[Effects of signaling-selective parathyroid hormone peptide analog on fracture healing in orchiectomized mouse models].
To assess the effect of intermittent subcutaneous injections of signal-selective parathyroid hormone (PTH) peptide analog on fracture healing in orchiectomized mouse models. Thirty-six 7-week-old C57/BL male mice were orchiectomized and injected with hPTH(1-34), the signal-selective PTH peptide analog [Gly(1), Arg(19)]hPTH (1-34), or an identical volume of vehicle 1 week after induction of femoral fracture. At 14 and 28 days after the operation, the mice were sacrificed for measurement of bone mineral density (BMD) and bone mineral content (BMC) of the callus using by dual energy X-ray absorptiometry. The bone healing was evaluated by radiography, biomechanical testing, micro-computed tomography (Micro-CT) and histological examination. At 14 days after the operation, BMD in PTH peptide analog group was significantly increased (P<0.05). The mouse models treated with the PTH peptide analog showed significantly lower ultimate bending force and bending rigidity than those with hPTH(1-34) treatment. X-ray and Micro-CT scanning showed that callus transformation and remodeling was better in PTH peptide analog group than in the vehicle control group but poorer than in hPTH(1-34) group. The signaling-selective PTH peptide analog G1, R19 (1-28) can accelerate fracture healing in orchiectomized mouse models, in which process cAMP/PKA pathway plays an important role.


Stereoselective Synthesis of Piperidines by Iridium-Catalyzed Cyclocondensation.
An iridium-catalyzed cyclocondensation of amino alcohols and aldehydes is reported. Intramolecular allylic substitution by an enamine intermediate and subsequent in situ reduction furnishes 3,4-disubstituted piperidines with high enantiospecificity and good diastereoselectivity. The modular approach and the broad functional group tolerance provide access to diverse piperidine derivatives, which were further functionalized to give a versatile set of products.


Organic acid formation in the gas-phase ozonolysis of alpha-pinene.
The mechanism of formation of pinonic and norpinonic acids from alpha-pinene ozonolysis has been investigated by studying the products of the ozonolysis of an enone derived from alpha-pinene using gas chromatography coupled to mass spectrometry.


Folinic acid (FA) plus 5-fluorouracil (FU) in progressive advanced colorectal cancer.
Treatment results (CR/PR** 30-40%) with the combination of 5-FU and FA--a biomodulator of 5-FU action--indicate that FA/5-FU is superior to 5-FU alone in the treatment of advanced colorectal cancer. However the "optimal" dose and time schedule has not been properly defined either for FA or for 5-FU. Moreover, in spite of the promising reports with FA/5-FU, the benefit of chemotherapy in colorectal carcinomas remains unproven. One way to better define the impact on survival and palliation might be to select patients with a documented tumor progression prior to chemotherapy. In 2 prospective phase II studies with FA/5-FU, tumor progression was the essential eligibility criterion. In both studies an overall tumor control (CR/PR/MR/NC)** of progressive disease with relief of tumor-related symptoms in most of the patients was achieved. The median survival times exceeded 12 months. In progressive colorectal cancer these treatment results can be regarded as a significant change in the natural history of the disease. Moreover, such a procedure will help to define more homogeneous patient groups and contribute to a better comparability of different studies. Additionally, overtreatment of patients with slowly proliferating tumors can be avoided, particularly with respect to the subjective and objective side-effects of FA/5-FU combinations.


First principles molecular dynamics of molten NaI: structure, self-diffusion, polarization effects, and charge transfer.
The structure and self-diffusion of NaI and NaCl at temperatures close to their melting points are studied by first principles Hellmann-Feynman molecular dynamics (HFMD). The results are compared with classical MD using rigid-ion (RI) and shell-model (ShM) interionic potentials. HFMD for NaCl was reported before at a higher temperature [N. Galamba and B. J. Costa Cabral, J. Chem. Phys. 126, 124502 (2007)]. The main differences between the structures predicted by HFMD and RI MD for NaI concern the cation-cation and the anion-cation pair correlation functions. A ShM which allows only for the polarization of I- reproduces the main features of the HFMD structure of NaI. The inclusion of polarization effects for both ionic species leads to a more structured ionic liquid, although a good agreement with HFMD is also observed. HFMD Green-Kubo self-diffusion coefficients are larger than those obtained from RI and ShM simulations. A qualitative study of charge transfer in molten NaI and NaCl was also carried out with the Hirshfeld charge partitioning method. Charge transfer in molten NaI is comparable to that in NaCl, and results for NaCl at two temperatures support the view that the magnitude of charge transfer is weakly state dependent for ionic systems. Finally, Hirshfeld charge distributions indicate that differences between RI and HFMD results are mainly related to polarization effects, while the influence of charge transfer fluctuations is minimal for these systems.


Specific depletion of mature T lymphocytes from human bone marrow.
An effective method for specific depletion of mature T lymphocytes from human bone marrow mononuclear cells (BMMC) with preservation of prethymic T cells and natural killer (NK) cells is presented. The BMMC were incubated with F101.01, a monoclonal antibody recognizing an epitope of the T-cell receptor-CD3 complex, and subsequently with immunomagnetic beads. Flow cytometric analysis demonstrated that mature T cells were efficiently depleted and that NK cells and prethymic T cells were preserved in the BMMC. Furthermore, T cell-mediated immune reaction as measured by thymidine incorporation after stimulation with phytohaemagglutinin was abolished, whereas NK activity as measured by 51Cr release using K562 as target cells was preserved. Recovery of colony-forming units of granulocyte-macrophages was 60-70%.


Direct Construction of 2-Aryliminochromenes from Arynes, N,S-Keteneacetals, and DMF.
A concise and direct synthetic strategy for the construction of 2-aryliminochromene skeleton by cascade three-component coupling reaction of arynes, N,S-keteneacetals, and DMF in good yields has been disclosed. The process demonstrates the first example of aryne chemistry combined with N,S-keteneacetals. Using this strategy, an expeditious synthesis of biologically important arylimino-2H-chromene-3- carboxamides was achieved.


Assessment of nutrition and physical activity practices using self-report and observation in early care and education across multiple US states.
The National Early Care and Education Learning Collaboratives (ECELC) Project aims to promote healthy physical activity and nutrition environments, policies and practices in early care and education (ECE) programmes across multiple states. The present pilot study sought to assess changes to the physical activity and nutrition practices in a sub-sample of ECE programmes participating in the ECELC using the Environment and Policy Assessment and Observation (EPAO). Additionally, it sought to compare results with the Nutrition and Physical Activity Self-Assessment for Child Care (NAP SACC). Quasi-experimental pre-post pilot study where paired-sample t tests examined changes to physical activity and nutrition practices from pre-assessment to post-assessment (P<0·05). Pearson correlation coefficients examined change scores from EPAO compared with NAP SACC with statistical significance set at a two-sided α level of P<0·10 to account for sample size. The study occurred among ECE programmes. Pre-school classrooms in nineteen ECE programmes across four US states were observed. EPAO data demonstrated an increase in total score from pre-assessment to post-assessment (150 (sd 30) to 176 (sd 35)). NAP SACC change scores demonstrated little relationship with EPAO domain change scores, with exceptions in Nutrition Policy and Physical Activity Policy (r=-0·4 and -0·6, respectively). The overall improvements reported through the EPAO suggest participation in the ECELC resulted in changes in critical nutrition- and physical activity-related practices. However, considerable differences in data reported using the NAP SACC compared with the EPAO suggest subjective data should be interpreted with caution and objective measurement should be used when feasible.


Screening for COPD: the gap between logic and evidence.
Chronic obstructive pulmonary disease (COPD) is a common disease leading to further morbidity and significant mortality. The first step for any condition is to make the appropriate diagnosis, and spirometry barriers abound in practice around the world. It is tempting to undertake mass screening on all smokers to detect COPD. While this would pick up cases of COPD, results of studies of its effect on COPD end-points such as exacerbations, hospitalisations and mortality are disappointing. As such, aggressive case finding of COPD by screening for symptoms that patients may not themselves perceive is very important in primary care, with subsequent spirometry defining the diagnosis.We also have to separate out population screening from individual patient interactions. Performing spirometry, even on a truly asymptomatic patient, may allow earlier diagnosis and modification of risk factors such as smoking (mostly) and exacerbation risk. It also recognises patients with early disease who are at high risk of comorbidities such as cardiac illness, such that appropriate treatment strategies can be implemented. Making a diagnosis, and even the fact of worrying about such a diagnosis, can affect the motivational level of the individual patient to cease smoking; all patients should of course be counselled to stop smoking. As such, consider the individual patient in front of you for unrecognised symptoms and therefore unrecognised illness, as making a diagnosis earlier can allow the institution of care, including smoking cessation, vaccination, bronchodilators and comorbidity management.


Investigation of pathogenic Escherichia coli and microbial pathogens in pulp and paper mill biosolids.
Biosolids produced from pulp and paper mill wastewater treatment have excellent properties as soil conditioners, but often contain high levels of Escherichia coli. E. coli are commonly used as indicators of fecal contamination and health hazard; therefore, their presence in biosolids causes concern and has lead to restrictions in land-spreading. The objectives of this study were to determine the following: (1) if E. coli from the biosolids of a wastewater-free pulp and paper mill were enteric pathogens, and (2) if other waterborne microbial pathogens were present. E. coli were screened for heat-labile and heat-stable enterotoxin and verocytotoxin virulence genes using a polymerase chain reaction. Ten isolates were also screened for invasion-associated locus and invasion plasmid antigen H genes. None of the 120 isolates carried these genes. Tests for seven other microbial pathogens were negative. Effluents and biosolids from this mill do not contain common microbial pathogens and are unlikely to pose a health hazard.


Physiologic 18F-FDG Uptake in Brown Adipose Tissue and Lactating Breast in a Patient with Hodgkin Lymphoma.
We present the case of a young woman with Hodgkin lymphoma exhibiting physiologic 18F-FDG uptake in brown adipose tissue and lactating breast on consecutive 18F-FDG PET/CT scans. Both entities are common imaging interpretation pitfalls and should be recognized in oncologic 18F-FDG PET/CT practice. We review the imaging features and differential diagnosis of these 2 entities and discuss the radiation safety precautions during breastfeeding.


Eosinophilia and Lung Cancer: Analysis From Real-World Data and Mendelian Randomization Study.
Growing evidence added to the results from observational studies of lung cancer patients exhibiting eosinophilia. However, whether eosinophils contributed to tumor immune surveillance or neoplastic evolution was unknown. This study aimed to analyze the causal association between eosinophilia and lung cancer. The causal effect of eosinophil count on lung cancer from a genome-wide association study (GWAS) was investigated using the two-sample Mendelian randomization (MR) method. Secondary results according to different histological subtypes of lung cancer were also implemented. Meanwhile, we compared the measured levels of blood eosinophil counts among different subtypes of lung cancer from real-world data. The median absolute eosinophilic count (unit: 109/L) [median (min, max): Lung adenocarcinoma 0.7 (0.5, 15); Squamous cell lung cancer 0.7 (0.5, 1.3); Small cell lung cancer 0.7 (0.6, 1.3); p = 0.96] and the median eosinophil to leukocyte ratio [median (min, max): Lung adenocarcinoma 8.7% (2.1, 42.2%); Squamous cell lung cancer 9.3% (4.1, 17.7%); Small cell lung cancer 8.9% (5.1, 24.1%); p = 0.91] were similar among different histological subtypes of lung cancer. MR methods indicated that eosinophilia may provide 28% higher risk for squamous cell lung cancer in East Asian [Weighted median method: odds ratio (OR) = 1.28, 95% CI: 1.04-1.57, p = 0.02]. Our study suggested that eosinophilia may be a potential causal risk factor in the progression of squamous cell lung cancer in East Asian.


Investigation of the role of electrostatic charge in activation of the Escherichia coli response regulator CheY.
In a two-component regulatory system, an important means of signal transduction in microorganisms, a sensor kinase phosphorylates a response regulator protein on an aspartyl residue, resulting in activation. The active site of the response regulator is highly charged (containing a lysine, the phosphorylatable aspartate, two additional aspartates involved in metal binding, and an Mg(2+) ion), and introduction of the dianionic phosphoryl group results in the repositioning of charged moieties. Furthermore, substitution of one of the Mg(2+)-coordinating aspartates with lysine or arginine in the Escherichia coli chemotaxis response regulator CheY results in phosphorylation-independent activation. In order to examine the consequences of altered charge distribution for response regulator activity and to identify possible additional amino acid substitutions that result in phosphorylation-independent activation, we made 61 CheY mutants in which residues close to the site of phosphorylation (Asp57) were replaced by various charged amino acids. Most substitutions (47 of 61) resulted in the complete loss of CheY activity, as measured by the inability to support clockwise flagellar rotation. However, 10 substitutions, all introducing a new positive charge, resulted in the loss of chemotaxis but in the retention of some clockwise flagellar rotation. Of the mutants in this set, only the previously identified CheY13DK and CheY13DR mutants displayed clockwise activity in the absence of the CheA sensor kinase. The absence of negatively charged substitution mutants with residual activity suggests that the introduction of additional negative charges into the active site is particularly deleterious for CheY function. Finally, the spatial distribution of positions at which amino acid substitutions are functionally tolerated or not tolerated is consistent with the presently accepted mechanism of response regulator activation and further suggests a possible role for Met17 in signal transduction by CheY.


The use of Fab-masking antigens to enhance the activity of immobilized antibodies.
This study demonstrates that masking the Feb regions of a monoclonal antibody (Mab) with synthetic antigens prior to covalent immobilization efficiency. Water-soluble adducts of poly(2-methyloxazoline) polymers and a synthetic-peptide epitope for the Mab were constructed. These synthetic antigens are referred to as Fab-masking antigents (FMAs). The antibody used in this study is a Ca(2+)-dependent murine monoclonal lgG directed against the plasma protein, human protein C (hPC). The FMAs were pre-equilibrated with Mab in the presence of calcium prior to immobilization and were then removed by EDTA, which destabilized the FMA-Mab complexes. The antigen binding efficiency and accessibility of the Fab domain of the immobilized antibody was significantly increased for Mab immobilized in the presence of FMA relative to those Mab immobilized without FMA. The increase in binding efficiency was most pronounced for the largest FMA employed. No appreciable differences were detected in the avidity of hPC-Mab complexes formed by immunosorbents produced by either masked or unmasked antibody. These results provide evidence that orientation may play an important role in the binding activity of immobilized antibodies.


Hemodynamic effects following injection of venom from the scorpion Leiurus quinquestriatus.
The present study tested the hypothesis that scorpion sting induces left ventricular (LV) hypokinesia and myocardial ischemia shortly after injection due to reduction of coronary blood flow (CBF) and increased oxygen demand. In 5 mechanically ventilated, open-chest dogs, we measured LV function following i.v. injection of venom (0.05 mg/kg) obtained from the scorpion Leiurus quinquestriatus. Hemodynamic responses to the venom were followed up for 90 minutes. The venom induced significant combined respiratory and metabolic acidosis (arterial pH progressed from 7.35 +/- 0.03 at baseline to 7.10 +/- 0.06 at 90 minutes). There were large increases in blood pressure, LV end systolic pressure, stroke work, and velocity of contraction. Twenty minutes following venom injection, cardiac output (CO) increased by 37% but then declined to 36% below baseline by 90 minutes (P < .05). CBF increased significantly in proportion to increased perfusion pressure; hence, there was no change in coronary vascular resistance. There was no evidence of myocardial ischemia or LV dysfunction because there was no change in myocardial pH, percentage fiber shortening, or LV end-diastolic pressure. Despite the fact that some variables returned to baseline at 90 minutes, they did not reach steady state; thus, the preparation would have continued to deteriorate. Myocardial ischemia does not occur in this dog model immediately following administration of scorpion venom. There are significant peripheral circulatory effects of the venom, which account for many of the hemodynamic changes.


Ion Structure Near a Core-Shell Dielectric Nanoparticle.
A generalized image charge formulation is proposed for the Green's function of a core-shell dielectric nanoparticle for which theoretical and simulation investigations are rarely reported due to the difficulty of resolving the dielectric heterogeneity. Based on the formulation, an efficient and accurate algorithm is developed for calculating electrostatic polarization charges of mobile ions, allowing us to study related physical systems using the Monte Carlo algorithm. The computer simulations show that a fine-tuning of the shell thickness or the ion-interface correlation strength can greatly alter electric double-layer structures and capacitances, owing to the complicated interplay between dielectric boundary effects and ion-interface correlations.


Friend or Foe: UCHL3 Mediated Carcinogenesis and Current Approaches in Small Molecule Inhibitors' Development.
As cancer continues to be one of the leading causes of death, various cancer treatments are being developed from traditional surgery to the more recent emergence of target therapy. However, therapy resistance is a restricting problem that needs to be overcome. Henceforth, the field of research shifts to new plausible drug targets, among which is the ubiquitin-proteasome system. This review is focused on the ubiquitin carboxyl-terminal hydrolase (UCH) protease family, which are members of Deubiquitinating enzymes (DUBs), specifically Ubiquitin carboxyl-terminal hydrolase L3 (UCHL3). DUBs regulate a broad array of regulatory processes, including cell-cycle progression, tissue development, and differentiation. DUBs are classified into seven subfamilies, including ubiquitin-specific proteases (USPs), JAB1/MPN/Mov34 metalloenzyme, ovarian tumor proteases (OTUs), Josephin and JAB1/MPN+(MJP), MIU-containing novel DUB (MINDY), zinc finger-containing ubiquitin peptidase 1 (ZUP1), and ubiquitin C-terminal hydrolases (UCHs). Having a significant role in tumorigenesis, UCHL3 is thus emerging as a therapeutic target. Knowing its involvement in cancer, it is important to understand the structure of UCHL3, its substrate specificity, and interaction to pave the way for the development of potential inhibitors. This review covers several directions of proteasome inhibitors drug discovery and small molecule inhibitors development.


[Water, sanitation and diarrheal risk in Nouakchott Urban Community, Mauritania].
Drinking water and sanitation are two factors of inter-linked inextricably public health especially in the city of Nouakchott where the low availability of these services leads to a multitude of use and hygiene practices involving a complex socio-ecological system with an increased risk of waterborne diseases transmission (diarrhea, cholera, etc.). Thus, this contribution analyzes the impact of socio-ecological system on the development of diarrheal diseases by using socio-environmental and epidemiological data from various sources (national surveys and registries consultation). Overall, the results show that only 25.6% of households have access to drinking water sources while 69.8% of the populations dispose improved latrines. Hence, the weakness in environmental sanitation conditions explains the level of diarrheal morbidity averring 12.8% at the urban level, with an unequal spatial distribution showing less affected communes such as Tevragh Zeina (9.1%) and municipalities more affected like Sebkha (19.1%). The distribution according to the age categories shows that children under 5 years are the most affected with 51.7% followed by people aged over 14 with 34.2%. The correlation analysis between socio-economic, environmental and epidemiological variables reveals a number of significant associations: untreated water consumption and diarrhea (R = 0.429); collection of wastewater and occurrence of diarrhea ; existence of improved latrine and reduction of diarrheal risk (R = 0.402). Therefore, exposure to diarrheal diseases through the prism of water and sanitation is a real public health problem that requires a systemic and integrated approach to improving environmental health.


The influence of edge and corner evolution on plasmon properties and resonant edge effect in gold nanoplatelets.
In this paper a simulation of the properties of surface plasmons on gold nanoplatelets with various cross-sections inscribed in a circle and an investigation of their field distributions to assign multiple SPRs are described. The manipulated propagation can be obtained through the evolution of edges and corners. Furthermore, the particle morphology and the associated spectral positions alone do not uniquely reflect the important details of the local field distribution or the resonance modes. The plasmon modes were investigated and found to be mainly excited along the edges and in the side and sloped side surfaces. The strong field distributions can generally be found around the corners and how the plasmons transmit through the corners to adjacent edges was also investigated. Besides the plasmons excited along the edges as were found for the triangular nanoplatelets, plasmons were excited in the interior region of the triangular surfaces and were also investigated. Despite this in the infrared region, plasmon modes were found to be along the edges for the hexagonal nanoplatelets. Also, it can be seen that the change of nanoplatelet thickness can support different plasmon modes ranging from dipolar resonance mode to quadrupole resonance mode. The thickness far below the skin depth can display complex plasmon modes along the edges and on the side and sloping side surfaces as well as the strong coupling between the top and bottom surfaces. The observed plasmon resonance modes in this simulation reflect the interference of all these contributions including the plasmons along the edges and on the side surfaces. This is an essential step towards a thorough understanding of plasmon modes and the effect of edge and corner evolution in polygonous nanoplatelets.


Pan-European study of genotypes and phenotypes in the Arabidopsis relative Cardamine hirsuta reveals how adaptation, demography, and development shape diversity patterns.
We study natural DNA polymorphisms and associated phenotypes in the Arabidopsis relative Cardamine hirsuta. We observed strong genetic differentiation among several ancestry groups and broader distribution of Iberian relict strains in European C. hirsuta compared to Arabidopsis. We found synchronization between vegetative and reproductive development and a pervasive role for heterochronic pathways in shaping C. hirsuta natural variation. A single, fast-cycling ChFRIGIDA allele evolved adaptively allowing range expansion from glacial refugia, unlike Arabidopsis where multiple FRIGIDA haplotypes were involved. The Azores islands, where Arabidopsis is scarce, are a hotspot for C. hirsuta diversity. We identified a quantitative trait locus (QTL) in the heterochronic SPL9 transcription factor as a determinant of an Azorean morphotype. This QTL shows evidence for positive selection, and its distribution mirrors a climate gradient that broadly shaped the Azorean flora. Overall, we establish a framework to explore how the interplay of adaptation, demography, and development shaped diversity patterns of 2 related plant species.


Driving Under the Influence of Antidepressants: A Systematic Review and Update of the Evidence of Experimental and Controlled Clinical Studies.
Introduction This review provides an update of experimental and clinical studies on the effects of antidepressants on driving performance. Methods A systematic literature search on the PubMed database (1980-2016) was performed. Results Twenty-eight studies could be included in this review, whereas only 5 studies investigated driving performance under antidepressants in patients. Most tri- and tetracyclics have acute deleterious effects on driving performance that, except for mianserin, attenuate after subchronic use. Selective serotonin reuptake inhibitors and the serotonin norepinephrine reuptake inhibitor's venlafaxine and milnacipran did not affect driving ability. Trazodone appears to have dose-related acute effects on driving skills. Acute use of mirtazapine does produce impairments that diminish when given as a nocturnal dose and cannot be seen in healthy subjects when initially given as a low dose or after repeated dosing. Additive effects with alcohol were most pronounced with sedating antidepressants. Most patients definitely benefit from treatment with newer antidepressants with respect to driving skills. Discussion Much more patient studies are needed to elucidate a crucial question: from which antidepressant treatment do patients benefit most with respect to driving performance?


Molecular dynamics studies of the P pilus rod subunit PapA.
Adhesion of uropathogenic Escherichia coli to host tissues is mediated by pili, which extend from the outer cell membrane of the bacterium. Here we report molecular dynamics (MD) characterizations of the major constituent of P pili from the uropathogenic E. coli, PapA, in unliganded state and in complex with the G1 strand of the chaperone PapD. To mimic the PapA response to the gradual dissociation of the PapD G1 strand and to evaluate the role of PapA chaperone recognition sites, we also carried out MD simulations of complexes of PapA with fragments of PapD G1 strand, that leave either the P4 or both P3 and P4 sites unoccupied. Data on the unbound form of PapA indicate that, upon release of the chaperone, PapA evolves toward compact states that are likely not prone to subunit-subunit association. In line with recent experimental reports, this finding implies that chaperone release and subunit-subunit association must be concerted. Our data also indicated that the gradual unbinding of the chaperone from the PapA groove has increasingly strong structural consequences. Indeed, the release of the chaperone from the site P4, which is closest to the initiation site (P5), does not have dramatic effects on the domain structure, whereas its release from both the P4 and the adjacent P3 sites induces a quick structural transition toward a collapsed state, where the subunit groove is obstructed.


Monoclonality of both pale cells and cuboidal cells of sclerosing hemangioma of the lung.
Sclerosing hemangioma of the lung remains poorly understood, and it is still unclear whether this lesion is neoplastic or not. It consists of two major cell types, pale cells and cuboidal cells. We analyzed the clonality of each cell types from six female cases of surgically resected sclerosing hemangioma. The pale cells and cuboidal cells were separated by microdissection from methanol-fixed sections, and DNA was extracted for clonal analysis based on an X-chromosome-linked polymorphic marker, the human androgen receptor (HUMARA) gene or the phosphoglycerate kinase (PGK) gene. The HUMARA and PGK genes were found to be amplified with or without digestion by the methylation-sensitive restrictive endonuclease HpaII. Five of six cases were informative. Pale cells and cuboidal cells showed the same monoclonality in all of the informative cases, whereas the control cells showed a polyclonal pattern. Our results demonstrated that sclerosing hemangioma is caused by monoclonal expansion of cells, confirming that it is a neoplasia. Moreover, the present data indicate that both pale cells and cuboidal cells are derived from the same cell.


Novel cis-element in intron 1 represses somite expression of zebrafish myf-5.
Myf-5 is a basic helix-loop-helix (bHLH) transcription factor that controls muscle differentiation. During early embryogenesis, myf-5 expression is transient, somite- and stage-specific. However, the negative regulation of myf-5 is poorly understood. We constructed a plasmid [(-9977/-1)/E1/I1/E2/GFP] that contains the sequence -9977 to -1, exon 1 (E1), intron 1 (I1), and exon 2 (E2) of zebrafish (Danio rerio) myf-5 and a reporter GFP gene. This plasmid was microinjected into zebrafish zygotes. Surprisingly, the somite-specific expression rate of reporter GFP in the transgenic embryos was extremely low (2%, n=392), compared to that of (-9977/-1)/GFP (92%, n=210). Dramatic repression of myf-5 expression was also observed in embryos microinjected with plasmids in which the sequence -8600/-1, -2937/-1 or -290/-1 was linked to E1/I1/E2/GFP. Thus, intron 1 contains a silencer that specifically represses the activity of myf-5. Functional analysis of intron 1 showed a strong, negative, cis-regulatory element was located at +502/+835. Its function was orientation- and position-dependent. The repressive capability of this silencer was completely dependent on two core motifs, IE1 (+502/+527) and IE2 (+816/+835), and a 156-bp spanning sequence that lies between them. This is the first study to identify a novel, cis-acting silencer in intron 1 that is crucial to negatively regulating zebrafish myf-5 expression.


Leukocyte telomere length is inversely associated with post-load but not with fasting plasma glucose levels.
Type 2 diabetes mellitus is characterized by shorter leukocyte telomere length, but the relationship between leukocyte telomere length and type 2 diabetes mellitus development is rather questioned. Fasting and post-load glycaemia associated with different types of insulin resistance and their relation with leukocyte telomere length remains unknown. We compared leukocyte telomere length and fasting or post-load glucose levels in persons who do not receive glucose lowering treatment. For 82 randomly selected rural residents of Ukraine, aged 45+, not previously diagnosed with type 2 diabetes mellitus, the WHO oral glucose tolerance test and anthropometric measurements were performed. Leukocyte telomere length was measured by standardized method of quantitative monochrome multiplex polymerase chain reaction in real time. Spearman's or Pearson's rank correlation was used for correlation analysis between fasting plasma glucose or 2-h post-load plasma glucose levels and leukocyte telomere length. Logistical regression models were used to evaluate risks of finding short or long telomeres associated with fasting plasma glucose or 2-h post-load plasma glucose levels. No association of fasting plasma glucose and leukocyte telomere length was revealed, whereas 2-h post-load plasma glucose levels demonstrated a negative correlation ( P < 0.01) with leukocyte telomere length. Waist circumference and systolic blood pressure were negatively related ( P = 0.03) with leukocyte telomere length in men. Oral glucose tolerance test result-based glycemic categories did not show differences between mean leukocyte telomere length in categories of normal fasting plasma glucose and 2-h post-load plasma glucose (NGT, n = 33); diabetes mellitus (DM), n = 18 and impaired fasting glucose/tolerance (IFG/IGT, n = 31) levels. A correlation relationship between leukocyte telomere length and 2-h post-load plasma glucose level in NGT; IFG/IGT and DM groups ( P = 0.027; 0.029 and 0.049, respectively) was revealed; the association between leukocyte telomere length and fasting plasma glucose was confirmed in DM group only ( P = 0.009). Increase of 2-h post-load plasma glucose (but not fasting plasma glucose) level improves the chances of revealing short telomeres: OR 1.52 (95% CI 1.04-2.22), P = 0.03. After the adjustment for age, gender, waist circumference, systolic blood pressure, and fasting plasma glucose, these phenomena remain significant. We conclude that 2-h post-load plasma glucose but not fasting plasma glucose is inversely associated with leukocyte telomere length. Impact statement • Contradictory epidemiologic data have been obtained about the link between the leucocyte telomere length (LTL) and diabetes. Type 2 diabetes (T2D) is likely to be pathophysiologically heterogeneous, but comparison of the association of LTL separately with fasting plasma glucose (FPG) and 2-h post-load plasma glucose (2hPG) levels has not been done before. Thus, the study of LTL changes associated with different types of hyperglycaemia, that largely determine the heterogenity of T2D is important. • In a population-based study of rural Ukrainians, we were the first to demonstrate that the increase of 2hPG (but not FPG) level increases the chances of revealing short telomeres. • The obtained data can help to clarify the relationship between the LTL shortening and different conditions of the insulin resistance (mainly liver resistance in high FPG and mostly muscle and adipose tissue resistance in high 2hPG).


High-throughput methods of regulatory element discovery.
With the number of organisms whose genomes have been sequenced, a vast amount of information concerning the genetic structure of an organism's genome has been collected. However, effective experiment means to study how this information is accessed have only recently been developed. In this review, three basic methods for identifying regions of protein-DNA interaction will be introduced. The first two, chromatin immunoprecipitation (ChIP)-chip and ChIP-PET (for paired-end ditag), rely on the enrichment provided by chromosomal immunoprecipitation to interrogate the genomic sequence for the interaction sites of a protein of interest. In contrast, protein microarrays allow the identification of DNA binding protein that interacts with a DNA sequence of interest. These complementary methods of exploring protein-DNA interactions will increase our fundamental knowledge of how the information contained within the genome sequence is accessed and processed.


Alteration of gut microbiota affects expression of adiponectin and resistin through modifying DNA methylation in high-fat diet-induced obese mice.
Adiponectin and resistin are typically secreted by the adipose tissue and are abnormally expressed in obesity. However, the underlying influential factors and mechanisms are to be elucidated. It is well known that the expression of genes is regulated by epigenetics while gut microbiota participates in epigenetic processes through its metabolites such as folate, biotin, and short-chain fatty acids (SCFAs). Therefore, we supposed that alteration of gut microbiota might affect the transcriptional expression of adiponectin and resistin through epigenetic regulation in obesity. C57BL/6J mice were fed either a high-fat diet (34.9% fat by wt., 60% kcal) or a normal-fat diet (4.3% fat by wt., 10% kcal) for 16 weeks, with ampicillin and neomycin delivered via drinking water to interfere with gut microbiota development. Fecal microbiota was analyzed by 16S rRNA high-throughput sequencing. The mRNA expression levels of genes were measured by real-time quantitative RT-PCR. SCFA contents in feces were examined using gas chromatography. Alteration of the gut microbiota induced by antibiotic use, characterized by a dramatic reduction of the phylum Firmicutes and Actinobacteria and an increase of Proteobacteria with reductions of genera including Lactobacillus, norank_f_Bacteroidales_S24-7_group, Alistipes, Desulfovibrio, Helicobacter, etc., and increases in Bacteroides, Enterobacter, Klebsiella, inhibited the body weight gain in mice fed the high-fat diet instead of the normal-fat diet. The mRNA expression of adiponectin and resistin was upregulated by antibiotic use in mice fed the high-fat diet, accompanied by increased expression of fat oxidation and thermogenesis-related genes (PPAR-α, Pgc-1α, and Atgl) in the fat and/or liver, whereas no change in the expression of adiponectin and resistin was found in mice fed the normal-fat diet. Furthermore, antibiotic use reduced DNA methylation fractions of the adiponectin and resistin promoters and downregulated the expression of DNA methyltransferase 1 and 3a (DNMT1 and DNMT3a) with the high-fat diet feeding. Alteration of gut microbiota induced by antibiotic use may affect the expression of adiponectin and resistin in mice fed the high-fat diet by modifying promoter DNA methylation, thus leading to increased fatty acid oxidation and less body weight gain.


Do cherished children age successfully? Longitudinal findings from the Veterans Affairs Normative Aging Study.
Although early adversity has been linked to worse mental and physical health in adulthood, few studies have investigated the pathways through which positive and negative dimensions of early experiences can jointly influence psychological well-being in later life. This study examined: (a) profiles of early experiences across multiple domains, (b) the relations of these profiles to hedonic and eudaimonic well-being in later life, and (c) whether midlife social support mediated these relations. We first conducted latent class analysis of early experiences using data from 1,076 men in the VA Normative Aging Study who completed the Childhood Experiences Scale (age: M = 69, SD = 7). Analyses yielded 3 profiles of early experiences, labeled as cherished (strong support and some losses), harshly disciplined (harsh parental discipline, low positive reinforcement, and nonnormative stressors), and ordinary (few stressors and low parental attention). Next, we applied structural equation modeling to data on a subset of this sample assessed 7 years later on hedonic and eudaimonic well-being (n = 496; age: M = 76, SD = 7). In general, the cherished group reported stronger qualitative social support in midlife than the harshly disciplined and ordinary groups, which in turn was related to greater hedonic (life satisfaction, positive affect) and eudaimonic (competence, positive relations with others) well-being in later life. The cherished group also reported higher autonomy than the ordinary group, but this association was independent of midlife social support. Our findings suggest that experiencing adversity in the context of a nurturing early environment can promote successful aging through the maintenance of supportive relationships in midlife.


First-order multivariate calibration applied to the simultaneous fluorometric determination of the anticancer agents CPT-11 and SN-38 in serum and urine samples.
The first-order multivariate calibration method was used for the simultaneous determination of the camptothecin derivative, CPT-11 and its main metabolite, SN-38. The method is based on the fluorescence emission of these compounds in acidic media (acetate buffer, pH 4.75) and in the presence of ethanol (50%). The experimental calibration matrix was constructed with 12 samples using a central composite design. The cross-validation method was used for selecting the optimum number of factors. The results showed that simultaneous determination could be performed in the range 0.08 - 1.50 and 0.10 - 0.40 µg mL(-1) for CPT-11 and SN-38, respectively. The method was successfully applied to the simultaneous determination of both analytes in human urine and in serum samples previously extracted with chloroform.


[Skin prick testing versus immumofluorescence testing for mites allergens].
To discuss the characteristics of skin prick test (SPT) and immumofluorescence method (IFM) in detecting the atopy of dermatophagoides pteronyssinus (Dp) and dermatophagoides farinae (Df)and explore the relationship of them. Four hundred and ninety-one patients with two or more symptoms of nasal obstruction,itching, sneezing and rhinorrhea received SPT and serum specific IgE detection using IFM. SPT was more sensitive than IFM in detecting the atopy of Dp and Df (P < 0.05). If using the IFM as the gold standard, the sensitivity of SPT was all above 95% with the specificity a little bit lower than 80%. These two methods had a positive correlation in detecting the atopy of Dp and Df (r = 0.779, 0.776; P < 0.01). The sIgE concentrations of these two mites were highly correlated with each other (r = 0.954, P < 0.01), the SPT was highly correlated with each other (r = 0. 946, P < 0.01). SPT was more sensitive than IFM in detecting the atopy of Dp and Df. In most cases, SPT can replace IFM to detect patients' allergia on mites. Besides, it is good enough to detect either of the serum specific IgE concentrations of Dp and Df.


Selective ablation of the androgen receptor in mouse sertoli cells affects sertoli cell maturation, barrier formation and cytoskeletal development.
The observation that mice with a selective ablation of the androgen receptor (AR) in Sertoli cells (SC) (SCARKO mice) display a complete block in meiosis supports the contention that SC play a pivotal role in the control of germ cell development by androgens. To delineate the physiological and molecular mechanism responsible for this control, we compared tubular development in pubertal SCARKO mice and littermate controls. Particular attention was paid to differences in SC maturation, SC barrier formation and cytoskeletal organization and to the molecular mediators potentially involved. Functional analysis of SC barrier development by hypertonic perfusion and lanthanum permeation techniques and immunohistochemical analysis of junction formation showed that SCARKO mice still attempt to produce a barrier separating basal and adluminal compartment but that barrier formation is delayed and defective. Defective barrier formation was accompanied by disturbances in SC nuclear maturation (immature shape, absence of prominent, tripartite nucleoli) and SC polarization (aberrant positioning of SC nuclei and cytoskeletal elements such as vimentin). Quantitative RT-PCR was used to study the transcript levels of genes potentially related to the described phenomena between day 8 and 35. Differences in the expression of SC genes known to play a role in junction formation could be shown from day 8 for Cldn11, from day 15 for Cldn3 and Espn, from day 20 for Cdh2 and Jam3 and from day 35 for ZO-1. Marked differences were also noted in the transcript levels of several genes that are also related to cell adhesion and cytoskeletal dynamics but that have not yet been studied in SC (Actn3, Ank3, Anxa9, Scin, Emb, Mpzl2). It is concluded that absence of a functional AR in SC impedes the remodeling of testicular tubules expected at the onset of spermatogenesis and interferes with the creation of the specific environment needed for germ cell development.


Analysis on the willingness and influencing factors of choosing primary healthcare institutions among patients with chronic conditions in China: a cross-sectional study.
To assess the willingness and factors influencing the choice of primary healthcare (PHC) institutions among patients with chronic conditions in China. A nationwide population-based study with binary logistic regression was conducted and used to estimate the ORs of the influencing factors of health-seeking at PHC institutions using the Anderson model as a theoretical framework. The China Family Panel Studies (CFPS) database. The study sample included 7967 patients with chronic conditions identified from the 2016 and 2018 CFPS databases. From 2016 to 2018, the rate of choosing PHC institutions for patients with chronic conditions dropped from 51.0% to 47.7%. The logistic regression results showed that patients with low family income (OR value of >60 000 group was 0.57, 95% CI 0.43 to 0.74), low education level (OR value of bachelor degree or above was 0.54, 95% CI 0.35 to 0.83;), older age (OR value of >65 group was 1.31, 95% CI 1.08 to 1.60;), hypertension and diabetes (OR 1.26, 95% CI 1.13 to 1.41), living in rural areas (OR value of urban was 0.47, 95% CI 0.38 to 0.60), immigrating from rural to urban areas (OR 1.64, 95% CI 1.26 to 2.13), reporting good health (OR value of very good was 1.33, 95% CI 1.05 to 1.68) and those from areas with a high proportion of PHC institutions (OR 1.05, 95% CI 1.02 to 1.07) were more inclined to choose PHC institutions. Conversely, patients with urban employee health insurance (OR 0.62, 95% CI 0.49 to 0.80) and more than one chronic disease (OR 0,83, 95% CI 0.75 to 0.92) preferred choosing a hospital. The patients' willingness to choose PHC institutions was low. The health-seeking preference of patients with chronic conditions is derived from medical needs and is influenced by the predisposing factors and tendencies of enabling resources. Measures should be taken to improve the capacity of PHC institutions.


Runx2 downregulation, migration and proliferation inhibition in melanoma cells treated with BEL β-trefoil.
Malignant melanoma is a lethal form of skin cancer and highly metastatic tumor with poor prognosis; BEL β-trefoil, a lectin, obtained by our group, possesses the ability to act specifically on malignant cells. Therefore, the aim of our study was to investigate the effects of BEL β-trefoil in melanoma cells in an attempt to evaluate its potential usage as anticancer agent. BEL β-trefoil was purified by chromatography and A375 and MeWo melanoma cells were treated. Viability and proliferation were evaluated as well as apoptosis, RUNX2 gene expression and migration ability. The treated tumor cells decreased viability as well as proliferative ability. Flow cytometry analysis showed a lessen effect of the treatment on apoptosis. The gene expression analysis showed a reduction of RUNX2 expression in a dose-dependent manner and migration ability was reduced significantly in both treated cell lines. Our findings suggest that BEL β-trefoil can be considered a useful tool against malignancy due to its effect based on the simultaneous proliferation ability reduction as well as the inhibition of migration capacity on melanoma tumor cells.


Synthesis, Antiinflammatory and Antibacterial Activity of Novel Indolyl-isoxazoles.
Chalcones were synthesized by reacting indole-3-aldehyde, prepared by Vilsemeir Haack reaction with 4-substituted acetophenone in ethanolic KOH solution. These chalcones were immediately reacted with hydroxylamine hydrochloride in presence of glacial acetic acid as reagent to obtain the corresponding isoxazole derivatives. The synthesized heterocycles were characterized on the basis of physical, chemical tests and spectroscopic data. These compounds were tested for the acute antiinflammatory activity and antibacterial activity using carrageenan-induced rat paw edema method and cup-plate method, respectively.


Urinary tract infections.
Urinary tract infections (UTIs) are still the precipitating cause for 7 million patient visits per year with total costs exceeding one billion dollars. Diagnostic modalities have become more "friendly" for the smaller laboratory with "dip stick" culture tests providing a rapid method of isolation of pathogens. In many cases, empiric therapy is more cost effective than culture in uncomplicated UTIs in women. The etiologic organisms implicated in UTIs have not changed dramatically over the past two decades, with E. coli still accounting for the majority of cases. Antibiotic susceptibility patterns have changed dramatically, with ampicillin losing utility die to the emergence of resistance. Quinolones, which have been exceedingly active against gram-negative enteric pathogens, are no longer universally active and more pathogenic organisms, such as pseudomonas, may be resistant. The emergence of other highly resistant organisms, such as Enterococcus faecium, must be watched for.


Peripheral lymphocyte subpopulations in recurrent aphthous ulceration.
Peripheral lymphocyte subsets--T-helper (CD4+), T-suppressor/cytotoxic (CD8+), and naive/virgin T cells/natural killer cells (CD45RA)--were studied quantitatively in 30 patients with recurrent aphthous ulceration (RAU) and 29 sex- and age-matched RAU-free control donors. The CD4+ percentage was significantly lower in the patients than in the control group (P less than 0.0001), whereas CD8+ and CD4/CD8 ratio figures did not differ significantly between patients and controls. The CD45RA+ counts were significantly higher in the patient group (P less than 0.01). The study supports previous investigations with regard to the demonstration of immunologic disturbances in RAU patients. Whether the imbalance is primary or secondary with regard to the basic etiology remains to be resolved.


Formalehyde in personal care products.
Personal care products reported to cause allergic contact dermatitis from the presence of formaldehyde need to be re-examined in light of recent chemical developments in our understanding of the film former, toluene sulfonamide formaldehyde resin, the preservatives diazolidinyl urea and imidazolidinyl urea, and formalin. This paper will elucidate these chemistries as well as review how formaldehyde is used in personal care products in raw materials and formaldehyde donor preservatives.


[Immunoglobulin therapy for systemic lupus erythematosus].
A 25-year-old patient with lupus erythematosus was admitted with myositis and erythema of the skin under chloroquine therapy. After improvement of clinical symptoms with cyclophosphamide and prednisolone he was again progredient with myositis. The changing of therapy to methotrexate showed a hepatotoxic side effect with elevated liver enzymes. Under subsequent therapy with azathioprine and prednisolone he developed leukopenia and sepsis. Because of persistent erythema of the skin under therapy with different immunosuppressives we performed a therapy with high-dose intravenous immunoglobulins. After application of immunoglobulins we observed an improvement of the erythema after 10 days, which was persistent after dose reduction for about 4 months.


Detection of Antibodies to Seven Priority Pathogens in Backyard Poultry in Trinidad, West Indies.
Backyard poultry farms in Trinidad and Tobago (T&T) play a vital role in providing food and income for rural communities. There is currently no information on the presence and circulation of pathogens in backyard poultry farms in T&T, and little is known in relation to the potential risks of spread of these pathogens to the commercial poultry sector. In order to address this, serum samples were collected from 41 chickens on five backyard farms taken from selected locations in Trinidad. Samples were tested for antibodies to seven priority pathogens of poultry by enzyme-linked immunosorbent assay (ELISA). Antibodies were detected in 65% (CI 95%: 50-78%) of the sampled birds for Infectious bronchitis virus (IBV), 67.5% (CI 95%: 52-80%) for Infectious bursal disease virus (IBDV), 10% (CI 95%: 4-23%) for Newcastle disease virus (NDV), 0% (CI 95%: 0-0%) for Avian influenza virus (AIV), 0% (CI 95%: 0-0%) for West Nile virus (WNV), 31.7% (CI 95%: 20-47%) for Mycoplasm gallisepticum/synoviae and 0% (CI 95%: 0-0%) for Salmonella enterica serotype Enteritidis. These results reveal the presence and circulation of important pathogens of poultry in selected backyard farms in Trinidad. The results provide important information which should be taken into consideration when assessing the risks of pathogen transmission between commercial and backyard poultry farms, as well as between poultry and wild birds.


Catalytic diastereoselective petasis reactions.
Multicomponent Petasis reactions: the first diastereoselective Petasis reaction catalyzed by chiral biphenols that enables the synthesis of syn and anti β-amino alcohols in pure form has been developed. The reaction exploits a multicomponent approach that involves boronates, α-hydroxy aldehydes, and amines.


Finite element micromagnetism simulations on the magnetization reversal behaviors of cobalt nanotubes.
In this paper, we have used the finite element micromagnetism theory to simulate the magnetization (M) reversal behaviors of cobalt nanotubes with different lengths (L = 400, 600, 800 and 1000 nm). The inner radius and outer radius of nanotubes are 50 nm and 100 nm respectively. The simulation results show that all the nanotubes exhibit significantly anisotropic behaviors: the easy magnetization axis is along the longitudinal direction. The coercivity values are found dependent on the dimensions of Co nanotubes. For the nanotube with a length of 400 nm, M reversal processes along the Z axis starts from the inner wall and propagates from the inside toward the outside. However, for other nanotubes, M reversal processes start from both ends of nanotubes. When the magnetic field (H) is applied along the hard axis, magnetic moments gradually change their directions into the opposite directions. The variations of the total Gibbs free energy have been calculated to support the observed differences in reversal processes.


Are written and spoken recall of text equivalent?
Writing is less practiced than speaking, graphemic codes are activated only in writing, and the retrieved representations of the text must be maintained in working memory longer because handwritten output is slower than speech. These extra demands on working memory could result in less effort being given to retrieval during written compared with spoken text recall. To test this hypothesis, college students read or heard Bartlett's "War of the Ghosts" and then recalled the text in writing or speech. Spoken recall produced more accurately recalled propositions and more major distortions (e.g., inferences) than written recall. The results suggest that writing reduces the retrieval effort given to reconstructing the propositions of a text.


Diagnostic and therapeutic potential of exosomes in Alzheimer's disease.
Exosomes are small extracellular vesicles released by almost all cell types in physiological and pathological conditions. The exosomal potential to unravel disease mechanisms, or to be used as a source of biomarkers, is being explored, in particularly in the field of neurodegenerative diseases. Alzheimer's disease (AD) is the most prevalent neurodegenerative disease in the world and exosomes appear to have a relevant role in disease pathogenesis. This review summarizes the current knowledge on exosome contributions to AD as well as their use as disease biomarker resources or therapeutic targets. The most recent findings with respect to both protein and miRNA biomarker candidates for AD, herein described, highlight the state of the art in this field and encourage the use of exosomes derived from biofluids in clinical practice in the near future.


A systematic study of rare gas atoms encapsulated in small fullerenes using dispersion corrected density functional theory.
The most stable fullerene structures from C20 to C60 are chosen to study the energetics and geometrical consequences of encapsulating the rare gas elements He, Ne, or Ar inside the fullerene cage using dispersion corrected density functional theory. An exponential increase in stability is found with increasing number of carbon atoms. A similar exponential law is found for the volume expansion of the cage due to rare gas encapsulation with decreasing number of carbon atoms. We show that dispersion interactions become important with increasing size of the fullerene cage, where Van der Waals forces between the rare gas atom and the fullerene cage start to dominate over repulsive interactions. The smallest fullerenes where encapsulation of a rare gas element is energetically still favorable are He@C48, Ne@C52, and Ar@C58. While dispersion interactions follow the trend Ar > Ne > He inside C60 due to the trend in the rare gas dipole polarizabilities, repulsive forces become soon dominant with smaller cage size and we have a complete reversal for the energetics of rare gas encapsulation at C50.


Berberine bioisostere Q8 compound stimulates osteoblast differentiation and function in vitro.
The Q8 compound is a unique derivative of berberine. The present study investigated the functional role of Q8 to evaluate its potential for use in bone regeneration, especially in osteoblast differentiation. The safe concentration of Q8 increased BMP4-induced alkaline phosphatase (ALP) activity, and induced RNA expression of ALP, bone sialoprotein (BSP), and osteocalcin (OC). The activities of ALP-, BSP- and OC-luciferase reporters were also increased by Q8. During osteoblast differentiation, Q8 stabilized the Runx2 and Osterix protein abundance by blocking the ubiquitin-proteasome pathway, which in turn promoted Runx2 and Osterix induced transcriptional activity and subsequently increased the osteoblast differentiation. Meanwhile, depletion of Runx2 and Osterix markedly abolished the bone anabolic effect of Q8 on osteoblast differentiation. To evaluate the signal transduction pathway involved in the Q8-mediated regulation of Runx2 and Osterix, we examined the reporter assay using various kinase inhibitors. Treatment with a protein kinase A (PKA) inhibitor, H89 inhibited the Q8-mediated regulation of Runx2 and Osterix. Based on these findings, this study demonstrates that Q8 promotes the osteoblast differentiation by stabilization of Runx2/Osterix through the increased activation of PKA signaling. The enhancement of osteoblast function by Q8 may contribute to the prevention for osteoporosis.


Review: Milk Proteins as Nanocarrier Systems for Hydrophobic Nutraceuticals.
Milk proteins and milk protein aggregates are among the most important nanovehicles in food technology. Milk proteins have various functional properties that facilitate their ability to carry hydrophobic nutraceutical substances. The main functional transport properties that were examined in the reviewed studies are binding of molecules or ions, surface activity, aggregation, gelation, and interaction with other polymers. Hydrophobic binding has been investigated using caseins and isolated β-casein as well as whey proteins. Surface activity of caseins has been used to create emulsion-based carrier systems. Furthermore, caseins are able to self-assemble into micelles, which can incorporate molecules. Gelation and interaction with other polymers can be used to encapsulate molecules into protein networks. The release of transported substances mainly depends on pH and swelling behavior of the proteins. The targeted use of nanocarrier systems requires specific knowledge about the binding mechanisms between the proteins and the carried substances in a certain food matrix.


The role of IgE-receptors in IgE-dependent airway smooth muscle cell remodelling.
In allergic asthma, IgE increases airway remodelling but the mechanism is incompletely understood. Airway remodelling consists of two independent events increased cell numbers and enhanced extracellular matrix deposition, and the mechanism by which IgE up-regulates cell proliferation and extracellular matrix deposition by human airway smooth muscle cells in asthma is unclear. Characterise the role of the two IgE receptors and associated signalling cascades in airway smooth muscle cell remodelling. Primary human airway smooth muscle cells (8 asthmatics, 8 non-asthmatics) were stimulated with human purified antibody-activated IgE. Proliferation was determined by direct cell counts. Total collagen deposition was determined by Sircol; collagen species deposition by ELISA. IgE receptors were silenced by siRNA and mitogen activated protein kinase (MAPK) signalling was blocked by chemical inhibitors. IgE dose-dependently increased extracellular matrix and collagen deposition by airway smooth muscle cells as well as their proliferation. Specifically in cells of asthma patients IgE increased the deposition of collagen-type-I, -III, -VII and fibronectin, but did not affect the deposition of collagens type-IV. IgE stimulated collagen type-I and type-VII deposition through IgE receptor-I and Erk1/2 MAPK. Proliferation and deposition of collagens type-III and fibronectin involved both IgE receptors as well as Erk1/2 and p38 MAPK. Pre-incubation (30 minutes) with Omalizumab prevented all remodelling effects completely. We observed no changes in gelatinase activity or their inhibitors. CONCLUSION CLINCAL RELEVANCE: Our study provides the molecular biological mechanism by which IgE increases airway remodelling in asthma through increased airway smooth muscle cell proliferation and deposition of pro-inflammatory collagens and fibronectin. Blocking IgE action prevents several aspects of airway smooth muscle cell remodelling. Our findings may explain the recently described reduction of airway wall thickness in severe asthma patients treated with humanised anti-IgE antibodies.


The effects of cigarette smoking and gestational weight change on birth outcomes in obese and normal-weight women.
The associations of infant birth outcomes with maternal pregravid obesity, gestational weight gain, and prenatal cigarette smoking were examined. A retrospective analysis of 1343 obese and normal-weight gravidas evaluated the associations of cigarette smoking, gestational weight change, and pregravid body mass index with birthweight, low birthweight, and small- and large-for-gestational-age births. Smoking was associated with the delivery of lower-birthweight infants for both obese and normal-weight women, and gestational weight gain did not eliminate the birthweight-lowering effects of smoking. Women at highest risk of delivering lower-birthweight infants were obese smokers whose gestational gains were less than 7 kg and normal-weight smokers whose gestational gains were less than 11.5 kg. To balance the risks of small and large-size infants, gains of 7 to 11.5 kg for obese women and 11.5 to 16 kg for normal-weight women appear appropriate.


Placenta-associated plasma protein-A (PAPP-A, SP4) in trophoblastic tumours.
The immunoperoxidase technique was used to study the occurrence of placenta-associated plasma protein A (PAPP-A, SP4) in formalin-fixed paraffin-embedded tissue specimens from 15 hydatidiform moles, 6 invasive moles and 7 choriocarcinomas. PAPP-A was found in the syncytiotrophoblast of all hydatidiform moles, in 5 of the 6 invasive moles and in 6 of the 7 choriocarcinomata. No clinical difference was observed between PAPP-A positive and negative cases of invasive disease.


Regulation of human mesangial cell growth in culture by thromboxane A2 and prostacyclin.
Elevated eicosanoid biosynthesis characterizes certain forms of human and experimental glomerular proliferative disease. Thromboxane A2 (TxA2) and other prostaglandins (PG) act through specific receptors and mechanisms of intracellular signal transduction in human mesangial cells. We studied the actions of U-46619, a TxA2 mimetic which stimulates mesangial phospholipase C, and of the PGI2 analogue, Iloprost, a potent activator of adenylate cyclase, on proliferation of cultured human mesangial cells. When applied alone to quiescent cells, U-46619 had only weak mitogenic activity, as assessed by [3H]thymidine [( 3H]-TdR) incorporation and cell counts. On the other hand, addition of U-46619 10 minutes prior to stimulation of the cells with 1 to 17% fetal bovine serum (FBS) for 24 hours, potently and dose-dependently inhibited FBS-stimulated [3H]-TdR incorporation. Similarly, U-46619 inhibited the effects of 10 ng/ml platelet-derived growth factor (PDGF), epidermal growth factor or basic fibroblast growth factor on [3H]-TdR incorporation, by 55, 79 and 88%, respectively. The effects of U-46619 were not mimicked by another stimulus of phospholipase C, angiotensin II. Iloprost also inhibited FBS-activated proliferation. Neither eicosanoid inhibited the rise of cytosolic Ca2+ induced by FBS or PDGF. The actions of TxA2 and Iloprost in cultured cells point to multiple functional interactions between eicosanoids and growth factors in the control of mesangial cell proliferation.


Inhibitory effect of theaflavin-3,3'-digallate can involve its binding to the "stem" domain of α-hemolysin of Staphylococcus aureus.
Infections caused by Staphylococcus aureus are currently a worldwide threat affecting millions of individuals. The pathogenicity of S. aureus is associated with numerous virulence factors, including cell surface proteins, polysaccharides, and secreted toxins. The pore-forming α-hemolysin, known as α-toxin, is produced by nearly all virulent strains of S. aureus and is implicated in several diseases including skin and soft tissue infections, atopic dermatitis, and pneumonia. There are currently no vaccines available for the prevention of S. aureus infections and the efficacy of available antibiotics has been fading. In this study we examined the mode of antihemolytic activity of theaflavin-3,3'-digallate against α-hemolysin of methicillin-resistant S. aureus by molecular docking using AutoDock Vina as the molecular docking tool. The theaflavin-3,3'-digallate docked the molecular sequence of the Hla (PDB ID:7ahl). The scores of the top 10 binding modes obtained were between -9.0 and -8.5 kcal mol-1, and the best binding mode was -9.0 kcal mol-1. Direct binding sites of theaflavin-3,3'-digallate to the "stem" domain of Hla were revealed which primarily targeted of the residues Met113, Thr117, Asn139. The disclosure of this potential binding mode warrants further clinical evaluation of theaflavin-3,3'-digallate as an anti-hemolytic compound in order to practically validate our results.


Dorsal Scapular Osteochondroma in the Chiropractic Clinic: A Case Report and Literature Review.
Osteochondromas are benign bone tumors that occur only rarely in the scapula. We report a case of an eight-year-old boy with dorsal scapular osteochondroma that initially presented as middle back pain, scoliosis, and a winged scapula. Unlike in most reported cases, the patient did not report severe pain. The chiropractor reviewed his previous radiograph and ordered a computed tomography scan, which revealed a bony mass on the dorsal aspect of the left scapula consistent with an osteochondroma. Given the patient's age and lack of symptoms, a conservative chiropractic treatment plan, focusing on posture, flexibility, and close monitoring, was adopted. Scapular mobilization, spinal adjustment, and a tailored exercise program provided symptomatic relief from scoliosis and improved mobility. Follow-up evaluations revealed further enlargement of the osteochondroma without accompanying symptoms. This study highlights the importance of considering a broad range of differential diagnoses in pediatric patients with atypical or unclear presentations. This study also demonstrates the potential benefits of conservative chiropractic management in patients with osteochondroma-induced musculoskeletal issues.


Pharmacological treatment strategies for patients with monogenic obesity.
The leptin melanocortin signaling pathway is playing a pivotal role for body weight regulation. Genetic defects within this cascade are leading to severe hyperphagia and early onset obesity. In most cases, due to persistent hyperphagia the affected patients are not able to stabilize body weight for a longer period of time with conservative treatment strategies based on lifestyle interventions. Therefore, it is of importance to implement alternative treatment options for these patients. This review provides an overview about the published pharmacological treatment attempts in respect to monogenic forms of obesity and summarizes recent research progress about the role of MC4R signaling and POMC derivatives for body weight regulation.


The pituitary mediates production or release of an alarm chemosignal in rats.
Rodent alarm chemosignals elicit various behavioral and physiological responses in conspecifics. This study employed a bioassay method, using a modification of the forced swim test, to demonstrate that the pituitary mediates production and/or secretion of an alarm chemosignal in rats subjected to stress. This was shown by comparing the immobility times of rats in water soiled by hypophysectomized and sham-treated rats. Rats tested in water soiled by sham-treated rats exhibited very little immobility (the alarm chemosignal effect), whereas rats tested in water soiled by hypophysectomized rats exhibited considerably more immobility. The alarm chemosignal effect was restored in hypophysectomized rats by administration of ACTH. This is the first study to identify mediation of an alarm chemosignal in mammals.


Poly(butylene succinate-co-butylene adipate)/cellulose nanocrystal composites modified with phthalic anhydride.
As a kind of biomass nanofiller for polymers, cellulose nanocrystal (CNC) has good mechanical properties and reinforcing capability. To improve the compatibility of poly(butylene succinate-co-butylene adipate) (PBSA)/CNC composites, phthalic anhydride was used as a compatilizer during melt mixing, leading to the significant improvement of the mechanical properties and thermal stability of the composites, which is related to the better dispersion of CNC in the composites. The addition of phthalic anhydride could accelerate the crystallization of PBSA component as evidenced by the curves of isothermal crystallization of the composites, but had little effect on the crystalline polymorphs of PBSA component. The addition of phthalic anhydride could strongly improve the hydrophobicity of the composites. The good mechanical properties, fast crystallization and improved hydrophobicity of PBSA/CNC composites with phthalic anhydride are favor to their practical commercial utilization.


Elevated soluble HLA II protein levels in patients with alpha-1 antitrypsin deficiency with or without COPD.
Elevated levels of human leukocyte antigen (HLA) proteins have been reported in several pathologic conditions that are associated with increased concentrations of white blood cells (e.g., infection, inflammation, and lymphoproliferative disorders). The mechanisms by which HLA proteins are solubilized from cell membranes are insufficiently understood. We hypothesized that HLA proteins may be cleaved from cell membranes by insufficiently inhibited leukocytic elastase, as expected in alpha-1 antitrypsin deficiency (A1ATD), resulting in elevated plasma levels of soluble HLA (sHLA) proteins. Using an enzyme-linked immunosorbent assay, we measured sHLA II levels in the peripheral blood of patients with A1ATD with or without co-existing chronic obstructive pulmonary disease (COPD), with COPD only, and in a control group. Mean (±SD) sHLA II plasma levels were 110 ± 200 pg/mL in patients with A1ATD and COPD (Group 1), 10 ± 30 pg/mL in patients with COPD without A1ATD (Group 2), 70 ± 90 pg/mL in patients with A1ATD without COPD (Group 3), and 10 ± 30 pg/mL in healthy donors (Group 4). Soluble HLA II plasma levels were significantly higher in Group 1 (P = .001) and Group 3 (P = .002) versus Group 4. Our preliminary results suggest that leukocytic elastase and probably other proteinases solubilize HLA proteins from cell membranes. This mechanism would operate in inflammation with elevated leukocytic elastase levels but more so with inflammation and A1ATD, where elastase would be insufficiently inhibited. If this mechanism is verified, plasma sHLA levels could potentially be used to measure cell damage due to proteinases and, therefore, for monitoring the therapeutic efficacy of alpha-1 antitrypsin (A1AT) augmentation therapy.


The Influence of Heavy Metals and Trace Elements on Comatose Patients with Severe Traumatic Brain Injury in the First Week of Admission.
The aim of this study is to investigate the possible role of heavy metals (lead and cadmium) and imbalance of trace elements (chromium, iron, zinc, copper, and manganese) in death among patients with severe traumatic brain injury. A case-control study was conducted with 64 comatose patients with severe TBI, in the Department of Anesthesiology and Reanimation, Ibn Sina University Hospital and Hospital of Specialties in Rabat, Morocco; 22 healthy volunteers were recruited in Blood Transfusion Center of Rabat. Blood samples were collected from TBI patients, in the first week (3h after admission and each 48h during one week) and from healthy volunteers one time. Concentration of heavy metals and trace elements in serum was determined by electrochemical atomic absorption spectrometry. Statistical analysis was performed using Statistical software (SPSS) and the cases and controls were compared using the Mann-Whitney U test and Student's t-test for cadmium according to gender and final evolution. A P-value <0.05 was considered to be statistically significant. Our data showed that the difference of heavy metals concentration (lead and cadmium) between patients and healthy subjects was not statistically significant. However, the difference of some trace elements concentration (iron, copper, chromium, and selenium) between patients and healthy subjects was statistically significant. According to the final evolution, the concentration of manganese was higher in dead patients and statistically significant (p = 0.04) for heavy metals; the concentration of lead was not statistically significant while the concentration in cadmium was statistically significant (p = 0.004). By sex, lead and cadmium were statistically significant, respectively p = 0.02, p = 0.001, and cadmium was higher in women, while lead was higher in men. Among all studied heavy metals (lead and cadmium) and trace elements (iron, zinc, copper, selenium, chromium, and manganese), manganese and cadmium may play a role in the death of patients from severe traumatic brain injury.


Conscientious Objection in Healthcare: Neither a Negative Nor a Positive Right.
Conscientious objection in healthcare is often granted by many legislations regulating morally controversial medical procedures, such as abortion or medical assistance in dying. However, there is virtually no protection of positive claims of conscience, that is, of requests by healthcare professionals to provide certain services that they conscientiously believe ought to be provided, but that are ruled out by institutional policies. Positive claims of conscience have received comparatively little attention in academic debates. Some think that negative and positive claims of conscience deserve equal protection in terms of measures that institutions ought to take to accommodate them. However, in this issue of The Journal of Clinical Ethics (JCE), Abram Brummett argues against this symmetry thesis.1 He suggests that the relevant distinction is not between negative and positive claims of conscience, but between negative and positive rights of conscience. He argues that conscientious refusals and positive claims of conscience are both already protected as negative rights of conscience, but that this does not require institutions to accommodate positive claims of conscience. In this article I will argue that both Brummett and the authors he criticizes share a wrong view about the existence of conscience rights in healthcare. I will argue that there is no right to conscientious objection in healthcare, whether positive or negative. Thus, contra Brummett, I argue that the question whether such rights are positive or negative is as irrelevant as the question whether the claims of conscience are positive or negative.


The effect of dietary fiber on human pancreatic enzyme activity in vitro.
Human pancreatic juice was used as a source of amylase, lipase, trypsin, and chymotrypsin. The human pancreatic juice was incubated with one of several dietary fibers, including alfalfa, oat bran, pectin. Solka Floc, wheat bran, and xylan. In addition, the human pancreatic juice was incubated without any fiber, which was used as the control. Incubation with Solka Floc (cellulose) and xylan (a hemicellulose) resulted in a substantial loss of activity in all enzymes assayed. Wheat bran and oat bran decreased amylase and chymotrypsin activity, while alfalfa decreased trypsin and chymotrypsin activity. Incubation with pectin significantly increased amylase and chymotrypsin activity. The mechanism by which sources of dietary fiber can alter enzyme activity is currently unknown. This effect of a dietary component on the activity of human pancreatic enzymes emphasizes the need to investigate further the effects of dietary fiber on digestion and absorption in the small intestine to understand fully its effects on metabolism.


Sensitization to the motor stimulant effects of 3,4-methylenedioxypyrovalerone (MDPV) and cross-sensitization to methamphetamine in rats.
In recent years, there has been a dramatic increase in abuse of the synthetic cathinone 3,4-methylenedioxypyrovalerone (MDPV), often in combination with other illicit stimulants. We sought to determine if repeated exposure to MDPV would produce sensitization to the motor stimulant effects of the drug, and whether cross-sensitization would develop with the stimulant effects of methamphetamine (METH). Male Sprague-Dawley rats were administered MDPV (1 or 5 mg/kg) or saline once daily for 5 days at 24 hour intervals, or were administered MDPV (1 mg/kg) or saline once daily for 5 days at 48 hour intervals. For cross-sensitization experiments, rats were administered METH (1 mg/kg) or MDPV (1 or 5 mg/kg) once daily for 5 days at 48 hour intervals, and following a 5 day incubation period, were given an acute challenge injection of either MDPV (0.5 mg/kg) or METH (0.5 mg/kg), respectively. Rats repeatedly administered MDPV (1 mg/kg) every 48 hours, but not every 24 hours, demonstrated increased motor activity when given either a subsequent challenge of MDPV (0.5 mg/kg i.p.) or METH (0.5 mg/kg), indicating the development of behavioral sensitization and cross-sensitization, respectively. Moreover, rats repeatedly administered METH (1 mg/kg) every 48 hours did not exhibit cross-sensitization to the motor stimulating effects of a subsequent challenge with MDPV (0.5 mg/kg). These results suggest that specific patterns of MDPV administration may lead to lasting changes in behavioral responses to subsequent METH exposure.


Prognostic value of metabolic tumor burden in lung cancer.
Accurate prognosis in patients with lung cancer is important for clinical decision making and treatment selection. The TNM staging system is currently the main method for establishing prognosis. Using this system, patients are grouped into one of four stages based on primary tumor extent, nodal disease, and distant metastases. However, each stage represents a range of disease extent and may not on its own be the best reflection of individual patient prognosis. (18)F-fluorodeoxyglucose-positron emission tomography ((18)F-FDG-PET) can be used to evaluate the metabolic tumor burden affecting the whole body with measures such as metabolic tumor volume (MTV) and total lesion glycolysis (TLG). MTV and TLG have been shown to be significant prognostic factors in patients with lung cancer, independent of TNM stage. These metabolic tumor burden measures have the potential to make lung cancer staging and prognostication more accurate and quantitative, with the goal of optimizing treatment choices and outcome predictions.


Effect of oligofructose supplementation on gut microflora and well-being in young children attending a day care centre.
The effect of daily administration of oligofructose (OF) on 7-19 months old healthy children intestinal microflora, intestinal tolerance and well-being was assessed in a double blind placebo controlled study. The study comprised 8 days of observation, 21 days of supplementation, and 15 days of post-supplementation. Exclusion criteria included antibiotic use and intake of other prebiotic and probiotic at any time following enrolment. Faecal flora was analysed by culture methods, and health information was recorded daily. Bifidobacteria, tended to slightly increase with OF supplementation, but not with placebo (p=0.095). Simultaneously, a decrease in potential pathogens, significant for clostridia (p=0.05) but not for staphylococci (p=0.09) was observed in the OF group. These modifications did not persist during the post-supplementation period. OF supplementation were accompanied by less flatulence, diarrhoea, vomiting (p<0.001), and fever (p<0.05) events.


Altered levels of sex and stress steroid hormones assessed daily over a 28-day cycle in early abstinent cocaine-dependent females.
There is growing evidence of alterations in brain stress and reward circuits associated with cocaine dependence. Sex differences are also documented and sex steroid hormones have been linked to cocaine reinforcement. The current study therefore assessed daily fluctuations in stress and sex hormones in cocaine-dependent females compared with healthy females. Daily salivary samples of cortisol, progesterone, and estradiol were collected at waking across 28 days from 12 cocaine-dependent females receiving inpatient treatment and 10 healthy females. Participants also completed mood-rating scales each week corresponding to four phases of the menstrual cycle and cocaine craving was monitored in cocaine patients at each phase. Cocaine-dependent females in their first month of abstinence demonstrated significantly higher levels of both cortisol and progesterone across the menstrual cycle and significantly lower estradiol/progesterone (E2/P) ratios compared to healthy controls. They also showed significantly increased negative mood compared with controls, but no variation in cocaine craving across the menstrual cycle. Findings indicate altered stress and sex hormones suggestive of an overactive stress system during the first month of cocaine abstinence after chronic cocaine abuse. These increased levels of cortisol and progesterone could impact both abstinence-related symptoms such as negative mood and susceptibility to drug-seeking behavior in cocaine-dependent females.


[Effect of 120-day antiorthostatic hypokinesia on the reproductive function in women].
Original data on the peculiarities of adaptation to and functional status of the reproductive system in long-term antiorthostatic hypokinesia (AOH) have been obtained. The studies involved eight healthy female volunteers aged 26-37 years who were exposed to the head-down tilt (-6 degrees) for 120 days. The test subjects were divided into 2 groups of 4 persons each. In Group A, the countermeasures, i.e. physical exercise and pharmacological means, were used. In Group B, at no time did the test subjects use the countermeasures throughout the 120-day AOH. With and without the countermeasures, hypokinesia was found to impact the female reproductive system developing clinical symptoms of deficiency of the menstrual lutein phase and giving rise to small inclusions of functional fluids in the ovaries. Within 6 months after AOH, the ovarial function of the test subjects was fully recovered which may be indicative of the functional character of changes. These changes can be explained by dissociation of the functional relations in the hypothalamo-hypophyseal-ovarial system manifested by increases in the plasmic concentrations of luteinizing hormone (LH) against normal levels of follicle-stimulating hormone (FSH) and prolactin, and moderately increased levels of testosterone, relative hyperestrogenemia and hypoprogesteronemia. These clinical and hormonal developments are contrary to the observations usually made in various models of stress. Similarity of the hormonal profiles under hypokinesia and long-term immersion of female swimmers may be ascribed to common mechanisms underlying the disturbance of the reproductive function.


Drug-induced hypersensitivity syndrome with high procalcitonin levels due to piperacillin/tazobactam and meropenem: A case report.
Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare and life-threatening adverse drug reaction. It is characterized by a long latency period with rash, hematological abnormalities, and visceral damage. Clinical manifestations of DRESS vary. Thus, accurate clinical diagnosis and identification are essential to ensure timely treatment commencement for improving prognosis and speeding up recovery. We report the case of a 66-year-old male patient with a drug reaction induced by a beta-lactam antibiotic, piperacillin/tazobactam (Pip/Taz). This resulted in the manifestation of both eosinophilic and systemic symptoms. Ten days after the Pip/Taz treatment commencement, the patient developed hyperthermia and elevated serum procalcitonin (PCT), leading to a misdiagnosis of an exacerbated infection. Meropenem treatment was then started. However, after 72 h, the patient developed a generalized rash, eosinophilia, hematological abnormalities, and visceral damage. Moreover, PCT levels were significantly elevated. All these symptoms were associated with DRESS. The sensitizing drug was discontinued, and glucocorticoids were administered, resulting in gradual subsiding of symptoms and decreases in serum PCT levels. Clinicians should be aware that elevated PCT serum levels may be a diagnostic biomarker for DRESS, which requires specific treatment. Furthermore, studies are warranted to further evaluate and elucidate the role of PCT in response to DRESS.


ACE2 and angiotensin 1-7 are increased in a human model of cardiovascular hyporeactivity: pathophysiological implications.
ACE and ACE2 produce angiotensin II (Ang II), a vasopressor that induces cardiovascular remodeling, and Ang 1-7, a vasodilator with an antiremodeling effect. While Ang 1-7 has antiarrhythmic properties, at higher concentration it may induce ventricular tachycardia and sudden death. ACE2, therefore, may play an essential role in blood pressure homeostasis, in the long-term complications of hypertension (cardiovascular remodeling), and in the induction of cardiac electric abnormalities. This study evaluated the levels of ACE2 and Ang 1-7 in Bartter's/Gitelman's patients (BS/GS) who have elevated Ang II and endogenous blockade of Ang II type 1 receptor signaling compared with healthy subjects (C) and essential hypertensives (EH). BS/ GS patients were also considered because of their predisposition to cardiac arrhythmias, which has yet to be completely clarified. Mononuclear cell ACE2 and Ang 1-7 were evaluated using western blot. One-way ANOVA showed that ACE2 and Ang 1-7 levels were significantly different between the three groups (p=0.0074 and p=0.0001, respectively). Post-hoc analysis (Tukey's HSD) showed that both ACE2 (1.59+/-0.63) and Ang1-7 (2.26+/-1.18) were significantly elevated in BS/GS compared with either C (0.98+/-0.45; p=0.008; 1.12+/-0.48, p=0.002, respectively) or EH (1.06+/-0.24; p=0.043; 0.72+/-0.28; p=0.0001, respectively). ACE2 and Ang 1-7 directly correlated only in BS/GS (r=0.91, p<0.0003). The elevated ACE2 and Ang 1-7 in BS/ GS patients mirror those in hypertensives and are in line with the clinical, hemodynamic and pathophysiological characteristics of BS/GS, likely contributing to them. In consideration of the clinical picture of these syndromes, the opposite of hypertension, the results of this study further strengthen the importance of the ACE2/Ang 1-7 system in the regulation of vascular tone and cardiovascular biology.


The mediating roles of perceived social support and resources in the self-efficacy-suicide attempts relation among African American abused women.
The authors examined whether self-efficacy among African American abused women decreased their risk of suicide attempts through the mediating influences of perceived social support from friends, perceived social support from family, and perceived effectiveness for obtaining material resources. The sample consisted of 100 women who presented to a hospital following a suicide attempt and 100 women who presented to the same hospital for nonemergency medical problems. Results revealed that the association between self-efficacy and suicide attempt status was partially accounted for by the mediating roles of perceived social support from friends and family, and perceived effectiveness at obtaining resources. Findings suggest that interventions to increase abused women's self-efficacy should focus on increasing their capacity to obtain social and material resources.


[Urate nephropathy in patients with arterial hypertension].
Purine metabolism disturbances which may be responsible for urate nephropathy were revealed in 35% of the examinees with arterial hypertension. Gout manifestations occurred in many of the above patients. Purine metabolism disturbances contribute much to progression of renal disorders and arterial hypertension, require early diagnosis and treatment. Urate symptoms may serve a primary diagnostic indication.


Feasibility of application of an absorbable topical collagen hemostat sheet (INTEGRAN®) for prevention of postoperative recurrence of pneumothorax in youths.
Staple-line coverage is an effective method for prevention of postoperative recurrence of pneumothorax. However, the recurrence rate in young patients is still unsatisfactory using this method. Moreover, there is no consensus about the optimal material for use in this technique. To explore new material for this technique, we conducted this study to evaluate the safety of an absorbable topical collagen hemostat (INTEGRAN®) for staple-line coverage in pneumothorax surgery in young patients. A single-arm prospective interventional study was performed in 25 patients (age <25 years old) with primary spontaneous pneumothorax (PSP) who underwent wedge resection with staple-line coverage with INTEGRAN® between 2017 and 2020. The rate of material-related adverse events (defined as a body temperature ≥38 ℃ continuing for ≥2 days, postoperative WBC >18,000/mm3 and/or CRP >15 mg/dL, or acute empyema within 30 postoperative days) was defined as the primary endpoint. The 1-year postoperative rates of recurrence and of new bullae around the staple-line were also measured. The median age was 19 years old. None of the patients had a body temperature ≥38 ℃ continuing for ≥2 days, extra-abnormal examination data, and acute empyema findings. At 1-year postoperatively, the recurrence rate was 12.0%, and the rate of new bullae around the staple-line was 16.7%. This study showed the safety of use of INTEGRAN® for staple-line coverage in pneumothorax surgery in young adults. The short-term recurrence rate was acceptable given the high-risk cohort examined in the study. A prospective randomized controlled study is needed for evaluation of the efficacy of INTEGRAN® for prevention of recurrence of PSP. UMIN000026530 at UMIN Clinical Trials Registry.


Inhibiting long chain fatty Acyl CoA synthetase increases basal and agonist-stimulated NO synthesis in endothelium.
Endothelial nitric oxide synthase (eNOS) activation/deactivation is associated with cyclic depalmitoylation/repalmitoylation of specific Cys residues. The mechanism of depalmitoylation has been identified recently, but repalmitoylation remains undefined. We hypothesized that long chain fatty acyl CoA synthetase (LCFACoAS) modulates endothelial nitric oxide synthase repalmitoylation by limiting palmitoyl CoA availability. Human coronary endothelial cells were treated with triacsin-C, an inhibitor of long chain fatty acyl CoA synthetase, for 24 h. Media nitrite accumulation, eNOS activity, and eNOS palmitoylation were measured. Methacholine-induced NO synthesis or vascular relaxation were measured in endothelium-intact rat aortae in the presence and absence of triacsin-C. Triacsin-C significantly reduced incorporation of [3H] palmitate into immunoreactive endothelial nitric oxide synthase and over a concentration range of 0.1 to 10 microM, increased media nitrite accumulations 2- to 2.5-fold over baseline. Total in vitro catalytic activity of nitric oxide synthase in triacsin-C treated cells did not differ significantly from control. Triacsin-C significantly increased methacholine-induced NO synthesis in the isolated rat aorta, and significantly enhanced methacholine-induced relaxation of rat aortic rings. These data are consistent with the interpretation that inhibition of palmitoylation increases endothelial nitric oxide synthase activity without changing endothelial nitric oxide synthase expression, suggesting that inhibiting palmitoylation increases the catalytically active fraction of endothelial nitric oxide synthase.


Out of Amazonia: the unexpected trans-Andean distribution of Cochranella resplendens (Lynch and Duellman, 1978) (Anura: Centrolenidae).
The glassfrog genus Cochranella, with nine recognized species, is distributed in the lowlands and mid elevation of the Neotropical forests, from Nicaragua to Bolivia (Guayasamin et al. 2009; Twomey et al. 2014). Four species are trans-Andean-C. granulosa (Taylor 1949) occurs in the lowlands and mountains, at mid elevation, of Central America, C. litoralis (Ruiz-Carranza & Lynch 1996) and C. mache Guayasamin & Bonaccorso 2004 occur in the Pacific lowlands and the western cloud forests of Colombia and Ecuador, and C. euknemos (Savage & Starrett 1967) occurs both in Central America and South America (northwestern Colombia).-The other five species have cis-Andean distributions in the Amazonian slopes and lowlands, from Colombia to Bolivia: C. nola Harvey 1996, C. guayasamini Twomey, Delia & Castroviejo-Fisher 2014, C. resplendens (Lynch & Duellman 1973), C. erminea Torres-Gastello, Suárez-Segovia & Cisneros-Heredia 2007, and C. phryxa Aguayo-Vedia & Harvey 2006. In Colombia, C. resplendens is known from the foothills of the Amazon versant in Caquetá (Malambo et al. 2013) and Putumayo (Lynch & Duellman 1973; Ruiz-Carranza et al. 1996). The species is also known from Ecuador (Lynch & Duellman 1973) and Peru (Twomey et al. 2014). Here, we report two new records of Cochranella resplendens, extending the species distribution beyond the Amazonian lowlands into the northern Cordillera Central in Colombia.


Volume Navigation Technique for Ultrasound-Guided Biopsy of Breast Lesions Detected Only at MRI.
The purpose of this study is to assess the utility of a volume navigation technique (VNT) for ultrasound-guided biopsy of MRI-detected, but sonographically ambiguous or occult, breast lesions. Within a recruitment period of 13 months (January 1, 2014, through February 1, 2015), 22 patients with 26 BI-RADS category 4 or 5 lesions that were detected at MRI but missed at second-look ultrasound were reimaged using a rapid sequence and a flexible body coil in a 3-T MRI scanner. Patients were supine, with three skin markers placed on the breasts. MRI volume data were coregistered to real-time ultrasound in a dedicated platform, and MRI-detected lesions (six masses, 11 nonmass enhancements, eight foci, and one architectural distortion) were sought using VNT-guided ultrasound. Five needle biopsy specimens were obtained either from each sonographically detected lesion (n = 11) or from VNT-guided sonographically localized breast volume corresponding to the MRI-detected, but still ultrasound-occult, lesions (n = 15). Histopathologic analysis revealed 18 benign and six malignant lesions. The remaining two lesions, both of which appeared as masses at MRI, were high risk and were upgraded to carcinoma after excisional biopsy. All malignant lesions underwent curative surgery; the final histopathologic diagnoses remained unchanged. Of the six malignant lesions, one was a mass, three were nonmass enhancements, and two were enhancing foci at MRI. Three malignant lesions were occult at ultrasound, and three were discerned as subtle hypoechoic changes. No benign lesion was sonographically visualized as a mass, and none progressed, with 56% disappearing at MRI performed during the follow-up period (mean, 14 months). Coregistration of MRI and real-time ultrasound enables sonographic localization of breast lesions detected at MRI only. VNT is a feasible alternative to MRI-guided biopsy of ultrasound-occult breast lesions.


The effect of the platelet concentration in platelet-rich plasma gel on the regeneration of bone.
The aim of our study was to investigate the effect of platelet-rich plasma on the proliferation and differentiation of rat bone-marrow cells and to determine an optimal platelet concentration in plasma for osseous tissue engineering. Rat bone-marrow cells embedded in different concentrations of platelet-rich plasma gel were cultured for six days. Their potential for proliferation and osteogenic differentiation was analysed. Using a rat limb-lengthening model, the cultured rat bone-marrow cells with platelet-rich plasma of variable concentrations were transplanted into the distraction gap and the quality of the regenerate bone was evaluated radiologically. Cellular proliferation was enhanced in all the platelet-rich plasma groups in a dose-dependent manner. Although no significant differences in the production and mRNA expression of alkaline phosphatase were detected among these groups, mature bone regenerates were more prevalent in the group with the highest concentration of platelets. Our results indicate that a high platelet concentration in the platelet-rich plasma in combination with osteoblastic cells could accelerate the formation of new bone during limb-lengthening procedures.