Cytokine-regulated expression of survivin in myeloid leukemia.
Survivin, a member of the inhibitors-of-apoptosis gene family, is expressed in a cell-cycle-dependent manner in all the most common cancers but not in normal differentiated adult tissues. Survivin expression and regulation were examined in acute myeloid leukemia (AML). Survivin was detected by Western blot analysis in all myeloid leukemia cell lines and in 16 of 18 primary AML samples tested. In contrast, normal CD34(+) cells and normal peripheral blood mononuclear cells expressed no or very low levels of survivin. Cytokine stimulation increased survivin expression in leukemic cell lines and in primary AML samples. In cultured primary samples, single-cytokine stimulation substantially increased survivin expression in comparison with control cells, and the combination of G-CSF, GM-CSF, and SCF increased survivin levels even further. Conversely, all-trans retinoic acid significantly decreased survivin protein levels in HL-60, OCI-AML3, and NB-4 cells within 96 hours, parallel to the induction of myelomonocytic differentiation. Using selective pharmacologic inhibitors, the differential involvement of mitogen-activated protein kinase kinase (MEK) and phosphatidylinositol-3 kinase (PI3K) pathways were demonstrated in the regulation of survivin expression. The MEK inhibitor PD98059 down-regulated survivin expression in both resting and GM-CSF-stimulated OCI-AML3 cells, whereas the PI3K inhibitor LY294002 inhibited survivin expression only on GM-CSF stimulation. In conclusion, these results demonstrate that survivin is highly expressed and cytokine-regulated in myeloid leukemias and suggest that hematopoietic cytokines exert their antiapoptotic and mitogenic effects, at least in part, by increasing survivin levels.


A chimeric RNA characteristic of rhabdomyosarcoma in normal myogenesis process.
Gene fusions and their chimeric products are common features of neoplasia. Given that many cancers arise by the dysregulated recapitulation of processes in normal development, we hypothesized that comparable chimeric gene products may exist in normal cells. Here, we show that a chimeric RNA, PAX3-FOXO1, identical to that found in alveolar rhabdomyosarcoma, is transiently present in cells undergoing differentiation from pluripotent cells into skeletal muscle. Unlike cells of rhabdomyosarcoma, these cells do not seem to harbor the t(2;13) chromosomal translocation. Importantly, both PAX3-FOXO1 RNA and protein could be detected in the samples of normal fetal muscle. Overexpression of the chimera led to continuous expression of MYOD and MYOG-two myogenic markers that are overexpressed in rhabdomyosarcoma cells. Our results are consistent with a developmental role of a specific chimeric RNA generated in normal cells without the corresponding chromosomal rearrangement at the DNA level seen in neoplastic cells presumably of the same lineage. A chimeric fusion RNA, PAX3-FOXO1, associated with alveolar rhabdomyosarcoma, is also present in normal non-cancer cells and tissues. Its transient expression nature and the absence of t(2;13) chromosomal translocation are consistent with a posttranscriptional mechanism. When constantly expressed, PAX3-FOXO1 interfered with the muscle differentiation process, which presumably contributes to tumorigenesis.


Vascular phenotyping of brain tumors using magnetic resonance microscopy (μMRI).
Abnormal vascular phenotypes have been implicated in neuropathologies ranging from Alzheimer's disease to brain tumors. The development of transgenic mouse models of such diseases has created a crucial need for characterizing the murine neurovasculature. Although histologic techniques are excellent for imaging the microvasculature at submicron resolutions, they offer only limited coverage. It is also challenging to reconstruct the three-dimensional (3D) vasculature and other structures, such as white matter tracts, after tissue sectioning. Here, we describe a novel method for 3D whole-brain mapping of the murine vasculature using magnetic resonance microscopy (μMRI), and its application to a preclinical brain tumor model. The 3D vascular architecture was characterized by six morphologic parameters: vessel length, vessel radius, microvessel density, length per unit volume, fractional blood volume, and tortuosity. Region-of-interest analysis showed significant differences in the vascular phenotype between the tumor and the contralateral brain, as well as between postinoculation day 12 and day 17 tumors. These results unequivocally show the feasibility of using μMRI to characterize the vascular phenotype of brain tumors. Finally, we show that combining these vascular data with coregistered images acquired with diffusion-weighted MRI provides a new tool for investigating the relationship between angiogenesis and concomitant changes in the brain tumor microenvironment.


[Morphologic changes in the microcirculatory bed at stages of prolonged experimental fasting in animals].
In 40 white male rats with body mass 180-200 g, by means of silver nitrate impregnation, morphological changes have been studied in the blood microcirculatory bed of the small intestine mesentery, spinal trapezoid muscle and eye ball conjunctiva at various stages of a prolonged fasting. With an increasing time of the experiment, a gradual undirected character of the changes in the microvessels is noted. After 3 days of fasting the changes in diameters of the microvessels, comparing to the control ones, have not any significant values in all the organs studied. After 6 days of fasting significant changes in diameters in all the links of the microcirculatory bed of the eye ball conjunctiva and in that of the spinal trapezoid muscle are observed. The microvascular changes are mostly pronounced on the 9th day of fasting. The maximal decrease of the microvessel diameters is noted in the eye ball conjunctiva, and the minimal--in the small intestine mesentery. The changes in the spinal trapezoid muscle are of intermediate character. The highest points of the structural lability gradient fall on the capillary and postcapillary-venular links of the blood microcirculatory bed.


Seasonal abundance of the navel orangeworm, Amyelois transitella, in figs and the effect of peripheral aerosol dispensers on sexual communication.
We used flight traps baited with unmated female navel orangeworm Amyelois transitella (Walker) (Lepidoptera: Pyralidae) to examine, over two growing seasons, seasonal changes in the abundance of males in fig orchards and the impact of release of 48 mg per ha per day of the pheromone component (Z,Z)-11,13-hexadecadienal from peripherally-located timed-release dispensers on the ability of males to find unmated females within 16-ha treatment plots. Material was placed out and mating disruption was commenced at the beginning of April in the first year, and at the beginning of July the second year. This technique effectively prevented males from finding females in female-baited traps placed throughout the plot. Navel orangeworm abundance was high in figs during the first and third flight, but lower in June and July during the second flight. Since Calimyrna figs are not susceptible to attack by navel orangeworm until mid-to-late July, these findings suggest that materials cost can be reduced by beginning treatment later. Implications for insect pest management in figs and other California crops are discussed.


Exploring the spatially varying relationships between cadmium accumulations and the main influential factors in the rice-wheat rotation system in a large-scale area.
Cadmium (Cd) accumulations in crops and the effects of the related soil factors on them are critical to developing precise soil management measures for food safety. Traditionally-used non-spatial multiple linear regression (MLR) cannot adequately model the spatially varying effects of the related soil properties on Cd accumulations in crop (or soil). Moreover, the traditionally-used methods for exploring the spatial accumulation characteristics (e.g., ordinary kriging) and the effects of other factors on Cd accumulations (e.g., MLR) are sensitive to outliers. In this study, robust geostatistics, enrichment index, and bioavailability index were first used to explore the spatial accumulation characteristics of Cd in wheat grain (wheat-Cd), Cd in rice grain (rice-Cd), and soil DTPA-extractable Cd (DTPA-Cd) in Jintan County, a typical rice-wheat rotation area in China. Then, robust geographically weighted regression (RGWR), established in geographic space rather than variable space, was used to explore the spatially varying relationships between Cd accumulations and the corresponding main influential factors determined by stepwise regression. Last, the modelling accuracy of RGWR was compared with those of basic GWR and MLR. Results showed that (i) outliers affected the spatial predictions of soil total Cd, soil DTPA-Cd, wheat-Cd, and rice-Cd and robust variograms should be used; (ii) the enrichment index of wheat grain was significantly higher than that of rice grain in almost the whole study area; (iii) the areas with the high bioavailability index of soil Cd mainly located in the southeast, southwest, and centre of the study area; (iv) RGWR acquired higher modelling accuracy than GWR and MLR; (v) the spatially varying relationships between Cd accumulations and the corresponding influential factors were revealed by RGWR, which cannot be determined by MLR. The methods suggested in this study provided more precise spatial decision support for soil management measures to guarantee main agricultural product safety in large-scale areas.


The effect of phosphogypsum on greenhouse gas emissions during cattle manure composting.
Phosphogypsum (PG), a by-product of the phosphate fertilizer industry, reduces N losses when added to composting livestock manure, but its impact on greenhouse gas emissions is unclear. The objective of this research was to assess the effects of PG addition on greenhouse gas emissions during cattle feedlot manure composting. Sand was used as a filler material for comparison. The seven treatments were PG10, PG20, PG30, S10, S20, and S30, representing the rate of PG or sand addition at 10, 20, or 30% of manure dry weight and a check treatment (no PG or sand) with three replications. The manure treatments were composted in open windrows and turned five times during a 134-d period. Addition of PG significantly increased electrical conductivity (EC) and decreased pH in the final compost. Total carbon (TC), total nitrogen (TN), and mineral nitrogen contents in the final composted product were not affected by the addition of PG or sand. From 40 to 54% of initial TC was lost during composting, mostly as CO(2), with CH(4) accounting for <14%. The addition of PG significantly reduced CH(4) emissions, which decreased exponentially with the compost total sulfur (TS) content. The emission of N(2)O accounted for <0.2% of initial TN in the manure, increasing as compost pH decreased from alkaline to near neutral. Based on the total greenhouse gas budget, PG addition reduced greenhouse gas emissions (CO(2)-C equivalent) during composting of livestock manure by at least 58%, primarily due to reduced CH(4) emission.


Selenium inhibits growth of trastuzumab-resistant human breast cancer cells via downregulation of Akt and beclin-1.
The response rate to treatment with trastuzumab (Tz), a recombinant humanized anti-HER2 monoclonal antibody, is only 12-34% despite demonstrated effectiveness on improving the survival of patients with HER2-positive breast cancers. Selenium has an antitumor effect against cancer cells and can play a cytoprotective role on normal cells. This study investigated the effect of selenium on HER2-positive breast cancer cells and the mechanism in relation to the response of the cells to Tz. HER2-positive breast cancer cell lines, SK-BR-3 as trastuzumab-sensitive cells, and JIMT-1 as Tz-resistant cells were treated with Tz and sodium selenite (selenite). Cell survival rates and expression of Her2, Akt, and autophagy-related proteins, including LC3B and beclin 1, in both cell lines 72 h after treatment were evaluated. Significant cell death was induced at different concentrations of selenite in both cell lines. A combined effect of selenite and Tz at 72 h was similar to or significantly greater than each drug alone. The expression of phosphorylated Akt (p-Akt) was decreased in JIMT-1 after combination treatment compared to that after only Tz treatment, while p-Akt expression was increased in SK-BR-3. The expression of beclin1 increased particularly in JIMT-1 after only Tz treatment and was downregulated by combination treatment. These results showed that combination of Tz and selenite had an antitumor effect in Tz-resistant breast cancer cells through downregulation of phosphorylated Akt and beclin1-related autophagy. Selenite might be a potent drug to treat Tz-resistant breast cancer by several mechanisms.


Patient experiences of bladder problems following stroke.
To elicit the experiences of patients with bladder problems following stroke in one dedicated stroke unit and to share these findings with the multidisciplinary stroke team. A structured questionnaire was completed by 40 inpatients who had an identified bladder problem, had had a stroke more than two weeks previously and were able to give informed consent. Following analysis of the results, a focus group discussion was held with the multidisciplinary stroke team. The urinary symptom most frequently reported by patients two weeks following stroke was urgency (65%, n = 26), followed by leakage of urine (57%, n = 23), frequency (37%, n = 15) and nocturia (37%, n = 15). Depression and feelings of embarrassment were common. Patients were least satisfied with the use of bedpans for toileting purposes and a urethral catheter as a method of containment. The need for more proactive patient-focused continence management was identified by the multidisciplinary stroke team during the focus group discussion. Patient-focused management of urinary symptoms is important to alleviate concern, distress and discomfort, and reduce the potential effect that these symptoms may have on the patient's ability to participate in therapeutic activities that promote recovery.


Medicine and the Egyptian campaign: the development of the military medical officer during the Napoleonic Wars c. 1798-1801.
This article investigates how French and British army medical officers in Egypt at the turn of the 19th century were affected by campaign experiences. Their encounters with ophthalmia, plague, and other diseases influenced the practice of medicine in later campaigns and fostered the development of the idea amongst military practitioners that military diseases required specialised knowledge. Practitioners' campaign writings are used to demonstrate how British army doctors approached the investigation of the "new" diseases they encountered. In particular, the article focuses on how Dr. James McGrigor used the military system to control, direct, and disseminate the development of medical knowledge.


Role of LncMALAT1-miR-141-3p/200a-3p-NRXN1 Axis in the Impairment of Learning and Memory Capacity in ADHD.
As a prevalent neurodevelopmental disease, attention-deficit hyperactivity disorder (ADHD) impairs the learning and memory capacity, and so far, there has been no available treatment option for long-term efficacy. Alterations in gene regulation and synapse-related proteins influence learning and memory capacity; nevertheless, the regulatory mechanism of synapse-related protein synthesis is still unclear in ADHD. LncRNAs have been found participating in regulating genes in multiple disorders. For instance, lncRNA Metastasis Associated Lung Adenocarcinoma Transcript 1 (MALAT1) has an essential regulatory function in numerous psychiatric diseases. However, how MALAT1 influences synapse-related protein synthesis in ADHD remains largely unknown. Here, our study found that MALAT1 decreased in the hippocampus tissue of spontaneously hypertensive rats (SHRs) compared to the standard controls, Wistar Kyoto (WKY) rats. Subsequent experiments revealed that MALAT1 enhanced the expression of neurexin 1 (NRXN1), which promoted the synapse-related genes (SYN1, PSD95, and GAP43) expression. Then, the bioinformatic analyses predicted that miR-141-3p and miR-200a-3p, microRNAs belonging to miR-200 family and sharing same seed sequence, could interact with MALAT1 and NRXN1 mRNA, which were further confirmed by luciferase report assays. Finally, rescue experiments indicated that MALAT1 influenced the expression of NRXN1 by sponging miR-141-3p/200a-3p. All data verified our hypothesis that MALAT1 regulated synapse-related proteins (SYN1, PSD95, and GAP43) through the MALAT1-miR-141-3p/200a-3p-NRXN1 axis in ADHD. Our research underscored a novel role of MALAT1 in the pathogenesis of impaired learning and memory capacity in ADHD and may shed more light on developing diagnostic biomarkers and more effective therapeutic interventions for individuals with ADHD.


Long-term Exposure to Testosterone Therapy and the Risk of High Grade Prostate Cancer.
To our knowledge no population based studies have been done to examine whether long-term exposure to testosterone therapy is associated with an increased risk of high grade prostate cancer. We examined whether exposure to testosterone during a 5-year period was associated with an increased risk of high grade prostate cancer and whether this risk increased in a dose-response fashion with the cumulative number of testosterone injections. Using SEER (Surveillance, Epidemiology and End Results)-Medicare linked data we identified 52,579 men diagnosed with incident prostate cancer between January 1, 2001 and December 31, 2006 who had a minimum of 5 years continuous enrollment in Medicare before the cancer diagnosis. We excluded patients diagnosed at death or after autopsy, those enrolled in a health maintenance organization in the 60 months before diagnosis and those with unknown tumor grade or tumor stage. In the 5 years before diagnosis 574 men had a history of testosterone use and 51,945 did not. On logistic regression adjusting for demographic and clinical characteristics exposure to testosterone therapy was not associated with an increased risk of high grade prostate cancer (OR 0.84, 95% CI 0.67-1.05) or receipt of primary androgen deprivation therapy following diagnosis (OR 0.97, 95% CI 0.74-1.30). In addition the risk of high grade disease did not increase according to the total number of testosterone injections (OR 1.00, 95% CI 0.98-1.01). Our finding that testosterone therapy was not associated with an increased risk of high grade prostate cancer may provide important information regarding the risk-benefit assessment for men with testosterone deficiency considering treatment.


Lipidomics for diagnosis and prognosis of pulmonary hypertension.
Pulmonary hypertension (PH) poses a significant health threat with high morbidity and mortality, necessitating improved diagnostic tools for enhanced management. Current biomarkers for PH lack functionality and comprehensive diagnostic and prognostic capabilities. Therefore, there is a critical need to develop biomarkers that address these gaps in PH diagnostics and prognosis. To address this need, we employed a comprehensive metabolomics analysis in 233 blood based samples coupled with machine learning analysis. For functional insights, human pulmonary arteries (PA) of idiopathic pulmonary arterial hypertension (PAH) lungs were investigated and the effect of extrinsic FFAs on human PA endothelial and smooth muscle cells was tested in vitro . PA of idiopathic PAH lungs showed lipid accumulation and altered expression of lipid homeostasis-related genes. In PA smooth muscle cells, extrinsic FFAs caused excessive proliferation and endothelial barrier dysfunction in PA endothelial cells, both hallmarks of PAH.In the training cohort of 74 PH patients, 30 disease controls without PH, and 65 healthy controls, diagnostic and prognostic markers were identified and subsequently validated in an independent cohort. Exploratory analysis showed a highly impacted metabolome in PH patients and machine learning confirmed a high diagnostic potential. Fully explainable specific free fatty acid (FFA)/lipid-ratios were derived, providing exceptional diagnostic accuracy with an area under the curve (AUC) of 0.89 in the training and 0.90 in the validation cohort, outperforming machine learning results. These ratios were also prognostic and complemented established clinical prognostic PAH scores (FPHR4p and COMPERA2.0), significantly increasing their hazard ratios (HR) from 2.5 and 3.4 to 4.2 and 6.1, respectively. In conclusion, our research confirms the significance of lipidomic alterations in PH, introducing innovative diagnostic and prognostic biomarkers. These findings may have the potential to reshape PH management strategies.


Mechanical loading down-regulates peroxisome proliferator-activated receptor gamma in bone marrow stromal cells and favors osteoblastogenesis at the expense of adipogenesis.
Because a lack of mechanical information favors the development of adipocytes at the expense of osteoblasts, we hypothesized that the peroxisome proliferator-activated receptor gamma (PPARgamma)-dependent balance between osteoblasts and adipocytes is affected by mechanical stimuli. We tested the robustness of this hypothesis in in vivo rodent osteogenic exercise, in vitro cyclic loading of cancellous haversian bone samples, and cyclic stretching of primary stromal and C3H10T1/2 cells. We found that running rats exhibit a decreased marrow fat volume associated with an increased bone formation, presumably through recruitment of osteoprogenitors. In the tissue culture model and primary stromal cells, cyclic loading induced higher Runx2 and lower PPARgamma2 protein levels. Given the proadipocytic and antiosteoblastic activities of PPARgamma, we studied the effects of cyclic stretching in C3H10T1/2 cells, treated either with the PPARgamma activator, Rosiglitazone, or with GW9662, a potent antagonist of PPARgamma. We found, through both cytochemistry and analysis of lineage marker expression, that under Roziglitazone cyclic stretch partially overcomes the induction of adipogenesis and is still able to favor osteoblast differentiation. Conversely, cyclic stretch has additive effects with GW9662 in inducing osteoblastogenesis. In conclusion, we provide evidence that mechanical stimuli are potential PPARgamma modulators counteracting adipocyte differentiation and inhibition of osteoblastogenesis.


Transcription factor AP-2γ induces early Cdx2 expression and represses HIPPO signaling to specify the trophectoderm lineage.
Cell fate decisions are fundamental to the development of multicellular organisms. In mammals the first cell fate decision involves segregation of the pluripotent inner cell mass and the trophectoderm, a process regulated by cell polarity proteins, HIPPO signaling and lineage-specific transcription factors such as CDX2. However, the regulatory mechanisms that operate upstream to specify the trophectoderm lineage have not been established. Here we report that transcription factor AP-2γ (TFAP2C) functions as a novel upstream regulator of Cdx2 expression and position-dependent HIPPO signaling in mice. Loss- and gain-of-function studies and promoter analysis revealed that TFAP2C binding to an intronic enhancer is required for activation of Cdx2 expression during early development. During the 8-cell to morula transition TFAP2C potentiates cell polarity to suppress HIPPO signaling in the outside blastomeres. TFAP2C depletion triggered downregulation of PARD6B, loss of apical cell polarity, disorganization of F-actin, and activation of HIPPO signaling in the outside blastomeres. Rescue experiments using Pard6b mRNA restored cell polarity but only partially corrected position-dependent HIPPO signaling, suggesting that TFAP2C negatively regulates HIPPO signaling via multiple pathways. Several genes involved in regulation of the actin cytoskeleton (including Rock1, Rock2) were downregulated in TFAP2C-depleted embryos. Inhibition of ROCK1 and ROCK2 activity during the 8-cell to morula transition phenocopied TFAP2C knockdown, triggering a loss of position-dependent HIPPO signaling and decrease in Cdx2 expression. Altogether, these results demonstrate that TFAP2C facilitates trophectoderm lineage specification by functioning as a key regulator of Cdx2 transcription, cell polarity and position-dependent HIPPO signaling.


Interaction between purine and benzodiazepine: Inosine reverses diazepam-induced stimulation of mouse exploratory behavior.
Inosine, 2-deoxyinosine, and 2-deoxyguanosine completely reversed the increase in exploratory activity elicited in mice by diazepam. The inhibition of exploratory behavior by purines occurred at doses that when given alone have no effect on exploratory behavior. 7-Methylinosine, which does not bind to the brain benzodiazepine binding site in vitro, had no effect on the diazepam-induced increase in exploratory behavior. Behavioral effects produced by various combinations of inosine and diazepam indicate that the interaction between purine and benzodiazepine is antagonistic and support the hypothesis that the naturally occurring purines function in anxiety-related behaviors that respond to benzodiazepine treatment.


Human pluripotent stem cells on artificial microenvironments: a high content perspective.
Self-renewing stem cell populations are increasingly considered as resources for cell therapy and tools for drug discovery. Human pluripotent stem (hPS) cells in particular offer a virtually unlimited reservoir of homogeneous cells and can be differentiated toward diverse lineages. Many diseases show impairment in self-renewal or differentiation, abnormal lineage choice or other aberrant cell behavior in response to chemical or physical cues. To investigate these responses, there is a growing interest in the development of specific assays using hPS cells, artificial microenvironments and high content analysis. Several hurdles need to be overcome that can be grouped into three areas: (i) availability of robust, homogeneous, and consistent cell populations as a starting point; (ii) appropriate understanding and use of chemical and physical microenvironments; (iii) development of assays that dissect the complexity of cell populations in tissues while mirroring specific aspects of their behavior. Here we review recent progress in the culture of hPS cells and we detail the importance of the environment surrounding the cells with a focus on synthetic material and suitable high content analysis approaches. The technologies described, if properly combined, have the potential to create a paradigm shift in the way diseases are modeled and drug discovery is performed.


Confidentiality and the ethics of medical ethics.
In this paper we consider the use of cases in medical ethics research and teaching. To date, there has been little discussion about the consent or confidentiality requirements that ought to govern the use of cases in these areas. This is in marked contrast to the requirements for consent to publish cases in clinical journals, or to use personal information in research. There are a number of reasons why it might be difficult to obtain consent to use cases in ethics. Many cases concern people who are incompetent, and thus unable to give consent. Often the material is of a sensitive nature, it is not clear who should give consent, or the ethicist has no access to those involved. We argue that the use of cases in ethics research and teaching can be justified by appeal to the public interest argument, and suggest a number of areas for discussion and clarification.


[Compliance with low-protein diet in patients with chronic kidney disease].
Direct evaluation of the compliance with nutritional therapy is possible only in clinical trials while indirect methods such as self-reporting and interviews are used in clinical practice. Dietary history is the best method to evaluate nutritional habits in clinical practice; the same holds true for the compliance with low-protein diets in patients with chronic kidney disease. Other indexes to assess dietary compliance should be simple and easy to use in the clinical practice. Some of such functional and biological markers are blood urea nitrogen and serum phosphate levels (indirect markers of dietary intake), weight and body mass index (indirect markers of energy intake), and daily urinary excretion of nitrogen and sodium (indirect markers of protein and salt intake). The compliance with a low-protein diet in patients with chronic kidney disease is strongly influenced by psychosocial factors (e.g., satisfaction and comprehension), and thus by the supporting role of the physician and the dietitian, but also by the level of renal function and food characteristics. It must be pointed out that even a protein intake reduction of 0.2 g/kg/day improves blood urea nitrogen, phosphate levels, and acidosis.


Reducing Emergency Department Visits Among Dual Eligible Patients via a Comprehensive Wellness Assessment.
The objective was to assess whether a Comprehensive Wellness Assessment (CWA) is associated with reduced emergency department (ED) visits for Special Needs Program (SNP) enrollees with diabetes. This retrospective panel study used a Medicare Advantage plan's administrative claims data for 2010-2017 and pooled member-month observations. Multivariate regression and individual fixed-effects regression models were estimated. The outcome was ED visits measured as binary and continuous outcomes. Data were derived from claims data that included at least 1 ICD-9 or 10 code between January 2010 and December 2017. Regression results indicated that SNP enrollees completing a CWA was associated with a lower probability of any monthly ED use (β = -0.005, t-stat = -2.98) and fewer monthly visits (β = -0.008, t-stat = -2.95). Individual fixed-effects models also demonstrated a significant decline in SNP ED use after a CWA, though the strongest effects were confined to the first 4 months after a CWA. Care models with components such as CWAs may contribute an additional benefit in the form of a reduction in ED utilization. Completing a CWA appears to be effective in reducing ED utilization among SNP members with diabetes.


Imaging white matter in human brainstem.
The human brainstem is critical for the control of many life-sustaining functions, such as consciousness, respiration, sleep, and transfer of sensory and motor information between the brain and the spinal cord. Most of our knowledge about structure and organization of white and gray matter within the brainstem is derived from ex vivo dissection and histology studies. However, these methods cannot be applied to study structural architecture in live human participants. Tractography from diffusion-weighted magnetic resonance imaging (MRI) may provide valuable insights about white matter organization within the brainstem in vivo. However, this method presents technical challenges in vivo due to susceptibility artifacts, functionally dense anatomy, as well as pulsatile and respiratory motion. To investigate the limits of MR tractography, we present results from high angular resolution diffusion imaging of an intact excised human brainstem performed at 11.1 T using isotropic resolution of 0.333, 1, and 2 mm, with the latter reflecting resolution currently used clinically. At the highest resolution, the dense fiber architecture of the brainstem is evident, but the definition of structures degrades as resolution decreases. In particular, the inferred corticopontine/corticospinal tracts (CPT/CST), superior (SCP) and middle cerebellar peduncle (MCP), and medial lemniscus (ML) pathways are clearly discernable and follow known anatomical trajectories at the highest spatial resolution. At lower resolutions, the CST/CPT, SCP, and MCP pathways are artificially enlarged due to inclusion of collinear and crossing fibers not inherent to these three pathways. The inferred ML pathways appear smaller at lower resolutions, indicating insufficient spatial information to successfully resolve smaller fiber pathways. Our results suggest that white matter tractography maps derived from the excised brainstem can be used to guide the study of the brainstem architecture using diffusion MRI in vivo.


A partial sequence for nitric oxide synthase from a goldfish (Carassius auratus) macrophage cell line.
Expression of inducible nitric oxide synthase (iNOS) mRNA was detected in a recently developed goldfish macrophage cell line by RT-PCR, using degenerate primers designed against conserved nucleotide motifs within the different mammalian isoforms of NOS. Increased expression of iNOS poststimulation with LPS was found, and suggests that it is a functional enzyme in goldfish macrophages, supporting the view that iNOS regulation is pretranslational. The nucleotide sequence translated in one reading frame with no stop codons to produce a partial peptide containing 164 amino acids, with highest homology (85%) to a recently identified rainbow trout iNOS sequence. The peptide translation also gave an insight into the conservation of binding motifs, since two cofactor binding sites were present in the amplified PCR product (FMN and calmodulin). In addition, a 42 aa motif present in the region just upstream of the FMN binding motif of mammalian endothelial and neuronal NOS isoforms was absent in the translation, in agreement with every published sequence for iNOS. Finally, the translation was used to construct an unrooted phylogenetic tree.


Contextualising the Perceptions of Pharmacists Practicing Clinical Pharmacy in South Africa-Do We Practice what We Preach?
The National Department of Health published their Quality Standards for Healthcare Establishments in South Africa and introduced the National Health Insurance, with the pilot phase that commenced in 2012. The system requires an adequate supply of pharmaceutical personnel and the direct involvement of clinical pharmacists throughout the medication-use process to ensure continuity of care, minimised risk with increasing improvement of patient outcomes. The study aimed to provide insight into the pressing issues of clinical pharmacy practice in South Africa, and sets out to contextualise the current profile of the pharmacist performing clinical functions. The study used a quantitative, explorative, cross-sectional design. The population included pharmacists from private and public tertiary hospitals. A questionnaire was administered, using Typeform™. Ethics approval was obtained from Sefako Makgatho Health Sciences University, National Department of Health and Private Healthcare groups. Categorical data were summarised using frequency counts and percentages; continuous data were summarised by mean values and standard deviations. The sample size included 70 pharmacists practicing clinical pharmacy (private sector n = 59; public sector n = 11). Most participants hold a BPharm degree (busy with MPharm qualification) (64%; n = 70). No statistical significance was found between participants in private and public practice. Most pharmacist agreed (32% (private); n = 59) and strongly agreed (45% (public); n = 11) to have sufficient training to perform pharmaceutical care. The majority respondents felt that interventions made by the pharmacist improved the rational use of medicine (47% (private); 55% (public). Pharmacist interventions influence prescribing patterns (42% (private); 64% (public); and reduce polypharmacy (41% (private); 55% (public). The clinical functions mostly performed were evaluation of prescriptions (private 90%; public 82%), while the top logistical function is daily ordering of medication (40.7%; private), and checking of ward stock (36%; public). Although not all pharmacists appointed in South Africa has completed the MPharm degree in clinical pharmacy, the pharmacists at ward level perform numerous clinical functions, even if only for a small part of their workday. This paper sets the way to standardise practices of clinical pharmacy in South Africa, with a reflection on the differences in practice in different institutions.


Profiling of β-lactam selectivity for penicillin-binding proteins in Escherichia coli strain DC2.
Penicillin-binding proteins (PBPs) are integral players in bacterial cell division, and their catalytic activities can be monitored with β-lactam-containing chemical probes. Compounds that target a single PBP could provide important information about the specific role(s) of each enzyme, making identification of such molecules important. We evaluated 22 commercially available β-lactams for inhibition of the PBPs in live Escherichia coli strain DC2. Whole cells were titrated with β-lactam antibiotics and subsequently incubated with a fluorescent penicillin derivative, Bocillin-FL (Boc-FL), to label uninhibited PBPs. Protein visualization was accomplished by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) separation and fluorescent scanning. The examined β-lactams exhibited diverse PBP selectivities, with amdinocillin (mecillinam) showing selectivity for PBP2, aztreonam, piperacillin, cefuroxime, cefotaxime, and ceftriaxone for PBP3, and amoxicillin and cephalexin for PBP4. The remaining β-lactams did not block any PBPs in the DC2 strain of E. coli or inhibited more than one PBP at all examined concentrations in this Gram-negative organism.


A study on reduced support vector machines.
Recently the reduced support vector machine (RSVM) was proposed as an alternate of the standard SVM. Motivated by resolving the difficulty on handling large data sets using SVM with nonlinear kernels, it preselects a subset of data as support vectors and solves a smaller optimization problem. However, several issues of its practical use have not been fully discussed yet. For example, we do not know if it possesses comparable generalization ability as the standard SVM. In addition, we would like to see for how large problems RSVM outperforms SVM on training time. In this paper we show that the RSVM formulation is already in a form of linear SVM and discuss four RSVM implementations. Experiments indicate that in general the test accuracy of RSVM are a little lower than that of the standard SVM. In addition, for problems with up to tens of thousands of data, if the percentage of support vectors is not high, existing implementations for SVM is quite competitive on the training time. Thus, from this empirical study, RSVM will be mainly useful for either larger problems or those with many support vectors. Experiments in this paper also serve as comparisons of: 1) different implementations for linear SVM and 2) standard SVM using linear and quadratic cost functions.


Epigenetic Regulation of S100A9 and S100A12 Expression in Monocyte-Macrophage System in Hyperglycemic Conditions.
The number of diabetic patients in Europe and world-wide is growing. Diabetes confers a 2-fold higher risk for vascular disease. Lack of insulin production (Type 1 diabetes, T1D) or lack of insulin responsiveness (Type 2 diabetes, T2D) causes systemic metabolic changes such as hyperglycemia (HG) which contribute to the pathology of diabetes. Monocytes and macrophages are key innate immune cells that control inflammatory reactions associated with diabetic vascular complications. Inflammatory programming of macrophages is regulated and maintained by epigenetic mechanisms, in particular histone modifications. The aim of our study was to identify the epigenetic mechanisms involved in the hyperglycemia-mediated macrophage activation. Using Affymetrix microarray profiling and RT-qPCR we identified that hyperglycemia increased the expression of S100A9 and S100A12 in primary human macrophages. Expression of S100A12 was sustained after glucose levels were normalized. Glucose augmented the response of macrophages to Toll-like receptor (TLR)-ligands Palmatic acid (PA) and Lipopolysaccharide (LPS) i.e., pro-inflammatory stimulation. The abundance of activating histone Histone 3 Lysine 4 methylation marks (H3K4me1, H3K4me3) and general acetylation on histone 3 (AceH3) with the promoters of these genes was analyzed by chromatin immunoprecipitation. Hyperglycemia increased acetylation of histones bound to the promoters of S100A9 and S100A12 in M1 macrophages. In contrast, hyperglycemia caused a reduction in total H3 which correlated with the increased expression of both S100 genes. The inhibition of histone methyltransferases SET domain-containing protein (SET)7/9 and SET and MYND domain-containing protein (SMYD)3 showed that these specifically regulated S100A12 expression. We conclude that hyperglycemia upregulates expression of S100A9, S100A12 via epigenetic regulation and induces an activating histone code on the respective gene promoters in M1 macrophages. Mechanistically, this regulation relies on action of histone methyltransferases SMYD3 and SET7/9. The results define an important role for epigenetic regulation in macrophage mediated inflammation in diabetic conditions.


The use of fluoxetine by veterinarians in dogs and cats: a preliminary survey.
To describe the prescribing habits of a sample of small animal veterinarians pertaining to use of fluoxetine in dogs and cats. Exploratory descriptive survey using a questionnaire, available on paper and through email, distributed to small animal veterinarians by convenience sampling. Veterinarians practicing small animal medicine in North America contacted by email and at local veterinary meetings. Of 127 initial respondents, 106 prescribed fluoxetine for dogs and/or cats. The majority (91 per cent) indicated the drug be given once every 24 hours. Respondents used one or more formulations of fluoxetine. Of those who prescribed fluoxetine for both dogs and cats (57 per cent), 80 per cent used a generic form. A third prescribed fluoxetine only for dogs (31 per cent) and 72 per cent of these prescribed the US Food and Drug Administration approved product that was available at that time. The primary use of fluoxetine was related to behaviour problems. Overall for dogs, uses of fluoxetine were organised into five major categories by the investigators: Anxieties, Aggression, Compulsive Disorders, Phobias/Fear and Other, Anxieties being the most common. Of those who prescribed fluoxetine, 12 per cent did so only for cats and the majority of these prescribed generic (58 per cent) and or compounded (42 per cent) forms. Overall for cats, uses of fluoxetine were organised into six major categories: Elimination behaviours, Anxieties, Aggression, Dermatologic/Grooming, Compulsive Disorders and Other, Elimination behaviours being most common. This study indicates that practitioners prescribed fluoxetine in generic, proprietary and compounded formulations for a variety of behaviour problems of dogs and cats. The broad use by the respondents suggests how important psychotropic drugs are in veterinary medicine. Research, information and continuing education regarding such drugs and animal behaviour should be made available to the general practitioner.


Global Method for Electron Correlation.
The current work presents a new single-reference method for capturing at the same time the static and dynamic electron correlation. The starting point is a determinant wave function formed with natural orbitals obtained from a new interacting-pair model. The latter leads to a natural orbital functional (NOF) capable of recovering the complete intrapair, but only the static interpair correlation. Using the solution of the NOF, two new energy functionals are defined for both dynamic (E^{dyn}) and static (E^{sta}) correlation. E^{dyn} is derived from a modified second-order Møller-Plesset perturbation theory (MP2), while E^{sta} is obtained from the static component of the new NOF. Double counting is avoided by introducing the amount of static and dynamic correlation in each orbital as a function of its occupation. As a result, the total energy is represented by the sum E[over ˜]_{HF}+E^{dyn}+E^{sta}, where E[over ˜]_{HF} is the Hartree-Fock energy obtained with natural orbitals. The new procedure called NOF-MP2 scales formally as O(M^{5}) (where M is the number of basis functions), and is applied successfully to the homolytic dissociation of a selected set of diatomic molecules, paradigmatic cases of near-degeneracy effects. The size consistency has been numerically demonstrated for singlets. The values obtained are in good agreement with the experimental data.


Molluscicidal and antiparasitic activity of Solanum nigrum villosum against Galba truncatula infected or uninfected with Fasciola hepatica.
The present study was based on assessments of the molluscicidal and antiparasitic activities of Solanum nigrum villosum. This plant has been collected in Tozeur's traditional oases (south-western Tunisia). Molluscicidal activities of leaves, ripe fruit and unripe fruit extracts of S. n. villosum have been assessed in experimental and semi-field conditions on uninfected Galba truncatula. Antiparasitic activities have also been assessed on larval stages (rediae, intraredial germinal masses and cercariae) of the parasite Fasciola hepatica infecting G. truncatula naturally. The unripe fruit extract (LC50 = 41.2 mg l- 1) was more toxic than the leaf (LC50 = 132.5 mg l- 1) and the ripe fruit (LC50 = 172.8 mg l- 1) extracts on the snail after 48 h of treatment. One mg l- 1 of cupric chloride produced the death of 97% of G. truncatula after 25 days of treatment. Solanum n. villosum extracts used at the lethal laboratory concentration in semi-field conditions were also toxic to G. truncatula. The unripe fruit extract was more toxic than the leaf and the ripe fruit extracts on larval stages of F. hepatica. Maximum deterioration rates were obtained with the unripe fruit extract: 65.6% for rediae, 77.8% for cercariae and 27.6% for intraredial germinal masses after 48 h of treating the snails. The possibility of the unripe fruit extract application for the control of G. truncatula and F. hepatica larval stages should be considered.


Robot-assisted pediatric surgery: how far can we go?
The purpose of this study was to assess the safety and feasibility of performing robot-assisted pediatric surgery using the da Vinci Surgical System in a variety of surgical procedures. A retrospective review of 144 robot-assisted pediatric surgical procedures performed in our institution between June 2004 and December 2007 was done. The procedures included the following: 39 fundoplications; 34 cholecystectomies; 25 gastric bandings; 13 splenectomies; 4 anorectal pull-through operations for imperforate anus; 4 nephrectomies; 4 appendectomies; 4 sympathectomies; 3 choledochal cyst excisions with hepaticojejunostomies; 3 inguinal hernia repairs; two each of the following: liver cyst excision, repair of congenital diaphragmatic hernia, Heller's myotomy, and ovarian cyst excision; and one each of the following: duodeno-duodenostomy, adrenalectomy, and hysterectomy. A total of 134 procedures were successfully completed without conversion; 7 additional cases were converted to open surgery, and 3 were converted to laparoscopic surgery. There were no system failures (e.g., setup joint, arm, or camera malfunction; power error; monocular or binocular loss; metal fatigue or break of surgeon's console hand piece; software incompatibility). There was one esophageal perforation and two cases of transient dysphagia following Nissen fundoplication. The mean patient age was 8.9 years, and the mean patient weight was 57 kg. Robot-assisted surgery appears to be safe and feasible for a number of pediatric surgical procedures. Further system improvement and randomized studies are required to evaluate the benefits, if any, and the long-term outcomes of robotic surgery.


Food Safety Considerations Related to the Consumption and Handling of Game Meat in North America.
Emerging foodborne pathogens present a threat to public health. It is now recognized that several foodborne pathogens originate from wildlife as demonstrated by recent global disease outbreaks. Zoonotic spillover events are closely related to the ubiquity of parasitic, bacterial, and viral pathogens present within human and animal populations and their surrounding environment. Foodborne diseases have economic and international trade impacts, incentivizing effective wildlife disease management. In North America, there are no food safety standards for handling and consumption of free-ranging game meat. Game meat consumption continues to rise in North America; however, this growing practice could place recreational hunters and game meat consumers at increased risk of foodborne diseases. Recreational hunters should follow effective game meat food hygiene practices from harvest to storage and consumption. Here, we provide a synthesis review that evaluates the ecological and epidemiological drivers of foodborne disease risk in North American hunter populations that are associated with the harvest and consumption of terrestrial mammal game meat. We anticipate this work could serve as a foundation of preventive measures that mitigate foodborne disease transmission between free-ranging mammalian and human populations.


Comparison of aquatic macrophyte community structure between natural wetlands and rice fields with different cultivation ages.
Recent studies indicate that rice fields contribute to the conservation of aquatic plants, however, repeated cultivation can reduce the species diversity harbored by rice fields. Repeated tillage, agrochemical application and environmental homogeneity can reduce plant diversity and select for species more tolerant to disturbance. Our hypotheses were: 1) macrophyte richness and biomass decrease with increased rice crop age; and 2) macrophyte species of rice fields are a subsample of natural wetlands and species loss will increase with crop age. We investigated three rice fields of each different ages (old, intermediate and new ones) and three natural intermittent wetlands for this study. Each area was sampled four times throughout the rice cultivation cycle (off-season, initial growth, final growth and post-harvest). Our results showed that the mean macrophyte richness and biomass were similar between rice fields of different ages and lower than that of natural wetlands. Although species composition in the different-aged rice fields was not markedly different, there was nestedness in the rice fields as age increased. In this study, we verified that macrophyte richness and biomass in rice fields was lower than natural wetlands and the species composition was different among wetland types (rice fields and natural wetlands), however our hypothesis that species richness and biomass will decrease with crop age was not confirmed. All rice crops had similar macrophyte assemblage structure (richness, biomass and species composition). However, the another hypothesis tested was confirmed, macrophyte assemblage of rice fields is a subset of natural wetlands and as, the age of a rice field increases, the species that occur in older rice field are subsets of species that occur in younger ones.


Dose calculation differences between Monte Carlo and pencil beam depend on the tumor locations and volumes for lung stereotactic body radiation therapy.
Stereotactic body radiation therapy (SBRT) has been increasingly used as an efficacious treatment modality for early-stage non-small cell lung cancer. The accuracy of dose calculations is compromised due to the presence of inhomogeneity. For the purpose of a consistent prescription, radiation doses were calculated without heterogeneity correction in several RTOG trials. For patients participating in these trials, recalculations of the planned doses with more accurate dose methods could provide better correlations between the treatment outcomes and the planned doses. Using a Monte Carlo (MC) dose calculation algorithm as a gold standard, we compared the recalculated doses with the MC algorithm to the original pencil beam (PB) calculations for our institutional clinical lung SBRT plans. The focus of this comparison is to investigate the volume and location dependence on the differences between the two dose calculations. Thirty-one clinical plans that followed RTOG and other protocol guidelines were retrospectively investigated in this study. Dosimetric parameters, such as D1, D95, and D99 for the PTV and D1 for organs at risk, were compared between two calculations. Correlations of mean lung dose and V20 of lungs between two calculations were investigated. Significant dependence on tumor size and location was observed from the comparisons between the two dose calculation methods. When comparing the PB calculations without heterogeneity correction to the MC calculations with heterogeneity correction, we found that in terms of D95 of PTV: (1) the two calculations resulted in similar D95 for edge tumors with volumes greater than 25.1 cc; (2) an average overestimation of 5% in PB calculations for edge tumors with volumes less than 25.1 cc; and (3) an average overestimation of 9% or underestimation of 3% in PB calculations for island tumors with volumes smaller or greater than 22.6 cc, respectively. With heterogeneity correction, the PB calculations resulted in an average reduction of 23.8% and 15.3% in the D95 for the PTV for island and edge lesions, respectively, when compared to the MC calculations. For organs at risks, very small differences were found among all the comparisons. Excellent correlations for mean dose and V20 of lungs were observed between the two calculations. This study demonstrated that using a single scaling factor may be overly simplified when accounting for the effects of heterogeneity correction. Accurate dose calculations, such as the Monte Carlo algorithms, are highly recommended to understand dose responses in lung SBRT.


[Structural chromosome organisation and radiation-induced interchromosomal aberrations].
The quantitative prediction of the biological effects of radiation is one of the actual tasks of radiobiology. The experimental study may be impossible under certain conditions (low doses, complex radiation fields, etc). The development of theoretical tools is required to predict biological and medical consequence of the irradiation of cell and organism. The effect under the consideration in the present paper is chromosome aberrations (CA) induced by low and high LET radiation. One of the most uncertain factors in CA prediction is the impact of chromosomal and nuclear architecture. In the present study the quantitative evaluation of the mechanisms of CA induction are discussed in the framework of the biophysical modelling technique taking into account interphase chromosomes structure in the nucleus of living (human) cell. We show that the surface contacts mechanism of interchromosomal aberrations (interchange) formation does not explain the observed ratio of simple/complex interchanges induced by both low and high LET radiation. The chromatin structure repositioning following irradiation is proposed as a possible mechanism involved in the formation of the complex aberrations.


Ancestral and conserved cis-regulatory architectures in developmental control genes.
Among developmental control genes, transcription factor-target gene "linkages"--the direct connections between target genes and the factors that control their patterns of expression--can show remarkable evolutionary stability. However, the specific binding sites that mediate and define these regulatory connections are themselves often subject to rapid turnover. Here we describe several instances in which particular transcription factor binding motif combinations have evidently been conserved upstream of orthologous target genes for extraordinarily long evolutionary periods. This occurs against a backdrop in which other binding sites for the same factors are coming and going rapidly. Our examples include a particular Dpp Silencer Element upstream of insect brinker genes, in combination with a novel motif we refer to as the Downstream Element; combinations of a Suppressor of Hairless Paired Site (SPS) and a specific proneural protein binding site associated with arthropod Notch pathway target genes; and a three-motif combination, also including an SPS, upstream of deuterostome Hes repressor genes, which are also Notch targets. We propose that these stable motif architectures have been conserved intact from a deep ancestor, in part because they mediate a special mode of regulation that cannot be supplied by the other, unstable motif instances.


Brain circuitry of compulsivity.
Compulsivity is associated with alterations in the structure and the function of parallel and interacting brain circuits involved in emotional processing (involving both the reward and the fear circuits), cognitive control, and motor functioning. These brain circuits develop during the pre-natal period and early childhood under strong genetic and environmental influences. In this review we bring together literature on cognitive, emotional, and behavioral processes in compulsivity, based mainly on studies in patients with obsessive-compulsive disorder and addiction. Disease symptoms normally change over time. Goal-directed behaviors, in response to reward or anxiety, often become more habitual over time. During the course of compulsive disorders the mental processes and repetitive behaviors themselves contribute to the neuroplastic changes in the involved circuits, mainly in case of chronicity. On the other hand, successful treatment is able to normalize altered circuit functioning or to induce compensatory mechanisms. We conclude that insight in the neurobiological characteristics of the individual symptom profile and disease course, including the potential targets for neuroplasticity is an unmet need to advance the field.


Fatty acid-induced insulin resistance: role of insulin receptor substrate 1 serine phosphorylation in the retroregulation of insulin signalling.
Insulin resistance, when combined with impaired insulin secretion, contributes to the development of type 2 diabetes. Insulin resistance is characterized by a decrease in the insulin effect on glucose transport in muscle and adipose tissue. Tyrosine phosphorylation of IRS-1 (insulin receptor substrate 1) and its binding to PI 3-kinase (phosphoinositide 3-kinase) are critical events in the insulin signalling cascade leading to insulin-stimulated glucose transport. Various studies have implicated lipids as a cause of insulin resistance in muscle. Elevated plasma fatty acid concentrations are associated with reduced insulin-stimulated glucose transport activity as a consequence of altered insulin signalling through PI 3-kinase. Modification of IRS-1 by serine phosphorylation could be one of the mechanisms leading to a decrease in IRS-1 tyrosine phosphorylation, PI 3-kinase activity and glucose transport. Recent findings demonstrate that non-esterified fatty acids, as well as other factors such as tumour necrosis factor alpha, hyperinsulinaemia and cellular stress, increase the serine phosphorylation of IRS-1 and identified Ser(307) as one of the phosphorylated sites. Moreover, several kinases able to phosphorylate this serine residue have been identified. These exciting results suggest that Ser(307) phosphorylation is a possible hallmark of insulin resistance in biologically insulin-responsive cells or tissues. Identification of IRS-1 kinases could enable rational drug design in order to selectively inhibit the activity of the relevant enzymes and generate a novel class of therapeutic agents for type 2 diabetes.


Polygenic inheritance of predisposition to lung cancer.
Inherited predisposition to lung tumor development appears to be a complex genetic trait, in humans as well as in experimental animals. In humans, tobacco smoking represents the main risk factor for lung tumors. Familial clusterings of lung cancer cases are rare, although affected sib pairs are reported. However, several studies have reported an increased risk of lung cancer in first degree relatives of lung cancer patients, as compared with appropriate controls. Inheritence of particular alleles of genes or phenotypes for drug metabolizing enzymes are also associated with an increased lung cancer risk. In experimental models, murine inbred strains with high genetic predisposition to lung cancer are available, as well as resistant strains. A major locus affecting inherited predisposition to lung cancer in mice has been mapped on chromosome 6, near the Kras2 gene. The locus, pulmonary adenoma susceptibility 1 (Pas1) derives from the A/J strain. Additional "minor" loci have also been mapped. Dominant lung tumor resistance loci have also demonstrated in the mouse genome. Therefore, evidence for polygenic inheritance of predisposition to lung cancer is demonstrated in the mouse model, and it is strongly suggested for human lung cancer.


Arterial Stiffness Predicts Cognitive Decline in Japanese Community-dwelling Elderly Subjects: A One-year Follow-up Study.
The purpose of this study was to determine whether arterial stiffness can be used to predict one-year changes in the cognitive function in Japanese community-dwelling elderly subjects. A total of 103 Japanese community-dwelling elderly patients joined this study. Information regarding the age, height, weight, gender and past medical history of each participant was obtained. Additionally, arterial stiffness was determined according to the cardio-ankle vascular index (CAVI), and the cognitive function was assessed with the Mini-Mental State Examination (MMSE). One year later, we performed the MMSE in the same subjects. After dividing the cohort according to the 80th percentile of the CAVI (normal and arterial stiffness [AS] groups), we examined whether the degree of cognitive decline, as determined using the pre- and post-MMSE, was significantly different based on the severity of arterial stiffness, adjusted for age, BMI, gender and the pre-MMSE scores. Of the 103 subjects who participated in the pre-data collection, 74 (38 men and 36 women, 73.4±4.0 years) joined the post-data collection. We found a significant difference in the change in the post-MMSE scores between the normal and AS groups (pre-MMSE: normal group [27.4±2.1] and AS group [26.9±2.4] and post-MMSE: normal group [27.2±2.1] and AS group [25.5±2.3], F=5.95, p=0.02). For each domain of the MMSE, the changes in MMSE-attention-and-calculation (F=5.11, p=0.03) and MMSE-language (F=4.32, p=0.04) were significantly different according to an ANCOVA. We found that arterial stiffness predicts cognitive decline in Japanese community-dwelling elderly subjects regardless of the initial level of the global cognitive function. This finding indicates the potential use of the degree of arterial stiffness as an indicator for preventing or delaying the onset of dementia in the elderly.


Cografting of hamster (Phodopus sungorus) and marmoset (Callithrix jacchus) testicular tissues into nude mice does not overcome blockade of early spermatogenic differentiation in primate grafts.
The ectopic xenotransplantation of testicular tissues into nude mice is a tool to generate sperm from immature testes. Immunodeficient mice as recipients of xenografts offered an appropriate microenvironment for differentiation of testicular tissue from hamsters, goats, pigs, and macaques. One exception is the neotropical primate Callithrix jacchus. Spermatogenesis in testicular grafts from marmosets does not proceed beyond the spermatogonial stage. The most likely cause for the poor graft development of marmosets is a deletion of exon 10 in the luteinizing hormone-receptor (LHR) gene, which renders this species insensitive to LH but responsive to chorionic gonadotropin (CG). We investigated whether cografting of testicular tissue from Djungarian hamsters would overcome the blockade in marmoset graft development. We also tested if exogenous administration of human CG (hCG) to the recipient would stimulate development of the marmoset tissue. No difference in graft survival was noted between hamster and monkey tissue. Seminiferous lumina were present in marmoset and hamster grafts but were significantly larger in hamster grafts. In the hamster grafts, a high proportion of the tubules contained meiotic and postmeiotic germ cells. In contrast, the marmoset tubules were populated with gonocytes and premeiotic spermatogonia. These results indicate that neither normal serum androgen levels nor the high local testosterone levels were sufficient to initiate marmoset spermatogenesis, nor was administration of hCG successful in overcoming the developmental blockade in marmoset tissue. Our results indicate that the conditions needed for initiation of spermatogenesis in the marmoset are remarkably different from those present in most other mammals.


[Jejunum transplantation. Therapeutic progress?].
Either the musculocutaneous island flap (especially the pectoralis major flap) or the free jejunal transplant are used for large mucosal defects of the oro- and hypopharynx. As a jejunal transplant is more time consuming than the use of a musculocutaneous flap, its use must be justified. A review of the literature and our own experience show that the jejunal transplant should be preferred because (1) it is more versatile, (2) it can easily be handled, (3) it provides better functional results, (4) it avoids the functional and aesthetic morbidity of the donor site defect and (5) it has a lower complication rate than the pectoralis major flap.


Mediating and moderated effects of adolescent behavioral undercontrol and parenting in the prediction of drug use disorders in emerging adulthood.
This study tested whether the effects of parental alcoholism on drug use disorders in emerging adulthood were mediated by behavioral undercontrol and parenting in adolescence and whether parenting buffered the relation between undercontrol and drug use disorders. Participants were 175 children of alcoholics and 190 matched control participants from an ongoing longitudinal study (L. Chassin, F. Rogosch, & M. Barrera, 1991). Results showed that undercontrol and parental discipline mediated 58% of the effect of parental alcoholism on drug use disorders. The relation between behavioral undercontrol and drug use disorders was further moderated by parental support. This effect was "protective but reactive" (S. S. Luthar, D. Cicchetti, & B. Becker, 2000); at high levels of behavioral undercontrol the protective effect of parental support was lost. Highly undercontrolled adolescents may have such a strong diathesis for drug use disorders that buffers may not have the same effect as in those with better control.


Improvement from ixekizumab treatment in patients with psoriatic arthritis who have had an inadequate response to one or two TNF inhibitors.
To evaluate the efficacy of ixekizumab (IXE), a monoclonal antibody selectively targeting interleukin-17A, in patients with inadequate response to one or two TNF inhibitors (TNFi). A phase 3 study (SPIRIT-P2; NCT02349295) randomized patients with PsA with inadequate response or intolerance to one or two TNFi to receive 80-mg IXE every 2 weeks (n = 123) or every 4 weeks (n = 122) after a 160-mg starting dose or placebo (PBO; n = 118) through week 24. This post hoc analysis used data from inadequate responders to one or two TNFi, measuring the percentage achieving: ≥50% improvement in ACR response criteria (ACR50) and 100% improvement from baseline in the Psoriasis Area and Severity Index (PASI 100), ACR50, improvement in HAQ-Disability Index (HAQ-DI) ≥0.35, minimal disease activity (MDA), European League Against Rheumatism (EULAR) Good Response Criteria [improvement in Disease Activity Score 28 CRP (DAS28-CRP) >1.2], and Disease Activity in PsA (DAPSA) ≤14. There were no significant differences in baseline characteristics between inadequate responders to one and two TNFi. At week 24, significantly more patients irrespective of previous TNFi experience receiving IXE than PBO achieved ACR50, HAQ-DI ≥0.35 improvement, MDA, EULAR good response, and DAPSA ≤14, and significantly more patients with inadequate response to one TNFi receiving IXE than PBO achieved ACR50 and PASI 100. Improvement persisted in all measures through week 52. IXE improved the signs and symptoms of PsA in a population of difficult-to-treat patients with inadequate response to one or two TNFi.


[Biomedical colonialism or local autonomy? Local healers in the fight against tuberculosis].
The article explores the role played by indigenous medical agents, and their knowledge, within contemporary tuberculosis campaigns in sub-Saharan Africa. To understand the historical framework within which the World Health Organization devised its strategies to promote and develop traditional medicine as of the 1970s, the article contextualizes contemporary medicine as a cultural legacy of colonial medicine. Under the public healthcare projects analyzed in the article, local medical practices were assessed and indigenous agents trained so they could take part in strictly biomedical activities, like symptom identification, referrals to hospitals, or supervision of drug treatments.


Microglia-derived IL-1β promotes chemokine expression by Müller cells and RPE in focal retinal degeneration.
Chemokine signalling is required for the homing of leukocytes during retinal inflammation, and is associated with pathogenesis of diseases such as age-related macular degeneration (AMD). Here, we explore the role of interleukin-1β (IL-1β) in modulating AMD-associated chemokines Ccl2, Cxcl1, and Cxcl10 during photo-oxidative retinal damage, and the effect on both the accumulation of outer-retinal macrophages, and death of photoreceptors. Inhibition of retinal IL-1β expression was performed using either siRNA or antibody neutralisation, which was intravitreally injected in SD rats prior to photo-oxidative damage. Changes in the expression and localisation of Il-1β, Ccl2, Cxcl1 and Cxcl10 genes were assessed using qPCR and in situ hybridisation, while the recruitment of retinal macrophages was detected using immunohistochemistry for IBA1. Levels of photoreceptor cell death were determined using TUNEL. Photo-oxidative damage elevated the expression of Il-1β and inflammasome-related genes, and IL-1β protein was detected in microglia infiltrating the outer retina. This was associated with increased expression of Ccl2, Cxcl1, and Cxcl10. Intravitreal IL-1β inhibitors suppressed chemokine expression following damage and reduced macrophage accumulation and photoreceptor death. Moreover, in Müller and RPE cell cultures, and in vivo, Ccl2, Cxcl1 and Cxcl10 were variously upregulated when stimulated with IL-1β, with increased macrophage accumulation detected in vivo. IL-1β is produced by retinal microglia and macrophages and promotes chemokine expression by Müller cells and RPE in retinal degeneration. Targeting IL-1β may prove efficacious in broadly suppressing chemokine-mediated inflammation in retinal dystrophies such as AMD.


Health-related quality of life in people with psychotic disorders: The role of loneliness and its contributors.
Perception of loneliness has been identified as the strongest predictor of health-related quality of life assessed with the Assessment of Quality of Life-4D in people with psychotic disorders. We aimed to establish contributors to perceived loneliness, and ascertain the mediating role of loneliness in the relationship between identified contributors to loneliness and other known predictors of health-related quality of life with health-related quality of life. Data for 1642 people collected as part of the 2010 Australian National Survey of Psychosis were analysed. Health-related quality of life was assessed using the Assessment of Quality of Life-4D, and loneliness through a single-item five-level categorical variable. To identify independent contributors to loneliness, a statistical model was constructed with reference to a theoretical model comprising 23 variables. A predictive model with health-related quality of life as the dependent variable was then developed and tested to assess the mediating role of loneliness. Nine contributors to loneliness were found (social dysfunction, experienced stigma, contact with friends, diagnosis, depressive symptoms, anxiety, mental health service utilisation, arthritis and traumatic events in childhood), with social dysfunction the strongest. In the prediction of health-related quality of life, all contributors to loneliness were partially mediated through loneliness (except service utilisation) as were negative symptoms and use of psychotropic/anticholinergic medications. Assuming a plausible causal model of mediation, loneliness was found to have direct and indirect effects on health-related quality of life in people with psychotic disorders. Findings add impetus to efforts to develop and trial strategies aimed at reducing loneliness in this population, and, in turn, improving their health-related quality of life.


An evaluation of hybrid methods for matching biomedical terminologies: mapping the gene ontology to the UMLS.
Integration of disparate biomedical terminologies is becoming increasingly important as links between biological science and clinical medicine grow. Mapping concepts in the Gene Ontology (GO) to the UMLS may help further this integration and allow for more efficient information exchange among researchers. Using a gold standard of GO term--UMLS concept mappings provided by the NCI, we examined the performance of various published and combined mapping techniques, in order to maximize precision and recall. We found that for the previously published techniques precision varied between (0.61-0.95), and recall varied from (0.65-0.90), whereas for the hybrid techniques, precision varied between (0.66-0.97), and recall from (0.59-0.93). Our study reveals the benefits of using mapping techniques that incorporate domain knowledge, and provides a basis for future approaches to mapping between distinct biomedical vocabularies.


[Studies of directional sensitivity of neurons in the cat primary auditory cortex].
A set of impulsive transient signals has been synthesized for earphone delivery whose waveform and amplitude spectra, measured at the eardrum, mimic those of sounds arriving from a free-field source. The complete stimulus set forms a "virtual acoustic space" (VAS) for the cat. VAS stimuli are delivered via calibrated earphones sealed into the external meatus in cats under barbiturate anesthesia. Neurons recorded extracellularly in primary (AI) auditory cortex exhibit sensitivity to the direction of sound in VAS. The aggregation of effective sound directions forms a virtual space receptive field (VSRF). At about 20 dB above minimal threshold, VSRFs recorded in otherwise quiet and anechoic space fall into categories based on spatial dimension and location. The size, shape and location of VSRFs remain stable over many hours of recording and are found to be shaped by excitatory and inhibitory interactions of activity arriving from the two ears. Within the VSRF response latency and strength vary systematically with stimulus direction. In an ensemble of such neurons these functional gradients provide information about stimulus direction, which closely accounts for a human listener's spatial acuity. Raising stimulus intensity, introducing continuous background noise or presenting a conditioning stimulus all influence the extent of the VSRF but leave intact the gradient structure of the field. These and other findings suggest that such functional gradients in VSRFs of ensembles of AI neurons are instrumental in coding sound direction and robust enough to overcome interference from competing environmental sounds.


Tissue-specific distribution of carotenoids and vitamin E in tissues of newly hatched chicks from various avian species.
The aim of this study was to evaluate carotenoid and vitamin E distribution in egg and tissues of newly hatched chicks from wild mallard (Anas platyrhynchos), game pheasant (Phasianus colchicus), free-range guinea fowl (Numida meleagris), hen (Gallus domesticus) and domestic duck (Anas platyrhynchos) and intensively housed hens. Carotenoid concentrations in the egg yolk of free-range guinea fowl, pheasant and wild mallard were similar (61.3-79.2 microg/g). Egg yolks from ducks and intensively housed hens were characterised by the lowest carotenoid concentration comprising 11.2-14.8 microg/g. However, carotenoid concentration in eggs from free-range ducks and hens was less than half of that in free-range guinea fowl or pheasant. Depending on carotenoid concentration in the livers of species studied could be placed in the following descending order: free living pheasant>free-range guinea fowl>>free-range hen>>intensively housed hen>wild mallard>>housed duck>free-range duck. The carotenoid concentrations in other tissues of free-range guinea fowl and pheasant were substantially higher than in the other species studied. Egg yolk of housed hens was characterised by the highest alpha- and gamma-tocopherol concentrations. In accordance with the alpha-tocopherol concentration in the egg yolk, the birds can be placed in the following descending order: intensively housed hen>wild mallard>free-living pheasant>free-range duck>free-range hen=free-range guinea fowl>housed duck. The main finding of this work is species- and tissue-specific differences in carotenoid and vitamin E distribution in the various avian species studied.


Gut microbiota-related metabolite alpha-linolenic acid mitigates intestinal inflammation induced by oral infection with Toxoplasma gondii.
Oral infection with cysts is the main transmission route of Toxoplasma gondii (T. gondii), which leads to lethal intestinal inflammation. It has been widely recognized that T. gondii infection alters the composition and metabolism of the gut microbiota, thereby affecting the progression of toxoplasmosis. However, the potential mechanisms remain unclear. In our previous study, there was a decrease in the severity of toxoplasmosis after T. gondii α-amylase (α-AMY) was knocked out. Here, we established mouse models of ME49 and Δα-amy cyst infection and then took advantage of 16S rRNA gene sequencing and metabolomics analysis to identify specific gut microbiota-related metabolites that mitigate T. gondii-induced intestinal inflammation and analyzed the underlying mechanism. There were significant differences in the intestinal inflammation between ME49 cyst- and Δα-amy cyst-infected mice, and transferring feces from mice infected with Δα-amy cysts into antibiotic-treated mice mitigated colitis caused by T. gondii infection. 16S rRNA gene sequencing showed that the relative abundances of gut bacteria, such as Lactobacillus and Bacteroides, Bifidobacterium, [Prevotella], Paraprevotella and Macellibacteroides, were enriched in mice challenged with Δα-amy cysts. Spearman correlation analysis between gut microbiota and metabolites indicated that some fatty acids, including azelaic acid, suberic acid, alpha-linolenic acid (ALA), and citramalic acid, were highly positively correlated with the identified bacterial genera. Both oral administration of ALA and fecal microbiota transplantation (FMT) decreased the expression of pro-inflammatory cytokines and restrained the MyD88/NF-κB pathway, which mitigated colitis and ultimately improved host survival. Furthermore, transferring feces from mice treated with ALA reshaped the colonization of beneficial bacteria, such as Enterobacteriaceae, Proteobacteria, Shigella, Lactobacillus, and Enterococcus. The present findings demonstrate that the host gut microbiota is closely associated with the severity of T. gondii infection. We provide the first evidence that ALA can alleviate T. gondii-induced colitis by improving the dysregulation of the host gut microbiota and suppressing the production of pro-inflammatory cytokines via the MyD88/NF-κB pathway. Our study provides new insight into the medical application of ALA for the treatment of lethal intestinal inflammation caused by Toxoplasma infection. Video Abstract.


Investigation of CMV disease in immunocompromised patients.
Cytomegalovirus (CMV) is a recognised cause of morbidity and mortality in immunocompromised individuals. This review will concentrate on recent advances in the understanding of the complex interplay between the host and parasite and the pathological consequences of perturbation of the host immune system. The classic view of CMV as a slowly replicating virus is challenged by recent in vivo findings suggesting that active replication occurs dynamically in the human host, with a doubling time of approximately one day. In addition, CMV load plays a major role in viral pathogenesis, such that increased CMV replication is a significant risk factor for disease in all immunocompromised groups studied to date. These studies focus attention on understanding the virological and immunological determinants of enhanced viral replication and its pathological consequences.


A novel robot training system designed to supplement upper limb physiotherapy of patients with spastic hemiparesis.
Spasticity is velocity and acceleration dependent, and it is therefore important to execute physiotherapeutic exercises at a relatively low and constant velocity. This can be more accurately managed by a robot than by a person when such exercises are administered continuously for more than 15-20 min. The purpose of this project was to construct a robot-mediated system that could support upper limb physiotherapy of patients with spastic hemiparesis. The system, unlike any known robotic therapeutic system, uses unmodified industrial robots to carry out passive physiotherapy on the upper limb (including the movements of the shoulder and the elbow). An initial trial was executed in order to assess its safety and to gain experience of the robot-mediated therapy. Four healthy subjects and eight patients with spastic hemiparesis were included. Each subject received 30-min-long robotic physiotherapy sessions over 20 consecutive workdays. The 12 participants received, in total, 240 robot-mediated physiotherapeutic sessions. No dangerous situation or considerable technical problem occurred; the robots executed the therapy programme as intended. Investigation of the effectiveness of this kind of therapy was not an aim of this initial trial; however, the patients' clinical status was followed and some favourable changes were found regarding the spasticity of elbow flexors and shoulder abductors. According to the experiences of the first clinical investigation, the programming interface and the mechanical interface device between the patient and the robots had been improved. A controlled clinical study is under way to assess the effectiveness of the REHAROB movement therapy.


Advances in Hemodynamic Monitoring in Heart Failure Patients.
Abnormal hemodynamics are associated with poor clinical outcomes in patients with heart failure. Given the invasiveness and unfeasibility of routine right heart catheterization, non-invasive methodologies to monitor hemodynamics are needed. The CardioMEMS™ device is a recently developed technology that enables remote monitoring of pulmonary artery pressures via an implanted sensor located in the distal left pulmonary artery. Along with the CardioMEMS™, a remote dielectric system might be another promising device that reports indirect intra-thoracic filling pressures associated with pulmonary congestion. In patients with advanced heart failure who require left ventricular assist devices, non-invasive hemodynamic monitoring is particularly necessary, given the increased procedural risks of invasive assessments. The HeartWare ventricular assist device flow waveform is a variable under active investigation that might also provide an estimation of filling pressures. This methodology is expected to lead to the development of a smart pump that can adjust its own settings, including the pump speed, automatically by monitoring the hemodynamics.


[Ocular drug penetration].
The study of ocular drug penetration may take into account many factors connected to the ophthalmic route specificity: anatomical barriers of the eye, solubility, molecular weight and eyedrops concentration. The factors influencing ocular drug penetration are reviewed. The broad outlines of research focuses now on an increase of the bioavailability, a best tolerability and a reduction of systemic effects of drugs.


Idiopathic monomorphic ventricular tachycardia: clinical outcome, electrophysiologic characteristics and long-term results of catheter ablation.
Ventricular tachycardia (VT) without structural heart disease or any identifiable predisposing causes for arrhythmia is an uncommon but well-recognized clinical entity. The purpose of this study is to assess the results of catheter ablation therapy and the long-term outcome of patients with idiopathic monomorphic VT in a large patient group. Sixty-one consecutive patients (male/female=40/21; mean age 38+/-16 years) with idiopathic VT underwent electrophysiologic study and an attempt of catheter ablation therapy. The 'left VT' group included 31 patients with QRS morphology of right bundle branch block during VT suggestive of the VT originating from the left ventricle (LV), and the 'right VT' group consisted of 30 patients with QRS morphology of left bundle branch block with normal or right frontal axis deviation suggestive of VT arising from right ventricular outflow tract (RVOT). Idiopathic left VT has sustained VT during the clinical attacks, baseline electrophysiologic study or after isoproterenol infusion; it can be entrained by overdrive ventricular pacing, terminated by verapamil, but not by adenosine (except one case with VT focus at left ventricular free wall). Catheter ablation was successful in 22 (84%) of 26 patients, with recurrence rate of 9%. The successful ablation sites were located at LV inferior-apical septum (16 patients), mid-septum (three patients), high septum (two patients) and high anterior wall (one patient). In the right VT group, 20 (67%) of 30 patients presented clinically repetitive monomorphic VT. Most of the idiopathic right VT (22/30) required isoproterenol to facilitate induction of VT, and were sensitive to both verapamil and adenosine. Successful catheter ablation was achieved in 21 (84%) of 25 patients, with recurrence rate 19%. The successful ablation sites were located at RVOT-septum in 18 patients, and RVOT-free wall in three patients. During a mean follow-up period of 29.2+/-21.7 months (range 1-76 months) after hospital discharge, all patients were alive but one left VT case died of non-cardiovascular cause. We concluded that idiopathic left side and right side VTs have their distinct clinical, electrophysiologic and electropharmacological characteristics suggestive of different underlying mechanisms, and both have a benign prognosis. Furthermore, catheter ablation can be effective in eliminating idiopathic VT originating from the right ventricular outflow tract and left ventricle.


Bovine pepsinogens and pepsins. A series of zymogens and enzymes that differ in organic phosphate content.
Several minor pepsinogens, present in extracts of bovine fundic mucosa obtained from the fourth stomach or abomasum, were separated from the main pepsinogen by chromatography on hydroxyapatite at pH7.3. The major pepsinogen and two of these minor pepsinogens were studied in detail. All three zymogens have N-terminal Ser-Val-, C-terminal -Val-Ala and not more than 1mol of glucose/mol of protein; no significant differences in amino acid composition were found. The pepsinogens differ in their organic phosphate content, which accounts for their chromatographic separation. By activation at 0 degrees C and pH2, a corresponding series of pepsins is formed. These enzymes were separated by hydroxyapatite chromatography at pH5.7. All the pepsins have N-terminal valine, C-terminal alanine and are free from carbohydrate. Again the only difference detected among them is in their organic phosphate content. The pepsins of high phosphate content are converted by an acid phosphatase in vitro into pepsins of low phosphate content.


Parallel convolutional processing using an integrated photonic tensor core.
With the proliferation of ultrahigh-speed mobile networks and internet-connected devices, along with the rise of artificial intelligence (AI)1, the world is generating exponentially increasing amounts of data that need to be processed in a fast and efficient way. Highly parallelized, fast and scalable hardware is therefore becoming progressively more important2. Here we demonstrate a computationally specific integrated photonic hardware accelerator (tensor core) that is capable of operating at speeds of trillions of multiply-accumulate operations per second (1012 MAC operations per second or tera-MACs per second). The tensor core can be considered as the optical analogue of an application-specific integrated circuit (ASIC). It achieves parallelized photonic in-memory computing using phase-change-material memory arrays and photonic chip-based optical frequency combs (soliton microcombs3). The computation is reduced to measuring the optical transmission of reconfigurable and non-resonant passive components and can operate at a bandwidth exceeding 14 gigahertz, limited only by the speed of the modulators and photodetectors. Given recent advances in hybrid integration of soliton microcombs at microwave line rates3-5, ultralow-loss silicon nitride waveguides6,7, and high-speed on-chip detectors and modulators, our approach provides a path towards full complementary metal-oxide-semiconductor (CMOS) wafer-scale integration of the photonic tensor core. Although we focus on convolutional processing, more generally our results indicate the potential of integrated photonics for parallel, fast, and efficient computational hardware in data-heavy AI applications such as autonomous driving, live video processing, and next-generation cloud computing services.


Structural analysis of natural textures.
Many textures can be described structurally, in terms of the individual textural elements and their spatial relationships. This paper describes a system to generate useful descriptions of natural textures in these terms. The basic approach is to determine an initial, partial description of the elements using edge features. This description controls the extraction of the texture elements. The elements are grouped by type, and spatial relationships between elements are computed. The descriptions are shown to be useful for recognition of the textures, and for reconstruction of periodic textures.


Effect of germination temperatures on proteolysis of the gluten-free grains sorghum and millet during malting and mashing.
Our study showed that sorghum and millet followed a similar pattern of changes when they were malted under similar conditions. When the malt from these cereals was mashed, both cereal types produced wide spectra of substrates (sugars and amino acids) that are required for yeast fermentation when malted at either lower or higher temperatures. At the germination temperatures of 20, 25, and 30 °C used in malting both cereal types, production of reducing sugars and that of free amino nitrogen (FAN) were similar. This is an important quality attribute for both cereals because it implies that variation in temperature during the malting of sorghum and millet, especially when malting temperature is difficult to control, and also reflecting temperature variations, experienced in different countries, will not have an adverse effect on the production and release of amino acids and sugars required by yeast during fermentation. Such consistency in the availability of yeast food (substrates) for metabolism during fermentation when sorghum and millet are malted at various temperatures is likely to reduce processing issues when their malts are used for brewing. Although sorghum has gained wide application in the brewing industry, and has been used extensively in brewing gluten-free beer on industrial scale, this is not the case with millet. The work described here provides novel information regarding the potential of millet for brewing. When both cereals were malted, the results obtained for millet in this study followed patterns similar to those of sorghum. This suggests that millet, in terms of sugars and amino acids, can play a role similar to that of sorghum in the brewing industry. This further suggests that millet, like sorghum, would be a good raw material for brewing gluten-free beer. Inclusion of millet as a brewing raw material will increase the availability of suitable materials (raw material sustainability) for use in the production of gluten-free beer, beverages, and other products. The availability of wider range of raw materials will not only help to reduce costs of beer production, but by extension, the benefit of reduced cost of production can be gained by consumers of gluten-free beer as the product would be cheaper and more widely available.


A novel nutraceutical property of select sorghum (Sorghum bicolor) brans: inhibition of protein glycation.
Despite the high levels of polyphenolic phytochemicals in grain sorghum and its position as a major food staple, there has been a lack of research on its effects on both animal and human health and disease prevention. These phenolic compounds, mainly located in the bran fraction, result in the plant having substantial antioxidant properties. This study examined the effect of ethanol extracts of several varieties of sorghum (S. bicolor) bran on albumin glycation, a non-enzymatic process thought to be important in the pathogenesis of many diabetic complications. Sorghum brans with a high phenolic content and high antioxidant properties inhibited protein glycation, whereas sorghum brans that are low in these properties did not inhibit this process. Ethanol extracts of wheat, rice or oat bran did not inhibit protein glycation. Although one high phenolic sorghum bran variety (sumac) inhibited protein glycation by approximately 60%, it produced only a 20% decrease in methylglyoxal mediated albumin glycation. These results suggest that certain varieties of sorghum bran may affect critical biological processes that are important in diabetes and insulin resistance. These results distinguish select sorghum brans from the common food brans and suggest a nutraceutical rationale for its human consumption.


Limb apraxia in multiple sclerosis.
There are almost no studies on apraxia in people with multiple sclerosis. Although the white matter is damaged in MS, it is not the only location in which the pathological changes are present. Demyelinated lesions in the cortex have recently been recognized as important components of multiple sclerosis pathology. The aim of this study was to determine whether apraxia is present among people with MS, and the importance of demographic characteristics and impairment of functional systems at conceptualization and execution of movements. The experimental group consisted of 30 patients, mean age 51.34 +/- 7.70 years. The patients in the experimental group were diagnosed with MS according to the McDonald criteria. The control group consisted of 30 healthy subjects, mean age 50.30 +/- 10.47 years. For research purposes, we used the following instruments: Questionnaire for Collecting Demographic Data, Kurtzke Functional Systems Scores, Waterloo-Sunnybrook Apraxia Battery (WatAB). Execution of motion tasks that are a part of the WatAB were incorporated in the System for the Observation and Analysis of Motor Behavior. Our study showed that limb apraxia was common in people with MS. Apraxia was present during pantomime in 26.70% of the patients, and during the imitation of movements in 44.80% of the patients. Gender, age, education level, duration of disease and a form of MS did not determine the quality of conceptualization and execution of movements. The time elapsed from the last exacerbation was a determinant of quality of executed movements. Impairments of functional systems predicted impairments of movement execution. The expanded disability scale score correlated with the severity of apraxia. Our study confirm the presence of apraxia in MS. It is necessary to carry out further studies using functional magnetic resonance imaging, as well as the conduct longitudinal studies to determine the precise structure of motor behavior in people with MS.


Effect of vitamin E and beta carotene on the incidence of angina pectoris. A randomized, double-blind, controlled trial.
To examine the effect of supplementation with vitamin E (alpha tocopherol), beta carotene, or both on the incidence of angina pectoris in men without known previous coronary heart disease. Randomized, double-blind, placebo-controlled trial. Participants in the Alpha Tocopherol, Beta Carotene Cancer Prevention Study (N=29133) were male smokers aged 50 through 69 years who were living in southern and western Finland. Of these men, 22269 were considered free of coronary heart disease at baseline and were followed up for the incidence of angina pectoris. Participants were randomized to receive 50 mg/d of alpha tocopherol, 20 mg/d of beta carotene, both, or placebo in a 2x2 design. An incident case was defined as the first occurrence of typical angina pectoris identified in administering the annually repeated World Health Organization (Rose) Chest Pain Questionnaire. During a median follow-up time of 4.7 years (96427 person-years), 1983 new cases of angina pectoris were detected. Comparing alpha tocopherol-supplemented subjects with non-alpha tocopherol-supplemented subjects showed a relative risk (RR) of angina pectoris incidence of 0.91 (95% confidence interval[CI], 0.83 to 0.99; P=.04). The RR for incidence of angina pectoris for the beta carotene- supplemented subjects compared with those not receiving beta carotene was 1.06 (95% CI, 0.97 to 1.16; P=.19). Compared with those receiving placebo, the RRs for incidence of angina pectoris were 0.97 (95% CI, 0.85 to 1.10) and 0.96 (95% CI, 0.85 to 1.09) in the alpha tocopherol and alpha tocopherol plus beta carotene groups, respectively, and 1.13 (95% CI, 1.00 to 1.27) in the beta carotene group (P=.06). Baseline dietary intakes and serum levels of alpha tocopherol and beta carotene did not predict incidence of angina pectoris. Supplementation with alpha tocopherol was associated with only a minor decrease in the incidence of angina pectoris. Beta carotene had no preventive effect and was associated with a slight increase of angina.