Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Comprehensive Review.
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating chronic disease of unknown aetiology that is recognized by the World Health Organization (WHO) and the United States Center for Disease Control and Prevention (US CDC) as a disorder of the brain. The disease predominantly affects adults, with a peak age of onset of between 20 and 45 years with a female to male ratio of 3:1. Although the clinical features of the disease have been well established within diagnostic criteria, the diagnosis of ME/CFS is still of exclusion, meaning that other medical conditions must be ruled out. The pathophysiological mechanisms are unclear but the neuro-immuno-endocrinological pattern of CFS patients gleaned from various studies indicates that these three pillars may be the key point to understand the complexity of the disease. At the moment, there are no specific pharmacological therapies to treat the disease, but several studies' aims and therapeutic approaches have been described in order to benefit patients' prognosis, symptomatology relief, and the recovery of pre-existing function. This review presents a pathophysiological approach to understanding the essential concepts of ME/CFS, with an emphasis on the population, clinical, and genetic concepts associated with ME/CFS.


The Association of Comorbid Depression and Anxiety Symptoms With Disability Onset in Older Adults.
Despite the high prevalence of late-life depression and anxiety at threshold and subthreshold levels, their joint role in the disablement process remains unclear. This study aims to examine the association of comorbid occurring depression and anxiety across the full spectrum of symptom severity with disability onset in older adults. The study included 3663 participants from the 2011 National Health and Aging Trends Study, who reported no limitations in self-care and mobility activities at baseline. Disability onset was defined as a report of receiving help from another person in any of the activities for 3 consecutive months. Depression and anxiety symptoms were measured using the four-item Patient Health Questionnaire, grouped into low, mild, and moderate/severe symptom groups. Cox proportional hazards models were used to estimate relative risks for disability onset over a 5-year period by depression/anxiety symptom groups. A total of 1047 participants developed disability (24.6%; 6.0 per 1000 person-months). At baseline, one-fifth of the sample reported symptoms that were mild (n = 579 [14.9%]; 31.6% with disability onset) or moderate/severe (n = 156 [4.2%]; 38.1% with disability onset). After adjustment for sociodemographics, there was a dose-response relationship between depression/anxiety symptom groups and disability onset (mild versus low: hazard ratio [HR] = 1.43, 95% confidence interval [CI] = 1.20-1.70; moderate/severe versus low: HR = 1.94, 95% CI = 1.45-2.59). The increased risk remained significant after adjustment for health status variables for the mild symptom group (HR = 1.26, 95% CI = 1.07-1.49), but not for the moderate/severe symptom group (HR = 1.30, 95% CI = 0.94-1.79), possibly reflecting lower statistical power. Findings suggest that the full spectrum of depression and anxiety symptoms are associated with increased risk for disability in late life. Their role in the disablement process warrants further investigation.


Clinical studies in persistent diarrhea: dietary management with green banana or pectin in Bangladeshi children.
Because of the beneficial intestinal effects of dietary fibers, we have evaluated the therapeutic effects of green banana or pectin in children with persistent diarrhea. In a double-blind trial, 62 boys, age 5-12 months, were randomly given a rice-based diet containing either 250 g/L of cooked green banana (n = 22) or 4 g/kg pectin (n = 19) or the rice-diet alone (control, n = 21), providing 54 kcal/dL daily for 7 days. Stool weight and consistency, frequency of vomiting and purging, and duration of illness were measured. Most children (60%) had no pathogens isolated from stools, 17% had rotavirus, 5% Vibrio cholerae, 4% Salmonella group B, and 11% had enterotoxigenic Escherichia coli infections. By day 3 posttreatment, significantly (P < 0.001) more children recovered from diarrhea receiving pectin or banana than controls (59%, 55%, and 15%, respectively). By day 4, these proportions correspondingly increased to 82%, 78%, and 23%, respectively, the study diet groups being significantly (P < 0.001) different than controls. Green banana and pectin significantly (P < 0.05) reduced amounts of stool, oral rehydration solution, intravenous fluid, and numbers of vomiting, and diarrheal duration. Green banana and pectin are useful in the dietary management of persistent diarrhea in hospitalized children and may also be useful to treat children at home.


Transplanted adult human hepatic stem/progenitor cells prevent histogenesis of advanced hepatic fibrosis in mice induced by carbon tetrachloride.
Transplantation of adult human hepatic stem/progenitor cells (hHSPCs) has been considered as an alternative therapy, replacing donor liver transplantation to treat liver cirrhosis. This study assessed the antifibrotic effects of hHSPCs in mice with fibrosis induced by carbon tetrachloride (CCl4) and examined the actions of hHSPCs on the fibrogenic activity of human hepatic stellate cells (HSCs) in a coculture system. Isolated hHSPCs expressed stem/progenitor cell phenotypic markers. Mice were given CCl4 (twice weekly for 7 weeks) and hHSPC transplantation weekly. CCl4 induced advanced fibrosis (bridging fibrosis and cirrhosis) in mice, which was prevented by hHSPC transplantation. The liver of hHSPC-transplanted mice showed only occasional short septa and focal parenchymal fibrosis, and a 50% reduction in hepatic collagen, assessed by Sirius red stain histomorphometry. Moreover, the proteins for α-smooth muscle actin (α-SMA) and collagen I were decreased. While α-SMA, collagen α1(I), and tissue inhibitor of metalloproproteinase-1 mRNAs were decreased, matrix metalloproteinase (MMP)-1 mRNA was increased, consistent with decreased fibrogenesis. MMP-2 and transforming growth factor-β were not affected. Alanine aminotransferase and aspartate aminotransferase were lower, suggesting improvement of liver function/damage. In coculture, hHSPCs elicited changes of α-SMA and fibrogenic molecules in HSCs similar to those observed in vivo, providing evidence for a functional link between hHSPCs and HSCs. A decreased HSC proliferation was noted. Thus, transplantation of hHSPCs prevents histogenesis of advanced liver fibrosis caused by CCl4. hHSPCs mediate downregulation of HSC activation coincident with modulation of fibrogenic molecule expression, leading to suppression of fibrogenesis both in vivo and in vitro.


CD63 is a component of Weibel-Palade bodies of human endothelial cells.
Weibel-Palade bodies are secretory granules of vascular endothelial cells specialized in the storage of von Willebrand factor (vWF) and P-selectin, two adhesion proteins that can be rapidly mobilized to the cell surface by exocytosis in response to thrombin or other agonists. In this study, we attempted to identify additional components of Weibel-Palade bodies by raising monoclonal antibodies to these granules, purified by cell fractionation. One antibody, 2C6, was found to be specific for CD63, a membrane glycoprotein previously described in the lysosomes of platelets and other cell types. The immunopurified 2C6 antigen was recognized by an anti-CD63 reference antibody, 2.28, by Western blotting. Also, the biosynthetic profile of the 2C6 antigen in endothelial cells showed a nascent molecular mass and a glycosylation pattern identical to that of CD63. Immunofluorescence staining with 2C6 showed the lysosomes, and also elongated structures identified as Weibel-Palade bodies by their shape, distribution, and positive staining with anti-vWF antibodies, CD63 was also found by Western blotting of subcellular fractions highly enriched in Weibel-Palade bodies. Our results indicate that CD63 colocalizes with vWF and P-selectin in the Weibel-Palade bodies of endothelial cells, and together with these adhesion proteins it could be rapidly expressed on the cell surface in areas of vascular injury and inflammation.


Auditory white noise reduces postural fluctuations even in the absence of vision.
The contributions of somatosensory, vestibular, and visual feedback to balance control are well documented, but the influence of auditory information, especially acoustic noise, on balance is less clear. Because somatosensory noise has been shown to reduce postural sway, we hypothesized that noise from the auditory modality might have a similar effect. Given that the nervous system uses noise to optimize signal transfer, adding mechanical or auditory noise should lead to increased feedback about sensory frames of reference used in balance control. In the present experiment, postural sway was analyzed in healthy young adults where they were presented with continuous white noise, in the presence and absence of visual information. Our results show reduced postural sway variability (as indexed by the body's center of pressure) in the presence of auditory noise, even when visual information was not present. Nonlinear time series analysis revealed that auditory noise has an additive effect, independent of vision, on postural stability. Further analysis revealed that auditory noise reduced postural sway variability in both low- and high-frequency regimes (> or <0.3 Hz) of sway, suggesting that both spontaneous and feedback-driven aspects of postural fluctuations were influenced by acoustic noise. Our results support the idea that auditory white noise reduces postural sway, suggesting that auditory noise might be used for therapeutic and rehabilitation purposes in older individuals and those with balance disorders.


Silencing of the sulfur rich α-gliadin storage protein family in wheat grains (Triticum aestivum L.) causes no unintended side-effects on other metabolites.
Wheat is an important source of proteins and metabolites for human and animal nutrition. To assess the nutritional quality of wheat products, various protein and diverse metabolites have to be evaluated. The grain storage protein family of the α-gliadins are suggested to be the primary initiator of the inflammatory response to gluten in Celiac disease patients. With the technique of RNAi, the α-gliadin storage protein fraction in wheat grains was recently knocked down. From a patient's perspective, this is a desired approach, however, this study aims to evaluate whether such a down-regulation of these problematic α-gliadins also has unintended side-effects on other plant metabolites. Such uncontrolled and unknown arbitrary effects on any metabolite in plants designated for food production would surely represent an avoidable risk for the consumer. In general, α-gliadins are rich in sulfur, making their synthesis and content depended of the sulfur supply. For this reason, the influence of the application of increasing sulfur amounts on the metabolome of α-gliadin-deficient wheat was additionally investigated because it might be possible that e.g., considerable high/low amounts of S might increase or even induce such unintended effects that are not observable under moderate S nutrition. By silencing the α-gliadin genes, a recently developed wheat line that lacks the set of 75 corresponding α-gliadin proteins has become available. The plants were subsequently tested for RNAi-induced effects on metabolites that were not directly attributable to the specific effects of the RNAi-approach on the α-gliadin proteins. For this, GC-MS-based metabolite profiles were recorded. A comparison of wild type with gliadin-deficient plants cultivated in pot experiments revealed no differences in all 109 analyzed metabolites, regardless of the S-nutritional status. No unintended effects attributable to the RNAi-based specific genetic deletion of a storage protein fraction were observed.


Does an Ileostomy Rod Prevent Stoma Retraction? A Meta-analysis of Randomized Controlled Trials.
A rod passed through the mesenteric window is commonly used during maturation of ileostomies, but evidence for the effectiveness of this procedure is limited. The aim of this meta-analysis was to determine whether ileostomy rods decrease stoma retraction rates in patients undergoing loop ileostomy (LI). The PubMed, EMBASE, Cochrane Library, MEDLINE via Ovid, Cumulative Index of Nursing and Allied Health Literature, and Web of Science databases were systematically searched for randomized controlled trials (RCT) published in English from 1990 to the present date using the MeSH terms ostomy, rod, and bridge to compare ileostomies with a rod to those without a rod. Study information, patient demographics, characteristics, and stoma retraction rates were abstracted. The primary endpoint, stoma retraction, was defined as the disappearance of normal stomal protrusion to at, or below, skin level. The Mantel-Haenszel method of meta-analysis with odds ratio and 95% confidence interval (OR [95% CI]) was used. Among-study statistical heterogeneity was assessed using Cochrane chi-squared and I² tests. Tau² analysis to assess between-study variance was employed when I² was greater than 50%. The number needed to treat/harm (NNT) was calculated to assess clinical relevance of any statistical difference. Visual assessment of funnel plots and Egger's test were used to assess for publication bias. Of the 228 publications identified, 3 RCTs totaling 392 patients (194 LI with rod and 198 LI without rod) met the inclusion criteria for analysis. Overall bias risk was low. The stoma retraction rate was 3.1% (6/194) in patients with a rod versus 4.5% (9/198) in patients with LI without a rod at a mean follow-up of 3 months. This difference was not statistically or clinically significant (OR [95% CI] = 0.60 (0.21-1.72); P = .34; NNT = 69), with low statistical heterogeneity noted among the studies (I² = 0%). This meta-analysis found that ileostomy rods do not decrease stoma retraction rates at 3-month follow-up. Studies examining the rate of all potential complications in patients who do and do not receive rod placement following IL are needed to help surgeons make evidence-based decisions.


Trichoderma panacis sp. nov., an endophyte isolated from Panax notoginseng.
An endophytic member of the genus Trichoderma was isolated from the root of a healthy 3-year-old Panax notoginseng in Yunnan province, PR China. The results of phylogenetic analyses based on a combined of ITS, tef1 and rpb2 indicated that this isolate was distinct from other species of the genus Trichoderma and closely related to Trichoderma songyi. It can be distinguished from T. songyi by its slower growth rates on PDA and colony morphology. The novel isolate formed conidia in thick white pustules scattered mostly at the margin. Its conidiophores tended to be regularly verticillium-like, little branched, sometimes substituted by phialides singly or in whorls. Conidia are smooth, mostly broadly subglobose to ellipsoidal. In combination with the genotypic and phenotypic characteristics, all data demonstrated that the fungus studied represented a unique and distinguishable novel species of the genus Trichoderma, for which the name Trichoderma panacis sp. nov. is proposed.


A generic method for the evaluation of interval type-2 fuzzy linguistic summaries.
Linguistic summarization has turned out to be an important knowledge discovery technique by providing the most relevant natural language-based sentences in a human consistent manner. While many studies on linguistic summarization have handled ordinary fuzzy sets [type-1 fuzzy set (T1FS)] for modeling words, only few of them have dealt with interval type-2 fuzzy sets (IT2FS) even though IT2FS is better capable of handling uncertainties associated with words. Furthermore, the existent studies work with the scalar cardinality based degree of truth which might lead to inconsistency in the evaluation of interval type-2 fuzzy (IT2F) linguistic summaries. In this paper, to overcome this shortcoming, we propose a novel probabilistic degree of truth for evaluating IT2F linguistic summaries in the forms of type-I and type-II quantified sentences. We also extend the properties that should be fulfilled by any degree of truth on linguistic summarization with T1FS to IT2F environment. We not only prove that our probabilistic degree of truth satisfies the given properties, but also illustrate by examples that it provides more consistent results when compared to the existing degree of truth in the literature. Furthermore, we carry out an application on linguistic summarization of time series data of Europe Brent Spot Price, along with a comparison of the results achieved with our approach and that of the existing degree of truth in the literature.


Adoptive transfer of tumor-primed, in vitro-activated, CD4+ T effector cells (TEs) combined with CD8+ TEs provides intratumoral TE proliferation and synergistic antitumor response.
The importance of CD4+ Th1 cells during the effector phase of the antitumor response has been overshadowed by emphasis on CD8+ cytotoxic T lymphocytes (CTLs). To determine their respective functions, we purified antigen-primed T cells from tumor-draining lymph nodes and separately activated CD4+ and CD8+ subsets in vitro. Adoptive transfer of CD4+ T effector cells (T(E)s) combined with CD8+ T(E)s provided synergistic therapy for mice bearing subcutaneous, intracranial, or advanced pulmonary metastases. CD4+ T(E)s augmented IFN-gamma production by CD8+ T(E)s when cells were stimulated by tumor digest-containing antigen-presenting cells (APCs). CD4+ T(E)s infiltrated and proliferated extensively in pulmonary tumors, while also stimulating tumor antigen-specific CD8+ T cells. By contrast, CD8+ T(E)s showed minimal intratumoral proliferation in the absence of CD4+ cells or when systemically transferred CD4+ cells were prevented from infiltrating pulmonary tumors by pretreatment with pertussis toxin. Irradiation of CD4+ T cells immediately prior to adoptive transfer abrogated their intratumoral proliferation and direct antitumor efficacy but did not block their capacity to stimulate intratumoral CD8+ T(E) proliferation or tumor regression. These results highlight the importance of cross-presentation of tumor antigens during the effector phase of immunotherapy and suggest that approaches to stimulate CD4+ T(E) function and boost APC cross-presentation within tumors will augment cancer immunotherapy.


Functional properties of habenular neurons are determined by developmental stage and sequential neurogenesis.
The developing brain undergoes drastic alterations. Here, we investigated developmental changes in the habenula, a brain region that mediates behavioral flexibility during learning, social interactions, and aversive experiences. We showed that developing habenular circuits exhibit multiple alterations that lead to an increase in the structural and functional diversity of cell types, inputs, and functional modules. As the habenula develops, it sequentially transforms into a multisensory brain region that can process visual, olfactory, mechanosensory, and aversive stimuli. Moreover, we observed that the habenular neurons display spatiotemporally structured spontaneous activity that shows prominent alterations and refinement with age. These alterations in habenular activity are accompanied by sequential neurogenesis and the integration of distinct neural clusters across development. Last, we revealed that habenular neurons with distinct functional properties are born sequentially at distinct developmental time windows. Our results highlight a strong link between the functional properties of habenular neurons and their precise birthdate.


Arthroscopic approach and intra-articular anatomy of the equine atlanto-occipital joint.
To develop arthroscopic approaches to the atlanto-occipital (A-O) and describe associated arthroscopic anatomy. Experimental ex vivo study and clinical case report. Ten equine cadaver joints and 1 clinical case. CT arthrograms of 8 A-O joints were performed to determine the placement of an arthroscopic portal. Arthroscopy was performed via dorsal and/or ventral approaches (dorsal or ventral to the longissimus capitis tendon) in 10 cadaveric A-O joints and the A-O joint of a 2-week-old foal with septic arthritis. Accessible cartilage was debrided in 3 cadaver joints. Accessibility and risks were assessed by review of arthroscopic images, postoperative necropsy, and computed tomography (CT). Dorsal and ventral outpouchings of the A-O joint were identified with CT. Arthroscopy of the dorsal pouch provided access to 50% of the dorsocranial occipital condyle and 15% of the dorsocranial atlas articular surfaces. Joint distension caused displacement of the dura. Dura perforation occurred with a blind dorsal approach in 2 of 5 joints. Dura perforation did not occur after ultrasonography-guided approaches. Arthroscopic debridement of septic arthritis and osteomyelitis was successful in 1 clinical case. Approaches to the A-O joint were determined from CT examinations. The cranial aspect of the dorsal pouch of the A-O joint was accessed via arthroscopic triangulation in all horses of this study. Ultrasound-guided joint access prevented perforation of vital structures, including the spinal canal. Advanced imaging improves the diagnosis of A-O joint pathology. Descriptions of arthroscopic anatomy and accessibility provide important information for surgical intervention.


Selective recruitment of different Ca2+-dependent transcription factors by STIM1-Orai1 channel clusters.
Store-operated Ca2+ entry, involving endoplasmic reticulum Ca2+ sensing STIM proteins and plasma membrane Orai1 channels, is a widespread and evolutionary conserved Ca2+ influx pathway. This form of Ca2+ influx occurs at discrete loci where peripheral endoplasmic reticulum juxtaposes the plasma membrane. Stimulation evokes numerous STIM1-Orai1 clusters but whether distinct signal transduction pathways require different cluster numbers is unknown. Here, we show that two Ca2+-dependent transcription factors, NFAT1 and c-fos, have different requirements for the number of STIM1-Orai1 clusters and on the Ca2+ flux through them. NFAT activation requires fewer clusters and is more robustly activated than c-fos by low concentrations of agonist. For similar cluster numbers, transcription factor recruitment occurs sequentially, arising from intrinsic differences in Ca2+ sensitivities. Variations in the number of STIM1-Orai1 clusters and Ca2+ flux through them regulate the robustness of signalling to the nucleus whilst imparting a mechanism for selective recruitment of different Ca2+-dependent transcription factors.


Changes of calf muscle-tendon biomechanical properties induced by passive-stretching and active-movement training in children with cerebral palsy.
Biomechanical properties of calf muscles and Achilles tendon may be altered considerably in children with cerebral palsy (CP), contributing to childhood disability. It is unclear how muscle fascicles and tendon respond to rehabilitation and contribute to improvement of ankle-joint properties. Biomechanical properties of the calf muscle fascicles of both gastrocnemius medialis (GM) and soleus (SOL), including the fascicle length and pennation angle in seven children with CP, were evaluated using ultrasonography combined with biomechanical measurements before and after a 6-wk treatment of passive-stretching and active-movement training. The passive force contributions from the GM and SOL muscles were separated using flexed and extended knee positions, and fascicular stiffness was calculated based on the fascicular force-length relation. Biomechanical properties of the Achilles tendon, including resting length, cross-sectional area, and stiffness, were also evaluated. The 6-wk training induced elongation of muscle fascicles (SOL: 8%, P = 0.018; GM: 3%, P = 0.018), reduced pennation angle (SOL: 10%, P = 0.028; GM: 5%, P = 0.028), reduced fascicular stiffness (SOL: 17%, P = 0.128; GM: 21%, P = 0.018), decreased tendon length (6%, P = 0.018), increased Achilles tendon stiffness (32%, P = 0.018), and increased Young's modulus (20%, P = 0.018). In vivo characterizations of calf muscles and Achilles tendon mechanical properties help us better understand treatment-induced changes of calf muscle-tendon and facilitate development of more effective treatments.


The carcinogenic effect of various multi-walled carbon nanotubes (MWCNTs) after intraperitoneal injection in rats.
Biological effects of tailor-made multi-walled carbon nanotubes (MWCNTs) without functionalization were investigated in vivo in a two-year carcinogenicity study. In the past, intraperitoneal carcinogenicity studies in rats using biopersistent granular dusts had always been negative, whereas a number of such studies with different asbestos fibers had shown tumor induction. The aim of this study was to identify possible carcinogenic effects of MWCNTs. We compared induced tumors with asbestos-induced mesotheliomas and evaluated their relevance for humans by immunohistochemical methods. A total of 500 male Wistar rats (50 per group) were treated once by intraperitoneal injection with 10⁹ or 5 × 10⁹ WHO carbon nanotubes of one of four different MWCNTs suspended in artificial lung medium, which was also used as negative control. Amosite asbestos (10⁸ WHO fibers) served as positive control. Morbid rats were sacrificed and necropsy comprising all organs was performed. Histopathological classification of tumors and, additionally, immunohistochemistry were conducted for podoplanin, pan-cytokeratin, and vimentin to compare induced tumors with malignant mesotheliomas occurring in humans. Treatments induced tumors in all dose groups, but incidences and times to tumor differed between groups. Most tumors were histologically and immunohistochemically classified as malignant mesotheliomas, revealing a predominantly superficial spread on the serosal surface of the abdominal cavity. Furthermore, most tumors showed invasion of peritoneal organs, especially the diaphragm. All tested MWCNT types caused mesotheliomas. We observed highest frequencies and earliest appearances after treatment with the rather straight MWCNT types A and B. In the MWCNT C groups, first appearances of morbid mesothelioma-bearing rats were only slightly later. Later during the two-year study, we found mesotheliomas also in rats treated with MWCNT D - the most curved type of nanotubes. Malignant mesotheliomas induced by intraperitoneal injection of different MWCNTs and of asbestos were histopathologically and immunohistochemically similar, also compared with mesotheliomas in man, suggesting similar pathogenesis. We showed a carcinogenic effect for all tested MWCNTs. Besides aspect ratio, curvature seems to be an important parameter influencing the carcinogenicity of MWCNTs.


Surveillance of neural tube defects in Israel.
Open neural tube defects are among the most common malformations of the fetus. Secondary prevention by early diagnosis during pregnancy and abortion of affected fetuses result in a marked reduction of NTD incidence at birth. The dramatic effect of folic acid for primary prevention of these defects led to recommendations for folic acid supplementation in women of reproductive age. To describe the epidemiologic features of NTD in Israel in 1999-2000. A national registry of NTD was begun in 1999. During the years 1999-2000, a non-syndromic NTD was diagnosed in at least 394 pregnancies (166 anencephaly, 166 spina bifida, 43 encephalocele, and 19 with other types of NTD). The religious-ethnic affiliation was known in 392 cases (209 Jews and 183 non-Jews). Despite a marked decline in the rate of NTD at birth in the last few decades, the total rates during pregnancy did not change significantly, demonstrating that the changes were secondary to termination of affected pregnancies. At birth, NTD were almost four times more frequent among non-Jews (3.6 per 10,000 live births for anencephaly and 5.9 for spina bifida) than among Jews (anencephaly 1/10,000 live births, spina bifida 1.4/10,000 live births). The complete data of the registry showed an approximately twofold difference in the overall rates during pregnancy between Jews (anencephaly 5.3, spina bifida 4.6, total 11/10,000 live births) and non-Jews (anencephaly 8.8, spina bifida 10.3, total 22.3/10,000 live births). The registry demonstrated that the significant differences in NTD incidence observed at birth between Jews and non-Jews are secondary to a combined effect of a higher frequency of the malformations among non-Jews and a lower proportion of termination of affected pregnancies among non-Jews. The data presented here will serve as a basis for evaluating the impact of the Ministry of Health recommendations for folic acid supplementation on the incidence of NTD.


FGF23 and its role in X-linked hypophosphatemia-related morbidity.
X-linked hypophosphatemia (XLH) is an inherited disease of phosphate metabolism in which inactivating mutations of the Phosphate Regulating Endopeptidase Homolog, X-Linked (PHEX) gene lead to local and systemic effects including impaired growth, rickets, osteomalacia, bone abnormalities, bone pain, spontaneous dental abscesses, hearing difficulties, enthesopathy, osteoarthritis, and muscular dysfunction. Patients with XLH present with elevated levels of fibroblast growth factor 23 (FGF23), which is thought to mediate many of the aforementioned manifestations of the disease. Elevated FGF23 has also been observed in many other diseases of hypophosphatemia, and a range of animal models have been developed to study these diseases, yet the role of FGF23 in the pathophysiology of XLH is incompletely understood. The role of FGF23 in the pathophysiology of XLH is here reviewed by describing what is known about phenotypes associated with various PHEX mutations, animal models of XLH, and non-nutritional diseases of hypophosphatemia, and by presenting molecular pathways that have been proposed to contribute to manifestations of XLH. The pathophysiology of XLH is complex, involving a range of molecular pathways that variously contribute to different manifestations of the disease. Hypophosphatemia due to elevated FGF23 is the most obvious contributor, however localised fluctuations in tissue non-specific alkaline phosphatase (TNAP), pyrophosphate, calcitriol and direct effects of FGF23 have been observed to be associated with certain manifestations. By describing what is known about these pathways, this review highlights key areas for future research that would contribute to the understanding and clinical treatment of non-nutritional diseases of hypophosphatemia, particularly XLH.


Polysaccharide peptides from COV-1 strain of Coriolus versicolor inhibit tolbutamide 4-hydroxylation in the rat in vitro and in vivo.
Polysaccharide peptide (PSP), isolated from COV-1 strain of Coriolus versicolor, is commonly used as an adjunct in cancer chemotherapy in China. In this study, the effects of whole PSP extract and water extract of PSP on 4-hydroxylation of tolbutamide were investigated in rat liver microsomes in vitro and in vivo in the rat. Both the whole PSP extract and the water soluble fraction (0.5-20 microM) decreased the metabolism of tolbutamide to 4-hydroxytolbutamide in vitro. Enzyme kinetics studies showed that PSP inhibited tolbutamide 4-hydroxylase activity in a competitive, concentration-dependent manner. The whole PSP extract had a Ki value of 12.6 microM and IC50 at 18.4 microM, while the water extract had a Ki value of 6.9 microM and IC50 at 9.8 microM. Sulphaphenazole, a specific human CYP2C9 inhibitor, showed a Ki value of 30.8 microM and IC50 at 44.0 microM in the test system. In the pharmacokinetic studies in vivo, acute PSP (4 micromol/kg, i.p.) treatment did not produce significant changes in tolbutamide clearance, but produced a decrease in the Cinitial (7.4%) and an increase in the Vd (7.4%). Sub-chronic pre-treatment of PSP (1-2 micromol/kg/day, i.p.) for three days did not affect the clearance and AUC of tolbutamide, but the Cinitial was decreased, together with increases in the T1/2, and Vd. The formation of 4-hydroxytolbutamide in vivo was decreased in both acute and sub-chronic studies. Taken together, this study demonstrated the PSP can inhibit tolbutamide 4-hydroxylation both in vitro and in vivo. Despite the fact that CYP isoforms that metabolise tolbutamide are different between rat and human liver due to different catalytic characteristics, and rat studies may not be directly extrapolatable to man, the concomitant use of PSP with other CYP2C substrates should be carefully monitored.


Filling the gaps between tools and users: a tool comparator, using protein-protein interaction as an example.
Recently, several text mining programs have reached a near-practical level of performance. Some systems are already being used by biologists and database curators. However, it has also been recognized that current Natural Language Processing (NLP) and Text Mining (TM) technology is not easy to deploy, since research groups tend to develop systems that cater specifically to their own requirements. One of the major reasons for the difficulty of deployment of NLP/TM technology is that re-usability and interoperability of software tools are typically not considered during development. While some effort has been invested in making interoperable NLP/TM toolkits, the developers of end-to-end systems still often struggle to reuse NLP/TM tools, and often opt to develop similar programs from scratch instead. This is particularly the case in BioNLP, since the requirements of biologists are so diverse that NLP tools have to be adapted and re-organized in a much more extensive manner than was originally expected. Although generic frameworks like UIMA (Unstructured Information Management Architecture) provide promising ways to solve this problem, the solution that they provide is only partial. In order for truly interoperable toolkits to become a reality, we also need sharable type systems and a developer-friendly environment for software integration that includes functionality for systematic comparisons of available tools, a simple I/O interface, and visualization tools. In this paper, we describe such an environment that was developed based on UIMA, and we show its feasibility through our experience in developing a protein-protein interaction (PPI) extraction system.


Management of Anterior Cruciate Ligament Injuries in Adults Aged >40 Years.
Management of anterior cruciate ligament (ACL) injuries in adults aged >40 years has received increased attention in the literature because of an increase in the functional demands of aging athletes. Multiple structural and biomechanical age-dependent changes exist in the ACL, for example, fewer mesenchymal stem cells, decreased healing potential, decreased structural organization, decreased stiffness, and a decreased load to failure with age. As in younger patients, ACL insufficiency can predispose an older patient to the same risks of recurrent instability, meniscal and chondral injury, and osteoarthritis. The role of nonsurgical versus surgical management in these patients remains controversial. Lower-demand patients may be able to cope with ACL deficiency. Higher-demand patients may have functional instability, and the limited studies available suggest good functional outcomes with surgical reconstruction of the ACL in this population.


Erroneous and veridical recall are not two sides of the same coin: Evidence from semantic distraction in free recall.
Two experiments examined the extent to which erroneous recall blocks veridical recall using, as a vehicle for study, the disruptive impact of distractors that are semantically similar to a list of words presented for free recall. Instructing participants to avoid erroneous recall of to-be-ignored spoken distractors attenuated their recall but this did not influence the disruptive effect of those distractors on veridical recall (Experiment 1). Using an externalized output-editing procedure-whereby participants recalled all items that came to mind and identified those that were erroneous-the usual between-sequences semantic similarity effect on erroneous and veridical recall was replicated but the relationship between the rate of erroneous and veridical recall was weak (Experiment 2). The results suggest that forgetting is not due to veridical recall being blocked by similar events.


The role of law in the control of obesity in England: looking at the contribution of law to a healthy food culture.
Obesity levels in England are significantly higher than in much of the rest of Europe. This article examines aspects of the physical and cultural context of food consumption in England, and the evolution of government policy on obesity, as a background to an analysis of how law might play a role in obesity prevention. Research suggests that individual food choices are associated with cultural and socio-economic circumstances and that they can be manipulated by advertising, food packaging and presentation. This suggests that there might be ways of using law to manage the influences on food choices, and of using law in support of strategies to redirect food choices towards healthy food products. Law is a particularly useful tool in the protection of the individual against the economic power of the food industry, and there is much that law can do to change the physical, economic and social environment of food consumption.


The interplay between host biogeography and phylogeny in structuring diversification of the feather louse genus Penenirmus.
Parasite diversification is influenced by many of the same factors that affect speciation of free-living organisms, such as biogeographic barriers. However, the ecology and evolution of the host lineage also has a major impact on parasite speciation. Here we explore the interplay between biogeography and host-association on the pattern of diversification in a group of ectoparasitic lice (Insecta: Phthiraptera: Penenirmus) that feeds on the feathers of woodpeckers, barbets, and honeyguides (Piciformes) and some songbirds (Passeriformes). We use whole genome sequencing of 41 ingroup and 12 outgroup samples to develop a phylogenomic dataset of DNA sequences from a reference set of 2395 single copy ortholog genes, for a total of nearly four million aligned base positions. The phylogenetic trees resulting from both concatenated and gene-tree/species-tree coalescent analyses were nearly identical and highly supported. These trees recovered the genus Penenirmus as monophyletic and identified several major clades, which tended to be associated with one major host group. However, cophylogenetic analysis revealed that host-switching was a prominent process in the diversification of this group. This host-switching generally occurred within single major biogeographic regions. We did, however, find one case in which it appears that a rare dispersal event by a woodpecker lineage from North America to Africa allowed its associated louse to colonize a woodpecker in Africa, even though the woodpecker lineage from North America never became established there.


The endoscopic diagnosis of an aortoduodenal fistula.
An aortoduodenal fistula is a serious complication of aortic reconstructive surgery. This artile describes a case in which the diagnosis of an aortoduodenal fistula was made by upper gastrointestinal endoscopy. The endoscopic finding of a vascular prosthesis within the duodenum allowed immediate surgical intervention and control of the gastrointestinal hemorrhage.


Evaluation of entinostat alone and in combination with standard-of-care cytotoxic agents against rhabdomyosarcoma xenograft models.
Entinostat, a selective class I histone deacetylase inhibitor, has been reported to enhance the activity of cytotoxic agents and suppress expression of PAX3-FOXO1 in alveolar rhabdomyosarcoma (ARMS). Entinostat was tested against three rhabdomyosarcoma cell lines using 96-hour drug exposure. Entinostat alone or in binary combination with vincristine, actinomycin D or cyclophosphamide was tested in ARMS and two embryonal rhabdomyosarcoma (ERMS) xenograft models. Tumor growth was measured at weekly intervals. Drug-induced changes in acetylated histone H3(K9) and entinostat pharmacokinetics were determined. In vitro, the IC50 concentration of entinostat ranged from 280 to 1300 nM. In vivo, entinostat significantly inhibited the growth of only Rh10 xenografts. For most studies, entinostat did not potentiate the activity of the cytotoxic agent. Exceptions included the vincristine and entinostat combination for Rh10 and the entinostat and actinomycin D combination for Rh10 and Rh18, although the effects were modest. For Rh18, the combination of entinostat with vincristine showed evidence of an antagonistic interaction compared with single-agent vincristine. Pharmacokinetic studies showed the average Cmax was 569.4 ng/mL (1.51 μM) with Tmax at 15 minutes, and total exposure (AUC0-12 h ) was 435.6 h × ng/mL. Entinostat treatment increased acetylated histone H3. Entinostat demonstrated modest antitumor activity in only one of four models at dose and shedule that gave drug exposures relevant to human treatment. The addition of entinostat to standard-of-care cytotoxic agents was in most instances no more effective than the cytotoxic agents used alone. Entinostat demonstrated target inhibition with increased histone 2A acetylation.


Cluster nucleation and growth from a highly supersaturated adatom phase: silver on magnetite.
The atomic-scale mechanisms underlying the growth of Ag on the (√2×√2)R45°-Fe3O4(001) surface were studied using scanning tunneling microscopy and density functional theory based calculations. For coverages up to 0.5 ML, Ag adatoms populate the surface exclusively; agglomeration into nanoparticles occurs only with the lifting of the reconstruction at 720 K. Above 0.5 ML, Ag clusters nucleate spontaneously and grow at the expense of the surrounding material with mild annealing. This unusual behavior results from a kinetic barrier associated with the (√2×√2)R45° reconstruction, which prevents adatoms from transitioning to the thermodynamically favorable 3D phase. The barrier is identified as the large separation between stable adsorption sites, which prevents homogeneous cluster nucleation and the instability of the Ag dimer against decay to two adatoms. Since the system is dominated by kinetics as long as the (√2×√2)R45° reconstruction exists, the growth is not well described by the traditional growth modes. It can be understood, however, as the result of supersaturation within an adsorption template system.


Identification of transmitter systems and learning tag molecules involved in behavioral tagging during memory formation.
Long-term memory (LTM) consolidation requires the synthesis of plasticity-related proteins (PRPs). In addition, we have shown recently that LTM formation also requires the setting of a "learning tag" able to capture those PRPs. Weak training, which results only in short-term memory, can set a tag to use PRPs derived from a temporal-spatial closely related event to promote LTM formation. Here, we studied the involvement of glutamatergic, dopaminergic, and noradrenergic inputs on the setting of an inhibitory avoidance (IA) learning tag and the synthesis of PRPs. Rats explored an open field (PRP donor) followed by weak (tag inducer) or strong (tag inducer plus PRP donor) IA training. Throughout pharmacological interventions around open-field and/or IA sessions, we found that hippocampal dopamine D1/D5- and β-adrenergic receptors are specifically required to induce PRP synthesis. Moreover, activation of the glutamatergic NMDA receptors is required for setting the learning tags, and this machinery further required α-Ca(2+)/calmodulin-dependent protein kinase II and PKA but not ERK1/2 activity. Together, the present findings emphasize an essential role of the induction of PRPs and learning tags for LTM formation. The existence of only the PRP or the tag was insufficient for stabilization of the mnemonic trace.


Risk-benefit assessment of surgery for adult scoliosis: an analysis based on patient age.
Retrospective review of a prospective, multicenter database. The purpose of this study was to assess whether elderly patients undergoing scoliosis surgery had an incidence of complications and improvement in outcome measures comparable with younger patients. Complications increase with age for adults undergoing scoliosis surgery, but whether this impacts the outcomes of older patients is largely unknown. This is a retrospective review of a prospective, multicenter spinal deformity database. Patients complete the Oswestry Disability Index (ODI), SF-12, Scoliosis Research Society-22 (SRS-22), and numerical rating scale (NRS; 0-10) for back and leg pain. Inclusion criteria included age 25 to 85 years, scoliosis (Cobb ≥ 30°), plan for scoliosis surgery, and 2-year follow-up. Two hundred six of 453 patients (45%) completed 2-year follow-up, which is distributed among age groups as follows: 25 to 44 (n = 47), 45 to 64 (n = 121), and 65 to 85 (n = 38) years. The percentages of patients with 2-year follow-up by age group were as follows: 25 to 44 (45%), 45 to 64 (48%), and 65 to 85 (40%) years. These groups had perioperative complication rates of 17%, 42%, and 71%, respectively (P < 0.001). At baseline, elderly patients (65-85 years) had greater disability (ODI, P = 0.001), worse health status (SF-12 physical component score (PCS), P < 0.001), and more severe back and leg pain (NRS, P = 0.04 and P = 0.01, respectively) than younger patients. Mean SRS-22 did not differ significantly at baseline. Within each age group, at 2-year follow-up there were significant improvements in ODI (P ≤ 0.004), SRS-22 (P ≤ 0.001), back pain (P < 0.001), and leg pain (P ≤ 0.04). SF-12 PCS did not improve significantly for patients aged 25 to 44 years but did among those aged 45 to 64 (P < 0.001) and 65 to 85 years (P = 0.001). Improvement in ODI and leg pain NRS were significantly greater among elderly patients (P = 0.003, P = 0.02, respectively), and there were trends for greater improvements in SF-12 PCS (P = 0.07), SRS-22 (P = 0.048), and back pain NRS (P = 0.06) among elderly patients, when compared with younger patients. Collectively, these data demonstrate the potential benefits of surgical treatment for adult scoliosis and suggest that the elderly, despite facing the greatest risk of complications, may stand to gain a disproportionately greater improvement in disability and pain with surgery.


Microbiological status of periodontal diseases in Lagos, Nigeria.
The dynamic nature of oro-facial infections made it imperative to study the epidemiology of gingivitis and periodontitis which are significant clinical conditions in the Nigerian environment. The clinical and microbiological features of 162 patients with periodontal diseases (gingivitis 68, periodontitis 94) were analysed. The advantage of routine antibiotic susceptibility testing for oral pathogens in patients' management was investigated. The incidence of periodontal diseases was more in females than males with a ratio of 0.53 though the difference was not significant. A high incidence of gingivitis (55.9%) occurred within the first 29 years with a cluster of cases (48.6%) between 10 and 29 years of age with incidence tending to decline with advancing age. Though the incidence ofperiodontitis was highest amongst adults over 40 years (42.6%), the incidence of 8.5% in children below 10 years of age was high. Polybacterial aetiology was characteristic; aerobes were the predominant flora in gingivitis with a preponderance of Streptococcus spp, while anaerobes predominated in periodontitis with such species as Porphyromonas, Prevotella, Fusobacterium and Actinobacillus. Significant reduction in duration of treatment was obtained when patients were treated based on susceptibility results as opposed to empirical knowledge (p < 0.05). The diversity of microbial aetiology of periodontal infections may put much demand on routine laboratory investigations for patient management, but it may be necessary to weigh the benefit of additional cost against the cost of treatment failure associated with antibiotic resistance in bacteria.


Disconnected, fragmented, or united? a trans-disciplinary review of network science.
During decades the study of networks has been divided between the efforts of social scientists and natural scientists, two groups of scholars who often do not see eye to eye. In this review I present an effort to mutually translate the work conducted by scholars from both of these academic fronts hoping to continue to unify what has become a diverging body of literature. I argue that social and natural scientists fail to see eye to eye because they have diverging academic goals. Social scientists focus on explaining how context specific social and economic mechanisms drive the structure of networks and on how networks shape social and economic outcomes. By contrast, natural scientists focus primarily on modeling network characteristics that are independent of context, since their focus is to identify universal characteristics of systems instead of context specific mechanisms. In the following pages I discuss the differences between both of these literatures by summarizing the parallel theories advanced to explain link formation and the applications used by scholars in each field to justify their approach to network science. I conclude by providing an outlook on how these literatures can be further unified.


Color line search for illuminant estimation in real-world scenes.
The estimation of illuminant color is mandatory for many applications in the field of color image quantification. However, it is an unresolved problem if no additional heuristics or restrictive assumptions apply. Assuming uniformly colored and roundly shaped objects, Lee has presented a theory and a method for computing the scene-illuminant chromaticity from specular highlights [H. C. Lee, J. Opt. Soc. Am. A 3, 1694 (1986)]. However, Lee's method, called image path search, is less robust to noise and is limited in the handling of microtextured surfaces. We introduce a novel approach to estimate the color of a single illuminant for noisy and microtextured images, which frequently occur in real-world scenes. Using dichromatic regions of different colored surfaces, our approach, named color line search, reverses Lee's strategy of image path search. Reliable color lines are determined directly in the domain of the color diagrams by three steps. First, regions of interest are automatically detected around specular highlights, and local color diagrams are computed. Second, color lines are determined according to the dichromatic reflection model by Hough transform of the color diagrams. Third, a consistency check is applied by a corresponding path search in the image domain. Our method is evaluated on 40 natural images of fruit and vegetables. In comparison with those of Lee's method, accuracy and stability are substantially improved. In addition, the color line search approach can easily be extended to scenes of objects with macrotextured surfaces.


Cancer modeling by Transgene Electroporation in Adult Zebrafish (TEAZ).
Transgenic animals are invaluable for modeling cancer genomics, but often require complex crosses of multiple germline alleles to obtain the desired combinations. Zebrafish models have advantages in that transgenes can be rapidly tested by mosaic expression, but typically lack spatial and temporal control of tumor onset, which limits their utility for the study of tumor progression and metastasis. To overcome these limitations, we have developed a method referred to as Transgene Electroporation in Adult Zebrafish (TEAZ). TEAZ can deliver DNA constructs with promoter elements of interest to drive fluorophores, oncogenes or CRISPR-Cas9-based mutagenic cassettes in specific cell types. Using TEAZ, we created a highly aggressive melanoma model via Cas9-mediated inactivation of Rb1 in the context of BRAFV600E in spatially constrained melanocytes. Unlike prior models that take ∼4 months to develop, we found that TEAZ leads to tumor onset in ∼7 weeks, and these tumors develop in fully immunocompetent animals. As the resulting tumors initiated at highly defined locations, we could track their progression via fluorescence, and documented deep invasion into tissues and metastatic deposits. TEAZ can be deployed to other tissues and cell types, such as the heart, with the use of suitable transgenic promoters. The versatility of TEAZ makes it widely accessible for rapid modeling of somatic gene alterations and cancer progression at a scale not achievable in other in vivo systems.


Assessment of diet in young children with an emphasis on fruit and vegetable intake: using CADET--Child and Diet Evaluation Tool.
To develop a concise, simple tool for use by non-specialists to assess diet in children aged 3-7 years attending primary schools. A 24-hour food tick list covering all aspects of the diet and with a focus on fruit and vegetable consumption was developed. This was compared against a 24-hour semi-weighed food diary obtained for the same day as the tick list. Six primary schools with a range of socio-economic and ethnic backgrounds from a large city in the north of England (Leeds). One hundred and eighty children returned completed packs of information; a response rate of 77% of those who were willing to take part, 48% of those approached. On average, 2.4 items of fruit including juice (2.1 items as 5-a-day count) were eaten and 1.6 items of vegetables (excluding potato). Twenty-seven per cent and 36% of boys and 23% and 24% of girls reported not eating any fruit or vegetables, respectively, on the recording day. Correlations comparing the diary and tick list were high for both foods (range r=0.44 to 0.89) and nutrients (range r=0.41 to 0.68). The level of misclassification was much less than would be expected by chance. Parent and teacher evaluation of the tick list was very positive. Parents felt the tick list was easy and quick to complete. The Child and Diet Evaluation Tool (CADET) tick list has been used successfully for rapid collection of food and nutrient information from children aged 3-7 years from diverse social and ethnic backgrounds. The tool has performed better than many food-frequency questionnaires in comparison to a food diary.


Comparative analyses of C₄ and C₃ photosynthesis in developing leaves of maize and rice.
C₄ and C₃ photosynthesis differ in the efficiency with which they consume water and nitrogen. Engineering traits of the more efficient C₄ photosynthesis into C₃ crops could substantially increase crop yields in hot, arid conditions. To identify differences between C₄ and C₃ photosynthetic mechanisms, we profiled metabolites and gene expression in the developing leaves of Zea mays (maize), a C₄ plant, and Oryza sativa (rice), a C₃ plant, using a statistical method named the unified developmental model (UDM). Candidate cis-regulatory elements and transcription factors that might regulate photosynthesis were identified, together with differences between C₄ and C₃ nitrogen and carbon metabolism. The UDM algorithms could be applied to analyze and compare development in other species. These data sets together with community viewers to access and mine them provide a resource for photosynthetic research that will inform efforts to engineer improvements in carbon fixation in economically valuable grass crops.


Analysis of SARS-CoV-2 Emergent Variants Following AZD7442 (Tixagevimab/Cilgavimab) for Early Outpatient Treatment of COVID-19 (TACKLE Trial).
AZD7442 (tixagevimab/cilgavimab) comprises neutralising monoclonal antibodies (mAbs) that bind to distinct non-overlapping epitopes on the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein. Viral evolution during mAb therapy can select for variants with reduced neutralisation susceptibility. We examined treatment-emergent SARS-CoV-2 variants during TACKLE (NCT04723394), a phase 3 study of AZD7442 for early outpatient treatment of coronavirus disease 2019 (COVID-19). Non-hospitalised adults with mild-to-moderate COVID-19 were randomised and dosed ≤ 7 days from symptom onset with AZD7442 (n = 452) or placebo (n = 451). Next-generation sequencing of the spike gene was performed on SARS-CoV-2 reverse-transcription polymerase chain reaction-positive nasopharyngeal swabs at baseline and study days 3, 6, and 15 post dosing. SARS-CoV-2 lineages were assigned using spike nucleotide sequences. Amino acid substitutions were analysed at allele fractions (AF; % of sequence reads represented by substitution) ≥ 25% and 3% to 25%. In vitro susceptibility to tixagevimab, cilgavimab, and AZD7442 was evaluated for all identified treatment-emergent variants using a pseudotyped microneutralisation assay. Longitudinal spike sequences were available for 461 participants (AZD7442, n = 235; placebo, n = 226) and showed that treatment-emergent variants at any time were rare, with 5 (2.1%) AZD7442 participants presenting ≥ 1 substitution in tixagevimab/cilgavimab binding sites at AF ≥ 25%. At AF 3% to 25%, treatment-emergent variants were observed in 15 (6.4%) AZD7442 and 12 (5.3%) placebo participants. All treatment-emergent variants showed in vitro susceptibility to AZD7442. These data indicate that AZD7442 creates a high genetic barrier for resistance and is a feasible option for COVID-19 treatment.


Photoreactive DNA probes as a tool for studying the translesion synthesis system in Mammalian cell extracts.
Translesion synthesis (TLS) is one of the DNA damage tolerance strategies that has evolved to enable orga-nisms to replicate their genome despite the presence of unrepaired damage. TLS complexes are dynamic systems composed of DNA polymerases and associated protein factors. Therefore, it is hard to study these assembles by X-ray analysis or other instrumental methods. Here, we have suggested applying the photoaffinity labeling technique for studying the TLS system in nuclear/cellular extracts. As a tool we proposed to use partial DNA duplexes containing base-substituted photoreactive deoxynucleotides at the 3' end of primer opposite to DNA damage at the template strand. We demonstrated that photoreactive dNTPs can be potentially used to synthesize photoreactive DNA probes mimicking the DNA intermediates of the first stage of translesion synthesis by specialized DNA polymerases. We used synthetic apurinic/apyrimidinic site (AP-site) - tetrahydrofuran (THF) and 8 oxoguanine as damages in +1 position of the template strand with respect to 3' end of primer. Activity of human DNA polymerases beta and lambda was exploited for construction of photoreactive DNAs using photo derivatives of dNTPs. The kinetic parameters of the elongation reaction in model systems were estimated. Using photoaffinity crosslinking we found that only a few proteins in the bovine testis nuclear extract were strongly labeled by TLS probes.


Breast cancer-derived GM-CSF regulates arginase 1 in myeloid cells to promote an immunosuppressive microenvironment.
Tumor-infiltrating myeloid cells contribute to the development of the immunosuppressive tumor microenvironment. Myeloid cell expression of arginase 1 (ARG1) promotes a protumor phenotype by inhibiting T cell function and depleting extracellular l-arginine, but the mechanism underlying this expression, especially in breast cancer, is poorly understood. In breast cancer clinical samples and in our mouse models, we identified tumor-derived GM-CSF as the primary regulator of myeloid cell ARG1 expression and local immune suppression through a gene-KO screen of breast tumor cell-produced factors. The induction of myeloid cell ARG1 required GM-CSF and a low pH environment. GM-CSF signaling through STAT3 and p38 MAPK and acid signaling through cAMP were required to activate myeloid cell ARG1 expression in a STAT6-independent manner. Importantly, breast tumor cell-derived GM-CSF promoted tumor progression by inhibiting host antitumor immunity, driving a significant accumulation of ARG1-expressing myeloid cells compared with lung and melanoma tumors with minimal GM-CSF expression. Blockade of tumoral GM-CSF enhanced the efficacy of tumor-specific adoptive T cell therapy and immune checkpoint blockade. Taken together, we show that breast tumor cell-derived GM-CSF contributes to the development of the immunosuppressive breast cancer microenvironment by regulating myeloid cell ARG1 expression and can be targeted to enhance breast cancer immunotherapy.


Struma ovarii - ultrasound features of a rare tumor mimicking ovarian cancer.
To describe the ultrasound features of benign struma ovarii that often mimic ovarian cancer in the background of complex clinical and histopathological pictures. We retrospectively identified patients with histologically confirmed benign struma ovarii, treated in our institution between 2003-2016 with complete imaging, clinical, nd histopathological data available. Ultrasound findings were drawn from images, and reports using terms and definitions of the International Ovarian Tumor Analysis group and pattern recognition description was applied. In all, 19 patients were identified; 10 with pure and 9 with impure struma. Median age was 47 (range 24-69); 10 (53%) were premenopausal. Only four (21%) patients presented with pain, others were asymptomatic. Using pattern recognition, 74% strumas (14/19) were uni-/multilocular solid or solid tumors. The solid components were roundish with smooth contours. Six struma pearls were detected. The subjective color score was moderate or abundant in the majority of solid components. Only 5 (26%) tumors were purely cystic. The ultrasound characteristics differ widely from typical mature ovarian teratoma. Features such as, solid roundish components with smooth contours, struma pearls, acoustic shadowing and occasionally signs of dermoid are clues and may help preoperatively to differentiate benign struma from malignant adnexal lesions.


Adaptive Neural Tracking Control for a Class of Nonlinear Systems With Dynamic Uncertainties.
This paper considers the problem of adaptive neural control of nonlower triangular nonlinear systems with unmodeled dynamics and dynamic disturbances. The design difficulties appeared in the unmodeled dynamics and nonlower triangular form are handled with a dynamic signal and a variable partition technique for the nonlinear functions of all state variables, respectively. It is shown that the proposed controller is able to ensure the semi-global boundedness of all signals of the resulting closed-loop system. Furthermore, the system output is ensured to converge to a small domain of the given trajectories. The main advantage about this research is that a neural networks-based tracking control method is developed for uncertain nonlinear systems with unmodeled dynamics and nonlower triangular form. Simulation results demonstrate the feasibility of the newly presented design techniques.


The Curious Case of the OZ439 Mesylate Salt: An Amphiphilic Antimalarial Drug with Diverse Solution and Solid State Structures.
Efforts to develop orally administered drugs tend to place an exceptional focus on aqueous solubility as this is an essential criterion for their absorption in the gastrointestinal tract. In this work we examine the solid state behavior and solubility of OZ439, a promising single-dose cure for malaria being developed as the highly water-soluble mesylate salt. The aqueous phase behavior of the OZ439 mesylate salt was determined using a combination of small angle neutron and X-ray scattering (SANS and SAXS, respectively). It was found that this salt has low solubility at low concentrations with the drug largely precipitated in free base aggregates. However, with increasing concentration these crystalline aggregates were observed to dissociate into cationic micelles and lamellar phases, effectively increasing the dissolved drug concentration. It was also found that the dissolved OZ439 spontaneously precipitated in the presence of biologically relevant anions, which we attribute to the high lattice energies of most of the salt forms of the drug. These findings show that aqueous solubility is not always what it seems in the context of amphiphilic drug molecules and highlights that its use as the principal metric in selecting drug candidates for development can be perilous.


Icariin protects against brain injury by enhancing SIRT1-dependent PGC-1alpha expression in experimental stroke.
Icariin (ICA) has neuroprotection in oxygen-glucose deprivation (OGD) neurons by increasing Sirtuin1 (SIRT1). However, little is known about the role of ICA on stroke. SIRT1 is a class III histone deacetylase and activates peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) which stimulates mitochondrial activity. This study aims to investigate the expression of SIRT1 and PGC-1alpha during ICA's neuroprotection against ischemia. In vivo, behavioral test, infarct size and brain water content were evaluated on middle cerebral artery occlusion (MCAO) mouse models treated by ICA/saline. In vitro, primary cortical neurons were tortured by OGD in the presence of ICA or SIRT1 inhibitor III or PGC-1alpha siRNA. Cell viability and mortality were measured by MTT and flow cytometer assay. Knockdown efficiency of PGC-1alpha siRNA was measured by real time PCR. Expressions of SIRT1 and PGC-1alpha were also investigated. In result, neurological scores, infarct size and brain edema were all significantly improved, the cortical expressions of SIRT1 and PGC-1alpha were higher with ICA compared to the control (P < 0.05), and reversed by SIRT1 inhibitor III/PGC-1alpha siRNA. In conclusion, ICA protects against brain ischemic injury by increasing the SIRT1 and PGC-1alpha expression, potentially to be a neuroprotectant for ischemic brain injury.


Effect of prenatal EPA and DHA on maternal and umbilical cord blood cytokines.
Investigators have hypothesized that omega-3 fatty acid supplementation may modulate the immune response. However, available evidence is conflicting. We performed this study to investigate the effect of prenatal eicosapentaenoic acid (EPA)- and docosahexaenoic acid (DHA)-rich fish oil supplementation on maternal and fetal cytokine production. This study is a secondary analysis of a randomized controlled trial designed to assess whether prenatal EPA- or DHA-rich fish oil supplementation would prevent perinatal depressive symptoms among women at risk. Enrolled participants received EPA-rich fish oil (1060 mg EPA plus 274 mg DHA), DHA-rich fish oil (900 mg DHA plus 180 mg EPA) or soy oil placebo. Maternal venous blood was collected at enrollment (12-20 weeks gestation) and after supplementation (34-36 weeks gestation). Umbilical cord blood was collected at delivery. We analyzed stored plasma specimens for 16 human cytokines using multiplex immunoassays. Maternal and cord blood cytokine levels were compared among the treatment groups. Associations of serum DHA and EPA with maternal and cord blood cytokines were explored via regression analysis. We enrolled 126 women, of whom 118 completed the trial. Prenatal supplementation with EPA-rich fish oil significantly lowered maternal IL6, IL15, and TNFα concentrations. However, supplementation with DHA-rich fish oil had no significant effect on maternal cytokine profiles. Maternal serum DHA fraction was significantly associated with IL1α, and maternal serum DHA and EPA fractions were significantly associated with IL 10 concentrations after supplementation. Compared with placebo, supplementation with EPA- or DHA-rich fish oils had no significant effect on cord blood cytokine concentrations. Prenatal supplementation with EPA-rich fish oil significantly reduced levels of several inflammatory cytokines in maternal plasma, while prenatal DHA-rich fish oil had no significant effect on cytokine concentrations. Supplementation with EPA- and DHA- rich fish oil had no significant effect on umbilical cord blood cytokine concentrations. Clinical Trial Registration: registration number NCT00711971 7/7/2008.


Microsatellite Instability as a Biomarker for PD-1 Blockade.
Initial results by Le and colleagues, which were published in the June 25, 2015 issue of the New England Journal of Medicine, report significant responses of cancers with microsatellite instability (MSI) to anti-PD-1 inhibitors in patients who failed conventional therapy. This finding fits into a broader body of research associating somatic hypermutation and neoepitope formation with response to immunotherapy, with the added benefit of relying on a simple, widely used diagnostic test. This review surveys the pathogenesis and prognostic value of MSI, diagnostic guidelines for detecting it, and the frequency of MSI across tumors, with the goal of providing a reference for its use as a biomarker for PD-1 blockade. MSI usually arises from either germline mutations in components of the mismatch repair (MMR) machinery (MSH2, MSH6, MLH1, PMS2) in patients with Lynch syndrome or somatic hypermethylation of the MLH1 promoter. The result is a cancer with a 10- to 100-fold increase in mutations, associated in the colon with poor differentiation, an intense lymphocytic infiltrate, and a superior prognosis. Diagnostic approaches have evolved since the early 1990s, from relying exclusively on clinical criteria to incorporating pathologic features, PCR-based MSI testing, and immunohistochemistry for loss of MMR component expression. Tumor types can be grouped into categories based on the frequency of MSI, from colorectal (20%) and endometrial (22%-33%) to cervical (8%) and esophageal (7%) to skin and breast cancers (0%-2%). If initial results are validated, MSI testing could have an expanded role as a tool in the armamentarium of precision medicine.


Reduction of joint pain in patients with knee osteoarthritis who have received monthly telephone calls from lay personnel and whose medical treatment regimens have remained stable.
We previously reported that monthly telephone contact by lay personnel, to promote self-care for patients with osteoarthritis (OA), was associated with improved joint pain and physical function after 1 year of followup. The present study was a secondary analysis to determine whether improvement was contingent on intensified medical treatment. We reanalyzed control/treatment group differences in all 40 subjects with radiographically confirmed knee OA who had had no changes in antirheumatic drug therapy or institution of physical therapy during the period of observation. Group differences in measured pain remained significant (effect size [ES] = 0.65 SD, P less than 0.01). The same trend was observed for physical function (ES = 0.53 SD, P not significant). The findings in this reanalysis suggest that periodic telephone support interventions are effective enough to be regarded as an adjunctive treatment for OA.


Adsorption, uptake and distribution of gold nanoparticles in Daphnia magna following long term exposure.
Gold nanoparticles (nAu) have recently been studied and developed within the biological and photothermal therapeutic contexts. The major clinical interest is within the application of novel drug delivery systems. Environmental exposure to nanoparticles can occur in different stages of the lifecycle of the product; from their synthesis, applications, product weathering and their disposal. Freshwater Daphnids, specifically Daphnia magna, have been used since the 1960s as a standard species in acute and chronic aquatic toxicity testing. Visualization of the interactions and uptake of nAu by D. magna was related to reproduction and molting patterns. Exposure to nAu was done using a chronic reproduction test performed for 14 days at six concentrations (0.5mg/L, 2mg/L, 5mg/L, 10mg/L, 15mg/L and 20mg/L). Microscopy was used to determine whether there was any uptake or interaction of nAu with daphnia. However the concentration of nAu in the media and the charge of particles played a role in the uptake and surface adsorption. As exposure concentrations of nAu increased it appeared that the nAu aggregated onto the surface and in the gut of the organisms in higher concentrations. There was no evidence of nAu internalization into the body cavity of the daphnia. Aquatic exposure to nAu resulted in increased adhesion of the particles to the carapace of daphnia, ingestion and uptake into the gut of daphnia and had no significant effect on reproduction and molting patterns.


A novel mutation in the SCN5A gene is associated with Brugada syndrome.
Brugada syndrome (BS) is an inherited cardiac disorder associated with a high risk of sudden cardiac death and is caused by mutations in the SCN5A gene encoding the cardiac sodium channel alpha-subunit (Na(v)1.5). The aim of this study was to identify the genetic cause of familial BS and characterize the electrophysiological properties of a novel SCN5A mutation (W1191X). Four families and one patient with BS were screened for SCN5A mutations by PCR and direct sequencing. Wild-type (WT) and mutant Na(v)1.5 channels were expressed in tsA201 cells, and the sodium currents (I(Na)) were analyzed using the whole-cell patch-clamp technique. A novel mutation, W1191X, was identified in a family with BS. Expression of the WT or the mutant channel (Na(v)1.5/W1191X) co-transfected with the beta(1)-subunit in tsA201 cells resulted in a loss of function of Na(v)1.5 channels. While voltage-clamp recordings of the WT channel showed a distinct acceleration of Na(v)1.5 activation and fast inactivation kinetics, the Na(v)1.5/W1191X mutant failed to generate any currents. Co-expression of the WT channel and the mutant channel resulted in a 50% reduction in I(Na). No effect on activation and inactivation were observed with this heterozygous expression. The W1191X mutation is associated with BS and resulted in the loss of function of the cardiac sodium channel.


Abnormal Sleep Signals Vulnerability to Chronic Social Defeat Stress.
There is a tight association between mood and sleep as disrupted sleep is a core feature of many mood disorders. The paucity in available animal models for investigating the role of sleep in the etiopathogenesis of depression-like behaviors led us to investigate whether prior sleep disturbances can predict susceptibility to future stress. Hence, we assessed sleep before and after chronic social defeat (CSD) stress. The social behavior of the mice post stress was classified in two main phenotypes: mice susceptible to stress that displayed social avoidance and mice resilient to stress. Pre-CSD, mice susceptible to stress displayed increased fragmentation of Non-Rapid Eye Movement (NREM) sleep, due to increased switching between NREM and wake and shorter average duration of NREM bouts, relative to mice resilient to stress. Logistic regression analysis showed that the pre-CSD sleep features from both phenotypes were separable enough to allow prediction of susceptibility to stress with >80% accuracy. Post-CSD, susceptible mice maintained high NREM fragmentation while resilient mice exhibited high NREM fragmentation, only in the dark. Our findings emphasize the putative role of fragmented NREM sleep in signaling vulnerability to stress.


Amantadine in Huntington's disease: open-label video-blinded study.
Huntington's disease (HD) is characterized by chorea, cognitive and behavioral changes. Amantadine, a non-competitive NMDA receptor antagonist, has shown an antidyskinetic effect on levodopa-induced dyskinesias, which are known to have strict pathogenetic analogies with choreic hyperkinesias. The antidyskinetic efficacy of amantadine and its effects on cognitive and behavioural symptoms were evaluated. Eight HD patients received oral amantadine (100 mg tid) unblinded for a 1-year period. A significant reduction of dyskinesias was reported ( p<0.01). No changes were observed in neuropsychologic and psychiatric assessments after 6 and 12 months of therapy. These data may have relevance to the treatment of HD with amantadine.


A Randomized, Placebo-Controlled Clinical Trial of Efficacy and Safety: Modafinil in the Treatment of Fatigue in Patients With Primary Biliary Cirrhosis.
Fatigue is a common symptom of primary biliary cirrhosis (PBC), and is associated with an impaired quality of life. No studies have assessed the use of modafinil in fatigue related to PBC in a controlled manner. A randomized, double-blind, placebo-controlled study was conducted to determine the safety and efficacy of modafinil for the treatment of fatigue in PBC. Forty patients were randomized to modafinil (n = 20) or placebo (n = 20) for 12 weeks. A verbal report of fatigue for at least 6 months was required for enrollment. Modafinil was administered at 100 mg by mouth once daily; a change by 50 mg every 2 weeks (maximum: 200 mg once daily) was allowed, depending on the subject's response to treatment. The primary outcome was defined as a ≥50% improvement in fatigue severity [quantified by the Fisk Fatigue Impact Scale (FFIS)] after 12 weeks of treatment, compared with baseline values. Thirty-three PBC patients completed the study. After 12 weeks of therapy, only 5 patients had a ≥50% reduction in FFIS scores: 3 patients (17.6%) in the modafinil arm and 2 (12.5%) in the placebo arm (P = 1.00). Change in median FFIS score was not statistically different between patients in the 2 treatment groups (P = 0.36). Modafinil was associated with minimal adverse events (headaches, diarrhea, and rash). In patients with PBC who have fatigue, treatment with modafinil for 12 weeks was safe and fairly well tolerated; however, it did not result in beneficial effects on fatigue compared with patients treated with placebo (CONSORT Table 1). ClinicalTrials.gov identifier NCT00943176.


Fusion of spatial gray level dependency and fractal texture features for the characterization of thyroid lesions.
Thyroid is a small gland situated at the anterior side of the neck and one of the largest glands of the endocrine system. The abrupt cell growth or malignancy in the thyroid gland may cause thyroid cancer. Ultrasound images distinctly represent benign and malignant lesions, but accuracy may be poor due to subjective interpretation. Computer Aided Diagnosis (CAD) can minimize the errors created due to subjective interpretation and assists to make fast accurate diagnosis. In this work, fusion of Spatial Gray Level Dependence Features (SGLDF) and fractal textures are used to decipher the intrinsic structure of benign and malignant thyroid lesions. These features are subjected to graph based Marginal Fisher Analysis (MFA) to reduce the number of features. The reduced features are subjected to various ranking methods and classifiers. We have achieved an average accuracy, sensitivity and specificity of 97.52%, 90.32% and 98.57% respectively using Support Vector Machine (SVM) classifier. The achieved maximum Area Under Curve (AUC) is 0.9445. Finally, Thyroid Clinical Risk Index (TCRI) a single number is developed using two MFA features to discriminate the two classes. This prototype system is ready to be tested with huge diverse database.


Recent increase in sex ratio at birth in Viet Nam.
Since the 1980s, sex ratio at birth (male births per 100 female births) has increased in many Asian countries as a result of selective abortions, but to date there has been no such evidence for Viet Nam. Our aim in this paper is to ascertain the situation with respect to sex ratio at birth in Viet Nam over the past five years. Original data were obtained from sample population surveys in Viet Nam recording annual birth rates since 2000 of about 450,000 women, as well as from two successive birth surveys conducted for the first time in 2007 (1.1 million births). The annual population surveys include specific information on birth history and mothers' characteristics to be used for the analysis of trends and differentials in sex ratio at birth. Birth history statistics indicate that the SRB in Viet Nam has recorded a steady growth since 2001. Starting from a level probably close to the biological standard of 105, the SRB reached 108 in 2005 and 112 in 2006, a value significantly above the normal level. An independent confirmation of these results comes from the surveys of births in health facilities which yielded a SRB of 110 in 2006-07. High SRB is linked to various factors such as access to modern health care, number of prenatal visits, level of higher education and employment status, young age, province of residence and prenatal sex determination. These results suggest that prenatal sex determination followed by selective abortion has recently become more common in Viet Nam. This recent trend is a consequence of various factors such as preference for sons, declining fertility, easy access to abortion, economic development as well as the increased availability of ultrasonography facilities.


Would they dope? Revisiting the Goldman dilemma.
Discussions of doping often report Goldman's sensational results that half of the elite athletes asked would take a drug that guaranteed sporting success which would also result in their death in 5 years' time. There has never been any effort to assess the properties of the 'Goldman dilemma' or replicate the results in the post World Anti-Doping Agency context. This research evaluated the dilemma with contemporary elite athletes. Participants at an elite-level track and field meet in North America were segregated into an interview or online response. After basic demographics, participants were presented with three variant 'Goldman' dilemmas counter-balanced for presentation order. Only 2 out of 212 samples (119 men, 93 women, mean age 20.89) reported that they would take the Faustian bargain offered by the original Goldman dilemma. However, if there were no consequences to the (illegal) drug use, then 25/212 indicated that they would take the substance (no death condition). Legality also changes the acceptance rate to 13/212 even with death as a consequence. Regression modelling showed that no other variable was significant (gender, competitive level, type of sport) and there was no statistical difference between the interview and online collection method. Goldman's results do not match our sample. A subset of athletes is willing to dope and another subset is willing to sacrifice their life to achieve success, although to a much lesser degree than that observed by Goldman. A larger scale online survey is now viable to answer important questions such as variation across sports.


Sedative effect of Clozapine is a function of 5-HT2A and environmental novelty.
Antipsychotic drugs are the mainstay in the treatment of schizophrenia and bipolar disorder. However, antipsychotics often exhibit sedation or activity suppression among many other side effects, and the factors that influence them remain poorly understood. We now show, using a 5-HT2A knockout (Htr2a-/-) mouse, that environmental circumstances can affect suppression of activity induced by the atypical antipsychotic- Clozapine. We observed that Htr2a-/- mice were more resistant to Clozapine-induced suppression of activity (CISA) and this behaviour was dependent on the environment being 'novel'. In their 'home' environment, at identical doses the mice exhibited CISA. Interestingly, the effect of genotype and environmental novelty on CISA could not be extended to the other antipsychotics that were tested, i.e. Haloperidol and Risperidone. Haloperidol-induced activity suppression was independent of context and genotype. Whereas context affected Risperidone-induced activity suppression only in the Htr2a+/+ mice. Furthermore, we observed that caffeine, a stimulant, elicited resistance to CISA similar to that seen in the 'novel' context. Our study establishes a previously unknown interaction between the environmental context, 5-HT2A and CISA and emphasises the role of non-pharmacological factors such as environment on the effects of the drug, which seem antipsychotic-specific. Our findings should advance the understanding of the side effects of individual antipsychotics and the role of environment to overcome side effects such as sedation.


Evaluation of antigen-detecting and antibody-detecting diagnostic test combinations for diagnosing melioidosis.
Melioidosis, an infectious disease caused by Burkholderia pseudomallei, is endemic in many tropical developing countries and has a high mortality. Here we evaluated combinations of a lateral flow immunoassay (LFI) detecting B. pseudomallei capsular polysaccharide (CPS) and enzyme-linked immunosorbent assays (ELISA) detecting antibodies against hemolysin co-regulated protein (Hcp1) or O-polysaccharide (OPS) for diagnosing melioidosis. We conducted a cohort-based case-control study. Both cases and controls were derived from a prospective observational study of patients presenting with community-acquired infections and sepsis in northeast Thailand (Ubon-sepsis). Cases included 192 patients with a clinical specimen culture positive for B. pseudomallei. Controls included 502 patients who were blood culture positive for Staphylococcus aureus, Escherichia coli or Klebsiella pneumoniae or were polymerase chain reaction assay positive for malaria or dengue. Serum samples collected within 24 hours of admission were stored and tested using a CPS-LFI, Hcp1-ELISA and OPS-ELISA. When assessing diagnostic tests in combination, results were considered positive if either test was positive. We selected ELISA cut-offs corresponding to a specificity of 95%. Using a positive cut-off OD of 2.912 for Hcp1-ELISA, the combination of the CPS-LFI and Hcp1-ELISA had a sensitivity of 67.7% (130/192 case patients) and a specificity of 95.0% (477/502 control patients). The sensitivity of the combination (67.7%) was higher than that of the CPS-LFI alone (31.3%, p<0.001) and that of Hcp1-ELISA alone (53.6%, p<0.001). A similar phenomenon was also observed for the combination of CPS-LFI and OPS-ELISA. In case patients, positivity of the CPS-LFI was associated with a short duration of symptoms, high modified Sequential (sepsis-related) Organ Failure Assessment (SOFA) score, bacteraemia and mortality outcome, while positivity of Hcp1-ELISA was associated with a longer duration of symptoms, low modified SOFA score, non-bacteraemia and survival outcome. A combination of antigen-antibody diagnostic tests increased the sensitivity of melioidosis diagnosis over individual tests while preserving high specificity. Point-of-care tests for melioidosis based on the use of combination assays should be further developed and evaluated.


Hepatic glucose sensing is required to preserve β cell glucose competence.
Liver glucose metabolism plays a central role in glucose homeostasis and may also regulate feeding and energy expenditure. Here we assessed the impact of glucose transporter 2 (Glut2) gene inactivation in adult mouse liver (LG2KO mice). Loss of Glut2 suppressed hepatic glucose uptake but not glucose output. In the fasted state, expression of carbohydrate-responsive element-binding protein (ChREBP) and its glycolytic and lipogenic target genes was abnormally elevated. Feeding, energy expenditure, and insulin sensitivity were identical in LG2KO and control mice. Glucose tolerance was initially normal after Glut2 inactivation, but LG2KO mice exhibited progressive impairment of glucose-stimulated insulin secretion even though β cell mass and insulin content remained normal. Liver transcript profiling revealed a coordinated downregulation of cholesterol biosynthesis genes in LG2KO mice that was associated with reduced hepatic cholesterol in fasted mice and reduced bile acids (BAs) in feces, with a similar trend in plasma. We showed that chronic BAs or farnesoid X receptor (FXR) agonist treatment of primary islets increases glucose-stimulated insulin secretion, an effect not seen in islets from Fxr(-/-) mice. Collectively, our data show that glucose sensing by the liver controls β cell glucose competence and suggest BAs as a potential mechanistic link.


Role of VEGF-A in vascularization of pancreatic islets.
Blood vessel endothelium has been recently shown to induce endocrine pancreatic development. Because pancreatic endocrine cells or islets express high levels of vascular endothelial growth factors, VEGFs, we investigated the role of a particular VEGF, VEGF-A, on islet vascularization and islet function. By deleting VEGF-A in the mouse pancreas, we show that endocrine cells signal back to the adjacent endothelial cells to induce the formation of a dense network of fenestrated capillaries in islets. Interestingly, VEGF-A is not required for the development of all islet capillaries. However, the few remaining capillaries found in the VEGF-A-deficient islets are not fenestrated and contain an unusual number of caveolae. In addition, glucose tolerance tests reveal that the VEGF-A-induced capillary network is not strictly required for blood glucose control but is essential for fine-tuning blood glucose regulation. In conclusion, we speculate that islet formation takes place in two sequential steps: in the first step, signals from blood vessel endothelium induce islet formation next to the vessels, and in the second step, the islets signal to the endothelium. The second step involves paracrine VEGF-A signaling to elaborate the interaction of islets with the circulatory system.


Gray matter nulled and vascular space occupancy dependent fMRI response to visual stimulation during hypoxic hypoxia.
Two cerebral blood volume (CBV)-weighted fMRI techniques, gray matter nulled (GMN) and vascular space occupancy (VASO)-dependent techniques at spatial resolution of 2 × 2 × 5 mm(3), were compared in the study investigating functional responses in the human visual cortex to stimulation in normoxia (inspired O(2) = 21%) and mild hypoxic hypoxia (inspired O(2) = 12%). GMN and VASO signals and T(2)* were quantified in activated voxels. While the CBV-weighted signal changes in voxels activated by visual stimulation were similar in amplitude in both fMRI techniques in both oxygenation conditions, the number of activated voxels during hypoxic hypoxia was significantly reduced by 72 ± 22% in GMN fMRI and 66 ± 23% in VASO fMRI. T(2)* prolonged in GMN and VASO activated voxels in normoxia by 1.6 ± 0.5 ms and 1.7 ± 0.5 ms, respectively. In hypoxia, however, T(2)* shortened in GMN-activated voxels by 0.7 ± 0.6 ms (p < 0.001 relative to normoxia), but prolonged in VASO-activated ones by 1.1 ± 0.6 ms (p < 0.05 relative to normoxia). The data show that the hemodynamic responses to visual stimulation were not affected by hypoxic hypoxia, but T(2)* increases by both CBV-weighted fMRI techniques were smaller in activated voxels in hypoxia. The mechanisms influencing GMN fMRI signal in both oxygenation conditions were explored by simulating effects of the oxygen extraction fraction (OEF) and partial voluming with cerebral spinal fluid (CSF) and white matter in imaging voxels. It is concluded that while GMN fMRI data point to increased, rather than decreased OEF during visual stimulation in hypoxia, partial voluming by CSF is likely to affect the CBV quantification by GMN fMRI under the experimental conditions used.


Orbitofrontal cortex and dynamic filtering of emotional stimuli.
Event-related potentials (ER) were recorded in response to mildly aversive somatosensory and auditory stimuli. Patients with orbitofrontal lesions exhited enhanced ERPs (i.e., P3 amplitudes), as compared with control subjects. Moreover, these patients did not habituate to somatoensory stimuli across blocks of trials. The results were specific to orbitofrontal damage, since patients with damage to the dorsolateral prefontal cortex did not exhibit enhanced P3 amplitudes. These findings suggest damage to the orbitofrontal cortex impairs the ability to modulate or inhibit neural responses to aversive stimuli. The findings are couched in terms of dynamic filtering theory, which suggests that the orbitofrontal cortex is involved in the selection and active inhibition of neural circuits associated with emotional responses.


Catalase in fluvial biofilms: a comparison between different extraction methods and example of application in a metal-polluted river.
Antioxidant enzymes are involved in important processes of cell detoxification during oxidative stress and have, therefore, been used as biomarkers in algae. Nevertheless, their limited use in fluvial biofilms may be due to the complexity of such communities. Here, a comparison between different extraction methods was performed to obtain a reliable method for catalase extraction from fluvial biofilms. Homogenization followed by glass bead disruption appeared to be the best compromise for catalase extraction. This method was then applied to a field study in a metal-polluted stream (Riou Mort, France). The most polluted sites were characterized by a catalase activity 4-6 times lower than in the low-polluted site. Results of the comparison process and its application are promising for the use of catalase activity as an early warning biomarker of toxicity using biofilms in the laboratory and in the field.


Management of traumatic patellar dislocation in a regional hospital in Hong Kong.
The role of surgery for acute patellar dislocation without osteochondral fracture is controversial. The aim of this study was to report the short-term results of management of patellar dislocation in our institute. Patients who were seen in our institution with patella dislocation from January 2011 to April 2014 were managed according to a standardised management algorithm. Pretreatment and 1-year post-treatment International Knee Documentation Committee score, Tegner activity level scale score, and presence of apprehension sign were analysed. A total of 41 patients were studied of whom 20 were first-time dislocators and 21 were recurrent dislocators. Among the first-time dislocators, there was a significant difference between patients who received conservative treatment versus surgical management. The conservative treatment group had a 33% recurrent dislocation rate, whereas there were no recurrent dislocations in the surgery group. There was no difference in Tegner activity level scale score or apprehension sign before and 1 year after treatment, however. Among the recurrent dislocators, there was a significant difference between those who received conservative treatment and those who underwent surgery. The recurrent dislocation rate was 71% in the conservative treatment group versus 0% in the surgery group. There was also significant improvement in International Knee Documentation Committee score from 67.7 to 80.0 (P=0.02), and of apprehension sign from 62% to 0% (P<0.01). A management algorithm for patellar dislocation is described. Surgery is preferable to conservative treatment in patients who have recurrent patellar dislocation, and may also be preferable for those who have an acute dislocation.


Bypassing the EPR effect with a nanomedicine harboring a sustained-release function allows better tumor control.
The current enhanced permeability and retention (EPR)-based approved nanomedicines have had little impact in terms of prolongation of overall survival in patients with cancer. For example, the two Phase III trials comparing Doxil(®), the first nanomedicine approved by the US Food and Drug Administration, with free doxorubicin did not find an actual translation of the EPR effect into a statistically significant increase in overall survival but did show less cardiotoxicity. In the current work, we used a two-factor factorial experimental design with intraperitoneal versus intravenous delivery and nanomedicine versus free drug as factors to test our hypothesis that regional (intraperitoneal) delivery of nanomedicine may better increase survival when compared with systemic delivery. In this study, we demonstrate that bypassing, rather than exploiting, the EPR effect via intraperitoneal delivery of nanomedicine harboring a sustained-release function demonstrates dual pharmacokinetic advantages, producing more efficient tumor control and suppressing the expression of stemness markers, epithelial-mesenchymal transition, angiogenesis signals, and multidrug resistance in the tumor microenvironment. Metastases to vital organs (eg, lung, liver, and lymphatic system) are also better controlled by intraperitoneal delivery of nanomedicine than by standard systemic delivery of the corresponding free drug. Moreover, the intraperitoneal delivery of nanomedicine has the potential to replace hyperthermic intraperitoneal chemotherapy because it shows equal efficacy and lower toxicity. In terms of efficacy, exploiting the EPR effect may not be the best approach for developing a nanomedicine. Because intraperitoneal chemotherapy is a type of regional chemotherapy, the pharmaceutical industry might consider the regional delivery of nanomedicine as a valid alternative pathway to develop their nanomedicine(s) with the goal of better tumor control in the future.


[Short-term curative effects of daoyin-tuna qigong therapy in 103 cases of chronic atrophic gastritis].
Daoyin-Tuna Qigong therapy was applied to 103 cases with chronic atrophic gastritis (CAG). The average duration of disease was 7.8 years. Daoyin-Tuna Qigong exercises were done 4 times a day, 1 hour each time. 79 days made a course and no drug was given. 31 cases were checked with gastroscopy and biopsy, 30 cases with electrogastrogram and 34 cases with immunity detection before and after treatment course. In clinical symptoms, the therapy appeared markedly effective in 72 cases (69.9%). The effective cases were 28 (27.2%). The total effective rate was 97.1%. The body weight of 95 cases (92.2%) increased by 2.4 +/- 1.3 kg on the average at the end of the treatment course, and the capacity for eating was increased by 110 +/- 70 g a day in 99 cases (96.1%). In gastroscopy and pathology examination, the rates of marked effectiveness were 35.5% and 48.4%, the effective 29.0% and 38.7%, the total effective 64.5% and 87.1% respectively. Electrogastrogram check: the frequency and amplitude of the electrogastrogram increased markedly (P less than 0.05) in comparison with the pre-therapy. Immunology examination: E-rosette was 51.3 +/- 8.4% before treatment and 55.3 +/- 7.7% after treatment (P less than 0.05). It is suggested that Daoyin-Tuna Qigong therapy would be a better and new treatment for CAG.