Association between concomitant proton pump inhibitor use and survival of patients with metastatic prostate cancer receiving abiraterone acetate: a post-hoc analysis of pooled data from three randomized controlled trials.
Evidence suggests proton pump inhibitor (PPI) use may attenuate the effect of abiraterone acetate plus prednisone (AAP) in metastatic prostate cancer via the modification of gut microbiota. This study aimed to examine whether concomitant PPI use is associated with survival in patients with metastatic prostate cancer treated with androgen deprivation therapy (ADT) and AAP. Post-hoc analysis was conducted in patients with metastatic castration-sensitive prostate cancer (mCSPC) and metastatic castration-resistant prostate cancer (mCRPC) treated in the LATITUDE, COU-AA-301, and COU-AA-302 trials (ADT vs. ADT plus AAP). PPI users and non-users were compared for restricted mean overall survival time (RMOST) and restricted mean progression-free survival time (RMPFST) based on inverse probability of treatment weight (IPTW)-adjusted Kaplan-Meier curves. IPTW-adjusted Cox regression models were used to assess heterogeneity of treatment effect. In patients treated with AAP, PPI use was associated with inferior RMOST [difference (95% confidence interval): -4.2 (-7.0 to -1.4)] and RMPFST [-3.5 (-6.6 to -0.4)] compared with non-users. However, RMOST and RMPFST were similar between PPI users and non-users in patients treated with ADT alone [RMOST, -2.6 (-5.8 to 0.6); RMPFST, -1.7 (-4.8 to 1.4)]. Interaction term analyses did not show evidence of heterogeneity in treatment effect between AAP and ADT, despite the prominent treatment effect shown in mCSPC vs. mCRPC. PPI use may be associated with inferior survival in patients with metastatic prostate cancer who receive ADT plus AAP. Discontinuing unnecessary PPI use might improve those outcomes.


HIV pre-exposure prophylaxis and treatment as prevention: a review of awareness and acceptability among men who have sex with men in the Asia-Pacific region and the Americas.
This review assesses acceptability research for HIV pre-exposure prophylaxis (PrEP) and treatment as prevention (TasP) among men who have sex with men (MSM) in the Asia-Pacific region and the Americas, evaluating awareness and attitudes. There has been limited research on the acceptability of PrEP outside the United States and no research to date evaluating the acceptability of TasP since the findings of the HIV Prevention Trials Network 052 trial were released. Existing research suggests that PrEP is reasonably acceptable to MSM, but few men are likely to perceive the need for it. Studies of HIV treatment optimism suggest that MSM are likely to be sceptical of TasP.


Promoting motions in enzyme catalysis probed by pressure studies of kinetic isotope effects.
Use of the pressure dependence of kinetic isotope effects, coupled with a study of their temperature dependence, as a probe for promoting motions in enzymatic hydrogen-tunneling reactions is reported. Employing morphinone reductase as our model system and by using stopped-flow methods, we measured the hydride transfer rate (a tunneling reaction) as a function of hydrostatic pressure and temperature. Increasing the pressure from 1 bar (1 bar = 100 kPa) to 2 kbar accelerates the hydride transfer reaction when both protium (from 50 to 161 s(-1) at 25 degrees C) and deuterium (12 to 31 s(-1) at 25 degrees C) are transferred. We found that the observed primary kinetic isotope effect increases with pressure (from 4.0 to 5.2 at 25 degrees C), an observation incompatible with the Bell correction model for hydrogen tunneling but consistent with a full tunneling model. By numerical modeling, we show that both the pressure and temperature dependencies of the reaction rates are consistent with the framework of the environmentally coupled tunneling model of Kuznetsov and Ulstrup [Kuznetsov AM, Ulstrup J (1999) Can J Chem 77:1085-1096], providing additional support for the role of a promoting motion in the hydride tunneling reaction in morphinone reductase. Our study demonstrates the utility of "barrier engineering" by using hydrostatic pressure as a probe for tunneling regimes in enzyme systems and provides added and independent support for the requirement of promoting motions in such tunneling reactions.


Vitamin D Regulates Fatty Acid Composition in Subcutaneous Adipose Tissue Through Elovl3.
Fatty acids (FAs) are a major energy source in the body. White adipose tissue (WAT) is a primary site where FAs are stored as triacylglycerols. Brown adipose tissue also stores and recruits FAs as a carbon source for uncoupled β-oxidation during thermogenesis. The deletion of the vitamin D nuclear hormone receptor (VDR) gene in mice (VDRKO) results in a lean WAT phenotype with increased levels of expression of the brown adipose tissue marker Ucp1 in the WAT. However, the impact of vitamin D/VDR on FA composition in WAT has not been explored in detail. To address this question, we examined the FA composition of sc and visceral white adipose depots of VDRKO mice. We found that the levels of a subset of saturated and monounsaturated FAs of C18-C24 are specifically increased in the sc adipose depot in VDRKO mice. We revealed that a specific elongase enzyme (Elovl3), which has an important role in brown fat biology, is directly regulated by VDR and likely contributes to the altered FA composition in VDRKO mice. We also demonstrate that Elovl3 is regulated by vitamin D in vivo and tissue specifically in the sc WAT depot. We discovered that regulation of Elovl3 expression is mediated by ligand-dependent VDR occupancy of a negative-response element in the promoter proximal region of the Elovl3 gene. These data suggest that vitamin D/VDR tissue specifically modulates FA composition in sc WAT through direct regulation of Elovl3 expression.


The impact of change from copayment to coinsurance on medical care usage and expenditure in outpatient setting in older Koreans.
Patient cost-sharing change was implemented on August 1, 2007, for outpatient care in the clinic setting in Korea from copayment to coinsurance. This study aims to estimate the effect of the policy change on medical care usage and expenditure in older Koreans. By using national health insurance claims data from the Health Insurance Reimbursement Assessment Service, this study analyzed the entire 137 million claims for a total of approximately 4.1 million patients aged 60 to 69 years who had been diagnosed and/or treated for outpatient care in clinics from January 1, 2007, to December 31, 2008. Medical care usage was defined as the proportion of all beneficiaries in each group who visited clinics and the mean number of visit days per beneficiary. Medical care expenditure per visit day was expressed as total costs, reimbursed amount, and patient's out-of-pocket payment. Data on January through June of 2008 were analyzed as compared with the same months of 2007. Raw difference-in-difference and multiple regression analyses were performed. The interaction coefficients, which measured the impact of cost-sharing change, was -0.078 in model 1 and -0.039 in model 2 (P < .0001). In conclusion, a cost-sharing change from copayment to coinsurance reduced medical care usage and expenditure.


Seasonal and Annual Variations in Atmospheric Hg and Pb Isotopes in Xi'an, China.
We present a 3-year time series of lead (Pb) and mercury (Hg) concentrations and isotope signatures in total suspended particulate (TSP) matter and as total gaseous Hg (TGM) in Xi'an, Northwestern China. Mean concentrations of TSP (299 ± 120 μg m-3), PbTSP (0.33 ± 0.15 μg m-3) and HgTSP (0.64 ± 0.54 ng m-3), and TGM (5.7 ± 2.7 ng m-3) were elevated. We find that atmospheric Pb levels in winter in Xi'an have decreased by 4.6% per year since 2003, yet remain elevated relative to air quality guidelines and therefore a major health concern. δ202HgTSP and Δ199HgTSP averaged -0.80 ± 0.30‰ (1σ) and -0.02 ± 0.10‰ (1σ) and δ202HgTGM and Δ199HgTGM averaged -0.08 ± 0.41‰ (1σ) and 0.00 ± 0.04‰ (1σ). Relative to raw coal from Shaanxi and surrounding provinces, δ202HgTSP is enriched in the light Hg isotopes, whereas δ202HgTGM is enriched in the heavy isotopes. TSP and TGM Δ199Hg signatures are indistinguishable from raw coal, indicating little photochemical mass independent fractionation of atmospheric Hg in the near-field urban-industrial environment. δ202HgTGM correlates significantly with TGM levels (r2 = 0.3, p < 0.01) and likely reflects binary mixing of local industrial TGM emissions with global background TGM.


Bioactive substances in food: identification and potential uses.
Bioactive substances in foods can represent "extranutritional" constituents naturally present in small quantities in the food matrix, produced upon either in vivo or industrial enzymatic digestion, the latter being a result of food-processing activities. Bioactive constituents of food evoke physiological, behavioral, and immunological effects. Evidence from both epidemiological and animal studies has suggested chemopreventative roles for phytochemicals in certain forms of cancers and in the control of hyperlipidemia. Secondary products of plant metabolism can modulate xenobiotic metabolizing and cholesterol synthetic enzymes. Unique physicochemical properties of food-derived peptides with characteristic amino acid composition and sequences have been reported to influence intestinal transit, modify nutrient absorption and excretion, and exhibit immunostimulating and antihypertensive activity. Biologically active peptides derived from casein, fish muscle, and plant protein hydrolysates have been isolated, purified, and identified in peptide sequence studies. Therapeutic proteins (e.g., specific antibodies) derived from animal products such as milk may offer the potential for developing specialized food products with prophylactic as well as nutritive quality. This paper discusses the physicochemical mechanism of action of specific bioactive substances naturally present in or derived from foods. The biotechnologies employed to develop these products and the issues concerning acceptance by consumer and regulatory bodies are also addressed.


Formation of Developmentally Toxic Phenanthrene Metabolite Mixtures by Mycobacterium sp. ELW1.
Mycobacterium sp. ELW1 co-metabolically degraded up to 1.8 μmol of phenanthrene (PHE) in ∼48 h, and hydroxyphenanthrene (OHPHE) metabolites, including 1-hydroxyphenanthrene (1-OHPHE), 3-hydroxyphenanthrene (3-OHPHE), 4-hydroxyphenanthrene (4-OHPHE), 9-hydroxyphenanthrene (9-OHPHE), 9,10-dihydroxyphenanthrene (1,9-OHPHE), and trans-9,10-dihydroxy-9,10-dihydrophenanthrene (trans-9,10-OHPHE), were identified and quantified over time. The monooxygenase responsible for co-metabolic transformation of PHE was inhibited by 1-octyne. First-order PHE transformation rates, kPHE, and half-lives, t1/2, for PHE-exposed cells were 0.16-0.51 h-1 and 1.4-4.3 h, respectively, and the 1-octyne controls ranged from 0.015-0.10 h-1 to 7.0-47 h, respectively. While single compound standards of PHE and trans-9,10-OHPHE, the major OHPHE metabolite formed by ELW1, were not toxic to embryonic zebrafish (Danio rerio), single compound standards of minor OHPHE metabolites, 1-OHPHE, 3-OHPHE, 4-OHPHE, 9-OHPHE, and 1,9-OHPHE, were toxic, with effective concentrations (EC50's) ranging from 0.5 to 5.5 μM. The metabolite mixtures formed by ELW1, and the reconstructed standard mixtures of the identified OHPHE metabolites, elicited a toxic response in zebrafish for the same three time points. EC50s for the metabolite mixtures formed by ELW1 were lower (more toxic) than those for the reconstructed standard mixtures of the identified OHPHE metabolites. Ten unidentified hydroxy PHE metabolites were measured in the derivatized mixtures formed by ELW1 and may explain the increased toxicity of the ELW1 metabolites mixture relative to the reconstructed standard mixtures of the identified OHPHE metabolites.


DepthTools: an R package for a robust analysis of gene expression data.
The use of DNA microarrays and oligonucleotide chips of high density in modern biomedical research provides complex, high dimensional data which have been proven to convey crucial information about gene expression levels and to play an important role in disease diagnosis. Therefore, there is a need for developing new, robust statistical techniques to analyze these data. depthTools is an R package for a robust statistical analysis of gene expression data, based on an efficient implementation of a feasible notion of depth, the Modified Band Depth. This software includes several visualization and inference tools successfully applied to high dimensional gene expression data. A user-friendly interface is also provided via an R-commander plugin. We illustrate the utility of the depthTools package, that could be used, for instance, to achieve a better understanding of genome-level variation between tumors and to facilitate the development of personalized treatments.


Complex Hydroindoles by an Intramolecular Nitrile-Intercepted Allylic Alkylation Cascade Reaction.
Bisnucleophilic reagents derived from malononitrile, ketones, benzaldehydes, and nitromethane can react with bisallylic electrophiles via a nitrile-intercepted allylic alkylation cascade reaction to yield complex hydroindole architectures. Also noteworthy is that the only stoichiometric byproducts from the preparation and reaction of the bisnucleophile and biselectrophile are water, acetic acid, and bicarbonate, making it a potentially "green" platform for multistep complex molecule synthesis. These scaffolds can be converted into hydrooxindoles by a unique olefin isomerization followed by Witkop-Winterfeldt-like oxidation.


Binding of CXCR4 Transmembrane Peptides to the Bacterial Chaperonin GroEL.
The Escherichia coli chaperonin GroEL represents the paradigmatic molecular machine of protein folding. Most of our knowledge on GroEL function is derived from studies with denatured water-soluble proteins or short peptide mimetics. In our earlier studies, we observed that newly translated membrane protein CXCR4 gained significant folding enhancement upon interacting with GroEL in the presence of ATP and GroES. This highlights the mechanistic flexibility and substrate diversity of the chaperonin. This work extends our previous observation to the study of binding of GroEL with CXCR4 transmembrane peptides. The model peptide corresponding to the first transmembrane α-helix in the native tertiary structure of CXCR4 was commercially synthesized. A fluorescent tag was attached to the Nterminus of the peptide for ease of fluorescence characterization. Binding of CXCR4 peptide to GroEL was investigated by fluorescence anisotropy as well as isothermal titration calorimetry (ITC). Through model fitting to the anisotropy and ITC data, important thermodynamic parameters were obtained for the binding. In identifying the binding site of GroEL apical domains for the CXCR4 peptide, competitive binding of the peptide and a model "strongly binding peptide" (SBP) was performed by ITC. Furthermore, the kinetics of the CXCR4 peptide binding to GroEL was also studied by anisotropy. Through anisotropic measurement of binding of CXCR4 peptide to GroEL, a dissociation constant and binding stoichiometry of 0.10µM and 7.00 was obtained. Thermodynamic parameters of the binding were also determined by ITC. By fitting the ITC data to one set of sites model, the values of the thermodynamic parameters were acquired directly as follows: ΔH=-627.10kcal/mol; ΔS=-186.23cal/mol; KD=0.23µM; N=5.96. The binding site of the CXCR4 peptide in GroEL was also probed through competitive binding with the model peptide SBP, pointing to the groove between paired α helices H and I in the apical domain. In addition, the binding kinetics suggests a slow dissociation of the peptide-GroEL complex. The CXCR4 model peptide has been shown to bind to GroEL with high affinity. The binding stoichiometry was estimated to be 6 or 7 depending on the analysis method. Furthermore, the two thermodynamic parameters ΔH and ΔS that define the binding affinity have also been measured by ITC. The binding site of the CXCR4 peptide in the GroEL apical domain was investigated through competitive binding studies with the model peptide SBP. Meanwhile, the kinetic studies indicate a slow dissociation of the peptide-GroEL complex. These results obtained by the reduced approach of employing CXCR4 transmembrane peptides would be beneficial to understanding the GroEL-CXCR4 interaction in the assisted folding.


Role of macrophage in in vitro augmentation of rat, mouse, and human natural killer activities.
Requirement for macrophages in in vitro augmentation, by interferon (IFN), polyinosinic-polycytidylic acid (poly I:C), or Corynebacterium parvum, of rat, mouse, and human natural killer (NK) activities was examined. Several differences were seen among the species. Mouse NK activity demonstrated some lability at 37 degrees C and a strict macrophage requirement for in vitro production of IFN, and augmentation of NK activity was demonstrated by either poly I:C or C. parvum. In contrast, human peripheral blood leukocytes (PBL) depleted of monocytes by adherence on nylon wool demonstrated NK activity, which was not labile but rather increased substantially upon overnight culture at 37 degrees C alone or with poly I:C or C. parvum. Monocyte-depleted human PBL also produced IFN in these cultures. The pattern of reactivity seen with rat spleen cell cultures was different from either that of mouse and human cells. This pattern of reactivity had no lability at 37 degrees C and had a macrophage requirement for IFN production and NK cell augmentation upon culture alone or with poly I:C but not with C. parvum. These results indicated some major differences among species in the regulation of NK activity in vitro and the requirement for macrophages for the in vitro production of IFN. A better understanding of these differences will be helpful in choosing appropriate models for in vitro and in vivo studies of NK cell activity.


The Bradyrhizobium japonicum phoB gene is required for phosphate-limited growth but not for symbiotic nitrogen fixation.
We identified by cloning and DNA sequence analysis the phosphate regulatory gene phoB of Bradyrhizobium japonicum. The deduced gene product displayed pronounced similarity to the PhoB protein of Sinorhizobium meliloti (71.4% identical amino acids). Escherichia coli (50.2%) and other bacterial species. Insertion of a kanamycin resistance cassette into phoB led to impaired growth of the B. japonicum mutant in media containing approximately 25 microM phosphate or less. A standard plant infection test using wild-type and phoB-defective B. japonicum strains showed that the phoB mutation had no effect on the symbiotic properties of B. japonicum with its soybean host plant.


[Up-regulation of serum- and glucocorticoid-inducible kinase 1 (SGK1) of CD4⁺ T cells is positively related to RORC and IL-17A in patients with Kawasaki disease].
To investigate the expression of serum- and glucocorticoid-inducible kinase 1 (SGK1) in Kawasaki disease (KD) and explore the correlations between SGK1 and Th17 cell-related cytokines [retinoic-acid-related orphan nuclear receptor C (RORC), interleukin 17A (IL-17A), IL-6] in KD. Thirty patients with KD [(2.8 ± 1.4) years old], 30 healthy volunteers [(2.6 ± 1.6) years old] and 25 patients with infectious disease (ID) [(2.2 ± 1.5) years old] were recruited. The percentage of Th17 cells in CD4⁺ T cells was analyzed using flow cytometry. The mRNA levels of RORC and SGK1 in CD4⁺ T cells were detected using real-time quantitative PCR. The serum levels of IL-17A and IL-6 were analyzed by ELISA. Compared with healthy volunteers and patients with ID, the percentage of Th17 cells in CD4⁺ T cells significantly increased in KD [(3.57 ± 0.62)% vs (0.51 ± 0.07)% or (1.72 ± 0.36)%]. The serum levels of IL-17A and IL-6 in KD were much higher than those in healthy volunteers and patients with ID. The mRNA levels of RORC and SGK1 in KD were remarkably elevated compared with healthy volunteers and patients with ID. The level of SGK1 in coronary artery lesion (CAL) group of KD was significantly higher than that in KD patients with normal coronary artery (CAN). SGK1 was reduced in KD after intravenous immunoglobulin (IVIG) treatment. What's more, the decrease of SGK1 was more obviously in the CAL group than in the CAN group. In addition, SGK1 expression in KD was positively correlated with RORC and IL-17A, but not with IL-6. SGK1 was up-regulated in CD4⁺ T cells and was positively correlated with RORC and IL-17A in the patients with KD.


Four-crystal camera at BSRF and its applications.
The four-crystal camera is one of the major items of equipment of the topography station at the Beijing Synchrotron Radiation Facility. The design and some applications of this camera are presented.


Massive pneumomediastinum following orbital fracture.
Pneumomediastinum is a rare complication of facial fractures, always persuading the physicians to search for other and potentially more serious injuries such as esophageal or tracheal rupture. A 75-year old man presented to the Emergency Department (ED) reporting an accidental fall while walking on the road. He did not report loss of consciousness (LOS), was not taking anticoagulant drugs, did not report chest, abdomen or limb trauma. On physical examination he only showed swelling of nose and right orbit. The patient underwent a Computed Tomography (CT) scan of head and facial bones, showing a complex fracture involving right nasal bone, ethmoid, right orbital lateral wall, and right maxillary sinus lateral wall. No intracranial lesions were found. Due to the finding of subcutaneous emphysema in the right cheek, the scan was extended to the whole neck and chest. The exam showed a massive pneumomediastinum, extending till the diaphragmatic hiatus. The patient thus underwent bronchoscopy and esophagogastroscopy, but no further lesions could be found. Antibiotics therapy was then administered, and was discharged in good conditions after a five-days observation. In our patient, air had probably escaped into the pharyngo-maxillary space from the right maxillary sinus and tracked into both the retropharyngeal space and, for contiguity, into the pre-tracheal space. As our case report shows, if the airway is secure, the pneumomediastinum does not necessarily require treatment other than clinical observation and management of the fracture. If no other injuries are present, resolution of the pneumomediastinum may be expected without further medical interventions.


Contribution of platelet P2Y12 receptors to chronic Complete Freund's adjuvant-induced inflammatory pain.
Essentials The role of platelet P2Y12 receptors in the regulation of chronic inflammatory pain is unknown. Complete Freund's Adjuvant (CFA)-induced chronic inflammatory pain model was used in mice. Gene deficiency and antagonists of P2Y12 receptors attenuate hyperalgesia and local inflammation. Platelet P2Y12 receptors contribute to these effects in the chronic phase of inflammation. Background P2Y12 receptor antagonists are widely used in clinical practice to inhibit platelet aggregation. P2Y12 receptors are also known to regulate different forms of pain as well as local and systemic inflammation. However, it is not known whether platelet P2Y12 receptors contribute to these effects. Objectives To explore the contribution of platelet P2Y12 receptors to chronic inflammatory pain in mice. Methods Complete Freund's adjuvant (CFA)-induced chronic inflammatory pain was induced in wild-type and P2ry12 gene-deficient (P2ry12-/- ) mice, and the potent, direct-acting and reversible P2Y12 receptor antagonists PSB-0739 and cangrelor were used. Results CFA-induced mechanical hyperalgesia was significantly decreased in P2ry12-/- mice for up to 14 days, and increased neutrophil myeloperoxidase activity and tumor necrosis factor (TNF)-α and CXCL1 (KC) levels in the hind paws were also attenuated in the acute inflammation phase. At day 14, increased interleukin (IL)-1β, IL-6, TNF-α and KC levels were attenuated in P2ry12-/- mice. PSB-0739 and cangrelor reversed hyperalgesia in wild-type mice but had no effect in P2ry12-/- mice, and PSB-0739 was also effective when applied locally. The effects of both local and systemic PSB-0739 were prevented by A-803467, a selective NaV1.8 channel antagonist, suggesting the involvement of NaV1.8 channels in the antihyperalgesic effect. Platelet depletion by anti-mouse CD41 antibody decreased hyperalgesia and attenuated the proinflammatory cytokine response in wild-type but not in P2ry12-/- mice on day 14. Conclusions In conclusion, P2Y12 receptors regulate CFA-induced hyperalgesia and the local inflammatory response, and platelet P2Y12 receptors contribute to these effects in the chronic inflammation phase.


Streptomyces colonosanans sp. nov., A Novel Actinobacterium Isolated from Malaysia Mangrove Soil Exhibiting Antioxidative Activity and Cytotoxic Potential against Human Colon Cancer Cell Lines.
Streptomyces colonosanans MUSC 93JT, a novel strain isolated from mangrove forest soil located at Sarawak, Malaysia. The bacterium was noted to be Gram-positive and to form light yellow aerial and vivid yellow substrate mycelium on ISP 2 agar. The polyphasic approach was used to determine the taxonomy of strain MUSC 93JT and the strain showed a range of phylogenetic and chemotaxonomic properties consistent with those of the members of the genus Streptomyces. Phylogenetic and 16S rRNA gene sequence analysis indicated that closely related strains include Streptomyces malachitofuscus NBRC 13059T (99.2% sequence similarity), Streptomyces misionensis NBRC 13063T (99.1%), and Streptomyces phaeoluteichromatogenes NRRL 5799T (99.1%). The DNA-DNA relatedness values between MUSC 93JT and closely related type strains ranged from 14.4 ± 0.1 to 46.2 ± 0.4%. The comparison of BOX-PCR fingerprints indicated MUSC 93JT exhibits a unique DNA profile. The genome of MUSC 93JT consists of 7,015,076 bp. The DNA G + C content was determined to be 69.90 mol%. The extract of strain MUSC 93JT was demonstrated to exhibit potent antioxidant activity via ABTS, metal chelating, and SOD assays. This extract also exhibited anticancer activity against human colon cancer cell lines without significant cytotoxic effect against human normal colon cells. Furthermore, the chemical analysis of the extract further emphasizes the strain is producing chemo-preventive related metabolites. Based on this polyphasic study of MUSC 93JT, it is concluded that this strain represents a novel species, for which the name Streptomyces colonosanans sp. nov. is proposed. The type strain is MUSC 93JT (= DSM 102042T = MCCC 1K02298T).


Tetanus immunization of adult members of an HMO.
Thirty-nine per cent of 1,900 randomly selected adult Health Plan members received one or more tetanus injections during a 10-year period of continuous eligibility. Age-specific immunization rates decreased from 47 per cent for 20-39 year olds to 28 per cent for those over age 70. Nearly half of the elderly, age 60+, received a booster of tetanus toxoid rather than tetanus-diphtheria toxoids as recommended by the Immunization Practices Advisory Committee of the Centers for Disease Control. Access to care does not appear to be a sufficient condition for achieving recommended levels of immunization, especially among the elderly.


Non-specific X-linked mental retardation: linkage analysis in MRX2 and MRX4 families revisited.
We have previously reported linkage analysis in 3 families with non-specific X-linked mental retardation (XLMR). This used RFLPs and was limited by the relatively low informativeness and density of markers available. We have performed a new linkage analysis using microsatellites (including new Genethon markers) in the two most informative families. In the MRX2 family, a lod score of 2.61 at theta = 0.05 had previously been obtained with DXS85 in Xp22.2. We now report a tighter linkage with AFM 135xe7 (DXS989, z = 4.62 at theta = 0.00) and established the order DXS85-DXS207-DXS999 (AFM234 y12)-MRX2, DXS365, DXS1052 (AFM 163yh2), DXS989-DXS1065 (AFM224zf2), DMD 3'. The localization of MRX2 in Xp22.2-p22.1 is thus clearly different from the more distal MRX gene defined by patients with contiguous gene syndromes. In the MRX4 family, a maximum lod score of 2.53 at theta = 0.00 had been obtained with DXS159 in Xq13. Our present study did not show recombination from ALAS2 in Xp11.21 to DXS441 in Xq13.3 (z = 3.38 at theta = 0.00 for the latter marker) and the closest flanking markers are DXS255 in Xp11.22 and DXYS1 in Xq21.3. Reduced recombination around the centromere prevents precise mapping. The localisation of MRX4 overlaps with that of several other MRX families.


Exploiting Shared Knowledge From Non-COVID Lesions for Annotation-Efficient COVID-19 CT Lung Infection Segmentation.
The novel Coronavirus disease (COVID-19) is a highly contagious virus and has spread all over the world, posing an extremely serious threat to all countries. Automatic lung infection segmentation from computed tomography (CT) plays an important role in the quantitative analysis of COVID-19. However, the major challenge lies in the inadequacy of annotated COVID-19 datasets. Currently, there are several public non-COVID lung lesion segmentation datasets, providing the potential for generalizing useful information to the related COVID-19 segmentation task. In this paper, we propose a novel relation-driven collaborative learning model to exploit shared knowledge from non-COVID lesions for annotation-efficient COVID-19 CT lung infection segmentation. The model consists of a general encoder to capture general lung lesion features based on multiple non-COVID lesions, and a target encoder to focus on task-specific features based on COVID-19 infections. We develop a collaborative learning scheme to regularize feature-level relation consistency of given input and encourage the model to learn more general and discriminative representation of COVID-19 infections. Extensive experiments demonstrate that trained with limited COVID-19 data, exploiting shared knowledge from non-COVID lesions can further improve state-of-the-art performance with up to 3.0% in dice similarity coefficient and 4.2% in normalized surface dice. In addition, experimental results on large scale 2D dataset with CT slices show that our method significantly outperforms cutting-edge segmentation methods metrics. Our method promotes new insights into annotation-efficient deep learning and illustrates strong potential for real-world applications in the global fight against COVID-19 in the absence of sufficient high-quality annotations.


An investigation into the use of low-frequency dielectric spectroscopy as a means of characterizing the structure of creams based on Aqueous Cream BP.
A range of creams based on Aqueous Cream BP have been analyzed using low-frequency dielectric spectroscopy, with accompanying circuit modeling in combination with rheological and microscopic supportive techniques, to explore the use of the dielectric approach as a novel means of characterizing cream systems. Creams based on the formula for Aqueous Cream BP were produced by hand-mixing and mechanical mixing, with and without the inclusion of the preservative phenoxyethanol. Dielectric analysis was performed over a frequency range of 10(-2)-10(5) Hz. Cream samples were also examined using stress scan rheology and differential interference contrast microscopy. Dielectric analysis indicated that the presence of preservative decreased the capacitance and loss of the creams. The responses were modeled in terms of a dispersive capacitance in series with two RC circuits (series and parallel). Rheological studies indicated higher viscosities for the hand-mixed and unpreserved systems. Differential interference contrast microscopy showed marked differences in the distribution of the oil droplets, depending on the method of mixing. The study has demonstrated that dielectric spectroscopy, with accompanying circuit analysis, may be used as a means of modeling the structure of cream systems. The investigation has also shown that the formulation and preparation method of Aqueous Cream BP may have a profound effect on sample structure.


Surgery in overweight patients with insulinoma: effects on weight loss.
Weight loss induced by the complete resection of insulinoma is controversial in overweight patients. The study sought to explore postoperative weight loss and metabolic changes in overweight insulinoma patients. A retrospective study was conducted to review the follow-up data of insulinoma patients with a BMI ≥25kg/m2 who underwent complete lesion resection between May 2010 and May 2015. Body mass index (BMI), weight loss (WL) and percentage weight loss (%WL) were main outcomes. Fifty-one patients were included with a median follow-up of 28 months. The BMI at 3 months, 1 year, 2 years and 3 years postoperatively were significantly lower than the preoperative BMI values (p < .01). The WL% was 12.9% at 3 months postoperatively without significant changes throughout the 3-year follow-up. WL and the %WL were significantly higher in the high BMI group (BMI≥ 27.5 kg/m2). Multivariate analysis indicated that higher initial BMI was associated with increased weight loss (p = .001). 63.8% of patients with hypertension recovered and improved sleep quality was evident in all patients with obstructive sleep apnea syndrome within 1 year postoperatively. Weight significantly decreased postoperatively in overweight insulinoma patients, which was more evident in patients with higher BMI and metabolic comorbidities were largely improved.


Venovenous Extracorporeal Membrane Oxygenation With Prophylactic Subcutaneous Anticoagulation Only: An Observational Study in More Than 60 Patients.
Extracorporeal lung support and therapeutic anticoagulation are dogmatically linked for most clinicians in fear of clotting of the extracorporeal circuit. In the last decade, however, we have learned that bleeding complications in the course of extracorporeal membrane oxygenation (ECMO) therapy are common and not occasionally limiting or fatal. Even though international guidelines lowered the PTT-target values, ECMO therapy without anticoagulation has only been reported sporadically in case reports heretofore. This monocentric, observational study was designed to evaluate a protocol for venovenous ECMO therapy without additional anticoagulation. Patients without former thrombotic events solely received thrombosis prophylaxis with 40 mg subcutaneous enoxaparin per day like every critical care patient. After approval by the local ethics committee (Albert-Ludwigs-University Freiburg ethics committee, EK 513/14) all consecutive patients treated with venovenous ECMO therapy since introduction of the protocol have been identified. Digital charts of the patients have been evaluated with special regard to bleeding and thrombotic or embolic events or breakdown of the extracorporeal circuit. Sixty-one patients received venovenous ECMO therapy with prophylactic subcutaneous enoxaparin only. Median duration of ECMO therapy was 7 days (2-32). Overall 560 ECMO days have been observed. No system exchange because of thrombotic occlusion was necessary within the permitted 5 days run time of the centrifugal pump. Overall we identified thrombotic complications in four patients. In three of them centrifugal pump after a runtime of more than 5 days unexpectedly stopped completely because of thrombotic occlusion. In all cases pump exchange was performed promptly and patients did not incur hypoxic deficit. One other patient received substitution of blood products and coagulation factor concentrates because of severe bleeding and sustained myocardial infarction the day after. Only 18% of patients presented with essential clinical bleeding after 7 days of therapy. No fatal bleeding event and no intracranial hemorrhage was observed. Patients required only a third of blood product transfusion compared to published data. Venovenous ECMO therapy with prophylactic anticoagulation only was feasible in this study. It was not associated with an increased rate of system exchanges compared to regimes with therapeutic anticoagulation in registry data. It provides the potential to relevantly decrease the incidence of severe bleeding events and blood transfusion requirements. The apodictic adherence to anticoagulation in therapeutic dosage should be critically scrutinized in every patient.


Induction of apoptosis by cladribine (2-CdA), gemcitabine and other chemotherapeutic drugs on CD34+/CD38+ and CD34+/CD38- hematopoietic progenitor cells: selective effects of doxorubicin and 2-CdA with protection of immature cells.
Due to the emerging role of high dose chemotherapy with stem cell rescue and ex vivo purging in hematological diseases, we examined the effect of chemotherapeutic drugs on the rate of apoptosis in more mature CD34+/CD38+ and less differentiated CD34+/CD38- stem cells. CD34+ cells were obtained by cell apheresis from healthy donors (n = 25) or patients (n = 25) prepared for high dose chemotherapy and stem cell transplantation. Cells were incubated with different concentrations of doxorubicin, mitoxantrone, mafosphamide, cladribine or gemcitabine. Apoptosis was determined after 24 and 48 h. Generally, the percentage of apoptotic cells was higher in the more mature CD34+/CD38+ progenitor population than in the less differentiated CD34+/CD38- cells. By analysis of variance (ANOVA) significantly (p < 0.05) more apoptotic cells within the CD34+/CD38+ progenitors were calculated after incubation with mafosphamide, doxorubicine and cladribine. Mafosphamide induced the highest rate of apoptosis on CD34+/CD38- cells, whereas doxorubicine had nearly no effect on this immature population. Dose effect plots for mafosphamide and doxorubicin were steep, suggesting a large therapeutic index. The dose response of cladribine showed a flat course. Furthermore we found a selective induction of apoptosis by doxorubicin and cladribine on more mature CD34+/CD38+ progenitors in contrast to simultaneous protection of CD34+/CD38- progenitors. From these findings, in particular the demonstrated low stem cell toxicity, we conclude that doxorubicin and cladribine might be efficient alternatives in ex vivo purging of autologous grafts, as well as safe components in primary treatment schedules of lymphomas or prior to stem cell harvest with respect to stem cell toxicity.


Association of Long-term Exposure to Air Pollution and Dementia Risk: The Role of Homocysteine, Methionine, and Cardiovascular Burden.
Growing evidence links air pollution with dementia risk, but the biological mechanisms are largely unknown. We investigated the role played by homocysteine (tHcy) and methionine in this association and explored whether this could be explained by cardiovascular diseases (CVDs). Data were extracted from the ongoing Swedish National study on Aging and Care in Kungsholmen (SNAC-K), a longitudinal population-based study. At baseline, 2,512 dementia-free participants were examined up to 2013 (mean follow-up: 5.18 ± 2.96 years). Two air pollutants (particulate matter ≤2.5 μm [PM2.5] and nitrogen oxides [NOx]) were assessed yearly from 1990 until 2013 using dispersion models at residential addresses. The hazard ratio of dementia over air pollution levels was estimated using Cox models adjusted for age, sex, education, smoking, socioeconomic status, physical activity, retirement age, creatinine, year of assessment, and the use of supplements. The total effect of air pollutants on dementia was decomposed into 4 pathways involving tHcy/methionine: (1) direct effect; (2) indirect effect (mediation); (3) effect due to interaction; and (4) effect due to both mediation and interaction. To test whether the association was independent from CVDs (ischemic heart disease, atrial fibrillation, heart failure, and stroke), we repeated the analyses excluding those individuals who developed CVDs. The mean age of the study participants was 73.4 years (SD: 10.4), and 62.1% were female individuals. During an average period of 5 years (mean: 5.18; SD: 2.96 years), 376 cases with incident dementia were identified. There was a 70% increased hazard of dementia per unit increase of PM2.5 during the 5 years before baseline (hazard ratio [HR]: 1.71; 95% CI 1.33-2.09). Overall, 50% (51.6%; 95% CI 9.0-94.1) of the total effect of PM2.5 on dementia was due to mediation of tHcy (6.6%; 95% CI 1.6-11.6) and/or interaction (47.8%; 95% CI 4.9-91.7) with tHcy and 48.4% (p = 0.03) to the direct effect of PM2.5 on dementia. High levels of methionine reduced the dementia hazard linked to PM2.5 by 31% (HR: 0.69; 95% CI 0.56-0.85) with 24.8% attributable to the interaction with methionine and 25.9% (p = 0.001) to the direct effect of PM2.5. No mediation effect was found through methionine. Attenuated results were obtained for NOx. Findings for tHcy were attenuated after excluding those who developed CVDs, while remained similar for methionine. High levels of homocysteine enhanced the dementia risk attributed to air pollution, while high methionine concentrations reduced this risk. The impact of homocysteine on cardiovascular conditions partly explains this association. Alternative pathways other than cardiovascular mechanisms may be at play between methionine and dementia.


The Frizzled-1/(beta(2))-adrenergic receptor chimera: pharmacological properties of a unique G protein-linked receptor.
The frizzled gene family of Wnt receptors encodes proteins that have a seven-transmembrane-spanning motif characteristic of G-protein-coupled receptors. Using a chimeric receptor composed of the exofacial and the transmembrane, ligand-binding domain of the beta(2)-adrenergic receptor (beta2AR) fused with the corresponding cytoplasmic domains of the rat Frizzled-1 receptor (Rfz1), we created a unique chimera between distant members of the superfamily of G protein-coupled receptors. Herein, we describe the pharmacological properties of the chimera, which represents a receptor in which the exofacial and cytoplasmic domains are minimized in length. This unique chimera retains much of the pharmacological character of the native beta2AR, whereas the coupling can be ascribed to Rfz1 domains which operate via G alpha q and not G alpha s. The Rfz1 chimera demonstrates a robust agonist (isoproterenol)-induced sequestration. Since the Rfz1 cytoplasmic domains possess canonical sites for several protein kinases, we were able to investigate the effects of kinase inhibitors on Rfz1 chimera sequestration. Only the protein kinase A inhibitor KT5720, but not inhibitors of protein kinase C, calcium/calmodulin-sensitive kinase-2, casein kinase-2, and Src, inhibited agonist-induced sequestration. Expression of a dominant-negative form of beta-arrestin blocked sequestration of the beta2AR, but only reduced modestly that of the Rfz1 chimera. These data demonstrate that the Frizzled-1 chimera displays cardinal features of a G protein-coupled receptor, including agonist-induced sequestration, but appears to do so largely even in the presence of dominant-negative beta-arrestins.


Atopic Eczema: Pathophysiological Findings as the Beginning of a New Era of Therapeutic Options.
Atopic eczema (AE) is a chronic inflammatory disease hallmarked by intense pruritus and eczematous lesions. It depicts one of the most common skin diseases affecting a major part of children and several percentages of adults.Both pathogenesis and pathophysiology are based on complex orchestrated interactions of skin barrier defects, immunological changes, the environment, and an abundance of other contributing factors. Frequently, AE displays the starting point for other allergic diseases such as allergic asthma and rhinoconjunctivitis. Additionally, the risk of developing food allergy is increased. Furthermore, the disease is accompanied by a susceptibility to bacterial, fungal, and viral infections. The development of new therapies received great impetus by an ample research of the pathophysiological mechanisms, leading to a new era in the treatment of severe atopic eczema due to targeted treatments, e.g. the IL-4R alpha specific monoclonal antibody dupilumab.This article provides an overview of the causative and pathophysiological characteristics, the clinical and diagnostic aspects as well as current and future therapeutical possibilities focusing allergic aspects contributing to the course of the disease.


Culture media and Chaos theory--predicting the unpredictable.
Undefined culture media have played a major role in diagnostic microbiology for 100 years. Chaos theory explains why increased knowledge of microbial systems has failed to predict defined nutritional requirements for the isolation of organisms. A brief description of Chaos theory is given and three microbiological areas of unpredictability are discussed: uncertain identity of isolates, unknown stress damage, unexplored variation of individual colony populations. Probably all living biological systems are non-linear, complex interactions and operate within Chaos theory.


Identification of Podocyte Cargo Proteins by Proteomic Analysis of Clathrin-Coated Vesicles.
Clathrin-mediated endocytosis (CME) plays a fundamental role in podocyte health. Genetic ablation of genes implicated in CME has been shown to cause severe proteinuria and foot process effacement in mice. However, little is known about the cargo of clathrin-coated vesicles (CCVs) in podocytes. The goal of this study was to isolate CCVs from podocytes and identify their cargo by proteomic analysis. Glomeruli isolated from Podocin-Cre Rosa-DTRflox mouse kidneys were seeded and treated with diphtheria toxin to obtain pure primary podocyte cultures. CCVs were isolated by differential gradient ultracentrifugation, and enrichment of CCVs was assessed by immunoblotting and electron microscopy (EM). Liquid chromatography-mass spectrometry (LC-MS) was performed for proteomic analysis. Proteins with higher abundance than transferrin receptor protein 1 were evaluated for CCV cargo potential against previously published literature. Immunofluorescence staining of identified cargo proteins and CCVs was performed in podocytes for further verification. Immunoblotting for multiple protein markers of CME revealed enrichment in the CCV fraction. Enrichment of CCVs among other small vesicles was observed via EM. Proteomics yielded a total of >1200 significant proteins. Multiple-step data analysis revealed 36 CCV-associated proteins, of which 10 represent novel, highly abundant cargo proteins in podocytes. Colocalization of cargo proteins and CCVs on immunostaining was observed. Our identification of podocyte CCV cargo proteins helps to elucidate the importance of endocytic trafficking for podocyte health and maintenance of the glomerular environment.


The Application of Diffusion Kurtosis Imaging on the Heterogeneous White Matter in Relapsing-Remitting Multiple Sclerosis.
To evaluate the microstructural damage in the heterogeneity of different white matter areas in relapsing-remitting multiple sclerosis (RRMS) patients by using diffusion kurtosis imaging (DKI) and its correlation with clinical and cognitive status. Kurtosis fractional anisotropy (KFA), fractional anisotropy (FA), mean kurtosis (MK), and mean diffusivity (MD) in T1-hypointense lesions (T1Ls), pure T2-hyperintense lesions (pure-T2Ls), normal-appearing white matter (NAWM), and white matter in healthy controls (WM in HCs) were measured in 48 RRMS patients and 26 sex- and age-matched HCs. All the participants were assessed with the Mini-Mental State Examination (MMSE), the Montreal Cognitive Assessment (MoCA), and the Symbol Digit Modalities Test (SDMT) scores as the cognitive status. The Kurtzke Expanded Disability Status Scale (EDSS) scores were used to evaluate the clinical status in RRMS patients. The lowest KFA, FA, and MK values and the highest MD values were found in T1Ls, followed by pure-T2Ls, NAWM, and WM in HCs. The T1Ls and pure-T2Ls were significantly different in FA (p = 0.002) and MK (p = 0.013), while the NAWM and WM in HCs were significantly different in KFA, FA, and MK (p < 0.001; p < 0.001; p = 0.001). The KFA, FA, MK, and MD values in NAWM (r = 0.360, p = 0.014; r = 0.415, p = 0.004; r = 0.369, p = 0.012; r = -0.531, p < 0.001) were correlated with the MMSE scores and the FA, MK, and MD values in NAWM (r = 0.423, p = 0.003; r = 0.427, p = 0.003; r = -0.359, p = 0.014) were correlated with the SDMT scores. Applying DKI to the imaging-based white matter classification has the potential to reflect the white matter damage and is correlated with cognitive impairment.


Kinetic analysis of mechanoradical formation during the mechanolysis of dextran and glycogen.
A detailed electron spin resonance (ESR) analysis of mechanically induced free radicals (mechanoradicals) formation of glucose-based polysaccharides, dextran (Dx) and glycogen (Gly) was performed in comparison with amylose mechanoradicals. The ESR spectra of the samples mechanically fractured at room temperature were multicomponent. The radical concentration of Dx and Gly mechanoradicals gradually decreased during vibratory milling after reaching the maximum value. Although the molecular weight of Dx or the particle diameter of Gly steeply diminished until reaching the each maximum value of radical concentration, after that the molecular weight or the particle diameter slowly decreased. These results suggested that Dx and Gly mechanoradicals might be more unstable than amylose radicals possessing an intramolecular helical structure due to the branched structure.


The ubiquitin ligase STUB1 regulates stability and activity of RUNX1 and RUNX1-RUNX1T1.
RUNX1 is a member of RUNX transcription factors and plays important roles in hematopoiesis. Disruption of RUNX1 activity has been implicated in the development of hematopoietic neoplasms. Chromosomal translocations involving the RUNX1 gene are associated with several types of leukemia, including acute myeloid leukemia driven by a leukemogenic fusion protein RUNX1-RUNX1T1. Previous studies have shown that RUNX1 is an unstable protein and is subjected to proteolytic degradation mediated by the ubiquitin-proteasome pathway. However, the precise mechanisms of RUNX1 ubiquitination have not been fully understood. Furthermore, much less is known about the mechanisms to regulate the stability of RUNX1-RUNX1T1. In this study, we identified several RUNX1-interacting E3 ubiquitin ligases using a novel high-throughput binding assay. Among them, we found that STUB1 bound to RUNX1 and induced its ubiquitination and degradation mainly in the nucleus. Immunofluorescence analyses revealed that the STUB1-induced ubiquitination also promoted nuclear export of RUNX1, which probably contributes to the reduced transcriptional activity of RUNX1 in STUB1-overexpressing cells. STUB1 also induced ubiquitination of RUNX1-RUNX1T1 and down-regulated its expression. Importantly, STUB1 overexpression showed a substantial growth-inhibitory effect in myeloid leukemia cells that harbor RUNX1-RUNX1T1, whereas it showed only a marginal effect in other non-RUNX1-RUNX1T1 leukemia cells and normal human cord blood cells. Taken together, these data suggest that the E3 ubiquitin ligase STUB1 is a negative regulator of both RUNX1 and RUNX1-RUNX1T1. Activation of STUB1 could be a promising therapeutic strategy for RUNX1-RUNX1T1 leukemia.


The polymorphism of the serotonin-2A receptor T102C is associated with age.
Epidemiological investigations suggest that T102C polymorphism of gene 5-HT2A may be associated with mean life span because diseases and behaviors related to this polymorphism, such as schizophrenia, suicide, aggression, and addiction, may potentially shorten mean life span. A sample of 687 individuals without previous neuropsychiatric disease was genotyped and separated into 3 groups according to their gender and age: 14-45 years old, 46-64 years old and 65-100 years old. Molecular genotyping was performed using the technique of polymerase chain reaction followed by restriction fragment length polymorphism using HpaII restriction enzyme. 5-HT2A genotype frequencies were: TT = 21.5% (148), CC = 16.6% (114) and TC = 61.9% (425) and allele frequencies were T = 52.5% and C = 46.5%. Significant differences were found between mean age of the TT genotype carriers (60.27 +/- 12.60 years) and TC genotype carriers (56.80 +/- 13.18 years) of T102C polymorphism of gene 5-HT2A (P = 0.026) as well as the age groups (P = 0.012). Carriers of genotype TT were older than the other two genotypes, whereas carriers of genotype CC had an intermediate age compared with TT and CC subjects. The present results demonstrate an association between T102C polymorphism of gene 5-HT2A and age. Our results suggest that T102C polymorphism of gene 5-HT2A is associated with mean life span, and thus this gene becomes a possible candidate for the group of adaptive genes to meat consumption proposed in the literature. Further studies should be conducted in order to elucidate this association.


A prospective, multicentre study of moxifloxacin concentrations in the sinus mucosa tissue of patients undergoing elective surgery of the sinus.
A pharmacokinetic study was carried out to determine moxifloxacin concentrations in sinus tissue, after oral moxifloxacin 400 mg once daily for 5 days to patients with chronic sinusitis, undergoing elective sinus surgery. Patients were randomly allocated to one of seven treatment groups, in which tissues were sampled 2, 3, 4, 6, 12, 24 or 36 h post-dose. A control group with non-infected nasal polyps was also included. Forty-eight patients (13 female, 35 male, mean age 47.1 years) were allocated to one of each active treatment group (n = 42) or to the control group (n = 6). Tissue and plasma samples were taken simultaneously and stored frozen until assayed by HPLC. Thirty-nine patients were fully valid for pharmacokinetic analysis. The geometric mean moxifloxacin plasma concentration increased from 2.32 mg/L at 2 h to a maximum of 3.37 mg/L at 4 h post-dose, decreasing to 0.37 mg/L at 36 h post-dose. The moxifloxacin concentration in sinus mucosa was consistently greater than that in plasma being 4.56-5.73 mg/kg from 2 to 6 h and 2.81-1.25 mg/kg from 12 to 36 h post-dose. The elimination rates in plasma and sinus tissues were similar. The tissue/plasma ratio was c. 200% between 2 and 6 h, and up to 328.9% at 36 h. Results were similar whatever the site of tissue sampling (maxillary sinus, anterior ethmoid sinus or nasal polyps). Tissue levels exceeded the MIC(90) of all pathogens commonly causing acute sinusitis (e.g. 5-30 x MIC for Streptococcus pneumoniae: 0.25 mg/L). These results sup-port the use of moxifloxacin 400 mg once daily as a regimen for the treatment of sinus infections.


Origin of Surface-Driven Passive Liquid Flows.
Passive liquid flow occurs in nature in the transport of water up tall trees and is desired for high-heat flux removal in thermal management devices. Typically, liquid-vapor surface tension is used to generate passive flows (e.g., capillary and Marangoni flows). In this work, we perform a fundamental molecular study on passive liquid flow driven by the solid-liquid surface tension force. Such surface tension values are first estimated by placing a liquid film over the surface and simulating various surface temperatures, followed by which simulations are performed by differential heating of the liquid film over the surface. Very strong passive liquid flows are obtained that lead to steady-state, continuous, and high-heat flux removal close to the maximum theoretical limit, as predicted by the kinetic theory of evaporation. Nondimensional empirical relations are developed for surface tension gradient, flow velocity, and evaporation rate.


Enriched environment enhances β-adrenergic signaling to prevent microglia inflammation by amyloid-β.
Environmental enrichment (EE) is a rodent behavioral paradigm that can model the cognitive benefits to humans associated with intellectual activity and exercise. We recently discovered EE's anti-inflammatory protection of brain microglia against soluble oligomers of human amyloid β-protein (oAβ). Mechanistically, we report that the key factor in microglial protection by EE is chronically enhanced β-adrenergic signaling. Quantifying microglial morphology and inflammatory RNA profiles revealed that mice in standard housing (SH) fed the β-adrenergic agonist isoproterenol experienced similar protection of microglia against oAβ-induced inflammation as did mice in EE Conversely, mice in EE fed the β-adrenergic antagonist propranolol lost microglial protection against oAβ. Mice lacking β1/β2-adrenergic receptors showed no protection of microglia by EE In SH mice, quantification of norepinephrine in hippocampus and interstitial fluid showed that oAβ disrupted norepinephrine homeostasis, and microglial-specific analysis of β2-adrenergic receptors indicated a decreased receptor level. Both features were rescued by EE Thus, enhanced β-adrenergic signaling at the ligand and receptor levels mediates potent benefits of EE on microglial inflammation induced by human Aβ oligomers in vivo.


The role of lysine in the action of bovine pancreatic ribonuclease A.
The involvement of lysine residues in the active site of pancreatic ribonuclease has been investigated by assessing (a) the degree of substrate and substrate analogue protection of individual lysine residues against acetylation, and (b) the individual contribution of remaining unacetylated lysine residues to the total catalytic activity of the enzyme. Different substrate analogues (RNA digest, CMP, ATP, and pyrophosphate) were found to give different degrees of protection against acetylation with acetic anhydride. Instead of the expected specific protection of active site lysine residues such as lysine-7 and lysine-41, however, a general decrease in reactivity of all the lysines was observed when the substrate analogues were present during the acetylation. The fraction of enzymatic activity remaining in the protected samples was consistently greater than the fraction of any one lysine remaining unacetylated, and was found to correspond fairly well with the sum of the fractions of unacetylated lysine-7, lysine-41, and a third residue, tentatively assigned as lysine-66. This is consistent with other observations of ribonuclease which suggest that while no lysine residue interacts with substrate and substrate analogues in the formation of the Michaelis-Menten complex, a lysine amino group is required for catalysis. It is proposed that this lysine amino group can be supplied by any one of two or three lysine residues (7, 41, and 66) located close to the substrate binding site.


[Determination of hydrazine ion in explosion dust of liquid explosive by ion chromatography].
A method for the determination of hydrazine ion in explosion dust of liquid explosive has been established by ion chromatography. The hydrazine ion in an explosion dust sample was extracted with deionized water by sonification and centrifugation. The large molecules and solid particles in supernatant were removed by an OnGuard II RP column and a 0.22 microm filtration membrane, respectively. The filtrate was separated on an IonPac CS-12A column with isocratic elution of 5 mmol/L methanesulfonic acid (MSA). Then 0.1 mol/L NaOH solution was post-column added and the resultant solution was detected by an ampere detector with golden electrode. The results showed that, the calibration curve was linear in the range of 0.02 - 2.0 mg/L with a correlation coefficient (r2 ) of 0.999 7. The limits of detection (LOD, S/N = 3) and quantification (LOQ, S/N = 10) of hydrazine were 5.0 microg/L and 16.6 microg/L, respectively. The recoveries ranged between 95.4% and 99.1% with the relative standard deviations (RSDs, n = 5) of 2.1% - 3.3%. The hydrazine content in a real explosion dust sample of liquid explosive was 10.3 mg/kg by this method. The method is simple, accurate, and suitable for the quantitative detection of hydrazine ions in explosion dust of liquid explosive, and the method can meet the needs of the criminal evidence identification work.


Developing a Culturally Appropriate Tool to Support Self-Care in Migrants with Type 2 Diabetes - A Co-Design Study.
Migrants, especially from the Middle East, experience poorer health outcomes and face greater difficulties in accessing healthcare compared to native populations and there is a need for culturally appropriate education for this vulnerable group. The purpose of this study is to describe the process of developing a culturally appropriate tool to support self-care in migrants with type 2 diabetes. In this Co-design study, a tool for supporting self-care in migrants with type 2 diabetes was developed. Migrant patients with type 2 diabetes, healthcare providers and researchers participated in the process, which was based on six elements; engage, plan, explore, develop, decide and change. From February 2021 to December 2022, idea groups were conducted, and a tool was developed through brainstorming, prioritizing and prototyping. In total, 14 migrant patients, ten health care providers and four researchers participated in the Co-design process. The patients wished to receive information about type 2 diabetes self-care behaviour in their own languages. The healthcare providers asked for clear instructions on where to guide their patients regarding reliable information about diabetes in the patient's own language. All participants agreed that information can be presented in different formats, either: text (paper or online), audio-visual via recorded videos and/or lectures and pictures. The Co-design process led to several important insights and experiences related to the importance of diverse cultural backgrounds. When conducting a Co-design study with end-users as stakeholders, it is significant that the stakeholders have a diverse background in experiences, both as patients as well as those who deliver or implement the health service. In this study it was of great importance to include patients with diverse backgrounds regarding; gender, age, health literacy, occupation, years living in Sweden and duration of diabetes.


Comparison of Antimicrobial Resistance Detected in Environmental and Clinical Isolates from Historical Data for the US.
Antimicrobial resistance (AMR) has become an urgent public health issue, as pathogens are becoming increasingly resistant to commonly used antimicrobials. While AMR isolate data are available in the NCBI Pathogen Detection Isolates Browser (NPDIB) database, few researches have been performed to compare antimicrobial resistance detected in environmental and clinical isolates. To address this, this work conducted the first multivariate statistical analysis of antimicrobial-resistance pathogens detected in NPDIB clinical and environmental isolates for the US from 2013 to 2018. The highly occurring AMR genes and pathogens were identified for both clinical and environmental settings, and the historical profiles of those genes and pathogens were then compared for the two settings. It was found that Salmonella enterica and E. coli and Shigella were the highly occurring AMR pathogens for both settings. Additionally, the genes fosA, oqxB, ble, floR, fosA7, mcr-9.1, aadA1, aadA2, ant(2")-Ia, aph(3")-Ib, aph(3')-Ia, aph(6)-Id, blaTEM-1, qacEdelta1, sul1, sul2, tet(A), and tet(B) were mostly detected for both clinical and environmental settings. Ampicillin, ceftriaxone, gentamicin, tetracycline, and cefoxitin were the antimicrobials which got the most resistance in both settings. The historical profiles of these genes, pathogens, and antimicrobials indicated that higher occurrence frequencies generally took place earlier in the environmental setting than in the clinical setting.


Identification of PER-1 extended-spectrum beta-lactamase producing Pseudomonas aeruginosa clinical isolates of the international clonal complex CC11 from Hungary and Serbia.
PER-1 extended-spectrum beta-lactamase-producing Pseudomonas aeruginosa clinical isolates from Budapest, Hungary, and Belgrade, Serbia, were characterized by molecular methods. Two PER-1-positive isolates were recovered from sporadic cases in Budapest and a small cluster of PER-1-positive infections involving four patients were identified at a Belgrade hospital. A class 1 integron harbouring a bla(OXA-2)beta-lactamase gene and four other gene cassettes was detected in both the Budapest and the Belgrade isolates. The two P. aeruginosa isolates from Budapest also carried another class 1 integron containing bla(OXA-74), aac(6')-Ib-cr and cmlA7 genes in its variable region. The aac(6')-Ib-cr fluoroquinolone-acetylating aminoglycoside acetyltransferase gene is described here for the first time in P. aeruginosa. Multilocus sequence typing (MLST) revealed that the PER-1 positive P. aeruginosa isolates identified in this study display ST235, a sequence type that belongs to clonal complex CC11. Two bla(PER-1)-positive P. aeruginosa reference isolates from France and Belgium could also be assigned to complex CC11 by MLST. Our results underscore the role of complex CC11 in the dissemination of bla(PER-1) among P. aeruginosa clinical isolates.


Incidence of alcoholic pancreatitis in Japanese alcoholics: survey of male sobriety association members in Japan.
To estimate the incidence of alcoholic pancreatitis, a dependence questionnaire survey was administered to male members of the sobriety association in Japan. Questionnaires asking about age, age at start of alcohol drinking, amount of alcohol consumption, duration of drinking, the initiated age of abstinence, medical history of pancreatitis, the age at diagnosis of pancreatitis, and the etiology of pancreatitis were sent to 7876 male members of a sobriety association in Japan. Of 4120 members who replied to the questionnaire, 857 (20.8%) had a medical history of pancreatitis. Of these 857 members, 418 (10.1%) had been diagnosed with alcoholic pancreatitis, 32 (0.8%) as gallstone pancreatitis, and 407 (9.9%) with unknown etiology or etiology forgotten. A clear history of pancreatitis and information on habitual heavy drinking and the consumed amount of alcohol could be obtained from 373 of the 418 members diagnosed with alcoholic pancreatitis and from 345 of the 407 members with pancreatitis of unknown etiology. These 718 respondents were considered to be true alcoholic pancreatitis cases, with an extrapolated incidence of 9.1% (718/7876) to 17.4% (718/4120) cases of alcoholic pancreatitis in alcoholics in Japan. Alcoholics with a history of pancreatitis began drinking at relatively younger age and consumed a significantly greater amount of alcohol per day compared with 3113 alcoholics without a medical history of pancreatitis. This survey suggests that the incidence of alcoholic pancreatitis in alcoholics is much higher than previously reported.


Cognitive stimulation therapy in the Italian context: its efficacy in cognitive and non-cognitive measures in older adults with dementia.
Cognitive stimulation therapy (CST) has been shown to have significant benefits in enhancing cognitive functioning and improving the quality of life of people with mild to moderate dementia. The present study examines the efficacy of the Italian version of the therapy (CST-IT). Older adults with mild to moderate dementia (n = 39) were randomly assigned to two programs: one group participated in the CST-IT, consisting of 14 sessions (twice a week for 7 weeks) and the active control group took part in alternative general activities. The outcome measures were cognitive functioning (measured by the Mini-Mental State Examination-MMSE-, the Alzheimer's Disease Assessment scale-cognitive subscale, the backward digit span test, and a narrative language test); quality of life (Quality of life--Alzheimer's Disease scale); mood (Cornell scale for depression in dementia and the social and emotional loneliness scale); functional activities in daily living (Disability Assessment for Dementia); and behavior (neuropsychiatric inventory). After the intervention, only the CST-IT group maintained its MMSE score, while the control group displayed deterioration. The CST-IT group also performed better in some of the cognitive measures (Alzheimer's Disease Assessment Scale-Cognitive subscale and narrative language), mood measures (Cornell scale, social and emotional loneliness scale with a decrease in reported loneliness), and the Quality of life--Alzheimer's Disease scale. No other treatment effect was observed. The findings confirm the efficacy, at least in the short term, of the CST in sustaining cognitive functions and perceived quality of life in older adults with dementia in the Italian care setting as well.


Statistical mechanics of kinetic proofreading in protein folding in vivo.
The statistical energy landscape picture of protein folding has led to the understanding that the energy landscape must have guiding forces leading to a protein folding funnel in order to avoid the Levinthal paradox in vitro. Since folding in vivo often requires the action of chaperone molecules and ATP hydrolysis, we must ask whether folding in a system maintained away from equilibrium can avoid the Levinthal paradox in other ways. We describe a model of the action of chaperone molecules in protein folding in vivo on the basis of a repetitive cycle of binding and unbinding, allowing the possibility of kinetic proofreading. We also study models in which chaperone binding is locally biased, depending on the similarity of the conformation to the native one. We show that while kinetic proofreading can modestly facilitate folding, it is insufficient by itself to overcome the Levinthal paradox. On the other hand, such kinetic proofreading with biasing can provide the nonequilibrium analog of a folding funnel and greatly enhance folding yields and speed up folding.


Epidemiology of primary biliary cirrhosis.
A multi-national survey of the clinical and epidemiological aspects of primary biliary cirrhosis (PBC) has been conducted in 10 countries in Western Europe, surveying a population of over 24 million. The prevalence on 31 December, 1981 was 23/million, but this showed a marked variation from centre to centre for reasons which are not clear. The annual incidence of PBC has remained constant at about 4/million over the past 4 years, while the point prevalence has continued to rise, suggesting that the true prevalence may be rather higher than present figures suggest. The female: male sex ratio is 10:1, but in stages I & II this ratio is 6.5:1 compared with 11.4:1 in stages III & IV. Possible reasons for this are discussed.


Cerebral emboli from intracranial aneurysms.
Cerebral vasospasm has been implicated as the major pathophysiologic mechanism responsible for the cerebral ischemia and infarction that sometimes follows the rupture of intracranial aneurysms. Two cases are reported in which aneurysms of the internal carotid arteries were the source of emboli resulting in infarctions. Embolic phenomena should be considered as a possible cause of the morbidity associated with intracranial aneurysms.


Patient-focused care: anatomy of a failure.
The article describes the experience of implementing patient-focused care from a physician's perspective. Pitfalls that guarantee failure are presented, many of which are avoidable with early participation by all parties involved: administrators, nursing staff, physicians, and patients. Contamination of the process with downsizing needs, lack of support for staff in dealing with necessary change, loss of administrative commitment, and withholding of appropriated funds are among the key errors to be avoided.


The zebrafish activating immune receptor Nitr9 signals via Dap12.
Both inhibitory and activating forms of natural killer (NK) cell receptors are found in mammals. The activating receptors play a direct role in the recognition of virally infected or transformed cells and transduce activating signals into the cell by partnering with an adaptor protein, which contains a cytoplasmic activation motif. Activating NK receptors encoded by the mammalian leukocyte receptor complex (e.g., killer cell immunoglobulin-like receptors) and the natural killer complex (e.g., Ly49s) partner with the adaptor protein DAP12, whereas NK receptors encoded in the CD94/NKG2 complex partner with the adaptor protein DAP10. Novel immune-type receptors (NITRs) found in bony fish share several common features with immunoglobulin-type NK receptors. Nitr9 is a putative activating receptor in zebrafish that induces cytotoxicity within the context of human NK cells. One isoform of Nitr9, Nitr9L, is shown here to preferentially partner with a zebrafish ortholog of Dap12. Cross-linking the Nitr9L-Dap12 complex results in activation of the phosphytidylinositol 3-kinase-->AKT-->extracellular signal-regulated kinase pathway suggesting that the DAP12-based activating pathway is conserved between bony fish and mammals.


Hormonal profile, endometrial histology and ovarian ultrasound assessment during 1 year of nomegestrol acetate implant (Uniplant).
The present study assesses the endocrinological, endometrial histology and vaginal ultrasound profiles of nomegestrol acetate subdermal implant users at varying times after insertion. Follicle stimulatory hormone, luteinizing hormone, oestradiol, progesterone, vaginal ultrasound assessment of the ovaries and the histological dating of the endometrium were serially assessed for a period of 50 days immediately after the insertion, and after at 6 months and 12 months of use. The endocrinological results of this prospective observational clinical trial indicated that 75% of the cycles across the study period in Uniplant users were anovulatory, 63% showing development of a persistent non-luteinized follicle. Anovulatory cycles devoid of follicular development were seen primarily in the first months after Uniplant insertion. Ovulatory cycles represented 25% of the Uniplant cycles. Inadequate luteal phase or disregulation of follicular growth was a common feature of ovulatory cycles. In conclusion, these findings suggest that the contraceptive mechanisms of a single nomegestrol acetate subdermal implant involve prevention of follicular growth, development of a persistent non-luteinized follicle, inadequate luteal phase and disruption of the endometrial architecture.


Systemic Immune-Inflammation Index for Predicting the Prognosis of Critically Ill Patients with Acute Pancreatitis.
Systemic immune-inflammation index (SII) has been identified as a prognostic biomarker in various diseases. However, its significance in acute pancreatitis (AP) has not been reported. Therefore, the main aim of this study was to determine the association of SII with clinical outcomes of AP patients, after adjusting for several confounders. This retrospective cohort study was conducted using data retrieved from the Medical Information Mart for Intensive Care III database (MIMIC-III). The study only included patients diagnosed with AP. SII was calculated as the platelet counts x neutrophil counts/lymphocyte counts. Cox regression models were employed to assess the impact of SII on the 30- and 90-day mortality of AP patients. Subgroup analysis was carried out to explore the stability of the relationship between SII and AP mortality. A total of 513 patients were found to be eligible based on the inclusion and exclusion criteria. For 30-day all-cause mortality, in the model adjusted for multiple confounders, the HR (95% CI) for mid-SII group (SII: 75.6-104.2) and high-SII groups (SII: >104.2) were 1.29 (0.65, 2.56) and 2.57 (1.35, 4.88), respectively, compared to the low-SII group (SII: <75.5). A similar trend was observed for 90-day mortality. Subgroup analyses presented a stable relationship between SII and 30-day all-cause mortality of AP patients. SII is a potentially useful prognostic biomarker for AP. However, prospective studies are needed to confirm this finding.


Thermodynamic analysis of protein kinase A Ialpha activation.
Thermodynamic analysis of protein kinase A (PKA) Ialpha activation was performed using Quantum 3.3.0 docking software and a Gaussian 03W quantum mechanical computational package. Expected stacking interactions between adenine of 3':5'-AMP and aromatic moieties of amino acids were taken into account by means of MP2/6-31G(d) IPCM (isodensity polarizable continuum model) computations (epsilon = 4.0). It is demonstrated that thermodynamically favorable agonist-induced PKA Ialpha activation is mediated by two processes. First, 3':5'-AMP binding is accompanied by structural changes leading to a thermodynamically favorable regulatory subunit conformation, which is hardly realized in the absence of the ligand (DeltaG degrees (R) = -23.9 +/- 8.2 kJ/mol). Second, 3':5'-AMP affinity to the regulatory subunit conformation observed after agonist-induced PKA Ialpha activation is higher than that to inactive holoenzyme complex (DeltaG degrees (3':5'-AMP) = -28.1 +/- 9.7 kJ/mol). ATP is capable of docking into the 3':5'-AMP-binding site B of the regulatory subunit complexed with the catalytic one, resulting in inhibition of kinase activation. True constants of 3':5'-AMP binding to PKA Ialpha holoenzyme were found to be 60 and 57 microM for the regulatory subunit domains A and B, respectively. These constants, unlike the binding equilibrium constant determined using established experimental techniques and ranging from 15 nM to 2.9 microM, are proved to be direct measures of 3':5'-AMP-PKA Ialpha binding affinity. Their values are in a reasonable agreement with the changes in 3':5'-AMP concentration in the cell (2-55 microM) and account for PKA Ialpha activation in response to adequate stimuli.


Faecal haemoglobin: Measurement, applications, and future potential.
Faecal hemoglobin concentrations (f-Hb) can be quantitated using faecal immunochemical test for haemoglobin (FIT) analytical systems. FIT are of proven value and widely used in colorectal cancer (CRC) screening. Several factors affect f-Hb including sex, age, deprivation, geographical region, and FIT system. Thus, FIT data may not be transferable. Women are disadvantaged in programmes using a single f-Hb threshold for all participants, but risk scoring or sex stratified thresholds could be used to minimise this problem. In addition, low but detectable f-Hb, below the threshold, implies future risk of CRC. In several countries, where colonoscopy resources are constrained, FIT are now accepted as of added value in assessment of patients presenting in primary or secondary care with symptoms, although some serious colorectal disease is missed. Elevated f-Hb in the absence of any discernible colorectal lesions is common and has been found in several diseases with a systemic inflammatory component, including circulatory, respiratory, digestive, neuropsychological, blood and endocrine diseases, and others. There is growing evidence for the value of f-Hb in post-polypectomy surveillance, potentially saving costs and colonoscopy. There may be a role for FIT systems which have lower limits of detection than currently available methods. The faecal material remaining in FIT specimen collection devices could be used for further studies, including assessment of the microbiome. The estimation of f-Hb is now a mature investigative tool but further research will undoubtedly expand applications of value.


[Once daily insulin detemir in patients with type 2 diabetes: results of German centers in a 6-month international observational study (SOLVE)].
Hypoglycemic risk and improved glycemic control have to be weightened when a decision on intensification of treatment of type 2 diabetes mellitus with basal insulin is made. Findings from randomized studies are available in this respect, and should be complemented by data from routine treatment. The international, prospective, open-label, observational study SOLVE (Study of Once-Daily Levemir) investigated add-on treatment with basal insulin in type 2 diabetes mellitus using once daily insulin detemir in patients currently receiving oral antidiabetic drugs (OAD). Data were collected between initiation of insulin treatment and the final visit after approximately 24 weeks. The primary objective of the study was to evaluate the incidence of serious adverse drug reactions (SADR), including major hypoglycemic events. In Germany, 2,090 patients were eligible for the full analysis set and 1,671 patients for the effectiveness analysis set. The mean age was 64.9 years, mean duration of diabetes 9.36 years, and mean duration of OAD treatment 7.29 years. Three patients (0.14%) experienced a SADR (1 fall resulting in death, 2 major hypoglycemic events). At the final visit, there was a significant reduction in major hypoglycemic events if compared with the period before starting insulin treatment (0.002 versus 0.120 events per patient year, p < 0.001), as were minor hypoglycemic events (0.880 versus 1.588 events per patient year, p = 0.006). The mean body weight and BMI decreased by -0.9 kg (p < 0.001) and-0.35 kg/m2 (p < 0.001) respectively and the mean HbA(1c) level improved from 8.45 +/- 1.19% to 7.30 +/- 0.92% (-1.15 +/- 1.08%; p < 0.001). The mean fasting plasma glucose level and plasma glucose variability were significantly reduced. Baseline data of the study underline the need for earlier intensification of antidiabetic therapy in type 2 diabetes in Germany. Study results show that within the German diabetes care system, initiation of basal insulin therapy with insulin detemir is able to result in significant HbA(1c) improvements without increased risk of hypoglycemia and/or weight gain.


[Description of the effect of polyclonal mitogens on a population of splenic lymphocytes in the presence of serum against isologous aggregated mouse immunoglobulins].
Antiserum against isologous aggregated mouse immunoglobulins was shown to be mitogenic for spleen cells during the first 48 hours of culture. The mitogenic effect of the serum factor is mediated through T lymphocytes and may be macrophage-dependent. Whe incubated with spleen cells the serum was demonstrated to inhibit the DNA synthesis in B cells in response to sulfate dextran and lipopolysaccharide. Experiments with B cells and the thymidine "suicide" test suggest that the target cells for the serum factor may reside in the population of radiosensitive and highly proliferating B lymphocytes. The degree of suppressing by the antiserum factor depends on the differentiation stage and the presence of antigen-binding receptors on the membrane of B cells.


Ultrasound-Guided DREZotomy: Technical Note.
Dorsal root entry zone (DREZ) lesioning is still used as a choice of treatment for some painful conditions as well as spasticity in selected patients. The most commonly used techniques to perform DREZotomy are the microsurgical one and DREZ radiofrequency (RF) coagulation. The technical difficulties using punctures to perform RF lesions include complications such as occurrence of lesions in the dorsal columns or in the corticospinal tract. This paper describes a new technical improvement in RF lesions at DREZ using intraoperative ultrasound (US) to optimize the lesions and to minimize the risk of complications. Using intraoperative US after laminotomy allows the surgeon to differentiate between the gray matter of the spinal cord and white matter, showing the correct entry zone, the angle to introduce the RF electrode, and the depth. Using intraoperative US to guide DREZ lesions provides real-time optimization of DREZotomy.


Formulation and Characterization of Phytostanol Ester Solid Lipid Nanoparticles for the Management of Hypercholesterolemia: An ex vivo Study.
Phytostanols are naturally occurring compounds that reduce blood cholesterol levels significantly. However, their aqueous insolubility poses formulation challenges. To formulate and characterize solid lipid nanoparticle carriers for phytostanol esters to enhance the bioavailability of phytostanols. Phytostanol ester solid lipid nanoparticles were formulated by the microemulsion method. They were characterized for particle size distribution, polydispersity index, shape, surface charge, entrapment efficiency, stability, chemical structure, and thermal properties. The uptake of the formulation by cell lines, HepG2 and HT-29, and its effect on cell viability were evaluated. The formulation of solid lipid nanoparticles was successfully optimised by varying the type of lipids and their concentration relative to that of surfactants in the present study. The optimised formulation had an average diameter of (171 ± 9) nm, a negative surface charge of (-23.0 ± 0.8) mV and was generally spherical in shape. We report high levels of drug entrapment at (89 ± 5)% in amorphous form, drug loading of (9.1 ± 0.5)%, nanoparticle yield of (67 ± 4)% and drug excipient compatibility. The biological safety and uptake of the formulations were demonstrated on hepatic and intestinal cell lines. Phytostanol ester solid lipid nanoparticles were successfully formulated and characterized. The formulation has the potential to provide an innovative drug delivery system for phytostanols which reduce cholesterol and have a potentially ideal safety profile. This can contribute to better management of one of the main risk factors of cardiovascular diseases.


Silencing of LncRNA-PVT1 ameliorates lipopolysaccharide-induced inflammation in THP-1-derived macrophages via inhibition of the p38 MAPK signaling pathway.
Sepsis is common in intensive care units and has a high mortality rate; yet, its pathogenesis and treatment remain unclear. Recent studies have shown that long non-coding RNA plasmacytoma variant translocation 1 (lncRNA-PVT1) plays a pro-inflammatory role in immune-related inflammatory diseases. Therefore, we investigated whether lncRNA-PVT1 plays an important pro-inflammatory effect in the inflammatory response of sepsis. Quantitative real-time PCR (RT-qPCR) was employed for the detection of lncRNA-PVT1, interleukin 1β (IL-1β), and tumor necrosis factor α (TNF-α) mRNA, and the correlations between their expressions were analyzed. After lncRNA-PVT1 knockdown by lncRNA Smart Silencer, abnormal expressions of lncRNA-PVT1, and IL-1β and TNF-α mRNA were detected. The expressions of total and phosphorylated protein of p38 were detected by western blotting. The effect of silencing lncRNA-PVT1 on p38 mitogen-activated protein kinase (MAPK) signaling pathway during lipopolysaccharide (LPS)-induced inflammation was subsequently analyzed. The MAPK selective inhibitor, SB202190, was used to block this signaling pathway, and the expressions of lncRNA-PVT1 and TNF-α were detected by RT-qPCR. Furthermore, the effect of partial blockade of the p38 MAPK signaling pathway by SB202190 on the levels of lncRNA-PVT1 was explored. Following treatment of THP-1-derived macrophages with different concentrations of LPS, the levels of lncRNA-PVT1 and IL-1β, TNF-α mRNA were increased in a dose-dependent manner. Silencing of lncRNA-PVT1 reduced the expressions of IL-1β and TNF-α mRNA via inhibition of the p38 MAPK signaling pathway. Specifically, inhibiting the p38 MAPK pathway significantly decreased the LPS-induced lncRNA-PVT1 elevation. Our observations suggest that lncRNA-PVT1 can be silenced to ameliorate LPS-induced inflammation in macrophages via inhibition of the p38 MAPK pathway. Further, the p38 MAPK pathway can regulate the expression of lncRNA-PVT1 via a positive feedback loop.


Near real-time classification of optical coherence tomography data using principal components fed linear discriminant analysis.
An optical coherence tomography (OCT) prediction algorithm is designed and tested on a data set of sample images (taken from vegetables and porcine tissues) to demonstrate proof of concept. Preprocessing and classification of data are fully automated, at a rate of 60,000 A-scansmin on a standard computer and can be considered to deliver in near real-time. A data set consisting of nine groups was classified correctly in 82% of cases after cross-validation. Sets of fewer groups reach higher rates. The algorithm is able to distinguish groups with strong visual similarity among several groups of varying resemblance. Surface recognition and normalizing to the surface are essential for this approach. The mean divided by the standard deviation is a suitable descriptor for reducing a set of surface normalized A-scans. The method enables grouping of separate A-scans and is therefore straightforward to apply on 3-D data. OCT data can reliably be classified using principal component analysis combined with linear discriminant analysis. It remains to be shown whether this algorithm fails in the clinical setting, where interpatient variation can be greater than the deviations that are investigated as a disease marker.


A Novel Desensitization Protocol for Infliximab Hypersensitivity in a 13-Year Old Patient with Pustular Psoriasis.
Drug hypersensitivity reactions to infliximab have been reported in pediatric patients. At times, these patients may need infliximab administration in spite of hypersensitivity. However, only a few reports of desensitization protocols are available in the literature in pediatric patients. We report a case of immediate hypersensitivity reaction to intravenous infliximab in a 13-year-old child suffering from pustular psoriasis who eventually underwent a 14 step desensitization protocol for the administration of infliximab in a pediatric intensive care unit. Although our desensitization protocol was safe and effective, we recommend the entire desensitization procedure to be performed under the supervision of experienced personnel in a pediatric intensive care unit. Future studies with larger sample size are needed to confirm our findings.


Health Information Systems in the Digital Health Ecosystem-Problems and Solutions for Ethics, Trust and Privacy.
Digital health information systems (DHIS) are increasingly members of ecosystems, collecting, using and sharing a huge amount of personal health information (PHI), frequently without control and authorization through the data subject. From the data subject's perspective, there is frequently no guarantee and therefore no trust that PHI is processed ethically in Digital Health Ecosystems. This results in new ethical, privacy and trust challenges to be solved. The authors' objective is to find a combination of ethical principles, privacy and trust models, together enabling design, implementation of DHIS acting ethically, being trustworthy, and supporting the user's privacy needs. Research published in journals, conference proceedings, and standards documents is analyzed from the viewpoint of ethics, privacy and trust. In that context, systems theory and systems engineering approaches together with heuristic analysis are deployed. The ethical model proposed is a combination of consequentialism, professional medical ethics and utilitarianism. Privacy enforcement can be facilitated by defining it as health information specific contextual intellectual property right, where a service user can express their own privacy needs using computer-understandable policies. Thereby, privacy as a dynamic, indeterminate concept, and computational trust, deploys linguistic values and fuzzy mathematics. The proposed solution, combining ethical principles, privacy as intellectual property and computational trust models, shows a new way to achieve ethically acceptable, trustworthy and privacy-enabling DHIS and Digital Health Ecosystems.


Multiple Myeloma Rather Than Metastatic Lung Cancer: An Unexpected Cause of Spinal Cord Compression.
Spinal cord compression caused by cancer metastasis is a medical emergency that should be managed positively. Both multiple myeloma and lung cancer can lead to metastatic deposits in the spinal column to induce compression of the spinal cord. However, co-occurring multiple myeloma and lung cancer in a single patient causing spinal cord compression are rarely reported in the literature. We describe a case of a 61-year-old female with multiple myeloma and lung cancer whose radiologic characteristics of spinal cord compression mimicked those of metastatic lung cancer. Finally, the diagnosis was multiple myeloma. We showed the systematic imaging manifestations of metastatic multiple myeloma and discussed their therapeutic management.


Racial Discrimination and Race-Based Biases on Orthopedic-Related Outcomes: An Integrative Review.
Musculoskeletal diseases often lead to functional limitations and debility. The burden of these debilitating diseases is not balanced across race and ethnicity. The Institute of Medicine (now referred to as the National Academy of Medicine) identified racial discrimination as a substantive cause of race-based health disparities for racial and ethnic minority groups. The purpose of this integrative review is to summarize the evidence on the relationship among racial discrimination, race-based implicit biases and other types of biases (e.g., gender and appearance), and orthopaedic-related outcomes. Nine studies met inclusion criteria and were included in this review. The orthopaedic outcomes addressed across the nine studies were osteoarthritis, rheumatoid arthritis, low back pain, pain tolerance, disability, and likelihood of being recommended for a total knee arthroplasty. The results reveal that experiences of racial discrimination, race-based implicit biases, and other types of biases contribute to unsatisfactory orthopaedic-related outcomes for minority groups. Orthopaedic nurses can leverage their expertise to address these disparities in orthopaedic-related outcomes across minority groups.


Establishing the tolerability to broiler chickens and laying hens of nonanoic acid at practical levels of use as a feed flavouring.
1. The following experiments were conducted to evaluate the effects of nonanoic acid (NA) in broilers and laying hens, at practical levels as a flavouring in complete feed.2. In the first experiment, 1100, one-day-old Ross 308 chicks, half male and female, were randomly assigned to 50 floor pens containing 22 chicks each. Chicks were fed one of five treatment diets containing either 0 (control), 100, 300, 500 or 1,000 mg NA/kg complete feed for 42 days.3. The NA treatment had no effect on ADFI, but there was a linear relationship with ADG and FCR. No differences were observed in blood parameters or tissue pathology among treatment groups.4. In a second study, 150 Hyline hens aged 24 weeks old were randomly assigned to 50 pens containing three birds each. Laying hens were fed one of five treatment diets containing 0 (control), 100, 300, 500 or 1,000 mg NA/kg complete feed for 56 days.5. Treatment with NA has no effect on live weight, ADFI or egg production in laying hens, and there were no observed changes in tissue pathology.6. The results supported the toleration of NA in broilers or layers at dietary levels of up to 1,000 mg/kg.


On the calibration process of film dosimetry: OLS inverse regression versus WLS inverse prediction.
The purpose of this study was both putting forward a statistically correct model for film calibration and the optimization of this process. A reliable calibration is needed in order to perform accurate reference dosimetry with radiographic (Gafchromic) film. Sometimes, an ordinary least squares simple linear (in the parameters) regression is applied to the dose-optical-density (OD) curve with the dose as a function of OD (inverse regression) or sometimes OD as a function of dose (inverse prediction). The application of a simple linear regression fit is an invalid method because heteroscedasticity of the data is not taken into account. This could lead to erroneous results originating from the calibration process itself and thus to a lower accuracy. In this work, we compare the ordinary least squares (OLS) inverse regression method with the correct weighted least squares (WLS) inverse prediction method to create calibration curves. We found that the OLS inverse regression method could lead to a prediction bias of up to 7.3 cGy at 300 cGy and total prediction errors of 3% or more for Gafchromic EBT film. Application of the WLS inverse prediction method resulted in a maximum prediction bias of 1.4 cGy and total prediction errors below 2% in a 0-400 cGy range. We developed a Monte-Carlo-based process to optimize calibrations, depending on the needs of the experiment. This type of thorough analysis can lead to a higher accuracy for film dosimetry.


The role of flexor tenolysis in the palm and digits.
Seventy-seven digitis in 70 patients undergoing a technique of thorough flexor tenolysis, with instillation of local triamcinolone, and immediate motion were studied. Classification of the results utilized a method which determined the percentage of passive joint flexion potential actively achieved and by a second system which graded the results in the finger as a whole. A further categorization into three patient groups, depending on the etiology of the tendon adhesions, was carried out. Using these classifications 84% or the proximal interphalangeal joints, 86% of the distal interphalangeal joints, and 80% of the fingers as a whole were improved by this procedure. These results were comparable or superior to those of other published reports. Improvement in digital flexion was consistent, often with restoration of near-normal function. The incidence of tendon rupture, infection, and delayed wound healing have not been great.


Neuropathological comparative studies on experimental allergic neuritis (EAN) induced in rabbits by P2 protein-ganglioside complexes.
The light microscopical examinations were performed on the peripheral nerve (PN) lesions in rabbits induced by bovine peripheral nerve (BPN) myelin and by its components. Morphology of the PN lesions induced by P2 protein-ganglioside complex were equivalent to those induced by PN myelin (original EAN); and some of them were more remarkable in severity than the original EAN. The lesions were composed of myelin destruction, numerous macrophages containing myelin debris, completely demyelinated axons and remyelinating fibers. P2-I, acid treated P2-I and P2-II proteins induced PN lesions. Histologically they were moderate to minimal in severity in that order. However, when each protein was injected as the complex with ganglioside, PN lesions obviously became severer, respectively. These findings indicate the possibility that the P2-ganglioside complex may be involved in the chemical principle of EAN, and also the findings strongly support the theory proposed by Nagai et al. that gangliosides may play an essential role in rabbit EAN to give P2 protein a special conformation necessary for antigenic activity.