A Combinatorial Solution to Point Symbol Recognition.
Recent work has shown that recognizing point symbols is an essential task in the field of map digitization. For the identification of symbols, it is generally necessary to compare the symbols with a specific criterion and find the most similar one with each known symbol one by one. Most of the works can only identify a single symbol, a small number of works are to deal with multiple symbols simultaneously with a low recognition accuracy. Given the two deficiencies, this paper proposes a deep transfer learning architecture, where the task is to learn a symbol classifier with AlexNet. For the insufficient dataset, we develop a method for transfer learning that uses a MNIST dataset to pretrain the model, which makes up for the problem of small training dataset and enhances the generalization of the model. Before the recognition process, preprocessing the point symbols in the map to coarse screening out the areas suspected of point symbols. We show a significant improvement over using point symbol images to keep a high performance in being able to deal with many more categories of symbols simultaneously.


Signatures of Breast Cancer Metastasis: aMENAble to Interpretation?
MenaINV, an isoform of the motility regulator protein Mena, contributes to prometastatic phenotypes. Tumor microenvironment of metastasis (TMEM), a three-cell structure associated with intravasation, contains a stationary Mena-expressing tumor cell. TMEM density and MenaINV expression both correlate with poor clinical outcome in breast cancer patients. However, is MenaINV involved in TMEM assembly and function?


Molecular characterization of the skin fungal microbiome in patients with psoriasis.
The skin surface is colonized by a wide variety of fungi and bacteria. While many of these organisms, including Malassezia, Candida, Streptococcus and Staphylococcus species, are associated with provocation and/or exacerbation of psoriasis, a detailed analysis of the cutaneous fungal microbiome in psoriatic patients has yet to be performed. To identify the disease-specific fungal microbiota on psoriatic scale samples, fungal rRNA gene sequences from 12 psoriatic patients and 12 healthy controls were analyzed by pyrosequencing. A total of 317 806 high-quality sequences were obtained, representing 142 genera. Malassezia species were the most abundant sequences in both populations (46.9 ± 14.0% in psoriasis vs. 76.0 ± 14.6% for healthy controls). Principal coordinate analysis revealed that the fungal microbiomes were independent. Although an association between the cutaneous fungal microbiome and psoriasis has yet to be established, our data indicate that the microbiome in patients with psoriasis is independent of that in healthy controls.


D-glucosamine trimethylene dithioacetal derivatives: formation of six- and seven-membered ring amino carbasugars. Synthesis of (-)-calystegine B3.
By virtue of carefully chosen protecting groups, d-glucosamine trimethylene dithioacetal derivatives were successfully oxidized to the corresponding 6-aldehydes. This methodology reverses the donor and acceptor position on a normal open chain sugar and changes the relative position of the N-substituent. From the 6-aldehydes, heptose epoxide derivatives were prepared by a Corey-Chaykovsky reaction, and cyclized by the Corey-Seebach method. Depending on the designed protecting groups, the orthogonally protected six- and seven-membered ring amino carbasugars can be produced selectively and efficiently. (-)-Calystegine B(3) was synthesized from one of those products with high yield. This is the first anionic cyclization pathway to calystegine type structures.


Mutation study of antithrombin: the roles of disulfide bonds in intracellular accumulation and formation of russell body-like structures.
Antithrombin (AT) is a major plasma protease inhibitor with three intramolecular disulfide bonds and a deficiency of it is associated with venous thrombosis. Recently, we prepared CHO cells overexpressing a novel mutant, AT(C95R), with a disulfide bond removed, and revealed that this mutant remained for a long time in the endoplasmic reticulum (ER) without being degraded and also accumulated in newly formed membrane structures that resembled Russell bodies (RB) [Tanaka, Y. et al. (2002) J. Biol. Chem. 277, 51058-51067]. In this study, we replaced each of the individual cysteine residues of AT with an arginine and also two paired cysteine residues with arginines. We stably expressed these mutant ATs in CHO cells, and examined the roles of each cysteine residue or disulfide bond in the accumulation of mutant ATs and the formation of RB-like structures. In pulse-chase experiments, the secretion of mutant ATs with single mutations decreased approximately 1/5-1/50 times compared to that of the wild type AT. All of the mutant ATs were retained in the ER and were also found to accumulate in the RB-like structures. On the other hand, the fates of mutant ATs with double mutations fell into two categories. Secretion of mutant AT(C8R,C128R) decreased only approximately 1/2 times and no RB-like structures appeared. Mutants AT(C21R,C95R) and AT(C247R,C430R) exhibited similar secretion kinetics to the mutant ATs with the single mutations and were found in RB-like structures. On a sucrose gradient, all of the mutant ATs that induced RB-like structures migrated as oligomeric structures, whereas wild type AT and AT(C8R,C128R) migrated as monomers. Further, to clarify the morphological pathway through which RB-like structures are formed, we prepared CHO cells in which the expression of AT(C95R) was controlled by the Tet-On system. During expression of AT(C95R), RB-like structures formed through expansion of the ER. These results suggest that the correct folding with each disulfide bond is essential for the secretion of AT and oligomerization of mutant ATs in the ER is involved in the formation of RB-like structures.


Transfemoral Transcatheter Aortic Valve-in-Valve Implantation for Aortic Valve Bioprosthesis Failure With the Fully Repositionable and Retrievable Lotus Valve: A Single-Center Experience.
To report a first case series of the Lotus valve (Boston Scientific) for the treatment of surgical aortic bioprosthesis failure. Valve-in-valve (VIV) transcatheter aortic valve implantation (TAVI) is an established management option for surgical aortic bioprosthesis failure. Although TAVI has proven efficacious, complications relating to suboptimal valve implantation have been reported in approximately 5% of patients. The Lotus valve is fully repositionable and retrievable, and therefore enables complete assessment of valve function prior to definitive deployment. However, data supporting its use for this indication are limited. Consecutive patients who underwent transfemoral VIV-TAVI at John Radcliffe Hospital between January 2015 and December 2016 were retrospectively analyzed. Procedural and 30-day outcomes were reported in accordance with Valve Academic Research Consortium-2 (VARC-2) definitions. Seven patients underwent VIV-TAVI with the Lotus valve. Device success according to VARC-2 criteria was achieved in 6 of the 7 patients. Following implantation, transvalvular hemodynamics were acceptable, with a mean gradient of 11.9 ± 6.6 mm Hg. All patients had mild or no residual aortic regurgitation. Specifically, no patient required further valve-related intervention, or suffered myocardial infarction, stroke, or acute kidney injury stage 2 or 3. There were no deaths during the follow-up period. Transfemoral VIV-TAVI for the treatment of surgical aortic bioprosthesis failure with the Lotus device appears to be safe and is associated with no significant residual aortic regurgitation, and offers favorable transvalvular hemodynamics at 30-day follow-up.


Peripheral NKT cells in simian immunodeficiency virus-infected macaques.
NKT cells are a specialized population of T lymphocytes that have an increasingly recognized role in immunoregulation, including controlling the response to viral infections. The characteristics of NKT cells in the peripheral blood of macaques during simian immunodeficiency virus (SIV) or chimeric simian/human immunodeficiency virus (HIV) (SHIV) infection were assessed. NKT cells comprised a mean of 0.19% of peripheral blood lymphocytes across the 64 uninfected macaques studied. Although the range in the percentages of NKT cells was large (0 to 2.2%), levels were stable over time within individual macaques without SIV/SHIV infection. The majority of NKT cells in macaques were CD4(+) (on average 67%) with smaller populations being CD8(+) (21%) and CD4/CD8 double positive (13%). A precipitous decline in CD4(+) NKT cells occurred in all six macaques infected with CXCR4-tropic SHIV(mn229) early after infection, with a concomitant rise in CD8(+) NKT cells in some animals. The depletion of CD4(+) NKT cells was tightly correlated with the depletion of total CD4(+) T cells. R5-tropic SIV(mac251) infection of macaques resulted in a slower and more variable decline in CD4(+) NKT cells, with animals that were able to control SIV virus levels maintaining higher levels of CD4(+) NKT cells. An inverse correlation between the depletion of total and CD4(+) NKT cells and SIV viral load during chronic infection was observed. Our results demonstrate the infection-driven depletion of peripheral CD4(+) NKT cells during both SHIV and SIV infection of macaques. Further studies of the implications of the loss of NKT cell subsets in the pathogenesis of HIV disease are needed.


Identify a DNA Damage Repair Gene Signature for Predicting Prognosis and Immunotherapy Response in Cervical Squamous Cell Carcinoma.
The DNA damage repair (DDR) genes are increasingly gaining attention as potential therapeutic targets in cancers. In this study, we identified the DDR genes associated with the tumor mutation burden (TMB) and prognosis of cervical squamous cell carcinoma (CESC) based on The Cancer Genome Atlas (TCGA) database. Through LASSO Cox regression, the prognostic signature involving five DDR genes (ACTR2, TEX12, UBE2V1, HSF1, and FBXO6) was established, and the risk score was identified as an independent risk factor for CESC. The nomogram consisting of the five genes accurately predicted the overall survival (OS) and the immunotherapeutic response of CESC patients. Finally, the loss of the copies of the transcription factor (TF) SP140 in CESC patients may decrease the expression of FBXO6, improve DNA repair function, and reduce the diversity of neoantigens, thereby lowering the response to immunotherapies. Therefore, the DDR gene signature is a novel prognostic model and a biomarker for immunotherapies in CESC patients.


Organ System Network Disruption in Nonsurvivors of Critically Ill Patients.
As interactions of each organ system have been conceptually known to play an important role during life-threatening conditions, we quantitatively evaluated the organ system interactions in critically ill patients and examined the difference in the organ system network structure between the survivors and the nonsurvivors. Prospective observational study. An ICU of a university hospital. Two hundred and eighty-two patients who were admitted to the ICU. Blood samples were obtained at ICU admission. We analyzed the associations among nine representative laboratory variables of each organ system using network analysis. We compared the network structure of the variables in the 40 nonsurvivors with that in the 40 survivors. Their baseline characteristics, including the degree of organ dysfunction, were matched using propensity score matching method. Network structure was quantitatively evaluated using edge (significant correlation among variables evaluated by the p value), weight (connective strength of edge evaluated by coefficient), and cluster (group with tight connection evaluated by edge betweenness). The number of edges among the nine variables was significantly fewer for the nonsurvivors than for the severity-matched survivors (3 vs 12; p = 0.035). The mean weight of edges was significantly smaller for the nonsurvivors (0.055 vs 0.119; p = 0.007). The nine laboratory variables for the nonsurvivors were divided into a significantly larger number of clusters (7 vs 2; p = 0.001). Statistical conclusions were preserved with Bonferroni multiple comparison procedure. These findings were consistently observed in comparison of the 40 nonsurvivors with all the survivors. This study, as a preliminary proof-of-concept, quantitatively demonstrated a more disrupted network structure of organ systems in the nonsurvivors compared with that in the survivors. These observations suggest the necessity of assessment for organ system interactions to evaluate critically ill patients.


The Nalp3 inflammasome is essential for the development of silicosis.
Inhalation of crystalline silica and asbestos is known to cause the progressive pulmonary fibrotic disorders silicosis and asbestosis, respectively. Although alveolar macrophages are believed to initiate these inflammatory responses, the mechanism by which this occurs has been unclear. Here we show that the inflammatory response and subsequent development of pulmonary fibrosis after inhalation of silica is dependent on the Nalp3 inflammasome. Stimulation of macrophages with silica results in the activation of caspase-1 in a Nalp3-dependent manner. Macrophages deficient in components of the Nalp3 inflammasome were incapable of secreting the proinflammatory cytokines interleukin (IL)-1beta and IL-18 in response to silica. Similarly, asbestos was capable of activating caspase-1 in a Nalp3-dependent manner. Activation of the Nalp3 inflammasome by silica required both an efflux of intracellular potassium and the generation of reactive oxygen species. This study demonstrates a key role for the Nalp3 inflammasome in the pathogenesis of pneumoconiosis.


Age independency of mobility decrease assessed using the Locomotive Syndrome Risk Test in elderly with disability: a cross-sectional study.
Mobility decrease is reportedly age-dependent in community dwelling elderly, and a major factor of disability in the geriatric population. The purpose of this study is to examine whether mobility decrease, as assessed using a set of tests, is similarly age-dependent in elderly adults who already have disability. One hundred thirty-five community-dwelling elderly (54 men, 81 women) with disability and 1469 independent community dwellers (1009 men, 460 women) were analyzed. Disability was defined having a certified need for care under the long-term care insurance system in Japan. Lower extremity mobility decrease was quantified using the Locomotive Syndrome Risk Test, which comprises the two-step test, stand-up test, and 25-Question Geriatric Locomotive Function Scale (GLFS-25). Multivariable regression analyses indicated no age-related decrease in the three test scores among elderly with disability, whereas these scores all decreased with age among independent community dwellers. All the test scores decreased as care level increased. Mobility decrease among elderly adults with disability is unrelated to age. However, the severity of care level is associated with mobility decrease.


VSViewer3D: a tool for interactive data mining of three-dimensional virtual screening data.
The VSviewer3D is a simple Java tool for visual exploration of three-dimensional (3D) virtual screening data. The VSviewer3D brings together the ability to explore numerical data, such as calculated properties and virtual screening scores, structure depiction, interactive topological and 3D similarity searching, and 3D visualization. By doing so the user is better able to quickly identify outliers, assess tractability of large numbers of compounds, visualize hits of interest, annotate hits, and mix and match interesting scaffolds. We demonstrate the utility of the VSviewer3D by describing a use case in a docking based virtual screen.


Two antigenic groups of human coronaviruses detected by using enzyme-linked immunosorbent assay.
Paired sera from volunteers inoculated with one of the five recently isolated strains of human coronavirus (HCV), AD, GI, HO, PA, and RO, none of which has been grown in tissue culture, or with strain OC38 were tested against coronavirus antigens by enzyme-linked immunosorbent assay. When HCV strains OC43, 229E, or the 229E-related tissue culture-adapted strains PR and TO were used as antigens, it was shown that all strains fell into one of two antigenic groups. The HCV OC43 group was comprised of strains OC43, GI, HO, and RO, and the HCV 229E group contained strains AD and PA as well as the tissue culture-adapted strains PR, TO, and KI. Enzyme-linked immunosorbent assay of the paired sera with the coronavirus mouse hepatitis virus strain 3 as antigen confirmed the relationship of this virus to the HCV OC43 group but not to the HCV 229E group.


C3 glomerulonephritis: clinicopathological findings, complement abnormalities, glomerular proteomic profile, treatment, and follow-up.
C3 glomerulonephritis (C3GN) is a recently described disorder that typically results from abnormalities in the alternative pathway (AP) of complement. Here, we describe the clinical features, kidney biopsy findings, AP abnormalities, glomerular proteomic profile, and follow-up in 12 cases of C3GN. This disorder equally affected all ages, both genders, and typically presented with hematuria and proteinuria. In both the short and long term, renal function remained stable in the majority of patients with native kidney disease. In two patients, C3GN recurred within 1 year of transplantation and resulted in a decline in allograft function. Kidney biopsy mainly showed a membranoproliferative pattern, although both mesangial proliferative and diffuse endocapillary proliferative glomerulonephritis were noted. AP abnormalities were heterogeneous, both acquired and genetic. The most common acquired abnormality was the presence of C3 nephritic factors, while the most common genetic finding was the presence of H402 and V62 alleles of Factor H. In addition to these risk factors, other abnormalities included Factor H autoantibodies and mutations in CFH, CFI, and CFHR genes. Laser dissection and mass spectrometry of glomeruli from patients with C3GN showed accumulation of AP and terminal complement complex proteins. Thus, C3GN results from diverse abnormalities of the alternative complement pathway leading to subsequent glomerular injury.


Metabolomic changes in the mouse retina after optic nerve injury.
In glaucoma, although axonal injury drives retinal ganglion cell (RGC) death, little is known about the underlying pathomechanisms. To provide new mechanistic insights and identify new biomarkers, we combined latest non-targeting metabolomics analyses to profile altered metabolites in the mouse whole retina 2, 4, and 7 days after optic nerve crush (NC). Ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry and liquid chromatography Fourier transform mass spectrometry covering wide spectrum of metabolites in combination highlighted 30 metabolites that changed its concentration after NC. The analysis displayed similar changes for purine nucleotide and glutathione as reported previously in another animal model of axonal injury and detected multiple metabolites that increased after the injury. After studying the specificity of the identified metabolites to RGCs in histological sections using imaging mass spectrometry, two metabolites, i.e., L-acetylcarnitine and phosphatidylcholine were increased not only preceding the peak of RGC death in the whole retina but also at the RGC layer (2.3-fold and 1.2-fold, respectively). These phospholipids propose novel mechanisms of RGC death and may serve as early biomarkers of axonal injury. The combinatory metabolomics analyses promise to illuminate pathomechanisms, reveal biomarkers, and allow the discovery of new therapeutic targets of glaucoma.


Electron dense staining affinities of mouse oxytalan and elastic fibers.
The staining affinity of electron dense stains to mouse palatal elastic fibers and periodontal oxytalan fibers was assessed and compared. Tissues were stained routinely with uranyl acetate and lead citrate or with elastic tissue stains including: (1) silver tetraphenylporphine sulfonate, (2) tannic acid technique, and (3) a high iron diamine sequence. Staining results were assessed with an electron microscope. Palatal elastic fibers demonstrated staining affinity to all elastic stain techniques. Oxytalan fibers did not demonstrate affinity to elastic fiber stains used. Based on electron dense stains, elastic and oxytalan fibers were dissimilar, in contrast to results reported utilizing light microscopic stains.


Effects of support groups on post traumatic stress responses in women experiencing stillbirth.
This research study explores the effects of support groups on traumatic stress responses of women experiencing stillbirth. Women (N = 47) responded to a mixed method questionnaire. Quantitative results utilizing the Impact of Event Scale Revised demonstrate that women who attend support group, when controlling for time, had fewer post traumatic stress symptoms than did the women who did not attend support group. Qualitative results elucidate the role of support groups in managing grief, suggesting that connectivity with other like women may be a useful strategy in reducing problematic psychological outcomes.


Distributed Interactive Visualization Using GPU-Optimized Spark.
With the advent of advances in imaging and computing technologies, large-scale data acquisition and processing have become commonplace in many science and engineering disciplines. Conventional workflows for large-scale data processing usually rely on in-house or commercial software that are designed for domain-specific computing tasks. Recent advances in MapReduce, which was originally developed for batch processing textual data via a simplified programming model of the map and reduce functions, have expanded its applications to more general tasks in big-data processing, such as scientific computing, and biomedical image processing. However, as shown in previous work, volume rendering and visualization using MapReduce is still considered challenging and impractical owing to the disk-based, batch-processing nature of its computing model. In this article, contrary to this common belief, we show that the MapReduce computing model can be effectively used for interactive visualization. Our proposed system is a novel extension of Spark, one of the most popular open-source MapReduce frameworks, which offers GPU-accelerated MapReduce computing. To minimize CPU-GPU communication and overcome slow, disk-based shuffle performance, the proposed system supports GPU in-memory caching and MPI-based direct communication between compute nodes. To allow for GPU-accelerated in-situ visualization using raster graphics in Spark, we leveraged the CUDA-OpenGL interoperability, resulting in faster processing speeds by several orders of magnitude compared to conventional MapReduce systems. We demonstrate the performance of our system via several volume processing and visualization tasks, such as direct volume rendering, iso-surface extraction, and numerical simulations with in-situ visualization.


[Health Related Quality of Life, Self-Esteem and Health Behaviour on Average 6 Years after an Obesity Outpatient Lifestyle Program].
Background Multimodal programs focusing on weight reduction are recommended in guidelines for the treatment of obese children. However, studies investigating the effects of such programs over time are still missing; there is especially a lack of studies considering longer periods after treatment. In the present study, adolescents' bodyweight, health-related quality of life (HRQoL), self-esteem and health behavior were assessed before and directly after the treatment as well as 3 years after the treatment. Methods Between 2005 and 2009 84 children and adolescents took part in a 10-month, multimodal training programme. A number of 55 participants were assessed before (T0), after (T1) and at least 3 years after the beginning of the programme (T2). Based on height and weight the Body mass index standard deviation score (BMI-SDS) was calculated. Further, HRQoL, self-esteem, physical activity and eating behavior were measured by means of standardized questionnaires. Results On average 6 years after program beginning the BMI-SDS decreased by 0.4 compared to program beginning (p<0.01). The HRQoL total score increased from 70.1±12.1 at T0 to 76.2±12.8 at T2 (p<0.05). The self-esteem also increased from 54.0±23.4 (T0) to 65.0±21.5 (T2; p<0.05). In addition, in the long run the physical activity (p<0.05) and the interest in sports (p<0.001) increased. However, the eating behavior did not improve significantly. Conclusion In addition to weight and health behaviour improvements participating in a multimodal training program is associated with a clinical relevant increase of HRQoL and self-esteem. These improvements of protective factors can diminish the risk of discrimination and should be analysed in further controlled studies.


Inferring the geometry of fourth-period metallic elements in arabidopsis thaliana seeds using synchrotron-based multi-angle X-ray fluorescence mapping.
Improving our knowledge of plant metal metabolism is facilitated by the use of analytical techniques to map the distribution of elements in tissues. One such technique is X-ray fluorescence (XRF), which has been used previously to map metal distribution in both two and three dimensions. One of the difficulties of mapping metal distribution in two dimensions is that it can be difficult to normalize for tissue thickness. When mapping metal distribution in three dimensions, the time required to collect the data can become a major constraint. In this article a compromise is suggested between two- and three-dimensional mapping using multi-angle XRF imaging. A synchrotron-based XRF microprobe was used to map the distribution of K, Ca, Mn, Fe, Ni, Cu and Zn in whole Arabidopsis thaliana seeds. Relative concentrations of each element were determined by measuring fluorescence emitted from a 10 microm excitation beam at 13 keV. XRF spectra were collected from an array of points with 25 or 30 microm steps. Maps were recorded at 0 and 90 degrees , or at 0, 60 and 120 degrees for each seed. Using these data, circular or ellipsoidal cross-sections were modelled, and from these an apparent pathlength for the excitation beam was calculated to normalize the data. Elemental distribution was mapped in seeds from ecotype Columbia-4 plants, as well as the metal accumulation mutants manganese accumulator 1 (man1) and nicotianamine synthetase (nasx). Multi-angle XRF imaging will be useful for mapping elemental distribution in plant tissues. It offers a compromise between two- and three-dimensional XRF mapping, as far as collection times, image resolution and ease of visualization. It is also complementary to other metal-mapping techniques. Mn, Fe and Cu had tissue-specific accumulation patterns. Metal accumulation patterns were different between seeds of the Col-4, man1 and nasx genotypes.


Evaluation of a new venom-based clotting assay of protein C.
Congenital protein C deficiency significantly increases the risk of venous thromboembolism, a serious and potentially lethal condition. Protein C levels can be determined by chromogenic, clotting and antigenic assays, each type of assay has differences in specificity and sensitivity to protein C deficiency. In principle, clotting-based assays of protein C are preferred over chromogenic assays, as they can detect some rare mutations that are missed by the chromogenic assay, however, clotting-based assays may be prone to inaccuracy because of poor specificity. We have evaluated a new venom-based clotting assay of protein C, and optimized it for use on Sysmex CA-1500 analyser. The assay was linear from 0 to 130 U/dl, a normal plasma demonstrated good inter-assay precision, with a coefficient of variation of 4.8%. The assay compared well with antigenic- and venom-based chromogenic protein C assay in normal individuals, subjects with lupus anticoagulant, and subjects with FV Leiden. Median protein C levels by clotting, chromogenic and antigen for the three subject groups were 108 U/dl, 108 IU/dl and 109 IU/dl for normal subjects, 94 U/dl, 106 IU/dl and 103 IU/dl for subjects with lupus anticoagulant, and 102 U/dl, 104 IU/dl and 100 IU/dl for subjects heterozygous for FV Leiden. Comparing levels of clotting protein C with protein C antigen by ratio (clotting/antigen), the three groups showed small differences that did not quite reach statistical significance, (mean ratios ranged from 0.95 to 1.01, anovaP = 0.0561), the lowest ratio was with the lupus anticoagulant group. Comparing clotting assay with chromogenic assay by ratio (clotting/chromogenic), the three groups did show a statistically significant difference (P = 0.0033) which was due to a difference in mean ratios between normal and lupus anticoagulant groups (ratios 1.00 and 0.91, respectively, P < 0.01). There was no statistical difference in any of the groups when comparing chromogenic protein C with protein C antigen (mean ratios ranged from 1.02 to 1.05, P = 0.3925). In a normal sample, the clotting-based protein C level was unaffected by increasing FVIII level by up to 1000 IU/dl, using intermediate purity FVIII concentrate. The new assay is considered to be a suitable assay for the routine diagnosis of protein C deficiency.


Potential role of statins in inflammation and atherosclerosis.
The mevalonate pathway plays a crucial role in regulation of cellular cholesterol synthesis and isoprenoid groups. The entire pathway is closely regulated by feedback from an enzyme in the cascade, 3-hydroxy-3-methyl-CoA (HMG-CoA) reductase, as well as LDL receptors. Clinically, inhibition of this pathway by statins, potent inhibitors of HMG-CoA reductase, has been shown to reduce plasma levels of LDL cholesterol and several clinical trials with this group of drugs have demonstrated a remarked improvement in cardiovascular risk reduction. Interestingly, the improvement in cardiovascular end points in those trials was superior to estimations calculated from the effect on LDL cholesterol lowering. These findings support the idea of non-lipid effects of statins in atherosclerosis. Further, recent observations using in vivo and in vitro models of atherosclerosis have shed light on their potential role for manipulation of various cellular functions via inhibition of the mevalonate pathway. Among them, recently identified inhibitory effects of statins on monocyte-endothelial interaction suggest their effect on inflammation. Herein, we discuss recent progress in this area of study, with special focus on the biological function of statins.


One disulfide bond in front of the second heavy chain constant region is necessary and sufficient for effector functions of human IgG3 without a genetic hinge.
We have created four IgG3 mutants without a normal hinge region: (i) m0 without a genetic hinge; (ii) m0/C131S, where Cys-131 in m0 was mutated to Ser; (iii) m0/231C232 (formerly HM-1), where a Cys residue was inserted in m0 between Ala-231 and Pro-232; (iv) m0/C131S/231C232, which is a hybrid of m0/231C232 and m0/C131S. The wild-type IgG3 and all mutants bind 5-iodo-4-hydroxy-3-nitrophenacetyl groups. The wild type and mutants, m15 (with 15 aa in the hinge), m0/231C232, and m0/C131S/231C232, were all positive for complement-mediated lysis, antibody-dependent cellular cytotoxicity mediated by peripheral blood leukocytes, and phagocytosis by U937. m0/C131S/231C232 was only weakly positive and sometimes negative for respiratory burst activity mediated by peripheral blood neutrophils (polymorphonuclear leukocytes), whereas m15, m0/231C232, and wild-type IgG3 were strongly positive. The m0 and m0/C131S mutants were mainly negative for complement-mediated lysis, antibody-dependent cell-mediated cytotoxicity, and phagocytosis by U937 and polymorphonuclear leukocytes. The results indicate that a hinge spacer region is not necessary, but the correct alignment of the two second heavy chain constant regions in the IgG3 molecule by a minimum of one disulfide bond is necessary and sufficient for effector functions.


The Relations between Systems of Oppression and Oral Care Access in the United States.
We applied a structural intersectionality approach to cross-sectionally examine the relationships between macro-level systems of oppression, their intersections, and access to oral care in the United States. Whether and the extent to which the provision of government-funded dental services attenuates the emerging patterns of associations was also assessed in the study. To accomplish these objectives, individual-level information from over 300,000 respondents of the 2010 US Behavioral Risk Factor Surveillance System was linked with state-level data for 2000 and 2010 on structural racism, structural sexism, and income inequality, as provided by Homan et al. Using multilevel models, we investigated the relationships between systems of oppression and restricted access to oral health services among respondents at the intersections of race, gender, and poverty. The degree to which extended provision of government-funded dental services weakens the observed associations was determined in models stratified by state-level coverage of oral care. Our analyses bring to the fore intersectional groups (e.g., non-Hispanic Black women and men below the poverty line) with the highest odds of not seeing a dentist in the previous year. We also show that residing in states where high levels of structural sexism and income inequality intersect was associated with 1.3 greater odds (95% confidence interval, 1.1-1.5) of not accessing dental services in the 12 mo preceding the survey. Stratified analyses demonstrated that a more extensive provision of government-funded dental services attenuates associations between structural oppressions and restricted access to oral health care. On the basis of these and other findings, we urge researchers and health care planners to increase access to dental services in more effective and inclusive ways. Most important, we show that counteracting structural drivers of inequities in dental services access entails providing dental care for all.


Facial swelling and dysphonia during labour: a case of Hamman's syndrome.
We present the case of a previously fit and well 30-year-old primiparous woman who developed Hamman's syndrome during the second stage of labour. This is an unusual and peculiar condition, characterised by spontaneous pneumomediastinum and subcutaneous emphysema. The rarity of the condition means it can easily be misdiagnosed. Its exact aetiology is unknown, but it is believed that extreme Valsalva manoeuvre during prolonged or difficult labours may contribute to its development. Chest X-ray is the first investigation of choice in this presentation, followed by CT scanning. Fortunately, it is usually a benign condition that can be managed conservatively and resolved quickly, with no long-term effects and low risk of recurrence in future pregnancies. We are pleased to say that this case does not differ in this respect. It is, however, important to rule other more serious pathologies that present in a similar way, for example, Boerhaave syndrome, pneumothorax or pulmonary embolism.


Nondestructive Raman Spectroscopy as a Tool for Early Detection and Discrimination of the Infection of Tomato Plants by Two Economically Important Viruses.
Global population forecasts dictate a rapid adoption of multifaceted approaches to fulfill increasing food requirements, ameliorate food dietary value and security using sustainable and economically feasible agricultural processes. Plant pathogens induce up to 25% losses in vegetable crops and their early detection would contribute to limit their spread and economic impact. As an alternative to time-consuming, destructive, and expensive diagnostic procedures, such as immunological assays and nucleic acid-based techniques, Raman spectroscopy (RS) is a nondestructive rapid technique that generates a chemical fingerprinting of a sample, at low operating costs. Here, we assessed the suitability of RS combined to chemometric analysis to monitor the infection of an important vegetable crop plant, tomato, by two dangerous and peculiarly different viral pathogens, Tomato yellow leaf curl Sardinia virus (TYLCSV) and Tomato spotted wilt virus (TSWV). Experimentally inoculated plants were monitored over 28 days for symptom occurrence and subjected to RS analysis, alongside with measuring the virus amount by quantitative real-time PCR. RS allowed to discriminate mock inoculated (healthy) from virus-infected specimens, reaching an accuracy of >70% after only 14 days after inoculation for TYLCSV and >85% only after 8 days for TSWV, demonstrating its suitability for early detection of virus infection. Importantly, RS also highlighted spectral differences induced by the two viruses, providing specific information on the infecting agent.


Intralipid Emulsion Therapy for the Treatment of Suspected Toxicity in 2 Avian Species.
Intravenous lipid emulsion (ILE) therapy has shown promise as a treatment option for a variety of lipophilic toxins. Two birds presented for suspected ingestion of a toxic substance. A blue-and-gold macaw (Ara ararauna) presented after chewing a block of bromethalin rodenticide without overt clinical signs at the time of presentation. Additionally, a free-ranging bald eagle (Haliaeetus leucocephalus) was found weak and depressed near a municipal landfill after presumptive ingestion of pentobarbital. Both birds were treated with ILE therapy for potential intoxication without any adverse events. The macaw was clinically normal after 3 days of hospitalization and at a 1-week reevaluation. The eagle was transferred to a rehabilitation center after markedly improved mentation and strength and was released 7 days later. Clinicians should consider ILE therapy for the treatment of lipophilic toxicities; however, monitoring is recommended for persistent lipemia and other adverse effects that have been reported in the veterinary literature.


Experimental investigation on preconditioned rate induced tipping in a thermoacoustic system.
Many systems found in nature are susceptible to tipping, where they can shift from one stable dynamical state to another. This shift in dynamics can be unfavorable in systems found in various fields ranging from ecology to finance. Hence, it is important to identify the factors that can lead to tipping in a physical system. Tipping can mainly be brought about by a change in parameter or due to the influence of external fluctuations. Further, the rate at which the parameter is varied also determines the final state that the system attains. Here, we show preconditioned rate induced tipping in experiments and in a theoretical model of a thermoacoustic system. We provide a specific initial condition (preconditioning) and vary the parameter at a rate higher than a critical rate to observe tipping. We find that the critical rate is a function of the initial condition. Our study is highly relevant because the parameters that dictate the asymptotic behavior of many physical systems are temporally dynamic.


Ex Vivo Rat Eye Model for Investigating Transport of Next Generation Precision-Polyester Nanosystems.
We present for the first time a robust ex vivo rat eye model for investigating the transport of precision-polyester nanosystems (P2Ns) across the blood-retinal barrier, intended for systemic administration. The P2Ns-GA actively transport exploiting transferrin receptors present in the inner retinal barrier and colocalize in ganglion cells. Such delivery approaches have the potential to deliver drugs to posterior segments of the eye, which is still a major challenge in treating posterior ocular disorders.


2-Methoxy-4-nitroaniline and its isomers induce cytochrome P4501A (CYP1A) enzymes with different selectivities in the rat liver.
We reported previously that 2-methoxy-4-nitroaniline (2-MeO-4-NA) is a selective inducer of cytochrome P4501A2 (CYP1A2) in the rat liver, and its molecular size is the smallest among known CYP1A2-selective inducers. In the present study, a structure-activity relationship on the CYP1A2-selective induction has been investigated using isomeric nitroanisidines and their related chemicals. Western blot analyses revealed that the chemicals removed a substituent (amino, methoxyl or nitro group) from a 2-MeO-4-NA molecule had no capacity for inducing CYP1A enzymes in rat livers. On the other hand, isomeric nitroanisidines such as 2-MeO-4-NA, 2-MeO-5-NA and 4-MeO-2-NA induced both CYP1A2 and CYP1A1 enzymes with different selectivities. As judged from the induced levels of CYP1A proteins, 2-MeO-4-NA (CYP1A2/CYP1A1 ratio; 9.5) and 4-MeO-2-NA (0.3) were the most selective inducers of CYP1A2 and CYP1A1, respectively, among the isomeric nitroanisidines (0.44 mmol/kg) used. The induced level of CYP1A2 protein was in the order 2-MeO-4-NA > 2-MeO-5-NA > 4-MeO-2-NA, although no significant difference was observed on their CYP1A2 mRNA level. On the contrary, increases in the levels of CYP1A1 mRNA and protein were in the order 4-MeO-2-NA > 2-MeO-5-NA > 2-MeO-4-NA. The present findings indicate that all three substituents (amino, methoxyl and nitro groups) are necessary components of nitroanisidines for induction of CYP1A enzymes, and also show that regio-isomeric positions of these substituents determine the selectivity in the induction of CYP1A enzymes.


Role of native Thiol, total Thiol and dynamic Disulphide in diagnosis of patient with prostate cancer and prostatitis.
Our study investigates whether Native Thiol, Total Thiol and disulphide levels measured in serum of patients with prostate cancer and prostatitis and of healthy subjects, have any role in differential diagnosis. Patients followed up for histopathologically verified diagnosis of prostate cancer and prostatitis in 2016-2017 at the Medicalpark Gaziantep Hospital Urology Clinic were included in the study. Native Thiol (NT), Total Thiol (TT), Dynamic Disulphide (DD) levels in serum were measured by a novel automated method. NT, TT, DD, NT / TT ratios, DD / TT ratio and DD / NT ratio were measured as 118.4 ± 36.8μmoL / L, 150.3 ± 45.3μmoL / L, 15.9 ± 7μmoL / L, 78.8 ± 7μmoL / L, 10.5 ± 3.5μmoL / L, 13.8 ± 5.8μmoL / L respectively in patients with prostate cancer; as 116.4 ± 40.5μmoL / L, 147.5 ± 50.1μmoL / L, 15.5 ± 8.7μmoL / L, 79.7 ± 9μmoL / L, 10.1 ± 4.5μmoL / L, 13.5 ± 7.2μmoL / L in patients with prostatitis and as 144.1 ± 21.2μmoL / L, 191 ± 32.3μmoL / L, 23.4 ± 10.1μmoL / L, 76.1 ± 98.3μmoL / L, 11.9 ± 4.1μmoL / L, 16.4 ± 6.9μmoL / L in healthy subjects. Significant difference was detected between groups of NT, TT and DD levels (p = 0.008, p = 0.001, p = 0.002). No significant difference was detected in terms of the NT / TT, DD / TT and DD / NT rates (p = 0.222, p = 0.222, p = 0.222). Serum NT, TT, DD levels in patients with prostatitis and prostate cancer were found significantly lower compared to the control group. This indicates that just as inflammation, prostate cancer also increases oxidative stress on tissues.


A Systematic Review of Tablet Computers and Portable Media Players as Speech Generating Devices for Individuals with Autism Spectrum Disorder.
Powerful, portable, off-the-shelf handheld devices, such as tablet based computers (i.e., iPad(®); Galaxy(®)) or portable multimedia players (i.e., iPod(®)), can be adapted to function as speech generating devices for individuals with autism spectrum disorders or related developmental disabilities. This paper reviews the research in this new and rapidly growing area and delineates an agenda for future investigations. In general, participants using these devices acquired verbal repertoires quickly. Studies comparing these devices to picture exchange or manual sign language found that acquisition was often quicker when using a tablet computer and that the vast majority of participants preferred using the device to picture exchange or manual sign language. Future research in interface design, user experience, and extended verbal repertoires is recommended.


History of the Collegium Internationale Allergologicum: A Very Special Society Devoted to Allergy and Immunology.
The Collegium Internationale Allergologicum (CIA) was founded on 15 October 1954 in London by a group of 48 international allergists and immunologists from 18 countries of all continents, among them such distinguished scientists as Carl Prausnitz-Giles, Sir Henry Dale, Paul Kallos, and many others. Contrary to other international associations in the field, this Collegium limited the number of members in order to allow more intense and open discussions in "the humble spirit of scientific enquiry, friendly cooperation, good fellowship and professional relationships in the field of allergy" as stated in the statutes. It is not possible to apply for membership, and one has to be proposed by at least 2 CIA members and invited to present at least once at a symposium. Over the decades, a rhythm of biannual symposia developed, the 32nd held in Palma de Mallorca in October 2018. These symposia went around the world from London, Rome, Copenhagen, New Orleans, Puerto Vallarta, Nantucket, Hakone, Konstanz, Goeteborg, and Sorrento, just to name a few places. Preferably they were held on islands such as Capri, Corfu, Martinique, Curacao, Bornholm, Malta, and Ischia in order to make it more difficult for people to arrive late or leave early. It is expected that participants stay over the whole length of the 5-day symposium. On these symposia, it is good custom to also present unpublished data, so participants get the latest news. The most important developments in the field of Allergy and Clinical Immunology have been discussed at early stage and sometimes by speakers who later won the Nobel Prize. While all presentations are equal, be it oral communications or posters, there are 3 special lectures, namely the Carl Prausnitz lecture, the Paul Kallos lecture, and a "Relaxing from Immunology" lecture which can be devoted to any interesting topic not necessarily related to medicine or allergy. Since many years, the contents of the symposium are published in a proceedings volume, over a longtime printed within the "International Archives of Allergy and Immunology" which until now is the official journal of the Collegium. Participants agree that in the flood of more and more scientific congresses and larger events, the CIA Symposia are unique in their openness and friendly scientific interchange.


Optimal batch determination for improved harmonization and prognostication of multi-center PET/CT radiomics feature in head and neck cancer.
Objective. To determine the optimal approach for identifying and mitigating batch effects in PET/CT radiomics features, and further improve the prognosis of patients with head and neck cancer (HNC), this study investigated the performance of three batch harmonization methods.Approach. Unsupervised harmonization identified the batch labels by K-means clustering. Supervised harmonization regarding the image acquisition factors (center, manufacturer, scanner, filter kernel) as known/given batch labels, and Combat harmonization was then implemented separately and sequentially based on the batch labels, i.e. harmonizing features among batches determined by each factor individually or harmonizing features among batches determined by multiple factors successively. Extensive experiments were conducted to predict overall survival (OS) on public PET/CT datasets that contain 800 patients from 9 centers.Main results. In the external validation cohort, results show that compared to original models without harmonization, Combat harmonization would be beneficial in OS prediction with C-index of 0.687-0.740 versus 0.684-0.767. Supervised harmonization slightly outperformed unsupervised harmonization in all models (C-index: 0.692-0.767 versus 0.684-0.750). Separate harmonization outperformed sequential harmonization in CT_m+clinic and CT_cm+clinic models with C-index of 0.752 and 0.722, respectively, while sequential harmonization involved clinical features in PET_rs+clinic model further improving the performance and achieving the highest C-index of 0.767.Significance. Optimal batch determination especially sequential harmonization for Combat holds the potential to improve the prognostic power of radiomics model in multi-center HNC dataset with PET/CT imaging.


Seropositivity to HCV in Macaca fascicularis.
Several non-human primate species are used as laboratory animals for research purposes. Non human primates represent a potential hazard for laboratory animal handlers as they exceed all other species in importance as potentiators of disease in laboratory personnel (Quist K.D., 1972). Hepatitis viruses cause some of the prevalent diseases in man which constitute an important public health problem. The first outbreak of the infection was related to non human primates and occurred in 1958-1960 in USA, with more then 200 human cases. Chimpanzee is the main species that has been implicated but others have also been involved. We report a case of seropositivity to HCV antigens in Macaca fascicularis using a third generation RIBA assay. The nature of reactivity of the positive samples could not be resolved as no animal in the breeder colony had been exposed to an HCV source. Furthermore, Macaca spp. did not appear to be a susceptible species in previous studies.


Switchable Opening and Closing of a Liquid Marble via Ultrasonic Levitation.
Liquid marbles have promising applications in the field of microreactors, where the opening and closing of their surfaces plays a central role. We have levitated liquid water marbles using an acoustic levitator and, thereby, achieved the manipulation of the particle shell in a controlled manner. Upon increasing the sound intensity, the stable levitated liquid marble changes from a quasi-sphere to a flattened ellipsoid. Interestingly, a cavity on the particle shell can be produced on the polar areas, which can be completely healed when decreasing the sound intensity, allowing it to serve as a microreactor. The integral of the acoustic radiation pressure on the part of the particle surface protruding into air is responsible for particle migration from the center of the liquid marble to the edge. Our results demonstrate that the opening and closing of the liquid marble particle shell can be conveniently achieved via acoustic levitation, opening up a new possibility to manipulate liquid marbles coated with non-ferromagnetic particles.


The Endonasal Endoscopic Approach to Different Sinonasal Fungal Balls.
Fungal ball sinusitis is a sinonasal fungus ball that usually affects immunocompetent adults with female predominance. The most affected sinus is the maxillary sinus. Aspergillus species is the most typically found fungus. Computed tomography (CT) scan is the gold standard tool in order to diagnose fungal ball sinusitis. The ultimate method for a fungal ball is functional endoscopic sinus surgery (FESS), which has a high success rate and a low morbidity rate. This study aims to demonstrate the various clinical presentations of fungal ball sinusitis including isolated maxillary sinus, sphenoid sinus, simultaneous occurrence of maxillary and sphenoid fungal ball, and post endonasal endoscopic pituitary surgery fungal ball with various age groups. Also, this study aims to emphasize the importance of early diagnosis and treatment in such cases. Patients and Methods. A retrospective study that was carried in the otorhinolaryngology department of two hospitals: King Fahad Specialist Hospital and Qatif Central Hospital, Eastern Region, Saudi Arabia. The study was conducted on a total of 16 patients who were diagnosed with paranasal sinuses fungal ball in an 11-year period from January 2008 and November 2019. Out of 16 patients with paranasal sinuses fungal ball, 11 cases were female and 5 males, with age ranging between 16 and 46 years. Results showed eight isolated sphenoid (50%), six isolated maxillary fungal ball (38%), one simultaneous occurrence of the sphenoid and maxillary fungal ball (6%), and one post endonasal endoscopic pituitary surgery for pituitary adenoma (6%). CT scan was performed for all 16 cases which is the standard tool for the diagnosis of the fungal ball. Fungal ball may present with variety of symptoms but most commonly with postnasal discharge (PND), headache, and facial pain. CT sinuses is the diagnostic radiological modality to confirm the diagnosis. The FESS functional endoscopic sinus surgery is the gold safe approach for patients with fungal ball to manage their symptoms, confirm the diagnosis, and removal of disease with no morbidities.


Allograft and autograft purging using immunotoxins in clinical bone marrow transplantation for hematologic malignancies.
Bone marrow manipulation is an essential procedure when bone marrow transplantation (BMT) is used to improve the chances of survival among high risk patients with hematologic malignancies. Ex vivo purging of donor T cells effectively prevents a fatal reaction known as graft-versus-host disease in allogeneic BMT. Ex vivo purging of residual leukemia cells from autologous marrow can virtually eliminate the risk of autograft contamination. Immunotoxins are powerful and selective reagents for these tasks. However, ex vivo purging may be insufficient by itself to overcome the high risk of relapse that confronts many patients undergoing autologous BMT. Bone marrow manipulation may even present problems of its own, such as loss of the graft-versus-leukemia effect when allogeneic marrow is T cell depleted. We are currently evaluating immunotoxins containing pokeweed antiviral protein in clinical trials as in vivo purging reagents that may reduce the risk of relapse for BMT patients.


Prevalence and Predictors of Sleep Apnea Risk among Ghanaian Stroke Survivors.
Sleep apnea (SA) has emerged as a potent risk factor for stroke recurrence and mortality. The burden of SA among stroke survivors in sub-Saharan Africa where stroke incidence and mortality are escalating is unknown. We sought to assess the prevalence of SA risk and its clinical correlates and predictors among Ghanaian stroke survivors. This cross-sectional study involved 200 consecutive stroke survivors attending a neurology clinic in a tertiary medical center in Kumasi, Ghana. The validated Berlin, STOP-BANG, and Epworth Sleepiness Scale questionnaires were administered to all eligible subjects to assess SA risk and daytime somnolence, and their demographic and clinical information, health-related quality of life, and symptoms of depression were collected using the questionnaires. The median (interquartile range) age of stroke survivors was 62 (52-72) years and 52.5% were male. Ninety-nine (49.5%) subjects were identified as high risk for SA using the Berlin questionnaire, whereas 26 (13%), 137 (68.5%), and 37 (18.5%) subjects were classified as low, intermediate, and high risk for SA, respectively, using the STOP-BANG questionnaire. Patients at high risk of SA were significantly older, used excess alcohol, and were less able to perform activities of daily living, although their mean National Institutes of Health Stroke Scale scores were significantly lower than those with low risk for SA. None of the stroke survivors had ever been screened for SA. One out of every 2 stroke survivors attending a neurology clinic in Ghana is at high risk for undiagnosed SA. Greater regional awareness about SA presence and outcomes among patients and providers is warranted.


Adrenal response to ACTH stimulation in Rusa deer (Cervus rusa timorensis).
Resting cortisol values in immobilized mature Rusa stags (Cervus rusa timorensis) and the response to synthetic ACTH were investigated. The mean level of cortisol in mature Rusa stags was found to be 3.80 ng/ml (SD = 0.87, N = 18). Over the range 0.37-6.0 i.u. the adrenal response to ACTH challenge was linearly related to the log dose ACTH administered (r = 0.998). More than 6 i.u. of ACTH caused maximal stimulation of the adrenal gland. Rusa deer appear to be much more sensitive to ACTH administration than other species.


The ethmoid labyrinth. An anatomical and radiological study.
After an osteological description of the ethmoid labyrinth, the authors examine the radiological techniques which best display the topography, interrelation and configuration of the ethmoid cells. On the basis of their observations they conclude that standard radiographic examinations cannot provide an adequately clear anatomical-radiological representation of these cells and must therefore be supplemented with polytomography and computerized tomography.


Is moral beauty different from facial beauty? Evidence from an fMRI study.
Is moral beauty different from facial beauty? Two functional magnetic resonance imaging experiments were performed to answer this question. Experiment 1 investigated the network of moral aesthetic judgments and facial aesthetic judgments. Participants performed aesthetic judgments and gender judgments on both faces and scenes containing moral acts. The conjunction analysis of the contrasts 'facial aesthetic judgment > facial gender judgment' and 'scene moral aesthetic judgment > scene gender judgment' identified the common involvement of the orbitofrontal cortex (OFC), inferior temporal gyrus and medial superior frontal gyrus, suggesting that both types of aesthetic judgments are based on the orchestration of perceptual, emotional and cognitive components. Experiment 2 examined the network of facial beauty and moral beauty during implicit perception. Participants performed a non-aesthetic judgment task on both faces (beautiful vs common) and scenes (containing morally beautiful vs neutral information). We observed that facial beauty (beautiful faces > common faces) involved both the cortical reward region OFC and the subcortical reward region putamen, whereas moral beauty (moral beauty scenes > moral neutral scenes) only involved the OFC. Moreover, compared with facial beauty, moral beauty spanned a larger-scale cortical network, indicating more advanced and complex cerebral representations characterizing moral beauty.


CADASIL and autoimmunity: coexistence in a family with the R169C mutation at exon 4 of the NOTCH3 gene.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited small vessel disease caused by mutations of the NOTCH3 gene, which result in degeneration of vascular smooth muscle cells, arteriolar stenosis, and impaired cerebral blood flow. For clinicians this is the commonest hereditary adult-onset condition causing stroke and vascular dementia at middle age. Atypical phenotypes have been recognized, and the disease is probably underdiagnosed in the wider stroke population. Coexistence of autoimmunity is atypical and has been described only in occasional patients. Three members of a Greek family from the island of Lesvos of North East Greece were evaluated. The patients come from a four-generation family in which there were at least seven members with clinical data suggestive of CADASIL. We describe here the clinical, imaging and biochemical findings in this family with R169C mutation at exon 4 and presenting additional clinical and biochemical findings suggestive of autoimmune disorder. DNA was extracted from whole blood using standard procedures for sequencing. Three affected members of this family carried the R169C. In a phenotypic analysis of affected individuals from four generations with CADASIL, the disease was characterized by migraine attacks, recurrent subcortical infarcts, and cognitive decline with typical anterior temporal lobe white matter lesions. At least 3 mutation carriers from two generations had increased antinuclear antibody (ANA) titers and various combinations of rash, joint pains, photosensitivity, and renal involvement. This is a rare description of the coexistence of autoimmunity in CADASIL patients with possible worsening clinical effects. The study extends the spectrum of atypical presentation of CADASIL. The coexistence of autoimmunity does not necessarily exclude CADASIL, but may cause an additional diagnostic and therapeutic challenge. This autoimmune disorder may have increased the severity of the disease and, additionally, may be related to the pathogenetic mechanisms of CADASIL. It is possible that the NOTCH3 mutation alone is not enough to trigger autoimmunity since, in the case of our family, the R169C mutation has already been described in other families with no evidence of coexistent autoimmunity. Other genetic or environmental factors or interactions and/or common pathways between the vascular and immune systems are probably co-operating. Further, prospective studies are needed to clarify the prevalence and types of autoimmune disorders present in CADASIL families.


2010 Triumph Award winners. AHIMA honors those who make a difference.
The AHIMA Triumph Awards are national awards designed to recognize those special individuals who make a difference in the HIM profession. The awards honor leadership in the HIM field, reward contributions that build our knowledge base, recognize excellence in preparing future HIM professionals, and encourage fresh talent and new leadership.


[Effect of somatotropin on cathepsin D in the liver of hypo- and hyperthyroid rats].
In experiments on albino male rats the dependence of the cathepsin D activity on the thyroid hormone- and somatotropin levels in the organism was studied. It was demonstrated that the total cathepsin D activity in the liver of hypothyroid rats is lowered by 37% and that of hyperthyroid animals is augmented by 63%. Somatotropin injected to intact rats within 10 days in doses of 0.5 mg/100 g body weight enhanced the total enzyme activity by 19%. Hormone injection to hypothyroid animals returns to the normal cathepsin D activity, whereas in hyperthyroid rats the enzyme effect is significantly lowered under hormone action. Protein content in the nucleus-free homogenate of the hypothyroid rat liver does not differ from that of intact rats and is increased by 27% in hyperthyroid animals. Exogenous somatotropin returns to normal protein content in hyperthyroid rats.


An overview of the evolution of enterovirus 71 and its clinical and public health significance.
Since its discovery in 1969, enterovirus 71 (EV71) has been recognised as a frequent cause of epidemics of hand-foot-and-mouth disease (HFMD) associated with severe neurological sequelae in a small proportion of cases. There has been a significant increase in EV71 epidemic activity throughout the Asia-Pacific region since 1997. Recent HFMD epidemics in this region have been associated with a severe form of brainstem encephalitis associated with pulmonary oedema and high case-fatality rates. The emergence of large-scale epidemic activity in the Asia-Pacific region has been associated with the circulation of three genetic lineages that appear to be undergoing rapid evolutionary change. Two of these lineages (B3 and B4) have not been described previously and appear to have arisen from an endemic focus in equatorial Asia, which has served as a source of virus for HFMD epidemics in Malaysia, Singapore and Australia. The third lineage (C2) has previously been identified [Brown, B.A. et al. (1999) J. Virol. 73, 9969-9975] and was primarily responsible for the large HFMD epidemic in Taiwan during 1998. As EV71 appears not to be susceptible to newly developed antiviral agents and a vaccine is not currently available, control of EV71 epidemics through high-level surveillance and public health intervention needs to be maintained and extended throughout the Asia-Pacific region. Future research should focus on (1) understanding the molecular genetics of EV71 virulence, (2) identification of the receptor(s) for EV71, (3) development of antiviral agents to ameliorate the severity of neurological disease and (4) vaccine development to control epidemics. Following the successful experience of the poliomyelitis control programme, it may be possible to control EV71 epidemics if an effective live-attenuated vaccine is developed.


Spectrum of severe chronic kidney disease in India: a clinicopathological study.
The healthcare burden due to chronic kidney disease has increased worldwide in the past decade. Elucidating the aetiology of chronic kidney disease may help in identifying strategies for prevention, both in the population and the Individual patient. Only a clinicopathological study can define the exact spectrum of chronic kidney disease since epidemiological studies have not shown a consistent aetiological profile. The histological evidence used to support the diagnosis varies with the degree to which renal biopsy is done. Renal biopsy is the gold standard in making an aetiological diagnosis in renal failure, but as a diagnostic tool in chronic kidney disease it is underutilized. This prospective study done at Christian Medical College, Vellore in southern India from 1998 to 2003 aimed to determine the aetiological profile of severe chronic kidney disease by analysing renal biopsies. The value of pre-renal biopsy clinical Judgement in predicting the histological diagnosis was also assessed. Patients with diabetic nephropathy were excluded from the study. Four hundred and fifty-seven patients had evidence of chronic kidney disease as evidenced on biopsy as well as on clinical parameters. Three hundred and twenty-two of these patients (70.5%) had glomerulonephritis as the histological diagnosis. Fifty-five (12%) had Interstitial nephritis, 30 (6.6%) had hypertensive arteriosclerosis and 28 (6.1%) had metabolic nephropathies. The positive predictive value of a pre-biopsy clinical diagnosis in predicting interstitial nephritis was very low (33%). A large number of patients clinically diagnosed to have chronic interstitial nephritis had other aetiologies of chronic kidney disease. Glomerulonephritis was the most common cause of chronic kidney disease, not including diabetic nephropathy, followed by interstitial disease and benign arterionephrosclerosis. In patients with unidentified severe chronic kidney disease, renal biopsy provided an aetiological diagnosis.


Physiological and pharmacological roles of nucleoside transporter proteins.
Nucleoside transporter proteins, CNT and ENT, encoded by gene families SLC28 and SLC29, respectively, mediate the uptake of natural nucleosides (among them adenosine) and are major routes of entry for a variety of nucleoside analogs used in anticancer and antiviral therapies. Expression of NT proteins is apparently redundant in most cell types, and the elucidation of their particular physiological roles still remains elusive. Moreover, transporter-mediated uptake of nucleoside-derived anticancer drugs is crucial for the pharmacogenomic response triggered by these molecules in tumor cells. This review focuses on recent data demonstrating that nucleoside transporters, particularly CNTs, can play physiological roles other than salvage, whereas particular NT isoforms can significantly contribute to the transcriptomic response triggered by nucleoside analogs in cancer cells.


Rubeosis iridis in patients with diabetes: not forgetting oculoischaemic syndrome as a differential.
This case illustrates an oculoischaemic syndrome presenting with iris neovascularisation in a patient with established diabetic retinopathy. It highlights the importance of considering the differential diagnosis of rubeosis in all patients, including those with an underlying vascular pathology. Moreover, it urges clinicians to consider the sequelae of a compromised vascular system, such as the iatrogenic central retinal artery occlusion as a result of intravitreal injections. Early diagnosis not only informs correct ophthalmic treatment, but is crucial in preventing ischaemic stroke and, therefore, reducing the risk of systemic morbidity and mortality.


Serotonin receptor subtypes required for ventilatory long-term facilitation and its enhancement after chronic intermittent hypoxia in awake rats.
Respiratory long-term facilitation (LTF), a serotonin-dependent, persistent augmentation of respiratory activity after episodic hypoxia, is enhanced by pretreatment of chronic intermittent hypoxia (CIH; 5 min 11-12% O2-5 min air, 12 h/night for 7 nights). The present study examined the effects of methysergide (serotonin 5-HT1,2,5,6,7 receptor antagonist), ketanserin (5-HT2 antagonist), or clozapine (5-HT2,6,7 antagonist) on both ventilatory LTF and the CIH effect on ventilatory LTF in conscious male adult rats to determine which specific receptor subtype(s) is involved. In untreated rats (i.e., animals not exposed to CIH), LTF, induced by five episodes of 5-min poikilocapnic hypoxia (10% O2) separated by 5-min normoxic intervals, was measured twice by plethysmography. Thus the measurement was conducted 1-2 days before (as control) and approximately 1 h after systemic injection of methysergide (1 mg/kg ip), ketanserin (1 mg/kg), or clozapine (1.5 mg/kg). Resting ventilation, metabolic rate, and hypoxic ventilatory response (HVR) were unchanged, but LTF ( approximately 18% above baseline) was eliminated by each drug. In CIH-treated rats, LTF was also measured twice, before and approximately 8 h after CIH. Vehicle, methysergide, ketanserin, or clozapine was injected approximately 1 h before the second measurement. Neither resting ventilation nor metabolic rate was changed after CIH and/or any drug. HVR was unchanged after methysergide and ketanserin but reduced in four of seven clozapine rats. The CIH-enhanced LTF ( approximately 28%) was abolished by methysergide and clozapine but only attenuated by ketanserin (to approximately 10%). Collectively, these data suggest that ventilatory LTF requires 5-HT2 receptors and that the CIH effect on LTF requires non-5-HT2 serotonin receptors, probably 5-HT6 and/or 5-HT7 subtype(s).


[Leiomyosarcoma of the esophagus].
The authors describe the anatomo-clinical characteristics of a case of leiomyosarcoma of the oesophagus which came under their observation, emphasizing its rarity: 39 cases in the literature examined. They then discuss the numerous problems that this neoplasia involves, especially diagnostic differentiation from other sarcomas and the pseudo-sarcomatous reaction of the stroma during the course of carcinomas. Lastly they divide leiomyosarcoma of the oesophagus into polypoid forms and infiltrating forms, owing to the different therapeutic and prognostic implications that such distinction implies.


Targeting type-2 metabotropic glutamate receptors to protect vulnerable hippocampal neurons against ischemic damage.
To examine whether metabotropic glutamate (mGlu) receptors have any role in mechanisms that shape neuronal vulnerability to ischemic damage, we used the 4-vessel occlusion (4-VO) model of transient global ischemia in rats. 4-VO in rats causes a selective death of pyramidal neurons in the hippocampal CA1 region, leaving neurons of the CA3 region relatively spared. We wondered whether changes in the expression of individual mGlu receptor subtypes selectively occur in the vulnerable CA1 region during the development of ischemic damage, and whether post-ischemic treatment with drugs targeting the selected receptor(s) affords neuroprotection. We found that 4-VO caused significantly reduction in the transcript of mGlu2 receptors in the CA1 region at times that preceded the anatomical evidence of neuronal death. Down-regulation of mGlu2 receptors was associated with reduced H3 histone acetylation at the Grm2 promoter. The transcripts of other mGlu receptor subtypes were unchanged in the CA1 region of 4-VO rats. Ischemia did not cause changes in mGlu2 receptor mRNA levels in the resistant CA3 region, which, interestingly, were lower than in the CA1 region. Targeting the mGlu2 receptors with selective pharmacologic ligands had profound effects on ishemic neuronal damage. Post-ischemic oral treatment with the selective mGlu2 receptor NAM (negative allosteric modulator), ADX92639 (30 mg/kg), was highly protective against ischemic neuronal death. In contrast, s.c. administration of the mGlu2 receptor enhancer, LY487379 (30 mg/kg), amplified neuronal damage in the CA1 region and extended the damage to the CA3 region. These findings suggest that the mGlu2 receptor is an important player in mechanisms regulating neuronal vulnerability to ischemic damage, and that mGlu2 receptor NAMs are potential candidates in the experimental treatments of disorders characterized by brain hypoperfusion, such as hypovolemic shock and cardiac arrest.


Extending Participatory Sensing to Personal Exposure Using Microscopic Land Use Regression Models.
Personal exposure is sensitive to the personal features and behavior of the individual, and including interpersonal variability will improve the health and quality of life evaluations. Participatory sensing assesses the spatial and temporal variability of environmental indicators and is used to quantify this interpersonal variability. Transferring the participatory sensing information to a specific study population is a basic requirement for epidemiological studies in the near future. We propose a methodology to reduce the void between participatory sensing and health research. Instantaneous microscopic land-use regression modeling (µLUR) is an innovative approach. Data science techniques extract the activity-specific and route-sensitive spatiotemporal variability from the data. A data workflow to prepare and apply µLUR models to any mobile population is presented. The µLUR technique and data workflow are illustrated with models for exposure to traffic related Black Carbon. The example µLURs are available for three micro-environments; bicycle, in-vehicle, and indoor. Instantaneous noise assessments supply instantaneous traffic information to the µLURs. The activity specific models are combined into an instantaneous personal exposure model for Black Carbon. An independent external validation reached a correlation of 0.65. The µLURs can be applied to simulated behavioral patterns of individuals in epidemiological cohorts for advanced health and policy research.


Assessing the Risk of Probiotic Dietary Supplements in the Context of Antibiotic Resistance.
Probiotic bacteria are known to harbor intrinsic and mobile genetic elements that confer resistance to a wide variety of antibiotics. Their high amounts in dietary supplements can establish a reservoir of antibiotic resistant genes in the human gut. These resistant genes can be transferred to pathogens that share the same intestinal habitat thus resulting in serious clinical ramifications. While antibiotic resistance of probiotic bacteria from food, human and animal sources have been well-documented, the resistant profiles of probiotics from dietary supplements have only been recently studied. These products are consumed with increasing regularity due to their health claims that include the improvement of intestinal health and immune response as well as prevention of acute and antibiotic-associated diarrhea and cancer; but, a comprehensive risk assessment on the spread of resistant genes to human health is lacking. Here, we highlight recent reports of antibiotic resistance of probiotic bacteria isolated from dietary supplements, and propose complementary strategies that can shed light on the risks of consuming such products in the context of a global widespread of antibiotic resistance. In concomitant with a broader screening of antibiotic resistance in probiotic supplements is the use of computational simulations, live imaging and functional genomics to harvest knowledge on the evolutionary behavior, adaptations and dynamics of probiotics studied in conditions that best represent the human gut including in the presence of antibiotics. The underlying goal is to enable the health benefits of probiotics to be exploited in a responsible manner and with minimal risk to human health.


Cefodizime (HR 221) potentiation of human neutrophil oxygen-independent bactericidal activity.
The enhanced bactericidal activity of human neutrophils induced by cefotaxime and cefodizime, two methoxy-imino-amino- 2-thiazolyl cephalosporins, is linked to the cell stimulation of oxygen-dependent and oxygen-independent killing systems, respectively. Cefotaxime enhances both the killing and the oxidative response of neutrophils to opsonized particulate stimuli (bacteria for both activities and opsonized zymosan for the oxidative burst). These effects were not observed with non-opsonized particles (bacteria or zymosan) or soluble stimuli. On the contrary, cefodizime enhances killing of opsonized and non-opsonized bacteria by neutrophils regardless of treatment with phenylbutazone which blocks neutrophil oxidative metabolism. Cefodizime does not universally alter the oxidative burst induced by various stimuli, but has been shown to enhance the bactericidal activity of crude extracts of neutrophil granules. The data suggest that cefodizime and non O2-dependent killing systems of neutrophils cooperate in killing bacteria.


Binding of [(3)H]prazosin to alpha(1A)- and alpha(1B)-adrenoceptors, and to a cimetidine-sensitive non-alpha(1) binding site in rat kidney membranes.
[(3)H]Prazosin bound to alpha(1A)- and alpha(1B)-adrenoceptors, as well as to a cimetidine-sensitive non-alpha(1)-adrenoceptor binding site in rat kidney membranes. An experimental design is presented where the alpha(1)-adrenoceptors are selectively exposed by blocking the non-alpha(1) binding site with 60 microM cimetidine. Conversely, the non-alpha(1) binding site can be selectively exposed by blocking the alpha(1)-adrenoceptors with 600 nM metitepine. The identity of the non-alpha(1) binding site for [(3)H]prazosin in the rat kidney, herein pharmacologically characterized by 33 competing substances, is still unknown.


Modulation of Macropinocytosis-Mediated Internalization Decreases Ocular Toxicity of Antibody-Drug Conjugates.
AGS-16C3F is an antibody-drug conjugate (ADC) against ectonucleotide pyrophosphatase/phosphodiesterase 3 (ENPP3) containing the mcMMAF linker-payload currently in development for treatment of metastatic renal cell carcinoma. AGS-16C3F and other ADCs have been reported to cause ocular toxicity in patients by unknown mechanisms. To investigate this toxicity, we developed an in vitro assay using human corneal epithelial cells (HCEC) and show that HCECs internalized AGS-16C3F and other ADCs by macropinocytosis, causing inhibition of cell proliferation. We observed the same mechanism for target-independent internalization of AGS-16C3F in fibroblasts and human umbilical vein endothelial cells (HUVEC). Macropinocytosis-mediated intake of macromolecules is facilitated by the presence of positive charges or hydrophobic residues on the surface of the macromolecule. Modification of AGS-16C3F, either by attachment of poly-glutamate peptides, mutation of residue K16 to D on AGS-16C3F [AGS-16C3F(K16D)], or decreasing the overall hydrophobicity via attachment of polyethylene glycol moieties, significantly reduced cytotoxicity against HCECs and other primary cells. Rabbits treated with AGS-16C3F showed significant ocular toxicity, whereas those treated with AGS-16C3F(K16D) presented with less severe and delayed toxicities. Both molecules displayed similar antitumor activity in a mouse xenograft model. These findings establish a mechanism of action for target-independent toxicities of AGS-16C3F and ADCs in general, and provide methods to ameliorate these toxicities.Significance: These findings reveal a mechanism for nonreceptor-mediated toxicities of antibody drug conjugates and potential solutions to alleviate these toxicities. Cancer Res; 78(8); 2115-26. ©2018 AACR.


Design of cationic nanostructured heterolipid matrices for ocular delivery of methazolamide.
Solid lipid nanoparticles (SLNs) formulated from one type of lipid (homolipid) suffer from low drug encapsulation and drug bursting due to crystallization of the lipid into the more ordered β modification, which leads to decreased drug entrapment and faster drug release. This study assessed the feasibility of using nanostructured lipid matrices (NLMs) for ocular delivery of methazolamide-(MZA) adopting heterolipids composed of novel mixtures of Compritol (®) and cetostearyl alcohol (CSA), and stabilized by Tween 80(®). The systems were prepared using the modified high shear homogenization followed by ultrasonication method, which avoids the use of organic solvents. A 3(2) full factorial design was constructed to study the influence of two independent variables, namely the ratio of CSA:Compritol and the concentration of Tween 80, each in three levels. The dependent variables were the entrapment efficiency percentages (EE%), mean particle size (PS), polydispersity index (PDI), and zeta potential (ZP). In vivo intraocular pressure (IOP) lowering activity for the selected formulae was compared to that of MZA solution. The results showed that increasing the ratio of CSA to Compritol increased the EE% and PS, while increasing the concentration of Tween 80, decreased PS with no significant effect on EE%. The ZP values of all formulae were positive, and greater than 30 mV. The best formula, composed of 4% CSA, 2% Compritol, 0.15% stearylamine, and 2% Tween 80, with EE% of 25.62%, PS of 207.1 nm, PDI of 0.243, and ZP of 41.50 mV, showed in vitro sustained release properties for 8 hours and lowered the intraocular pressure by 8.3 mmHg within 3 hours, with this drop in pressure lasting for 12 hours.


A province-wide school nutrition policy and food consumption in elementary school children in Prince Edward Island.
Although the majority of Canadian provinces have indicated that they have adopted new school nutrition policies, there have been few if any systematic evaluations of these policies. In Prince Edward Island, a nutrition policy for elementary schools was adopted province-wide in 2006. In the present study, we assessed the nutritional benefits of the new policy by examining changes in student food consumption prior to and one year following implementation of the policy. We surveyed fifth and sixth grade children from 11 elementary schools in Prince Edward Island in 2001/02 (pre-policy implementation) and fifth and sixth grade children from the same 11 schools in 2007 (post-policy implementation). Food consumption was assessed using a self-administered validated food frequency questionnaire. We applied multilevel logistic regression to compare pre-/post-policy implementation differences in the proportion of students meeting Canada's Food Guide recommendations for vegetables and fruit (VF) and milk and alternatives (MA) and in the proportion of students consuming < 3 servings of low nutrient dense foods (LNDF) daily. Relative to students in 2001/02, students surveyed in 2007 were 2.14 (95% CI 1.62-2.82) times more likely to report consuming less than three daily servings of LNDF and were more likely to meet recommendations for VF (OR 1.44, 95% CI 1.00-2.07) and MA (OR 1.27, 95% CI 0.98-1.64). The present study is the first in Canada to show favourable changes in student food consumption that parallel the introduction of a school nutrition policy.


In vitro screening for synergism of high-linear energy transfer 213Bi-radiotherapy with other therapeutic agents for the treatment of B-cell chronic lymphocytic leukemia.
External beam radiotherapy and beta-radioimmunotherapy (RIT) are effective treatments for lymphoid malignancies. The development of RIT with alpha-emitters is attractive, owing to the high (LET) nature and short path length of alpha particles allowing for higher tumor cell kill and lower toxicity to healthy tissues. The aim of this study was to assess the response of B-Cell chronic lymphocytic leukemia (B-CLL) cells in vitro after treatment with chemotherapy (cisplatin, fludarabine, doxorubicin, or vincristine) or other pharmaceuticals (colchicine, simvastatin, or cyclosporin A) in combination with (60)Co-gamma or (213)Bi-alpha-irradiation. (213)Bi was eluted from a (225)Ac generator. Apoptosis was scored by flow cytometric analysis of the cells stained with Annexin-V and 7 amino actinomycin D. Metabolic activity was assessed by a MTT assay. The response induced by alpha- irradiation is systematically higher than the response induced by gamma-irradiation. The combination of drug treatment with alpha-irradiation induced a systematic, higher response, compared to treatment with drugs alone, even for the highest concentrations used. For all the drugs used in this study, synergism or additivity was demonstrated for the combination of drugs and radiotherapy with a stronger effect for alpha-particles. The results of this in vitro study highlight a potential benefit of alpha-irradiation in combination with the drugs considered in this study.


Cellular interaction and the environment in lymphocyte development: the roles of antigen, histocompatibility, and growth factors in T cell-dependent B cell stimulation.
T cell-dependent B cell stimulation depends on cellular interactions between macrophages, T cells, and B cells. T cells recognize antigen in the context of Ia determinants on macrophages. This leads to the activation of helper T cells and to the production of helper factor(s) either by the activated helper T cells or by the macrophages. Cloned lines of helper T cells produce factors("help') for B cell replication and Ig secretion in the presence of histocompatible macrophages and of specific antigen. These factors stimulate histocompatible, as well as histoincompatible, mitogen-activated B cell blasts polyclonally. Thus, neither antigen nor histocompatibility, but antigen-unspecific, soluble factors are required to stimulate an activated B cell blast through the next round of division. Small resting B cells, however, are not stimulated to replication by these factors, but only to polyclonal, H-2-unrestricted maturation to Ig-secreting cells. Replication (and Ig secretion) of small resting B cells, however, is only induced when antigen-specific small B cells bind their specific antigen via surface Ig molecules and interact with histocompatible helper T cells. The preference of the resting B cells for such collaboration with T cell help is mapped to the K-end of the H-2 locus and probably constitutes the antigen expressed on B cells by the I region. It appears that a resting B cell is excited by the binding of specific antigen to surface Ig and by the interaction of its surface Ia with helper T cells. After this dual recognition the excited B cell can be stimulated by the antigen-unspecific factor(s) generated by the interaction of helper T cells, adherent cells and antigen to initiate growth. Immune induction of a B cell thus involves three controlling elements: Ig, Ia, and B cell growth factor receptors.


Rational Design, Synthesis, and Biological Evaluation of Heterocyclic Quinolones Targeting the Respiratory Chain of Mycobacterium tuberculosis.
A high-throughput screen (HTS) was undertaken against the respiratory chain dehydrogenase component, NADH:menaquinone oxidoreductase (Ndh) of Mycobacterium tuberculosis (Mtb). The 11000 compounds were selected for the HTS based on the known phenothiazine Ndh inhibitors, trifluoperazine and thioridazine. Combined HTS (11000 compounds) and in-house screening of a limited number of quinolones (50 compounds) identified ∼100 hits and four distinct chemotypes, the most promising of which contained the quinolone core. Subsequent Mtb screening of the complete in-house quinolone library (350 compounds) identified a further ∼90 hits across three quinolone subtemplates. Quinolones containing the amine-based side chain were selected as the pharmacophore for further modification, resulting in metabolically stable quinolones effective against multi drug resistant (MDR) Mtb. The lead compound, 42a (MTC420), displays acceptable antituberculosis activity (Mtb IC50 = 525 nM, Mtb Wayne IC50 = 76 nM, and MDR Mtb patient isolates IC50 = 140 nM) and favorable pharmacokinetic and toxicological profiles.


Dietary acrylamide and cancer risk: an updated meta-analysis.
The debate on the potential carcinogenic effect of dietary acrylamide is open. In consideration of the recent findings from large prospective investigations, we conducted an updated meta-analysis on acrylamide intake and the risk of cancer at several sites. Up to July 2014, we identified 32 publications. We performed meta-analyses to calculate the summary relative risk (RR) of each cancer site for the highest versus lowest level of intake and for an increment of 10 µg/day of dietary acrylamide, through fixed-effects or random-effects models, depending on the heterogeneity test. Fourteen cancer sites could be examined. No meaningful associations were found for most cancers considered. The summary RRs for high versus low acrylamide intake were 0.87 for oral and pharyngeal, 1.14 for esophageal, 1.03 for stomach, 0.94 for colorectal, 0.93 for pancreatic, 1.10 for laryngeal, 0.88 for lung, 0.96 for breast, 1.06 for endometrial, 1.12 for ovarian, 1.00 for prostate, 0.93 for bladder and 1.13 for lymphoid malignancies. The RR was of borderline significance only for kidney cancer (RR = 1.20; 95% confidence interval, CI, 1.00-1.45). All the corresponding continuous estimates ranged between 0.95 and 1.03, and none of them was significant. Among never-smokers, borderline associations with dietary acrylamide emerged for endometrial (RR = 1.23; 95% CI, 1.00-1.51) and ovarian (RR = 1.39; 95% CI, 0.97-2.00) cancers. This systematic review and meta-analysis of epidemiological studies indicates that dietary acrylamide is not related to the risk of most common cancers. A modest association for kidney cancer, and for endometrial and ovarian cancers in never smokers only, cannot be excluded.


Residential exposure to volatile organic compounds and asthma.
We critically analysed the literature concerning exposure to volatile organic compounds and asthma. Observational studies have consistently found a relation between volatile organic compounds and indicators of asthma, such as symptoms, peak flows, and objectively measured bronchial reactivity. In contrast, interventional studies have generally failed to find a relation between exposure to residential levels of formaldehyde and other volatile organic compounds and asthma. One hypothesis to explain the discrepancy in findings between interventional and observational studies is that the effect size is small requiring relatively large numbers of study subjects, common in observational studies but often not feasible in interventional studies. Another hypothesis is that longer duration of exposure is important, a common circumstance in observational studies where the home environment is the exposure setting. In contrast, duration of exposure in interventional studies is usually of minutes-to-hours in a chamber. Finally, the observed association in observational studies could be confounded by a factor which is a determinant of asthma and is also associated with exposure to volatile organic compounds.


A critical assessment of high-earning orthodontists in the General Dental Services of England and Wales (1990-1991)
Cases from the Dental Practice Board's 2 per cent random sample of completed cases which had been treated by orthodontic practitioners with high gross earnings, were compared to all the cases within the sample from other practitioners. They were assessed using the PAR index and IOTN. High earning orthodontists treated slightly more cases with lower objective need for treatment, but treated no more cases 'Unnecessarily' than other practitioners. They used more fixed appliances, and had marginally better levels of residual need for treatment at finish, although this was at least partially explained by lower levels at start. Generally, their standards were not substantially different to other practitioners. Appliance type had a marked effect on outcome, as did levels of malocclusion and need for treatment at start. Both groups of practitioners performed similarly (better) with dual arch fixed appliances: however, overall standards could only be described as mediocre. There is no justification to single out high earning orthodontists for special scrutiny. However, it may be beneficial if the system of remuneration in the General Dental Services could be modified to give more positive incentive to quality, rather than simply quantity of treatments.


Efficacy and safety of iota-carrageenan nasal spray versus placebo in early treatment of the common cold in adults: the ICICC trial.
Iota-carrageenan (I-C) is active against respiratory viruses in vitro and was effective as nasal spray in three previous clinical trials. The current trial served to further investigate I-C in patients with early common cold symptoms. This randomized, placebo-controlled, double-blind phase IV trial was conducted in 200 adult patients with self-diagnosed colds of <48 h' duration that were confirmed by baseline cold symptom scores. Patients were to self-administer 0.12 % I-C or placebo spray (NaCl 0.5 %) four times daily for four to ten days and record symptom information for ten days. Common respiratory viruses were quantified by RT-PCR during pretreatment and on Day 3 or 4. The primary endpoint was the mean total symptom score (TSS) of eight cold symptoms on Days 2-4 (TSS2-4). Patients in both treatment groups had similar baseline TSSs (mean TSS: 6.75 for I-C and 6.79 for placebo). Viruses were detected in baseline samples from 53 of 98 I-C patients (54.1 %) and 54 of 97 placebo patients (55.7 %). Mean ± SE for TSS2-4 was 5.78 ± 0.25 for I-C patients and 6.39 ± 0.25 for placebo (p = 0.0895). Exploratory analyses after unblinding (TSS2-4 excluding a patient with aberrantly high symptom scores [TSS2-4, ex 1pt]; mean of TSS over Days 1-4 [TSS1-4]; change in TSS1-4 relative to baseline [TSS1-4, rel]) demonstrated treatment differences in favor of I-C (p = 0.0364, p = 0.0495 and p = 0.0421, respectively). For patients with quantifiable rhinovirus/enterovirus at baseline, there was a trend towards greater reduction of virus load at Day 3 or 4 (p = 0.0958; I-C: 90.2 % reduction in viral load; placebo: 72.0 %). Treatments were well tolerated with no differences in adverse event rates. The primary endpoint did not demonstrate a statistically significant difference between I-C and placebo but showed a trend towards I-C benefit. Exploratory analyses indicated significant reduction of cold symptoms in the I-C group relative to placebo during the first four days when symptoms were most severe, and also substantiated I-C's activity against rhinovirus/enterovirus. NCT01944631 (clinicaltrials.gov).


Time course changes of oxidative stress markers in a rat experimental glaucoma model.
To evaluate the relationship between oxidative stress markers and increased intraocular pressure in experimental glaucoma. In vivo chemiluminescence (CL), total antioxidant capacity (TRAP), nitrite concentration (NC), and lipid peroxidation markers (TBARS) were evaluated. Wistar rats (n=18 for each time point) underwent operation, and two episcleral veins were cauterized. Decreases of 22%, 35%, and 27% at 7, 15, and 30 days and an increase of 22% at 60 days in CL were observed in glaucomatous eyes. In optic nerve, TBARS values were 6.9+/-0.5 nmol/mg protein (7 days), 9.4+/-0.4 nmol/mg protein (15 days), 18.0+/-1.2 nmol/mg protein (30 days), and 43.1+/-5.3 nmol/mg protein (60 days) (control, 6.2+/-0.4 nmol/mg protein; P<0.001). NC was 37.0+/-1.8 microM (7 days), 31.4+/-1.2 microM (15 days), 39.6+/-1.3 microM (30 days), and 40.0+/-1.3 microM (60 days) (control, 21.1+/-1.7 microM; P<0.001). In glaucomatous vitreous humor, TRAP decreased by 42% at 15 days and 78% at 60 days (control, 414+/-29 microM; P<0.001). In glaucomatous aqueous humor, TRAP values were 75+/-7 microM (7 days), 54+/-4 microM (15 days), 25+/-4 microM (30 days), and 50+/-3 microM (60 days) (control, 90+/-10 microM; P<0.001). Reactive species were increased in glaucoma, as evidenced by the increases in CL, TBARS, and NC. The decrease in the antioxidant levels may be a consequence of an increase in oxidative processes.


Cross talk between microRNA and epigenetic regulation in adult neurogenesis.
Both microRNAs (miRNAs) and epigenetic regulation have important functions in stem cell biology, although the interactions between these two pathways are not well understood. Here, we show that MeCP2, a DNA methyl-CpG-binding protein, can epigenetically regulate specific miRNAs in adult neural stem cells (aNSCs). MeCP2-mediated epigenetic regulation of one such miRNA, miR-137, involves coregulation by Sox2, a core transcription factor in stem cells. miR-137 modulates the proliferation and differentiation of aNSCs in vitro and in vivo. Overexpression of miR-137 promotes the proliferation of aNSCs, whereas a reduction of miR-137 enhances aNSC differentiation. We further show that miR-137 post-transcriptionally represses the expression of Ezh2, a histone methyltransferase and Polycomb group (PcG) protein. The miR-137-mediated repression of Ezh2 feeds back to chromatin, resulting in a global decrease in histone H3 trimethyl lysine 27. Coexpression of Ezh2 can rescue phenotypes associated with miR-137 overexpression. These results demonstrate that cross talk between miRNA and epigenetic regulation contributes to the modulation of adult neurogenesis.