses, we found increased risk for new onset of panic attacks with prior regular smoking (OR, 2.9; 95% confidence interval [CI], 1.0-8.4) and nicotine dependence (OR, 3.6; 95% CI, 1.2-10.5). Prior nicotine dependence increased also the risk for onset of panic disorder (OR, 3.3; 95% CI, 1.0-10.5), whereas preexisting panic was not associated with subsequent smoking or nicotine dependence. When using Cox regression with time-dependent covariates, prior nicotine dependence was confirmed to be related to subsequent panic attacks (hazard ratio, 2.7; 95% CI, 1.7-4.2), but not panic disorder (hazard ratio, 1.7; 95% CI, 0.7-3.9). Rather, we found indications that prior panic attacks/disorder might also have an effect on secondary development of nicotine dependence. In young adults, prospective analyses revealed a fairly unique and specific, unidirectional relationship between prior smoking and increased risk for subsequent panic attacks/disorder. However, we could not exclude the existence of a second, less frequent, reverse pathway of prior panic and secondary nicotine dependence.


Effects of rumen-protected folic acid and dietary protein level on growth performance, ruminal fermentation, nutrient digestibility and hepatic gene expression of dairy calves.
This study evaluated the effects of rumen-protected folic acid (RPFA) supplementation and dietary protein level on growth performance, ruminal fermentation, nutrient digestibility and hepatic gene expression in calves. Forty Holstein male calves (161 ± 5.7 days of age and 192 ± 5.4 kg of body weight) were assigned to one of four groups in a randomized experimental design with a 2 × 2 factorial arrangement. Moderate crude protein (130.1 g CP/kg [MCP] or high crude protein (150.2 g CP/kg [HCP]) diets were fed without (RPFA-) or with 3.6 mg FA (RPFA+) as RPFA per kg dietary dry matter (DM). Calves were fed a total mixed ration with a corn silage to concentrate ratio of 50:50 on a DM basis. The CP×RPFA interaction was not significant for any of the studied variables. The unchanged DM intake, higher average daily gain and lower feed conversion ratio were observed for HCP or RPFA+. Ruminal pH was lower, and total volatile fatty acids (VFA) concentration was higher for HCP or RPFA+. Acetate proportion was higher, and propionate proportion was lower for HCP or RPFA+. As a result, the higher acetate to propionate ratio was observed. Ruminal ammonia N was higher for HCP, but was lower with RPFA supplementation. The higher digestibility of DM, OM, CP and NDF was observed. Blood glucose and insulin were unchanged, but albumin, total protein, GH and IGF-1 were higher. Similarly, the higher hepatic expression of GH, IGF-1, GHR, IGF-1R, PI3K, mTOR and P70S6K was observed for HCP or RPFA+. The results indicated that increasing dietary CP content or supplementation with RPFA promoted growth performance of calves by improving nutrient utilization and up-regulating hepatic expression of gene related to protein synthesis.


Humanized Mouse Xenograft Models: Narrowing the Tumor-Microenvironment Gap.
Cancer research has long been hampered by the limitations of the current model systems. Both cultured cells and mouse xenografts grow in an environment highly dissimilar to that of their originating tumor, frequently resulting in promising treatments that are ultimately clinically ineffective. The development of highly immunodeficient mouse strains into which human immune systems can be engrafted can help bridge this gap. Humanized mice (HM) allow researchers to examine xenograft growth in the context of a human immune system and resultant tumor microenvironment, and recent studies have highlighted the increased similarities in attendant tumor structure, metastasis, and signaling to those features in cancer patients. This setting also facilitates the examination of investigational cancer therapies, including new immunotherapies. This review discusses recent advancements in the generation and application of HM models, their promise in cancer research, and their potential in generating clinically relevant treatments. This review also focuses on current efforts to improve HM models by engineering mouse strains expressing human cytokines or HLA proteins and implanting human bone, liver, and thymus tissue to facilitate immune cell maturation and trafficking. Finally, we discuss how these improvements may help direct future HM model cancer studies. Cancer Res; 76(21); 6153-8. ©2016 AACR.


Sofosbuvir plus ribavirin for treatment of hepatitis C virus in patients co-infected with HIV (PHOTON-2): a multicentre, open-label, non-randomised, phase 3 study.
Although interferon-free regimens are approved for patients co-infected with HIV and genotype-2 or genotype-3 hepatitis C virus (HCV), interferon-based regimens are still an option for those co-infected with HIV and HCV genotypes 1 or 4. These regimens are limited by clinically significant toxic effects and drug interactions with antiretroviral therapy. We aimed to assess the efficacy and safety of an interferon-free, all-oral regimen of sofosbuvir plus ribavirin in patients with HIV and HCV co-infection. We did this open-label, non-randomised, uncontrolled, phase 3 study at 45 sites in seven European countries and Australia. We enrolled patients (aged ≥18 years) co-infected with stable HIV and chronic HCV genotypes 1-4, including those with compensated cirrhosis. Once-daily sofosbuvir (400 mg) plus twice-daily ribavirin (1000 mg in patients with bodyweights <75 kg and 1200 mg in those with weights ≥75 kg) was given for 24 weeks to all patients except treatment-naive patients with genotype-2 HCV, who received a 12-week regimen. The primary efficacy endpoint was sustained virological response 12 weeks after treatment. We did analysis by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT01783678. Between Feb 7, 2013, and July 29, 2013, we enrolled 275 eligible patients, of whom 262 (95%) completed treatment; 274 patients were included in the final analysis. Overall rates of sustained virological response 12 weeks after treatment were 85% (95% CI 77-91) in patients with genotype-1 HCV, 88% (69-98) in patients with genotype-2 HCV, 89% (81-94) in patients with genotype-3 HCV, and 84% (66-95) in patients with genotype-4 HCV. Response rates in treatment-naive patients with HCV genotypes 2 or 3 (89% [95% CI 67-99] and 91% [81-97], respectively) were similar to those in treatment-experienced patients infected with those genotypes (83% [36-100] and 86% [73-94], respectively). There was no emergence of sofosbuvir-resistance mutations in patients with HCV viral relapse. Six (2%) patients discontinued treatment because of adverse events. The most common adverse events were fatigue, insomnia, asthenia, and headache. Four (1%) patients had serious adverse events regarded as related to study treatment. Additionally, four (1%) patients receiving antiretroviral treatment had a transient HIV viral breakthrough; however, none required changes in antiretroviral regimen. Sofosbuvir and ribavirin provided high rates of sustained virological response after 12 weeks of treatment in treatment-naive and treatment-experienced patients co-infected with HIV and HCV genotypes 1-4. The characteristics of this interferon-free combination regimen make sofosbuvir plus ribavirin a useful treatment option for this patient population. Gilead Sciences.


Lineages of Silene nutans developed rapid, strong, asymmetric postzygotic reproductive isolation in allopatry.
Reproductive isolation can rise either as a consequence of genomic divergence in allopatry or as a byproduct of divergent selection in parapatry. To determine whether reproductive isolation in gynodioecious Silene nutans results from allopatric divergence or from ecological adaptation following secondary contact, we investigated the pattern of postzygotic reproductive isolation and hybridization in natural populations using two phylogeographic lineages, western (W1) and eastern (E1). Experimental crosses between the lineages identified strong, asymmetric postzygotic isolation between the W1 and the E1 lineages, independent of geographic overlap. The proportion of ovules fertilized, seeds aborted, and seeds germinated revealed relatively little effect on the fitness of hybrids. In contrast, hybrid mortality was high and asymmetric: while half of the hybrid seedlings with western lineage mothers died, nearly all hybrid seedlings with E1 mothers died. This asymmetric mortality mirrored the proportion of chlorotic seedlings, and is congruent with cytonuclear incompatibility. We found no evidence of hybridization between the lineages in regions of co-occurrence using nuclear and plastid markers. Together, our results are consistent with the hypothesis that strong postzygotic reproductive isolation involving cytonuclear incompatibilities arose in allopatry. We argue that the dynamics of cytonuclear gynodioecy could facilitate the evolution of reproductive isolation.


Store-Operated Ca2+ Entry in Breast Cancer Cells: Remodeling and Functional Role.
Breast cancer is the most common type of cancer in women. It is a heterogeneous disease that ranges from the less undifferentiated luminal A to the more aggressive basal or triple negative breast cancer molecular subtype. Ca2+ influx from the extracellular medium, but more specifically store-operated Ca2+ entry (SOCE), has been reported to play an important role in tumorigenesis and the maintenance of a variety of cancer hallmarks, including cell migration, proliferation, invasion or epithelial to mesenchymal transition. Breast cancer cells remodel the expression and functional role of the molecular components of SOCE. This review focuses on the functional role and remodeling of SOCE in breast cancer cells. The current studies suggest the need to deepen our understanding of SOCE in the biology of the different breast cancer subtypes in order to develop new and specific therapeutic strategies.


[Chinese guideline for cataract surgery in adults (2023)].
Cataract is the leading cause of blindness worldwide. In recent years, the annual amount of adult cataract surgery is increasing rapidly. In order to promote the standardization of adult cataract surgery in our country, in accordance with the guiding principles and standards of clinical practice and the existing evidence-based data and expert consensus, Chinese Cataract and Refractive Surgery Society has developed the first clinical guideline in China specifically addressing the surgical treatment of adult cataracts. This guideline focuses on the major clinical issues encountered in adult cataract surgery and aims to provide guidance and reference for ophthalmologists in their clinical practice.


Stereotactic radiosurgical boost following radiotherapy in primary nasopharyngeal carcinoma: impact on local control.
Treatment of patients with nasopharyngeal carcinoma using external beam radiation therapy (EBRT) alone results in significant local recurrence. Although intracavitary brachytherapy can be used as a component of management, it may be inadequate if there is extension of disease to the skull base. To improve local control, stereotactic radiosurgery was used to boost the primary tumor site following fractionated radiotherapy in patients with nasopharyngeal carcinoma. Twenty-three consecutive patients were treated with radiosurgery following radiotherapy for nasopharyngeal carcinoma from 10/92 to 5/98. All patients had biopsy confirmation of disease prior to radiation therapy; Stage III disease (1 patient), Stage IV disease (22 patients). Fifteen patients received cisplatinum-based chemotherapy in addition to radiotherapy. Radiosurgery was delivered using a frame-based LINAC as a boost (range 7 to 15 Gy, median 12 Gy) following fractionated radiation therapy (range 64.8 to 70 Gy, median 66 Gy). All 23 patients (100%) receiving radiosurgery as a boost following fractionated radiation therapy are locally controlled at a mean follow-up of 21 months (range 2 to 64 months). There have been no complications of treatment caused by radiosurgery. However, eight patients (35%) have subsequently developed regional or distant metastases. Stereotactic radiosurgical boost following fractionated EBRT provides excellent local control in advanced stage nasopharynx cancer and should be considered for all patients with this disease. The treatment is safe and effective and may be combined with cisplatinum-based chemotherapy.


Titanium microbead-based porous implants: bead size controls cell response and host integration.
Openly porous structures in implants are desirable for better integration with the host tissue. Sintered microbead-based titanium implants for oto-rhinolaryngology applications, which create an environment where the cells can migrate in the areas between the microbeads, are developed. This structure promotes fibrovascular tissue formation within the implant in vivo. In this study, it is determine to what extent these events can be controlled by changing the physical environment of the implants both in vitro and in vivo. By cell tracking, it is observed that the size of the beads and the distance between the neighboring beads significantly affect the ability of cells to develop cell-to-cell contacts and to bridge the pores. Live cell staining shows that as the bead size gets smaller, the probability to observe cells that fill the porous areas is higher. This also affects the initial attachment and distribution of the cells and collagen secretion by fibroblasts. Obtaining a fast coverage of the system also enables co-culture systems where, the number and the distribution of the second cell type are boosted by the presence of the first. This concept is utilized to increase the attachment of vascular endothelial cells by an initial layer of fibroblasts. By decreasing the bead diameter, the overall colonization of the implant can be significantly increased in vivo. The effect of bead size has a similar pattern both in rats and rabbits, with faster colonization of smaller bead-based structures. Using smaller beads would improve clinical outcomes as faster integration facilitates the attainment of functionality by the implant.


High-Performance Nanowire Hydrogen Sensors by Exploiting the Synergistic Effect of Pd Nanoparticles and Metal-Organic Framework Membranes.
Herein, we report the fabrication of hydrogen gas sensors with enhanced sensitivity and excellent selectivity. The sensor device is based on the strategic combination of ZnO nanowires (NWs) decorated with palladium nanoparticles (Pd NPs) and a molecular sieve metal-organic framework (MOF) nanomembrane (ZIF-8). The Pd NPs permit the sensors to reach maximal signal responses, whereas the ZIF-8 overcoat enables for an excellent selectivity. Three steps were employed for the fabrication: (i) coating of a miniaturized sensor with vapor-grown ZnO NWs, (ii) decoration of these NWs with Pd NPs by atomic layer deposition, and (iii) partial solvothermal conversion of the tuned NWs surface to ZIF-8 nanomembrane. The microstructure and composition investigations of the ZIF-8/Pd/ZnO nanostructured materials confirmed the presence of both metallic Pd NPs and uniform ZIF-8 thin membrane layer. The integration of these nanomaterials within a miniaturized sensor device enabled the assessment of their performance for H2 detection at concentrations as low as 10 ppm in the presence of various gases such as C6H6, C7H8, C2H5OH, and CH3COCH3. Remarkably high-response signals of 3.2, 4.7, and 6.7 ( Ra/ Rg) have been measured for H2 detection at only 10, 30, and 50 ppm, whereas no noticeable response toward other tested gases was detected, thus confirming the excellent H2 selectivity obtained with such a sensor design. The results obtained showed that the performance of gas sensors toward H2 gas can be greatly increased by both the addition of Pd NPs and the use of ZIF-8 coating, acting as a molecular sieve membrane. Furthermore, the presented strategy could be extended toward the sensing of other species by a judicious choice of both the metallic NPs and MOF materials with tuned properties for specific molecule detection, thus opening a new avenue for the preparation of highly selective sensing devices.


Prognostic significance of Ki67-negative blast cell clone in the high risk group of children treated for acute myeloid leukaemia.
The aim of this study was to demonstrate the value of immunocytochemical staining of Ki67 antigen expression in blast cells of children with acute myeloid leukemia (AML) and to evaluate its correlation with treatment failure. The material included bone marrow specimens obtained during induction treatment from 46 children treated for AML between 1998-2003. Immunocytochemical staining for Ki67 was based on the ABC technique. Expression of Ki67 antigen on day 0 of induction treatment was confirmed in all patients. The percentage of immunopositive blasts ranged from 88.4% to 99.8% (mean 91.8%). On day 15, according to chemotherapy response, patients were divided into two groups: G1-36 children who responded to induction treatment and reached remission (blast level 5%, low risk group) and G2-10 patients who did not meet remission criterion (blast level > 5%) and were assigned to the high risk (HR) group. Out of 10 children assigned to this group, Ki67 expression in blast cells was confirmed in 4 cases. The fraction of immunopositive blasts ranged from 78.4% to 88.6%. In the other 6 cases, blasts were Ki67-negative. In 12-month period after beginning the treatment, 18 cases of treatment failure (including 7 deceases) were observed in both groups. Five deaths, observed in the HR group, concerned the patients characterized by Ki67-negative blasts. The results indicate a possible correlation between the Ki67-immunonegative blast pattern on day 15 of treatment induction and early decease of AML children assigned to HR group.


Hyperediting by ADAR1 of a new herpesvirus lncRNA during the lytic phase of the oncogenic Marek's disease virus.
Marek's disease virus, or Gallid herpesvirus 2 (GaHV-2), is an avian alphaherpesvirus that induces T-cell lymphoma in chickens. During transcriptomic studies of the RL region of the genome, we characterized the 7.5 kbp gene of the ERL lncRNA (edited repeat-long, long non-coding RNA), which may act as a natural antisense transcript (NAT) of the major GaHV-2 oncogene meq and of two of the three miRNA clusters. During infections in vivo and in vitro, we detected hyperediting of the ERL lncRNA that appeared to be directly correlated with ADAR1 expression levels. The ERL lncRNA was expressed equally during the lytic and latent phases of infection and during viral reactivation, but its hyperediting increased only during the lytic infection of chicken embryo fibroblasts. We also showed that chicken ADAR1 expression was controlled by the JAK/STAT IFN-response pathway, through an inducible promoter containing IFN-stimulated response elements that were functional during stimulation with IFN-α or poly(I:C). Like the human and murine miR-155-5p, the chicken gga-miR-155-5p and the GaHV-2 analogue mdv1-miR-M4-5p deregulated this pathway by targeting and repressing expression of suppressor of cytokine signalling 1, leading to the upregulation of ADAR1. Finally, we hypothesized that the natural antisense transcript role of the ERL lncRNA could be disrupted by its hyperediting, particularly during viral lytic replication, and that the observed deregulation of the innate immune system by mdv1-miR-M4-5p might contribute to the viral cycle.


Combination of radiofrequency ablation and immunotherapy.
The enhancement of immune response against tumor antigens has shown some efficacy when used as a single mode of systemic treatment in patients with late stage disease. Novel strategies of active immunotherapy could be more effective in patients with less advanced disease who receive standard therapies supporting concomitant stimulation of the immune system. Radio-Frequency Ablation (RFA) is a minimally invasive technique which is used as standard local therapy of primary and metastatic liver tumors. Tumor ablation by RFA induces effects important for boosting anti-tumor immune responses. Tumor cell necrosis generates a permanent immunogenic source of tumor antigens. These antigens can be uptaken, processed and presented by dendritic cells for effective immunization without requirement for ex vivo antigen loading. Further immune activation can be originated by RFA through induction of heat shock proteins on tumor cells, acute phase response which causes the release of pro-inflammatory cytokines, and mobilization of antigen presenting cells and effector lymphocytes. Thus, RFA can facilitate immune responses to tumor antigens driven by active immunotherapy. On the other hand, immunotherapy is expected to eradicate residual disease after RFA and prevent tumor recurrences. The combination of RFA and active immunotherapy may well have synergistic effects for cancer treatment.


Dominantly inherited cutaneous small-vessel lymphocytic vasculitis maps to chromosome 6q26-q27.
Outside the context of hereditary deficiencies of complement and IgA, Mendelian inherited predisposition to small vessel lymphocytic vasculitis (SVLV) has rarely been documented. Here we report a large, multigenerational family segregating symmetrical cutaneous SVLV affecting the cheeks, thighs and hands. In all affected family members the disease presented in early infancy and there was no evidence for an association with systemic disease. Skin biopsy of lesions showed a lymphocytic vasculitis with red blood cell extravasation. Complementary studies, with extensive investigation focused on dysfunction of the immunological system were negative. The pattern of inheritance of SVLV in the family was compatible with an autosomal dominantly acting disease gene with incomplete penetrance. To localize the disease causing gene in the family a genome-wide linkage search was conducted using a high-density SNP array. Haplotype construction and analysis of recombination events permitted the minimal interval defining the disease locus to be refined to a 4.7 Mb region on chromosome 6q26-q27. The genes CCR6 and GPR31, which map to the linked region represent plausible candidates for the disease on the basis of their biological function. Extensive screening of both genes by mutational analysis failed to identify a deleterious mutation in the family.


Non-recurrent SEPT9 duplications cause hereditary neuralgic amyotrophy.
Genomic copy number variants have been shown to be responsible for multiple genetic diseases. Recently, a duplication in septin 9 (SEPT9) was shown to be causal for hereditary neuralgic amyotrophy (HNA), an episodic peripheral neuropathy with autosomal dominant inheritance. This duplication was identified in 12 pedigrees that all shared a common founder haplotype. Based on array comparative genomic hybridisation, we identified six additional heterogeneous tandem SEPT9 duplications in patients with HNA that did not possess the founder haplotype. Five of these novel duplications are intragenic and result in larger transcript and protein products, as demonstrated through reverse transcription-PCR and western blotting. One duplication spans the entire SEPT9 gene and does not generate aberrant transcripts and proteins. The breakpoints of all the duplications are unique and contain regions of microhomology ranging from 2 to 9 bp in size. The duplicated regions contain a conserved 645 bp exon within SEPT9 in which HNA-linked missense mutations have been previously identified, suggesting that the region encoded by this exon is important to the pathogenesis of HNA. Together with the previously identified founder duplication, a total of seven heterogeneous SEPT9 duplications have been identified in this study as a causative factor of HNA. These duplications account for one third of the patients in our cohort, suggesting that duplications of various sizes within the SEPT9 gene are a common cause of HNA.


Expression of GLUT-1 glucose transporter in borderline and malignant epithelial tumors of the ovary.
Cancer cells have increased rates of glucose metabolism when compared to normal cells. One of the mechanisms proposed for the accelerated glucose use in malignant cells is the overexpression of glucose transporters. In this study we evaluated the expression of the GLUT-1 glucose transporter in borderline and malignant epithelial neoplasms of the ovary. Histologic sections of tumor tissues from 21 borderline and 82 malignant epithelial neoplasms of the ovary were stained for GLUT-1 using polyclonal GLUT-1 antibody (Dako, Carpinteria, CA) and the labeled streptavidin biotin procedure. DAB was used as chromagen and tissues were counterstained with hematoxylin. Normal ovarian surface epithelial cells were either negative or weakly positive. Of the 82 carcinomas, 81 (98.8%) were positive for GLUT-1. The staining intensity was significantly associated with the grade of tumor (P = 0.001). Of the 21 borderline neoplasms, 20 (95.2%) were positive for GLUT-1. Carcinomas had a significantly stronger stain than borderline tumors (P = 0.0001). The intensity of the stain was also stronger in serous carcinomas compared to other subtypes (P = 0. 0001). Positive cells demonstrated a cytoplasmic membrane staining that was more intense in tumor cells farther away from blood supply. Overexpression of the GLUT-1 transporter is associated with the histology and grade of the tumors. Our findings show a progressive increase in the expression of the GLUT-1 transporter from the borderline tumor to the high-grade carcinomas. These data suggest that the expression of this transporter may be closely related to the malignant transformation of epithelial ovarian tumors.


Botulinum toxin: mechanism of presynaptic blockade.
The mechanism of action of botulinum toxin was analyzed by the use of calcium ionophores and black widow spider venom. Addition of calcium ionophores to nerve-muscle preparations blocked by botulinum toxin did not increase the frequency of miniature end plate potentials. However, the spider venom elicited a barrage of miniature end plate potentials after blockade by botulinum. Electron micrographs of preparations treated with botulinum toxin and then the spider venom revealed clumping of synaptic vesicles at release sites in the otherwise depleted nerve terminals. These findings indicate that the action of botulinum toxin is not due to deficient storage of acetylcholine in vesicles or blockade of calcium entry into nerve terminals. They suggest that the toxin interferes with the acetylcholine release process itself, possibly by blocking exocytosis at the release sites.


Evidence for spatial proximity of two distinct receptor regions in the substance P (SP)*neurokinin-1 receptor (NK-1R) complex obtained by photolabeling the NK-1R with p-benzoylphenylalanine3-SP.
Substance P (SP) belongs to the tachykinin family of bioactive peptides and exerts its many biological effects through functional interaction with its cell-surface, G protein-coupled neurokinin-1 receptor (NK-1R). Previous studies from our laboratory have shown that (125)I-Bolton-Hunter reagent-labeled p-benzoylphenylalanine(8)-SP (Bpa(8)SP) covalently attaches to Met(181), whereas (125)I-Bolton-Hunter reagent-labeled Bpa(4)SP covalently attaches to Met(174), both of which are located on the second extracellular loop (EC2) of the NK-1R. In this study, evidence has been obtained that at equilibrium, the photoreactive SP analogue (125)I-[D-Tyr(0)]Bpa(3)SP covalently labels residues in two distinct extracellular regions of the NK-1R. One site of (125)I-[D-Tyr(0)]Bpa(3)SP photoinsertion is located on EC2 within a segment of the receptor extending from residues 173 to 177; a second site of (125)I-[D-Tyr(0)]Bpa(3)SP photoinsertion is located on the extracellular N terminus within a segment of the receptor extending from residues 11 to 21, a sequence that contains both potential sites for N-linked glycosylation. Since competition binding data presented in this study do not suggest the existence of multiple peptide.NK-1R complexes, it is reasonable to assume that the receptor sequences within EC2 and N terminus identified by peptide mapping are in close proximity in the equilibrium complex.


Genes, Roommates, and Residence Halls: A Multidimensional Study of the Role of Peer Drinking on College Students' Alcohol Use.
Peer drinking is one of the most robust predictors of college students' alcohol use and can moderate students' genetic risk for alcohol use. Peer effect research generally suffers from 2 problems: selection into peer groups and relying more on perceptions of peer alcohol use than peers' self-report. The goal of the present study was to overcome those limitations by capitalizing on a genetically informed sample of randomly assigned college roommates to examine multiple dimensions of peer influence and the interplay between peer effects and genetic predisposition on alcohol use, in the form of polygenic scores. We used a subsample (n = 755) of participants from a university-wide, longitudinal study at a large, diverse, urban university. Participants reported their own alcohol use during fall and spring and their perceptions of college peers' alcohol use in spring. We matched individuals into their rooms and residence halls to create a composite score of peer-reported alcohol use for each of those levels. We examined multiple dimensions of peer influence and whether peer influence moderated genetic predisposition to predict college students' alcohol use using multilevel models to account for clustering at the room and residence hall level. We found that polygenic scores (β = 0.12), perceptions of peer drinking (β = 0.37), and roommates' self-reported drinking (β = 0.10) predicted alcohol use (all ps < 0.001), while average alcohol use across residence hall did not (β = -0.01, p = 0.86). We found no evidence for interactions between peer influence and genome-wide polygenic scores for alcohol use. Our findings underscore the importance of genetic predisposition on individual alcohol use and support the potentially causal nature of the association between peer influence and alcohol use.


General Overview of Phenolics from Plant to Laboratory, Good Antibacterials or Not.
The emergence and rapid development of seriously drug-resistant pathogens have created the greatest danger to public health and made the treatment of infectious diseases ineffective; to control the antibiotic-resistant microbes, the discovery of new effective antibacterials with new mechanisms of action against bacteria remains an urgent task to control the bacterial resistance. The paucity of infections in wild plants supports the role of innate defense system of plants. Many researchers nominate the natural extracts to act against bacterial resistance mechanisms, and the majority of them have now been focused on the combination of plant extracts and antibiotics to define the availability of resistance modification agents. Only very few numbers of natural products are successful to reach experiments circle beyond the in vitro assays. Phenols and phenolic acids could serve as good candidates to the natural antibacterial arsenal. The pyrogallol-based compounds are more potent than others such as catechol or resorcinol, gallic acid, and the hydroxycinnamic acid (ferulic acid) are destructing the bacterial cell wall of Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa, leading to leakage of cellular contents. These compounds have stronger activity against Gram-positive microorganisms, and some of them showed good synergism with antibiotics, for example, pentagalloylglucopyranose, is shown a synergism with penicillin G against methicillin-resistant S. aureus, another example is the interesting synergism between epicatechin gallate and oxacillin where the minimal inhibitory concentrations of oxacillin reduced around 500 times by the addition of epicatechin gallate to the antibiotic.


Entrapment of organic fluorophores in calcium phosphate nanoparticles with slow release.
Two organic fluorophores, fluorescein (F) and rhodamine B (Rd), were entrapped in calcium phosphate nanoparticles. The as-obtained nanoparticles can be used for biological release applications. For this aim, calcium phosphate nanoparticles were synthesized using the precipitation method. Structural analysis of these nanoparticles was performed using XRD, FTIR, and Raman spectroscopy, confirming that the synthesized nanoparticles were hydroxyapatite. TEM and SEM analyses demonstrated that these nanoparticles had a size of 20 nm and a well-defined morphology. F and Rd (about 0.5 wt.%) were entrapped in these nanoparticles and their release, as a function of time, was studied via UV-Vis spectroscopy. The obtained results showed that the release of both fluorophores was progressive over time. The trapping efficiencies of the fluorophores were 67.15% and 90.76% for F and Rd, respectively.


The effects of a single bout of exercise on resting energy expenditure and respiratory exchange ratio.
We investigated the effects of a single bout of aerobic and resistance exercise of similar relative intensity and duration on resting energy expenditure (REE) and substrate utilisation. Ten young healthy males volunteered [age 22 (1.8) years, weight 76 (7.9) kg, height 176 (4.1) cm, percentage body fat 10.5 (4.0)%; mean (SEM)]. They randomly underwent three conditions in which they either lifted weights for 60 min at 70-75% of 1-RM (WL), ran for 60 min at 70-75% of maximal oxygen intake (R) or did not exercise (C). REE and substrate utilisation, determined via respiratory exchange ratio ( R), were measured prior to exercise, and 10, 24, 48 and 72 h post-exercise. It was revealed that REE was significantly elevated ( P<0.05) 10 and 24 h after the end of WL [2,124 (78) and 2,081 (76) kcal, respectively] compared to pre-exercise [1,972 (82) kcal]. REE was also significantly increased ( P<0.05) 10 and 48 h after the completion of R [2,150 (73) and 1,995 (74) kcal, respectively] compared to pre-exercise data [1,862 (70) kcal]. R was lower 10 and 24 h following either WL or R [0.813 (0.043); 0.843 (0.040) and 0.818 (0.021); 0.832 (0.021), respectively] compared to baseline measurements [0.870 (0.025) and 0.876 (0.04), respectively]. Creatine kinase was significantly elevated ( P<0.05) 24 h after both WL and R, whereas delayed onset muscle soreness became significantly elevated ( P<0.05) 24 h after only WL. There were no significant changes for any treatment in thyroid hormones (T(3) and T(4)). These results suggest that a single bout of either WL or R exercise, characterised by the same relative intensity and duration, increase REE and fat oxidation for at least 24 h post-exercise.


[The treatment of fecal incontinence].
The treatment of faecal incontinence includes: the education of the patient, medical therapy, biofeedback and sphincteric exercises, surgical therapy. Conservative, non-surgical treatment is almost always the initial therapeutic approach, except in those cases in which an evident defect of the sphincter muscle is present. Surgical treatment has seen a noteworthy increase in the last fifteen years as a consequence of the development of new surgical techniques. These techniques include: external anal sphincter plasty, pelvic floor plasties, sacral neuromodulation, muscular transpositions with or without electrostimulation, artificial anal sphincter. These procedures may be employed as first or second level treatment depending on the type of pathology considered and its aetiology. The 1st results achieved by surgical treatment authorise us to believe that reconversion with artificial sphincter is a valid alternative to graciloplasty, notwithstanding the fact that its costs are higher. Attentive pre- operative assessment of patients is important. Patients must be strongly motivated and able to manage the new condition. Although further studies are necessary, the degree of satisfactory of the 1st patients operated is the best stimulus for pursuing the development of this technique.


Effects of Observable Parent Alcohol Consequences and Parent Alcohol Disorder on Adolescent Alcohol Expectancies.
Parental drinking and parent alcohol use disorder (AUD) are known predictors of adolescent positive alcohol expectancies, but their link to negative expectancies is unclear. Research suggests that parent drinking may indirectly predict adolescent expectancies through exposure to parental drinking events. However, exposure to parent negative alcohol consequences may be more relevant to adolescents' expectancies. The present study tested the mediating effect of parent observable negative alcohol consequences in the association between parent AUD and adolescent expectancies. This study used parent and adolescent data from the Adult and Family Development Project. A total of 581 adolescents reported on their alcohol expectancies across 2 waves of data, and their parents reported on potentially observable alcohol-related negative consequences during the first wave. Past-year and lifetime parent AUD were assessed with diagnostic interviews across 6 waves of data. Mothers' observable consequences mediated the effect of her past-year AUD on adolescent negative expectancies in adolescence, but this effect did not hold at a 1.5-year follow-up. Mothers' lifetime AUD was the only prospective predictor of later adolescent negative expectancies. No father drinking variables predicted expectancies, and all models were invariant across child biological sex. Finally, older adolescent age prospectively predicted higher positive expectancies, whereas the adolescents' own drinking predicted lower negative expectancies. These findings, in line with other recent studies, suggest that exposure to mothers' negative experiences with alcohol may counterintuitively normalize negative alcohol effects. This may paradoxically increase risk for adolescents rather than buffering the effects of a family history of parental AUD.


Newly Characterized Murine Undifferentiated Sarcoma Models Sensitive to Virotherapy with Oncolytic HSV-1 M002.
Despite advances in conventional chemotherapy, surgical techniques, and radiation, outcomes for patients with relapsed, refractory, or metastatic soft tissue sarcomas are dismal. Survivors often suffer from lasting morbidity from current treatments. New targeted therapies with less toxicity, such as those that harness the immune system, and immunocompetent murine sarcoma models to test these therapies are greatly needed. We characterized two new serendipitous murine models of undifferentiated sarcoma (SARC-28 and SARC-45) and tested their sensitivity to virotherapy with oncolytic herpes simplex virus 1 (HSV-1). Both models expressed high levels of the primary HSV entry molecule nectin-1 (CD111) and were susceptible to killing by interleukin-12 (IL-12) producing HSV-1 M002 in vitro and in vivo. M002 resulted in a significant intratumoral increase in effector CD4+ and CD8+ T cells and activated monocytes, and a decrease in myeloid-derived suppressor cells (MDSCs) in immunocompetent mice. Compared to parent virus R3659 (no IL-12 production), M002 resulted in higher CD8:MDSC and CD8:T regulatory cell (Treg) ratios, suggesting that M002 creates a more favorable immune tumor microenvironment. These data provide support for clinical trials targeting sarcomas with oncolytic HSV-1. These models provide an exciting opportunity to explore combination therapies for soft tissue sarcomas that rely on an intact immune system to reach full therapeutic potential.


[Chemotaxis of Yersinia pseudotuberculosis as a mechanism in its search for target tissues of the host organism].
Y. pseudotuberculosis cells grown at biologically low temperature have been shown capable of chemotaxis with respect to carbohydrates and amino acids. During cultivation at 36-37 degrees C Y. pseudotuberculosis cells retain this property for 10-15 hours and then lose it. The mechanism of chemotaxis makes it possible for Y. pseudotuberculosis to "find" human and animal tissues and can facilitate the realization of the pathogenicity potential of these bacteria. When administered orally to mice motile bacteria, i. e. those grown at 6-8 degrees C, have been more virulent for the animals than nonmotile ones cultivated at 36-37 degrees C.


Pathogenicity of an avian influenza virus serotype H9N2 in chickens.
A low pathogenic avian influenza virus (AIV) serotype H9N2 affected many commercial flocks in the Middle East in late 1990s and early 2000s. Due to the varying pathogenicity ofAIV H9N2 reported in previous studies, this study was carried out to determine the pathogenicity of a Jordanian isolate of H9N2 in broiler and specific-pathogen-free (SPF) chickens. Mild tracheal rales were observed in the broilers but not in the SPF birds starting 3 days postinfection (DPI) and until the end of the experiment at 16 DPI. Infected chickens had gross and histologic changes limited to the respiratory system (sinuses, trachea, lungs, and air sacs) characterized by congestion and lymphoplasmacytic inflammation. However, the lesions in the broiler chickens were more severe than those in the SPF chicks. Furthermore, the virus caused significant (P = 0.004) reduction (230 g) in average body weight of the infected broiler group compared with the uninfected broiler group. Both broiler and SPF-infected groups seroconverted, and they had a geometric mean titer of 2(8.2) and 2(9.3), respectively, on the hemagglutination inhibition test at 16 DPI. Cloacal virus shedding was not detected by 9 DPI and 15 DPI in broiler and SPF-infected groups, respectively. This study demonstrated the pathogenic nature of the local Jordanian H9N2 isolate and the variation from what it has been reported in other countries of the region. Regional effort should be directed to start an eradication program of this disease because of its pathogenicity for chickens, wide distribution, and possible interference with surveillance for H5N1 serotype.


The human polyomaviruses: from orphans and mutants to patchwork family.
For almost 40 years, polyomavirus JC and BK were the only known human polyomaviruses but in the last 7 years, increased interest and innovative molecular screening techniques have led to the identification of 10 previously unknown polyomaviruses in humans. Two of these, Merkel cell polyomavirus and Trichodysplasia spinulosa polyomavirus, have also been found to cause disease in immunocompromised patients. Seroprevalence studies indicate that human polyomaviruses are transmitted independently of one another in humans and carry different risks of exposure and reexposure throughout life. The potential coexistence of 12 or more different polyomavirus species in the same host and possibly even in the same organ raises the question of potential interactions. Careful review of polyomavirus biology may facilitate new discoveries concerning these formerly underestimated viral agents and their influence on human health.


Treatment of difficult-to-treat depression - clinical guideline for selected interventions.
Difficult-to-treat-depression (DTD) is a clinical challenge. The interventions that are well-established for DTD are not suitable or effective for all the patients. Therefore, more treatment options are highly warranted. We formulated an evidence-based guideline concerning six interventions not well-established for DTD in Denmark. Selected review questions were formulated according to the PICO principle with specific definitions of the patient population (P), the intervention (I), the comparison (C), and the outcomes of interest (O), and systematic literature searches were performed stepwise for each review question to identify relevant systematic reviews/meta-analyses, and randomized controlled trials. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was used to assess the methodological quality of the included studies. Clinical recommendations were formulated based on the evidence, the risk-benefit ratio, and perceived patient preferences. We found sufficient evidence for a weak recommendation of repetitive transcranial magnetic stimulation (rTMS) and cognitive behavioural analysis system of psychotherapy (CBASP). The use of bright light therapy in DTD was not sufficiently supported by the evidence, but should be considered as good clinical practice. The interventions should be considered in addition to ongoing antidepressant treatment. We did not find sufficient evidence to recommend intravenous ketamine/esketamine, rumination-focused psychotherapy, or cognitive remediation to patients with DTD. The evidence supported two of the six reviewed interventions, however it was generally weak which emphasizes the need for more good quality studies. This guideline does not cover all treatment options and should be regarded as a supplement to relevant DTD-guidelines.


Neutropenic enterocolitis in adults with acute leukemia.
Neutropenic enterocolitis has been previously described only by case reports and literature reviews. Of 499 adults with acute leukemia seen over a 23-year period (1962 to 1985), 13 cases (2.6%) of neutropenic enterocolitis have been reported. Eleven of these 13 patients were profoundly neutropenic (mean white blood cell count, 472/cu mm) and developed abdominal symptoms during either initial induction or relapse of acute leukemia. Histologic confirmation was available in ten cases, five cases after surgical resection and five cases at autopsy after nonoperative management. Three patients with isolated ileocecal inflammation without infarction at the time of surgery were successfully managed without resection. Five patients treated with surgery died four to 64 weeks postoperatively (mean survival, 21.6 weeks) of nonsurgical complications of leukemia. Three patients were still alive, one patient 42 months after right hemicolectomy and two patients five months after exploration only. All five patients managed medically died an average of 1.4 days (range, zero to four days) after the onset of abdominal pain. Survival in patients with acute leukemia who develop neutropenic enterocolitis is determined by early recognition and appropriate surgical exploration that can be expected to yield an acceptable operative mortality.


Diurnal variation of serum iron, iron-binding capacity, transferrin saturation, and ferritin levels.
Serum iron levels vary throughout the day. Morning levels are generally assumed to be higher than afternoon or evening levels. We studied whether our practice of restricting serum iron collections to the morning was necessary. Serum iron, iron-binding capacity, transferrin saturation, and ferritin levels were determined on blood specimens obtained from 20 healthy adult volunteers at 8 AM, noon, and 4 PM (day 1) and 8 AM (day 2). Although statistically significant differences among mean values for the collection times were observed for iron, iron-binding capacity, and (log) ferritin, no consistent diurnal variation was seen. Morning iron levels were higher than afternoon levels for only half of the subjects. Between-day variation for all 4 analytes was similar to within-day variation. We conclude that the practice of restricting iron specimen collections to a specific time of day does not improve the reliability of the test result.


A chemical phosphorylation-inspired design for Type I collagen biomimetic remineralization.
Type I collagen alone cannot initiate tissue mineralization. Sodium trimetaphosphate (STMP) is frequently employed as a chemical phosphorylating reagent in the food industry. This study examined the feasibility of using STMP as a functional analog of matrix phosphoproteins for biomimetic remineralization of resin-bonded dentin. Equilibrium adsorption and desorption studies of STMP were performed using demineralized dentin powder (DDP). Interaction between STMP and DDP was examined using Fourier transform-infrared spectroscopy. Based on those results, a bio-inspired mineralization scheme was developed for chemical phosphorylation of acid-etched dentin with STMP, followed by infiltration of the STMP-treated collagen matrix with two etch-and-rinse adhesives. Resin-dentin interfaces were remineralized in a Portland cement-simulated body fluid system, with or without the use of polyacrylic acid (PAA) as a dual biomimetic analog. Remineralized resin-dentin interfaces were examined unstained using transmission electron microscopy. Analysis of saturation binding curves revealed the presence of irreversible phosphate group binding sites on the surface of the DDP. FT-IR provided additional evidence of chemical interaction between STMP and DDP, with increased in the peak intensities of the PO and P-O-C stretching modes. Those peaks returned to their original intensities after alkaline phosphatase treatment. Evidence of intrafibrillar apatite formation could be seen in incompletely resin-infiltrated, STMP-phosphorylated collagen matrices only when PAA was present in the SBF. These results reinforce the importance of PAA for sequestration of amorphous calcium phosphate nanoprecursors in the biomimetic remineralization scheme. They also highlight the role of STMP as a templating analog of dentin matrix phosphoproteins for inducing intrafibrillar remineralization of apatite nanocrystals within the collagen matrix of incompletely resin-infiltrated dentin.


C-X-C Motif Chemokine Receptor 4-Targeted Radioligand Therapy in Hematological Malignancies-Myeloablative Effects, Antilymphoma Activity, and Safety Profile.
After C-X-C motif chemokine receptor 4 (CXCR4)-directed radioligand therapy (RLT), lymphoma patients are scheduled for conditioning therapy (CON) followed by hematopoietic stem cell transplantation (HSCT). We aimed to determine whether CXCR4-RLT can achieve bone marrow ablation and direct antilymphoma activity independent from CON/HSCT and also evaluated the safety profile of this theranostic approach in an acute setting. After CXCR4-directed 68Ga-pentixafor PET/CT, 21 heavily pretreated patients with hematological malignancies underwent CXCR4-directed RLT using 90Y-pentixather. The extent of myeloablative efficacy was determined by investigating hematologic laboratory parameters before RLT (day -1), at the day of RLT (day 0), 2 days after RLT (day 2), and before CON (median day 10). Serving as surrogate marker of antilymphoma activity, lactate dehydrogenase (LDH) levels were also assessed until CON. We also screened for laboratory-defined tumor lysis syndrome after the Cairo-Bishop definition and recorded acute laboratory adverse events using the Common Terminology Criteria for Adverse Events version 5.0. After RLT, we observed a significant decline of leukocyte levels by 79.4% ± 18.7% till CON (granulocytes, drop by 70.3% ± 21%; platelets, reduction by 43.1% ± 36%; P ≤ 0.0005 vs day 0, respectively). After RLT, LDH levels already reached a peak at day 2, which was followed by a rapid decline thereafter (peak vs day of CON, P = 0.0006), indicating that 90Y-pentixather exhibits direct antilymphoma activity. At day of CON, LDH levels were also significantly lower when compared with day -1 (P = 0.04), suggestive for durable response mediated by RLT. No patient fulfilled the criteria of tumor lysis syndrome, whereas 25 laboratory adverse events attributable to CXCR4-directed treatment were identified (≥grade 3 in 2/25 [8%]). During further treatment course, all patients (100%) received HSCT. CXCR4-directed RLT causes effective myeloablation, which allows for HSCT. In addition, it also exerts direct antilymphoma activity independent of subsequent therapeutic steps, whereas safety profile was acceptable.


Retrofitting of continuous glucose monitoring traces allows more accurate assessment of glucose control in outpatient studies.
Glucose control in artificial pancreas (AP) studies is commonly assessed by metrics such as the percentage of time with blood glucose (BG) concentration below 70 mg/dL or in the nearly normal range 70-180 mg/dL (in brief, time in hypoglycemia and time in target, respectively). In outpatient studies these control metrics can be computed only from continuous glucose monitoring (CGM) sensor data, with the risk of an unfair assessment because of their inaccuracy. The aim of the present article is to show that the control metrics can be much more accurately determined if CGM data are preprocessed by a recently proposed retrofitting algorithm. Data from 47 type 1 diabetes subjects are considered. Subjects were studied in a closed-loop control trial prescribing three 24-h admissions. Glucose concentration was monitored using the Dexcom(®) (San Diego, CA) SEVEN(®) Plus CGM sensor. Frequent BG reference values were collected in parallel with the YSI analyzer (Yellow Springs Instrument, Yellow Springs, OH). To simulate the few reference values available in outpatient conditions, we down-sampled the YSI data and provided to the retrofitting algorithm only the reference values that would have been collected in outpatient protocols. Time in hypoglycemia, time in target, mean, and SD of glucose profile were computed on the basis of both the original and the retrofitted CGM traces and compared with those computed using the frequently obtained YSI data. Using the retrofitted traces, the average error affecting the estimation of time in hypoglycemia and time in target was approximately halved with respect to the original CGM traces (from 4.5% to 1.9% and from 8.7% to 4.4%, respectively). Error in mean and SD was reduced even further, from 10.0 mg/dL to 3.5 mg/dL and from 8.6 mg/dL to 2.9 mg/dL, respectively. The improved accuracy of retrofitted CGM with respect to the original CGM traces allows a more reliable assessment of glucose control in outpatient AP studies.


Estimating the distribution of time to extinction of infectious diseases in mean-field approaches.
A key challenge for many infectious diseases is to predict the time to extinction under specific interventions. In general, this question requires the use of stochastic models which recognize the inherent individual-based, chance-driven nature of the dynamics; yet stochastic models are inherently computationally expensive, especially when parameter uncertainty also needs to be incorporated. Deterministic models are often used for prediction as they are more tractable; however, their inability to precisely reach zero infections makes forecasting extinction times problematic. Here, we study the extinction problem in deterministic models with the help of an effective 'birth-death' description of infection and recovery processes. We present a practical method to estimate the distribution, and therefore robust means and prediction intervals, of extinction times by calculating their different moments within the birth-death framework. We show that these predictions agree very well with the results of stochastic models by analysing the simplified susceptible-infected-susceptible (SIS) dynamics as well as studying an example of more complex and realistic dynamics accounting for the infection and control of African sleeping sickness (Trypanosoma brucei gambiense).


Difficult separation from cardiopulmonary bypass and deltaPCO2.
Veno-arterial and regional differences of the partial pressure in CO2 (deltaPCO2), may be used as index to evaluate the adequacy of the cardiac output to the oxygen consumption. To determine the incidence of elevated deltaPCO2 and its relationship with difficult separation from bypass (DSB) in patients undergoing cardiac surgery, we conducted a prospective observational cohort study. Data were collected from 58 consecutive patients undergoing various cardiac operations requiring cardiopulmonary bypass (CPB). During the procedure, arterial and venous blood gases and lactate were sampled. Blood was drawn after induction of anesthesia, during bypass and at the closure of the chest wall. Difficult separation from bypass was defined as a systolic arterial pressure < 80 mmHg, and diastolic pulmonary artery pressure > 15 mmHg during progressive separation from CPB with inotropic or mechanical support of cardiac function, or hemodynamic instability resulting in reintroduction of extra-corporeal circulation or insertion of an intra-aortic balloon pump. In our study, 65% of the samples were associated with elevated deltaPCO2 (> 6 mmHg). Variables associated with difficult weaning were LVEF; duration of bypass and aortic cross-clamping, pre-bypass deltaPCO2 and in-bypass lactate values (P < 0.05). Multivariable analysis identified the pre-bypass deltaPCO2 and the duration of bypass as predictors of DSB. Elevated deltaPCO2 is frequently observed during cardiac surgery and values obtained before bypass were associated with DSB. The deltaPCO2 gradients could be used as marker of the adequacy of tissue perfusion during cardiac surgery.


Renal manifestations of systemic diseases.
During childhood, the kidney may be involved in several different systemic diseases including the vasculitic syndromes, collagen vascular diseases, and the thrombotic microangiopathic diseases. This article discusses three of the more common systemic disease including Henoch Schonlein Purpura (HSP), systemic lupus erythematosus (SLE), and the hemolytic uremic syndrome (HUS), which occur during childhood. Each of these diseases have important renal manifestations that may present with hematuria with or without proteinuria, hypertension, rapidly progressive glomerulonephritis, and/or with acute renal failure. The occurrence of these diseases during childhood raises lifelong concerns for the child's renal function. As in glomerulonephritis associated with SLE, reactivation of the underlying disease can result in additional renal injury, whereas late extrarenal and renal complications may be observed following HUS or nephritis associated with HSP. These diseases are not only an important cause of acquired chronic renal failure during childhood, but may also lead to end-stage renal disease or other complications that do not become apparent until adulthood. In each disease, we will review the clinical manifestations, the pathology, pathophysiology, and current management and therapy.


[Primary leptomeningeal gliomatosis treated with temozolomide: a case report].
A 35-year-old man was admitted to our department for loss of consciousness. CT and MRI revealed diffuse enhancement of the subarachnoid space surrounding the brainstem and the cerebellar sulci, without any parenchymal lesions in the brain or the spinal cord. Furthermore, gadolinium-enhanced MRI revealed a nodular lesion with heterogeneous enhancement in the right prepontine cistern, at the site from which a biopsy was obtained via right lateral suboccipital craniotomy on the day following admission. Histopathological examination of the resected specimen revealed glioblastoma multiforme. Based on the radiological and histopathological findings, the patient was diagnosed with primary leptomeningeal gliomatosis (PLG). The patient received temozolomide chemotherapy with concurrent radiotherapy and showed radiological remission, 12 months after diagnosis. However, he developed local recurrence 6 months later and died 23 months after diagnosis. Autopsy findings showed tumor cell infiltration of the leptomeninges, as well as the brain and spinal parenchyma. PLG should be considered in the differential diagnosis in patients with diffuse leptomeningeal enhancement even without parenchymal lesions on radiological imaging. A surgical biopsy is recommended for prompt and accurate diagnosis in such cases.


Effect of coenzymes and thyroid hormones on the dual activities of Xenopus cytosolic thyroid-hormone-binding protein (xCTBP) with aldehyde dehydrogenase activity.
A cytosolic thyroid-hormone-binding protein (xCTBP), predominantly responsible for the major binding activity of T3 in the cytosol of Xenopus liver, has been shown to be identical to aldehyde dehydrogenase class 1 (ALDH1) [Yamauchi, K., Nakajima, J., Hayashi, H., Horiuchi, R. & Tata, J.R. (1999) J. Biol. Chem. 274, 8460-8469]. Within this paper we surveyed which signaling, and other, compounds affect the thyroid hormone binding activity and aldehyde dehydrogenase activity of recombinant Xenopus ALDH1 (xCTBP/xALDH1) while examining the relationship between these two activities. NAD+ and NADH (each 200 microm), and two steroids (20 microm), inhibit significantly the T3-binding activity, while NADH and NADPH (each 200 microm), and iodothyronines (1 microm), inhibit the ALDH activity. Scatchard analysis and kinetic studies of xCTBP/xALDH1 indicate that NAD+ and T3 are noncompetitive inhibitors of thyroid-hormone-binding and ALDH activities, respectively. These results indicate the formation of a ternary complex consisting of the protein, NAD+ and thyroid hormone. Although the in vitro studies indicate that NAD+ and NADH markedly decrease T3-binding to xCTBP/xALDH1 at approximately 10-4 m, a concentration equal to the NAD content in various Xenopus tissues, photoaffinity-labeling of [125I]T3 using cultured Xenopus cells demonstrates xCTBP/xALDH1 bound T3 within living cells. These results raise the possibility that an unknown factor(s) besides NAD+ and NADH may modulate the thyroid-hormone-binding activity of xCTBP/xALDH1. In comparison, thyroid hormone, at its physiological concentration, would poorly modulate the enzyme activity of xCTBP/xALDH1.


Beta(2)-microglobulin identified as an apoptosis-inducing factor and its characterization.
Major histocompatibility complex (MHC) molecules play an important role in antigen presentation for induction of tumor as well as cellular and humoral immunities. Recent studies using anti-MHC antibodies demonstrated that antibodies specific for HLA class I molecules induced cellular activation and a type of apoptosis that may be distinct from Fas-dependent or TNFR (tumor necrosis factor-alpha receptor)-dependent processes. We purified a previously untested apoptosis-inducing factor from HL-60 human leukemic cell-conditioned media to homogeneity and sequenced it. It was identified as beta(2)-microglobulin (beta(2)m), which has been previously known as thymotaxin and is a part of the HLA class I antigen complex. beta(2)m acts on both T-leukemic cells and myeloid leukemic cells to induce apoptosis, which then activates caspase 1 and 3. Cross-linking studies showed that biotinilated beta(2)m recognized an epitope distinct from those recognized by the anti-HLA class I antibody, as reported previously. We demonstrated that beta(2)m plays a previously unrecognized and important role in regulating the elimination of tumor cells, which occurs as a result of the action of beta(2)m as an apoptosis-inducing factor.


Cellular and subcellular localization, N-terminal acylation, and calcium binding of Caenorhabditis elegans protein phosphatase with EF-hands.
The RdgC/PPEF family of serine/threonine protein phosphatases is distinguished by the presence of C-terminal EF-hands and neuron-specific expression, including frequent expression in primary sensory neurons. Here we report that the sole Caenorhabditis elegans PPEF (CePPEF) homolog is also highly expressed in primary sensory neurons and is not found outside the nervous system. Neurons expressing CePPEF include the ciliary chemosensory neurons AWB and AWC; and within these neurons, CePPEF is highly enriched in the sensory cilia. In transgenic C. elegans and in transfected 293 cells, CePPEF is membrane-associated, and the N terminus of CePPEF is necessary and sufficient for this membrane association. [(3)H]Myristate and [(3)H]palmitate labeling studies in 293 cells demonstrated that this association was mediated by myristoylation at Gly(2) and palmitoylation at Cys(3). Introducing the G2A or C3S mutation into CePPEF greatly reduced membrane association in 293 cells and in transgenic nematodes. A recombinant C-terminal fragment of CePPEF containing two putative EF-hands bound between one and two Ca(2+) ions/protein, and mutation of residues presumed to ligand calcium in the two putative EF-hands led to diminished calcium binding. These results establish the first direct evidence for fatty acylation and calcium binding of a PPEF family member and demonstrate a remarkable conservation of sensory neuron expression among the members of this distinctive family of protein phosphatases.


Five-Membered Rings Create Off-Zero Modes in Nanographene.
The low-energy electronic structure of nanographenes can be tuned through zero-energy π-electron states, typically referred to as zero-modes. Customizable electronic and magnetic structures have been engineered by coupling zero-modes through exchange and hybridization interactions. Manipulation of the energy of such states, however, has not yet received significant attention. We find that attaching a five-membered ring to a zigzag edge hosting a zero-mode perturbs the energy of that mode and turns it into an off-zero mode: a localized state with a distinctive electron-accepting character. Whereas the end states of typical 7-atom-wide armchair graphene nanoribbons (7-AGNRs) lose their electrons when physisorbed on Au(111) (due to its high work function), converting them into off-zero modes by introducing cyclopentadienyl five-membered rings allows them to retain their single-electron occupation. This approach enables the magnetic properties of 7-AGNR end states to be explored using scanning tunneling microscopy (STM) on a gold substrate. We find a gradual decrease of the magnetic coupling between off-zero mode end states as a function of GNR length, and evolution from a more closed-shell to a more open-shell ground state.


Expression patterns of cytochrome P450 3B and 3C genes in model fish species.
Cytochrome P450 (CYP) 3 enzymes are highly expressed in detoxification organs and play an important role in xenobiotic metabolism. In fish, the CYP3 family is diversified and includes several subfamilies (CYP3B, CYP3C, and CYP3D) not found in mammals. The functional role and expression patterns of these novel genes are unknown. In this study, the expression patterns of novel teleost CYP3 genes were determined in medaka(Oryzias latipes; CYP3B4, CYP3B5, CYP3B6) and zebrafish (Danio rerio; CYP3C1, CYP3C2, CYP3C3, CYP3C4), two important model fish species. Expression was quantified with real time PCR in multiple internal organs from adult male and female fish. CYP3C gene expression was determined in zebrafish embryos. Expression in all organs was detected for all genes, except for CYP3B4 in male organs. CYP3C1, CYP3C3, CYP3B4, CYP3B5, and CYP3B6 were more highly expressed in liver and/or intestine from at least one gender, suggesting a role in xenobiotic metabolism. Expression of CYP3C1 and CYP3B5 in olfactory rosette was comparable to liver. CYP3C1, CYP3C4, CYP3B5 and CYP3B6 expression was higher in the female organs; CYP3C2 and CYP3B5 were higher in testis. Estrogen and androgen response elements were found upstream of the start site of many of these genes raising the hypothesis that they are under steroid regulation. CYP3C1-3 were expressed in all developmental stages examined and appear to be maternally deposited. The expression patterns suggest that some of these CYP genes are involved in xenobiotic metabolism.


Attributing selected costs to intimate partner violence in a sample of women who have left abusive partners: a social determinants of health approach.
Selected costs associated with intimate partner violence were estimated for a community sample of 309 Canadian women who left abusive male partners on average 20 months previously. Total annual estimated costs of selected public- and private-sector expenditures attributable to violence were $13,162.39 per woman. This translates to a national annual cost of $6.9 billion for women aged 19–65 who have left abusive partners; $3.1 billion for those experiencing violence within the past three years. Results indicate that costs continue long after leaving, and call for recognition in policy that leaving does not coincide with ending violence.


Scenes from the past: radiologic evidence of anthropogenic mummification in the Capuchin Catacombs of Palermo, Sicily.
The purpose of this study was to use paleoradiologic analyses to investigate a sample of the mummies in the Capuchin Catacombs in Palermo, Sicily, in order to assess skeletal abnormalities and the state of preservation, especially the condition of the internal organs, and to determine radiologic evidence of anthropogenic mummification. Ten 19th and early 20th century mummies with good external preservation were investigated by using a portable direct radiography unit inside the Capuchin Catacombs. The radiographs clearly demonstrated signs of anthropogenic mummification in nine of the 10 mummies investigated. The embalming methods that had been used included (a) evisceration and arterial injection; (b) the placement of foreign materials into the orbits and the nasal and oral cavities; and (c) filling of the thoracic, abdominal, and rectal cavities with foreign materials. Organ preservation varied greatly among the mummies, although brain tissue was found in all of the mummies. Analyses of the skeletal material of the mummies showed evidence of healed vertebral fractures, age-related degenerative changes, and, in one of the child mummies, a remarkable skeletal pathologic condition. The radiographs clearly illustrated different methods of anthropogenic mummification in the catacomb mummies of Palermo, allowed assessment of the preservation of the mummies, and demonstrated skeletal abnormalities.


Inhibition of miR-221 influences bladder cancer cell proliferation and apoptosis.
Janus kinase (JAK) - signal transducer and activator of transcription (STAT) signaling pathway participate in cell proliferation and apoptosis. Suppressors of cytokine signaling 3 (SOCS3) are negative regulators of JAK-STAT3. SOCS3 was found significantly declined, while microRNA-221 (miR-221) obviously up-regulated in bladder cancer tissue. Bioinformatics analysis revealed the complementary binding site between miR-221 and 3'-UTR of SOCS3. This study investigated the role of miR-221 in regulating SOCS3/JAK-STAT3 signaling pathway and bladder cancer cell proliferation and apoptosis. Bladder cancer tumor tissue and para-carcinoma tissue were collected from patients to test miR-221 and SOCS3 expressions. Dual luciferase assay was used to test the targeting regulatory effect of miR-221 on SOCS3. MiR-221, SOCS3, p-JAK1, p-JAK2, and survivin expressions were compared in T24 and HBEC cells. T24 cells were divided into miR-NC, miR-221 inhibitor, pSicoR-blank, pSicoR-SOCS3, and miR-221 inhibitor + pSicoR-SOCS3 groups. Flow cytometry was applied to detect cell apoptosis. EdU staining was adopted to evaluate cell proliferation. MiR-221 significantly increased, while SOCS3 obviously reduced in bladder cancer tissue compared with para-carcinoma tissue. MiR-221 targeted inhibited SOCS3 expression. MiR-221, phosphorylated JAK1 (p-JAK1), phosphorylated JAK2 (p-JAK2), phosphorylated STAT3 (p-STAT3), and survivin levels markedly up-regulated, whereas SOCS3 expression apparently declined in T24 cells compared with that in HBEC cells. MiR-221 inhibitor and/or pSicoR-SOCS3 elevated SOCS3 expression, decreased p-JAK1, p-JAK2, p-STAT3, and survivin levels, enhanced cell apoptosis, and attenuated cell proliferation. MiR-221 elevated, while SOCS3 reduced in bladder cancer tissue. Inhibition of miR-221 suppressed T24 cell proliferation and induced apoptosis by up-regulating SOCS3 expression, lowering JAK-STAT3 signaling pathway activity, and attenuating survivin expression.


DTaP combination vaccine use and adherence: A retrospective cohort study.
Despite universal recommendation of the 4-dose diphtheria, tetanus, and pertussis (DTaP) vaccine series, coverage and timeliness in the US remain suboptimal. DTaP-containing combination vaccines (i.e. quadrivalent and pentavalent) are presumed to improve vaccine coverage rates and timeliness, but research supporting this claim is limited. We sought to investigate the associations between DTaP-containing vaccine use and adherence to the recommended DTaP immunization schedule among children in the US. Using a large claims database, we identified privately insured children born between 2009 and 2016 that received ≥1 DTaP-containing vaccine and had ≥24 months of enrollment from birth, excluding those with DTaP vaccinations not aligned with approved dose indications. Children were classified by DTaP-containing vaccine receipt: combination vaccines only, stand-alone vaccines only, or a mixture of both. Outcome measures included: 1) completion of the 4-dose series and 2) timely receipt of doses. Outcomes were adjusted for gender, birth year, race, and socioeconomic status. The study cohort contained 412,441 children. Of these, 40.5% (167,084) received combination vaccines only, 14.9% (61,342) received stand-alone vaccines only, and 44.6% (184,015) received a mixture of both. Combination vaccine recipients were nearly 3 times as likely to complete the 4-dose series (OR 2.93 (95% CI: 2.88, 2.99)) and for all doses received, more than 4 times as likely to receive doses on time (OR 4.12 (4.04, 4.21), relative to stand-alone vaccine recipients. Significance disparities in adherence were also observed, where minorities were up to 30% less likely (OR 0.70 (0.68, 0.71)) to complete the 4-dose series and up to 27% less likely (OR 0.73 (0.72, 0.75)) to receive doses on time, relative to white children. Our findings demonstrated that adherence to the recommended DTaP immunization schedule was significantly greater among combination vaccine recipients, relative to stand-alone recipients. Further research is needed to investigate underlying causes of disparities in adherence.


[State of autonomic regulation mechanisms in arterial hypotension].
To investigate the role of suprasegmental and segmental parts of autonomic nervous systems (ANS) in genesis of arterial hypotension (AH) 75 individuals with arterial hypotension as well as 30 healthy persons were examined using clinical and psychological methods, evaluation of the state of ANS segmental part by means of evoked skin sympathetic potentials, spectral analysis of the variability of the heart rhythm, 5 standard cardiovascular tests according to Ewing. The conclusion was made that individuals with AH had combination of alterations of both emotional-personality sphere and autonomic functions in all systems of organism tested. Exactly they had psychoautonomic syndrome presenting as combination of asthenic manifestations, elements of Reynaud phenomenon and headaches pronounced differently (headaches of tension more frequently). Clinical alterations were combined with changes of indices of functional testing, that reflected disorders in some link of sympathetic regulation including baroreflex one. Decompensation in individuals with AH and change for the worse of the indices of functional testing were due both to the increase of psychoautonomic disorders, growing of desintegrational processes in ANS and the decrease of adaptive mechanisms in its sympathetic part.


The incorporation of plutonium by the embryo and fetus of rats and guinea-pigs.
The transfer of 238Pu from the maternal circulation to the developing embryo and fetus was studied in rats and guinea-pigs to provide data for the development of dosimetric models for the human embryo and fetus. Following administration at different stages of gestation, measurements were made after 3 days in the rat and 7 days in guinea-pigs. The amount transferred was greater after administration at later stages of gestation, up to a maximum of about 0.8-0.9% of the injected activity per fetoplacental unit (FPU) and about 0.2% per fetus in both species. In advanced gestation the yolk sac, the initial site of haemopoietic stem cells, contained up to 80% of the total activity in the FPU in rats, compared with about 25% for the guinea-pig; retention in placental trophoblast was greater in the guinea-pig. The concentrations of 238Pu in the yolk sac were generally about two to three orders of magnitude greater than fetal concentrations and of the same order as in maternal liver and bone. In both species, concentrations in the embryo and fetus were greatest after injection early in gestation, reached their lowest around mid-organogenesis and increased again in later gestation. The fetus:mother whole-body concentration ratios in late gestation were about 0.1 and 0.05 in rats and guinea-pigs, respectively. Measurements were also made of the 238Pu retention in neonates at birth. In guinea-pigs the liver accounted for about 6-9% of retained activity; similar values for femora indicated skeletal retention of about 60-80%. For administration at each stage of gestation, and particularly at early stages, transfer of 238Pu to the fetus continued throughout gestation but concentrations decreased due to fetal growth.


ABCA3 gene mutations in newborns with fatal surfactant deficiency.
Pulmonary surfactant forms a lipid-rich monolayer that coats the airways of the lung and is essential for proper inflation and function of the lung. Surfactant is produced by alveolar type II cells, stored intracellularly in organelles known as lamellar bodies, and secreted by exocytosis. The gene for ATP-binding cassette transporter A3 (ABCA3) is expressed in alveolar type II cells, and the protein is localized to lamellar bodies, suggesting that it has an important role in surfactant metabolism. We sequenced each of the coding exons of the ABCA3 gene in blood DNA from 21 racially and ethnically diverse infants with severe neonatal surfactant deficiency for which the etiologic process was unknown. Lung tissue from four patients was examined by high-resolution light and electron microscopy. Nonsense and frameshift mutations, as well as mutations in highly conserved residues and in splice sites of the ABCA3 gene were identified in 16 of the 21 patients (76 percent). In five consanguineous families with mutations, each pair of siblings was homozygous for the same mutation and each mutation was found in only one family. Markedly abnormal lamellar bodies were observed by ultrastructural examination of lung tissue from four patients with different ABCA3 mutations, including nonsense, splice-site, and missense mutations. Mutation of the ABCA3 gene causes fatal surfactant deficiency in newborns. ABCA3 is critical for the proper formation of lamellar bodies and surfactant function and may also be important for lung function in other pulmonary diseases. Since it is closely related to ABCA1 and ABCA4, proteins that transport phospholipids in macrophages and photoreceptor cells, it may have a role in surfactant phospholipid metabolism.


Mesenchymal Stem Cells Accelerate the Remodeling of Bladder VX2 Tumor Interstitial Microenvironment by TGFβ1-Smad Pathway.
Background: Mesenchymal stem cells (MSCs) have been proved to be able to differentiate into cells that are conducive to tumor growth and invasion. The mechanism is not clear. This present study was aimed to find out whether TGFβ1-Smad pathway was involved in this process. Methods: For the in vitro experiment, five groups of MSCs were cultured to test whether VX2 culture supernatant could induce the differentiation of MSCs into myofibroblasts. And then transforming growth factor β1(TGFβ1) receptor or Smad2 of MSCs were blocked by RNA interference technique to test whether TGFβ1-Smad pathway was involved in the differentiation. In the animal experiment, different kinds of MSCs were co-inoculated with VX2 cells in bladder to test whether the blockage of TGFβ1 receptor or Smad2 of MSCs could affect the expression of TGFβ1, epidermal growth factor (EGF), fibroblast activation protein alpha (FAPa), and matrix metalloprotein 9 (MMP9) in five animal groups. Results: VX2 culture supernatant could up-regulate the expression of α-SMA and Vimentin in MSCs, which indicated that VX2 culture supernatant could induce the differentiation of MSCs into myofibroblasts. Either the Blockage of TGFβ1 receptor or Smad2 of MSCs could lead to decreased expression of α-SMA and Vimentin in MSCs. In the animal experiment, MSCs could favor VX2 bladder tumor growth and up-regulate the expression of TGFβ1, EGF, FAPa, MMP9 in VX2 tumor tissue. However, when TGFβ1 receptor or Smad2 of MSCs was blocked, the above effects were attenuated. Conclusions: Under the induction of tumor microenvironment, MSCs can differentiate into myofibroblasts and then affect tumor interstitial microenvironment remodeling. This process is mediated by TGFβ1-Smad2 pathway.


[Influence of tumor drug resistance phenotype on the dynamics of cisplatin-induced changes of rat peripheral lymphocyte chromatin structure in Guerin's carcinoma].
The correlation between the tumor drug sensitivity and the degree of lymphocyte interphase nuclei chromatin damages induced by cisplatin in rats was found using sensitive and resistant to cisplatin variants of Guerin's carcinoma. Increased optical density of lymphocyte chromatin in first minutes after cisplatin injection both in rats without Guerin's carcinoma and with sensitive to cisplatin variants of this tumor was observed. Lymphocyte chromatin structure remains unchanged in rats with cisplatin resistant carcinoma. Normal blood cells are suppose to change their sensitiveness to cisplatin under the humoral influence of the growing tumor in according with its phenotype.