Targeting JAK/STAT pathway in Takayasu's arteritis.
Takayasu's arteritis (TAK) is a large vessel vasculitis with important infiltration of proinflammatory T cells in the aorta and its main branches, but its aetiology is still unknown. Our work aims to explore the involvement of Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) signalling pathway in proinflammatory T cells differentiation and disease activity of TAK. We analysed transcriptome and interferons gene signatures of fluorescence-activated cell sorting (FACS-sorted) CD4+ and CD8+ T cells from healthy donors (HD) and in 25 TAK (median age of 37.6 years including 21 active TAK with National Institutes of Health (NIH) score >1). Then we tested, in vitro and in vivo, the effects of JAK inhibitors (JAKinibs) in TAK. Transcriptome analysis showed 248 and 432 significantly dysregulated genes for CD4+ and CD8+ samples between HD and TAK, respectively. Among dysregulated genes, we highlighted a great enrichment for pathways linked to type I and type II interferons, JAK/STAT and cytokines/chemokines-related signalling in TAK. We confirmed by Real Time Reverse Transcription Polymerase Chain Reaction (RT-qPCR) the upregulation of type I interferons gene signature in TAK as compared with HD. JAKinibs induced both in vitro and in vivo a significant reduction of CD25 expression by CD4+ and CD8+ T cells, a significant decrease of type 1 helper T cells (Th1) and Th17 cells and an increase of Tregs cells in TAK. JAKinibs also decreased C reactive protein level, NIH score and corticosteroid dose in TAK patients. JAK/STAT signalling pathway is critical in the pathogenesis of TAK and JAKinibs may be a promising therapy.


The genome sequence of the commercially cultivated mushroom Agrocybe aegerita reveals a conserved repertoire of fruiting-related genes and a versatile suite of biopolymer-degrading enzymes.
Agrocybe aegerita is an agaricomycete fungus with typical mushroom features, which is commercially cultivated for its culinary use. In nature, it is a saprotrophic or facultative pathogenic fungus causing a white-rot of hardwood in forests of warm and mild climate. The ease of cultivation and fructification on solidified media as well as its archetypal mushroom fruit body morphology render A. aegerita a well-suited model for investigating mushroom developmental biology. Here, the genome of the species is reported and analysed with respect to carbohydrate active genes and genes known to play a role during fruit body formation. In terms of fruit body development, our analyses revealed a conserved repertoire of fruiting-related genes, which corresponds well to the archetypal fruit body morphology of this mushroom. For some genes involved in fruit body formation, paralogisation was observed, but not all fruit body maturation-associated genes known from other agaricomycetes seem to be conserved in the genome sequence of A. aegerita. In terms of lytic enzymes, our analyses suggest a versatile arsenal of biopolymer-degrading enzymes that likely account for the flexible life style of this species. Regarding the amount of genes encoding CAZymes relevant for lignin degradation, A. aegerita shows more similarity to white-rot fungi than to litter decomposers, including 18 genes coding for unspecific peroxygenases and three dye-decolourising peroxidase genes expanding its lignocellulolytic machinery. The genome resource will be useful for developing strategies towards genetic manipulation of A. aegerita, which will subsequently allow functional genetics approaches to elucidate fundamentals of fruiting and vegetative growth including lignocellulolysis.


The Changing Epidemiological Profile of HIV-1 Subtype B Epidemic in Ukraine.
While HIV-1 subtype B has caused a large epidemic in the Western world, its transmission in Ukraine remains poorly understood. We assessed the genetic diversity of HIV-1 subtype B viruses circulating in Ukraine, characterized the transmission group structure, and estimated key evolutionary and epidemiological parameters. We analyzed 120 HIV-1 subtype B pol sequences (including 46 newly generated) sampled from patients residing in 11 regions of Ukraine between 2002 and 2017. Phylogenies were estimated using maximum likelihood and Bayesian phylogenetic methods. A Bayesian molecular clock coalescent analysis was used to estimate effective population size dynamics and date the most recent common ancestors of identified clades. A phylodynamic birth-death model was used to estimate the effective reproductive number (Re) of these clades. We identified two phylogenetically distinct predominantly Ukrainian (≥75%) clades of HIV-1 subtype B. We found no significant transmission group structure for either clade, suggesting frequent mixing among transmission groups. The estimated dates of origin of both subtype B clades were around early 1970s, similar to the introduction of HIV-1 subtype A into Ukraine. Re was estimated to be 1.42 [95% highest posterior density (HPD) 1.26-1.56] for Clade 1 and 1.69 (95% HPD 1.49-1.84) for Clade 2. Evidently, the subtype B epidemic in the country is no longer concentrated in specific geographical regions or transmission groups. The study results highlight the necessity for strengthening preventive and monitoring efforts to reduce the further spread of HIV-1 subtype B.


Soluble guanylyl cyclase activator YC-1 protects white matter axons from nitric oxide toxicity and metabolic stress, probably through Na(+) channel inhibition.
In the rat isolated optic nerve, nitric oxide (NO) activates soluble guanylyl cyclase (sGC), resulting in a selective accumulation of cGMP in the axons. The axons are also selectively vulnerable to NO toxicity. The experiments initially aimed to determine any causative link between these two effects. It was shown, using a NONOate donor, that NO-induced axonal damage occurred independently of cGMP. Unexpectedly, however, the compound YC-1, which is an allosteric activator of sGC, potently inhibited NO-induced axonopathy (IC(50) = 3 microM). This effect was not attributable to increased cGMP accumulation. YC-1 (30 microM) also protected the axons against damage by simulated ischemia, which (like NO toxicity) is sensitive to Na(+) channel inhibition. Although chemically unrelated to any known Na(+) channel inhibitor, YC-1 was effective in two biochemical assays for activity on Na(+) channels in synaptosomes. Electrophysiological recording from hippocampal neurons showed that YC-1 inhibited Na(+) currents in a voltage-dependent manner. At a concentration giving maximal protection of optic nerve axons from NO toxicity (30 microM), YC-1 did not affect normal axon conduction. It is concluded that the powerful axonoprotective action of YC-1 is unrelated to its activity on sGC but is explained by a novel action on voltage-dependent Na(+) channels. The unusual ability of YC-1 to protect axons so effectively without interfering with their normal function suggests that the molecule could serve as a prototype for the development of more selective Na(+) channel inhibitors with potential utility in neurological and neurodegenerative disorders.


Helicobacter pylori DNA obtained from the stomach specimens of two 17th century Korean mummies.
Helicobacter pylori is a bacterium that grows in the stomach mucosal epithelium, and can induce gastric diseases. Although many studies on modern H. pylori genomes have been reported from all over the world, a comprehensive picture of H. pylori is still lacking. Therefore, there is a pressing need to obtain archaeological specimens and to subject the ancient DNA (aDNA) extracted therefrom to analysis. Considering the typically excellent state of preservation of Joseon mummies discovered in Korea, we thus tried to isolate ancient H. pylori DNA from their mummified stomach specimens. After screening Korean mummy stomachs containing remnant H. pylori DNA, vacA (s- and m-region) alleles were successfully identified in the stomach isolates of two samples. The H. pylori strains identified had vacA s1/m2 (Cheongdo mummy) and s1 (Dangjin mummy) alleles. This paper is significant in that it is the first report of presumptive ancient H. pylori DNA obtained from East Asian archaeological specimens. However, full characterization and exploitation of ancient H. pylori DNA remnant in Joseon mummy specimens will require subsequent investigations utilizing the most cutting-edge techniques established for the analysis of ancient intestinal-content samples, such as next-generation sequencing (NGS).


Noise reduction of supercontinua via optical feedback.
The impact of delayed optical feedback on the supercontinuum noise properties is investigated numerically and experimentally. The supercontinuum is generated by coupling femtosecond laser pulses into a microstructured fiber within a ring resonator, which introduces the optical feedback. The power noise and spectral amplitude noise properties of this feedback system are numerically and experimentally compared with single-pass supercontinuum generation. In a demonstrative experiment via optical feedback the power noise could be reduced by 15 dB and the spectral amplitude noise could be reduced by up to 28 dB.


Real-time visualization and interaction with static and live optical coherence tomography volumes in immersive virtual reality.
Virtual reality (VR) head-mounted displays are an attractive technology for viewing intrasurgical optical coherence tomography (OCT) volumes because they liberate surgeons from microscope oculars. We demonstrate real-time, interactive viewing of OCT volumes in a commercial HTC Vive immersive VR system using previously reported ray casting techniques. Furthermore, we show interactive manipulation and sectioning of volumes using handheld controllers and guidance of mock surgical procedures in porcine eyes exclusively within VR. To the best of our knowledge, we report the first immersive VR-OCT viewer with stereo ray casting volumetric renders, arbitrary sectioning planes, and live acquisition support. We believe VR-OCT volume displays will advance ophthalmic surgery towards VR-integrated surgery.


Analysis of C-shaped canal systems in mandibular second molars using surgical operating microscope and cone beam computed tomography: A clinical approach.
The study was aimed to acquire better understanding of C-shaped canal systems in mandibular second molar teeth through a clinical approach using sophisticated techniques such as surgical operating microscope and cone beam computed tomography (CBCT). A total of 42 extracted mandibular second molar teeth with fused roots and longitudinal grooves were collected randomly from native Indian population. Pulp chamber floors of all specimens were examined under surgical operating microscope and classified into four types (Min's method). Subsequently, samples were subjected to CBCT scan after insertion of K-files size #10 or 15 into each canal orifice and evaluated using the cross-sectional and 3-dimensional images in consultation with dental radiologist so as to obtain more accurate results. Minimum distance between the external root surface on the groove and initial file placed in the canal was also measured at different levels and statistically analyzed. Out of 42 teeth, maximum number of samples (15) belonged to Type-II category. A total of 100 files were inserted in 86 orifices of various types of specimens. Evaluation of the CBCT scan images of the teeth revealed that a total of 21 canals were missing completely or partially at different levels. The mean values for the minimum thickness were highest at coronal followed by middle and apical third levels in all the categories. Lowest values were obtained for teeth with Type-III category at all three levels. The present study revealed anatomical variations of C-shaped canal system in mandibular second molars. The prognosis of such complex canal anatomies can be improved by simultaneous employment of modern techniques such as surgical operating microscope and CBCT.


Beta 3-endonexin, a novel polypeptide that interacts specifically with the cytoplasmic tail of the integrin beta 3 subunit.
The adhesive and signaling functions of integrins are regulated through their cytoplasmic domains. We identified a novel 111 residue polypeptide, designated beta 3-endonexin, that interacted with the cytoplasmic tail of the beta 3 integrin subunit in a yeast two-hybrid system. This interaction is structurally specific, since it was reduced by 64% by a point mutation in the beta 3 cytoplasmic tail (S752-->P) that disrupts integrin signaling. Moreover, this interaction is integrin subunit specific since it was not observed with the cytoplasmic tails of the alpha IIb, beta 1, or beta 2 subunits. beta 3-Endonexin fusion proteins bound selectively to detergent-solubilized beta 3 from platelets and human umbilical vein endothelial cells, and beta 3-endonexin mRNA and protein were detected in platelets and other tissues. A related mRNA encoded a larger polypeptide that failed to bind to beta integrin tails. The apparent specificity of beta 3-endonexin for the beta 3 integrin subunit suggests potential mechanisms for selective modulation of integrin functions.


Novel Tools and Investigative Approaches for the Study of Oligodendrocyte Precursor Cells (NG2-Glia) in CNS Development and Disease.
Oligodendrocyte progenitor cells (OPCs), also referred to as NG2-glia, are the most proliferative cell type in the adult central nervous system. While the primary role of OPCs is to serve as progenitors for oligodendrocytes, in recent years, it has become increasingly clear that OPCs fulfil a number of other functions. Indeed, independent of their role as stem cells, it is evident that OPCs can regulate the metabolic environment, directly interact with and modulate neuronal function, maintain the blood brain barrier (BBB) and regulate inflammation. In this review article, we discuss the state-of-the-art tools and investigative approaches being used to characterize the biology and function of OPCs. From functional genetic investigation to single cell sequencing and from lineage tracing to functional imaging, we discuss the important discoveries uncovered by these techniques, such as functional and spatial OPC heterogeneity, novel OPC marker genes, the interaction of OPCs with other cells types, and how OPCs integrate and respond to signals from neighboring cells. Finally, we review the use of in vitro assay to assess OPC functions. These methodologies promise to lead to ever greater understanding of this enigmatic cell type, which in turn will shed light on the pathogenesis and potential treatment strategies for a number of diseases, such as multiple sclerosis (MS) and gliomas.


Sonographic Features of a Myeloid Sarcoma of the Breast as a Relapse of Acute Myeloid Leukemia After Stem-Cell Transplantation: A Case Report.
BACKGROUND Myeloid sarcoma is a rarely observed extramedullary presentation of myeloid leukemia that seldom manifests in the breast. Myeloid sarcoma can occur before, concurrently with, or following acute myeloid leukemia presentation. Few reports have focused on the imaging findings in cases of myeloid sarcoma of the breast, and the existing findings are variable and nonspecific; the present case report aimed to bridge this gap. CASE REPORT A 24-year-old female presented with a palpable lump at the upper outer quadrant of her right breast. She had noticed the mass 2 days prior to presentation. She was first diagnosed with acute myelogenous leukemia 18 months before the lump presentation and had undergone haploidentical stem cell transplantation 6 months prior. At the time of the breast lump presentation, she was undergoing chemotherapy for relapsed acute myeloid leukemia. Ultrasonography of her right breast revealed a circumscribed, oval mass corresponding to the palpable lump. Ultrasonography-guided 14-gauge core needle biopsy was performed on the breast mass, leading to a pathological diagnosis of myeloid sarcoma. CONCLUSIONS We reported a case of myeloid sarcoma involving the breast. On sonography, although the internal echotexture resembled that of breast hamartoma, the observed hard elasticity and high vascularity raised suspicions of malignancy.


Impaired Innate COPD Alveolar Macrophage Responses and Toll-Like Receptor-9 Polymorphisms.
Dysfunctional innate responses of alveolar macrophages to nontypeable Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pneumoniae contribute to morbidity in chronic obstructive pulmonary disease (COPD). Our earlier studies discovered impaired COPD alveolar macrophage responses to Toll-like receptor (TLR) ligands of nontypeable H. influenzae and provide rationale for further evaluation of TLR signaling. While the role of TLR single nucleotide polymorphisms is increasingly recognized in inflammatory diseases, TLR single nucleotide polymorphisms in COPD have only recently been explored. We hypothesized that specific TLR polymorphisms are associated with dysfunctional innate immune COPD alveolar macrophage responses and investigated polymorphisms of TLR2(Arg753Gln), TLR4(Thr399Ile; Asp299Gly), and TLR9(T1486C; T1237C). DNA was purified from cells of 1) healthy nonsmokers (n = 20); 2) COPD ex-smokers (n = 83); 3) COPD active smokers (n = 93). DNA amplifications (polymerase chain reaction) were performed for each SNP. Alveolar macrophages from each group were incubated with nontypeable H. influenzae, M. catarrhalis and S. pneumoniae. Cytokine induction of macrophage supernatants was measured and the association with TLR single nucleotide polymorphism expression was determined. No significant inter-group differences in frequency of any TLR SNP existed. However both TLR9 single nucleotide polymorphisms were expressed in high frequency. Among COPD ex-smokers, diminished IL-8 responsiveness to nontypeable H. influenzae, M. catarrhalis and S. pneumoniae was strongly associated with carriage of TLR9(T1237C) (p = 0.02; p = 0.008; p = 0.02), but not TLR9(T1486C). Carriage of TLR9(T1237C), but not TLR9(T1486C), correlated with diminished FEV1%predicted (p = 0.037). Our results demonstrate a notable association of TLR9(T1237C) expression with dysfunctional innate alveolar macrophage responses to respiratory pathogens and with severity of COPD.


A critical thinking disposition scale for nurses: short form.
The aim of this study was to test the Chinese version of the Critical Thinking Disposition Inventory (CTDI-CV) among nurses in Taiwan. Critical thinking is the use of purposeful self-regulatory judgments to identify patient's problems and provide patient care. Critical thinking influences nurses' decision making. To date, no inventory to understand nurse's critical thinking disposition has been developed. This was a survey design with a stratified random sampling to test the reliability and validity of the CTDI-CV. The participants comprised 864 registered nurses who were chosen by stratified random sampling from seven hospitals in Taiwan. Data were collected through self-administered structured questionnaires. A new scale, short form (SF) CTDI-CV, contains 18 items with three subscales: 'systematic analysis', 'thinking within the box' and 'thinking out of the box', was generated from the analysis with 44% explained variance. Cronbach's alpha coefficients and intra-class correlation coefficients for overall and subscale were above 0.8. Goodness-of-fit test for the final model of SF-CTDI-CV revealed an acceptable result in the overall fit (χ(2)/df = 4.04, p < 0.05, GFI = 0.93, AGFI = 0.91, SRMR = 0.076, RMSEA = 0.059). On the basis of these results, the SF-CTDI-CV is a reliable instrument for assessing critical thinking disposition for nurses. A short and valid critical thinking instrument for nurses will facilitate critical thinking research in the clinical practice arena. When designing continuing education activities, clinical educators will be able to efficiently and effectively evaluate the quality of critical thinking among practicing nurses.


Chloroanisoles may explain mold odor and represent a major indoor environment problem in Sweden.
Indoor mold odor is associated with adverse health effects, but the microbial volatiles underlying mold odor are poorly described. Here, chloroanisoles were studied as potential key players, being formed by microbial metabolism of chlorophenols in wood preservatives. Using a three-stage approach, we (i) investigated the occurrence of chloroanisoles in buildings with indoor air quality problems, (ii) estimated their frequency in Sweden, and (iii) evaluated the toxicological risk of observed chloroanisole concentrations. Analyses of 499 building materials revealed several chloroanisole congeners in various types of buildings from the 1950s to 1970s. Evaluation of Swedish records from this time period revealed three coinciding factors, namely an unprecedented nationwide building boom, national regulations promoting wood preservatives instead of moisture prevention, and use of chlorophenols in these preservatives. Chlorophenols were banned in 1978, yet analysis of 457 indoor air samples revealed several chloroanisole congeners, but at median air levels generally below 15 ng/m(3) . Our toxicological evaluation suggests that these concentrations are not detrimental to human health per se, but sufficiently high to cause malodor. Thereby, one may speculate that chloroanisoles in buildings contribute to adverse health effects by evoking odor which, enhanced by belief of the exposure being hazardous, induces stress-related and inflammatory symptoms.


Peptide vocabulary analysis reveals ultra-conservation and homonymity in protein sequences.
A new algorithm is presented for vocabulary analysis (word detection) in texts of human origin. It performs at 60%-70% overall accuracy and greater than 80% accuracy for longer words, and approximately 85% sensitivity on Alice in Wonderland, a considerable improvement on previous methods. When applied to protein sequences, it detects short sequences analogous to words in human texts, i.e. intolerant to changes in spelling (mutation), and relatively context-independent in their meaning (function). Some of these are homonyms of up to 7 amino acids, which can assume different structures in different proteins. Others are ultra-conserved stretches of up to 18 amino acids within proteins of less than 40% overall identity, reflecting extreme constraint or convergent evolution. Different species are found to have qualitatively different major peptide vocabularies, e.g. some are dominated by large gene families, while others are rich in simple repeats or dominated by internally repetitive proteins. This suggests the possibility of a peptide vocabulary signature, analogous to genome signatures in DNA. Homonyms may be useful in detecting convergent evolution and positive selection in protein evolution. Ultra-conserved words may be useful in identifying structures intolerant to substitution over long periods of evolutionary time.


Evaluation of arterial stiffness by finger-toe pulse wave velocity: optimization of signal processing and clinical validation.
Carotid-femoral pulse wave velocity (PWV) (cf-PWV) is the gold standard for measuring aortic stiffness. Finger-toe PWV (ft-PWV) is a simpler noninvasive method for measuring arterial stiffness. Although the validity of the method has been previously assessed, its accuracy can be improved. ft-PWV is determined on the basis of a patented height chart for the distance and the pulse transit time (PTT) between the finger and the toe pulpar arteries signals (ft-PTT). The objective of the first study, performed in 66 patients, was to compare different algorithms (intersecting tangents, maximum of the second derivative, 10% threshold and cross-correlation) for determining the foot of the arterial pulse wave, thus the ft-PTT. The objective of the second study, performed in 101 patients, was to investigate different signal processing chains to improve the concordance of ft-PWV with the gold-standard cf-PWV. Finger-toe PWV (ft-PWV) was calculated using the four algorithms. The best correlations relating ft-PWV and cf-PWV, and relating ft-PTT and carotid-femoral PTT were obtained with the maximum of the second derivative algorithm [PWV: r = 0.56, P < 0.0001, root mean square error (RMSE) = 0.9 m/s; PTT: r = 0.61, P < 0.001, RMSE = 12 ms]. The three other algorithms showed lower correlations. The correlation between ft-PTT and carotid-femoral PTT further improved (r = 0.81, P < 0.0001, RMSE = 5.4 ms) when the maximum of the second derivative algorithm was combined with an optimized signal processing chain. Selecting the maximum of the second derivative algorithm for detecting the foot of the pressure waveform, and combining it with an optimized signal processing chain, improved the accuracy of ft-PWV measurement in the current population sample. Thus, it makes ft-PWV very promising for the simple noninvasive determination of aortic stiffness in clinical practice.


Subglacial Lake Vostok (Antarctica) accretion ice contains a diverse set of sequences from aquatic, marine and sediment-inhabiting bacteria and eukarya.
Lake Vostok, the 7(th) largest (by volume) and 4(th) deepest lake on Earth, is covered by more than 3,700 m of ice, making it the largest subglacial lake known. The combination of cold, heat (from possible hydrothermal activity), pressure (from the overriding glacier), limited nutrients and complete darkness presents extreme challenges to life. Here, we report metagenomic/metatranscriptomic sequence analyses from four accretion ice sections from the Vostok 5G ice core. Two sections accreted in the vicinity of an embayment on the southwestern end of the lake, and the other two represented part of the southern main basin. We obtained 3,507 unique gene sequences from concentrates of 500 ml of 0.22 µm-filtered accretion ice meltwater. Taxonomic classifications (to genus and/or species) were possible for 1,623 of the sequences. Species determinations in combination with mRNA gene sequence results allowed deduction of the metabolic pathways represented in the accretion ice and, by extension, in the lake. Approximately 94% of the sequences were from Bacteria and 6% were from Eukarya. Only two sequences were from Archaea. In general, the taxa were similar to organisms previously described from lakes, brackish water, marine environments, soil, glaciers, ice, lake sediments, deep-sea sediments, deep-sea thermal vents, animals and plants. Sequences from aerobic, anaerobic, psychrophilic, thermophilic, halophilic, alkaliphilic, acidophilic, desiccation-resistant, autotrophic and heterotrophic organisms were present, including a number from multicellular eukaryotes.


Characterization of the cell surface receptor for human granulocyte/macrophage colony-stimulating factor.
125I-labeled recombinant human GM-CSF was used to identify and characterize receptors specific for this lymphokine on both a mature primary cell, human neutrophils, and on the undifferentiated promyelomonocytic leukemia cell line, HL-60. Human GM-CSF also bound to primary human monocytes and to the myelogenous leukemia cell line, KG-1, but not to any of the murine cells known to express the murine GM-CSF receptor. In addition, although some murine T lymphomas can express the GM-CSF receptor, none of the human cell lines of T cell lineage that we examined bound iodinated human GM-CSF. Binding to all cell types was specific and saturable. Equilibrium binding studies revealed that on all cell types examined, GM-CSF bound to a single class of high affinity receptor (100-500 receptors per cell) with a Ka of 10(9)-10(10)/M. More extensive characterization with neutrophils and HL-60 cells showed that in both cases, binding of GM-CSF was rapid at 37 degrees C with a slow subsequent dissociation rate that exhibited marked biphasic kinetics. Among a panel of lymphokines and growth hormones, only human GM-CSF could compete for binding of human 125I-GM-CSF to these cells. GM-CSF can not only stimulate the proliferation and differentiation of granulocyte/macrophage precursor cells, but can modulate the functional activity of mature granulocytes and macrophages as well. No significant differences in the kinetic parameters of receptor binding were seen between mature neutrophils and the undifferentiated promyelocytic leukemia cell line HL-60, indicating that maturation-specific responses to GM-CSF are not mediated by overt changes in the binding characteristics of the hormone for its receptor.


Age at onset of non-affective psychosis in relation to cannabis use, other drug use and gender.
Cannabis use is associated with an earlier age at onset of psychotic illness. The aim of the present study was to examine whether this association is confounded by gender or other substance use in a large cohort of patients with a non-affective psychotic disorder. In 785 patients with a non-affective psychotic disorder, regression analysis was used to investigate the independent effects of gender, cannabis use and other drug use on age at onset of first psychosis. Age at onset was 1.8 years earlier in cannabis users compared to non-users, controlling for gender and other possible confounders. Use of other drugs did not have an additional effect on age at onset when cannabis use was taken into account. In 63.5% of cannabis-using patients, age at most intense cannabis use preceded the age at onset of first psychosis. In males, the mean age at onset was 1.3 years lower than in females, controlling for cannabis use and other confounders. Cannabis use and gender are independently associated with an earlier onset of psychotic illness. Our findings also suggest that cannabis use may precipitate psychosis. More research is needed to clarify the neurobiological factors that make people vulnerable to this precipitating effect of cannabis.


Vulvar Melanoma with Isolated Metastasis to the Extraocular Muscles: Case Report and Brief Literature Review.
Orbital metastasis of systemic cancer is exceedingly rare. This is a case report of a patient treated for locally recurrent vulvar melanoma who later presented with unilateral proptosis and was found to have an isolated biopsy-proven extraocular muscle metastasis. A 94-year-old female with locally recurrent vulvar melanoma presented with eye discomfort and blurry vision. Patient underwent histopathological, genetic, and imaging studies. All prior work-up, including brain MRI and PET/CT, was negative for disease elsewhere from local recurrence. Orbital MRI demonstrated a mass involving the extraocular muscle, and immunohistochemistry staining of biopsy was consistent with metastasis. The patient underwent radiation therapy and tolerated treatment well. This is the first reported case of vulvar melanoma with extraocular muscle metastasis. The absence of findings on imaging as part of the staging work-up underscores the importance of considering extraocular muscle (EOM) metastasis as a differential for patients with vulvar melanoma who present with proptosis.


Protein kinase involved in lung injury susceptibility: evidence from enzyme isoform genetic knockout and in vivo inhibitor treatment.
Acute lung injury (ALI) associated with sepsis and iatrogenic ventilator-induced lung injury resulting from mechanical ventilation are major medical problems with an unmet need for small molecule therapeutics. Prevailing hypotheses identify endothelial cell (EC) layer dysfunction as a cardinal event in the pathophysiology, with intracellular protein kinases as critical mediators of normal physiology and possible targets for drug discovery. The 210,000 molecular weight myosin light chain kinase (MLCK210, also called EC MLCK because of its abundance in EC) is hypothesized to be important for EC barrier function and might be a potential therapeutic target. To test these hypotheses directly, we made a selective MLCK210 knockout mouse that retains production of MLCK108 (also called smooth-muscle MLCK) from the same gene. The MLCK210 knockout mice are less susceptible to ALI induced by i.p. injection of the endotoxin lipopolysaccharide and show enhanced survival during subsequent mechanical ventilation. Using a complementary chemical biology approach, we developed a new class of small-molecule MLCK inhibitor based on the pharmacologically privileged aminopyridazine and found that a single i.p. injection of the inhibitor protected WT mice against ALI and death from mechanical ventilation complications. These convergent results from two independent approaches demonstrate a pivotal in vivo role for MLCK in susceptibility to lung injury and validate MLCK as a potential drug discovery target for lung injury.


Clinical spectrum of premature pubarche: links to metabolic syndrome and ovarian hyperandrogenism.
Premature pubarche-defined as the appearance of pubic hair before age 8 years in girls and 9 years in boys-has been traditionally considered a benign entity. However, recent evidence supports the notion that premature pubarche in girls may be a forerunner of the metabolic syndrome, and may precede the development of clinical ovarian androgen excess in adolescence. This sequence seems to occur more frequently when premature pubarche was preceded by reduced fetal growth and followed by excessive postnatal catch-up in height and particularly in weight; hyperinsulinemia appears to be a key factor in the development of this sequence of events. In girls with premature pubarche and a history of a low birth weight, puberty tends to start earlier and to have a faster course, so that final height may be moderately reduced. In these girls, metformin therapy may reverse the progression to clinical ovarian hyperandrogenism, normalize body composition and excess visceral fat, and delay pubertal progression without attenuating linear growth and bone mineralization, suggesting that adult height may be improved. Long-term follow-up of these patients is needed to fully determine the ultimate effects of insulin sensitization as well as the maintenance of these benefits after discontinuation of therapy.


Genomes of three tomato pathogens within the Ralstonia solanacearum species complex reveal significant evolutionary divergence.
The Ralstonia solanacearum species complex includes thousands of strains pathogenic to an unusually wide range of plant species. These globally dispersed and heterogeneous strains cause bacterial wilt diseases, which have major socio-economic impacts. Pathogenicity is an ancestral trait in R. solanacearum and strains with high genetic variation can be subdivided into four phylotypes, correlating to isolates from Asia (phylotype I), the Americas (phylotype IIA and IIB), Africa (phylotype III) and Indonesia (phylotype IV). Comparison of genome sequences strains representative of this phylogenetic diversity can help determine which traits allow this bacterium to be such a pathogen of so many different plant species and how the bacteria survive in many different habitats. The genomes of three tomato bacterial wilt pathogens, CFBP2957 (phy. IIA), CMR15 (phy. III) and PSI07 (phy. IV) were sequenced and manually annotated. These genomes were compared with those of three previously sequenced R. solanacearum strains: GMI1000 (tomato, phy. I), IPO1609 (potato, phy. IIB), and Molk2 (banana, phy. IIB). The major genomic features (size, G+C content, number of genes) were conserved across all of the six sequenced strains. Despite relatively high genetic distances (calculated from average nucleotide identity) and many genomic rearrangements, more than 60% of the genes of the megaplasmid and 70% of those on the chromosome are syntenic. The three new genomic sequences revealed the presence of several previously unknown traits, probably acquired by horizontal transfers, within the genomes of R. solanacearum, including a type IV secretion system, a rhi-type anti-mitotic toxin and two small plasmids. Genes involved in virulence appear to be evolving at a faster rate than the genome as a whole. Comparative analysis of genome sequences and gene content confirmed the differentiation of R. solanacearum species complex strains into four phylotypes. Genetic distances between strains, in conjunction with CGH analysis of a larger set of strains, revealed differences great enough to consider reclassification of the R. solanacearum species complex into three species. The data are still too fragmentary to link genomic classification and phenotypes, but these new genome sequences identify a pan-genome more representative of the diversity in the R. solanancearum species complex.


The epidemiology of thyroid cancer in the Czech Republic in comparison with other countries.
Thyroid cancer includes a broad spectrum of tumours with different prognoses. The global incidence has been increasing in recent years. Variables affecting its etiology are dietary, especially iodine intake and to a lesser extent selenium, environmental, like - ionizing radiation and, increased TSH level. These factors interplay with epigenetic and genetic changes within the cell. This review article presents thyroid cancer epidemiology, describes its main characteristics and the influence of environmental and lifestyle risk factors in the Czech Republic in comparison with other countries. An epidemiological study of Czech patients with malignant thyroid carcinoma was made on the basis of the National Oncologic Registry (NOR) and Czech Statistical Office data summarized on the web portal SVOD. The data were compared with international data from the project GLOBOCAN 2008 Cancer Incidence and Mortality Worldwide. Apart from risk factors, prognostic factors with effect on patient survival were also analyzed. The survey showed that the incidence of thyroid cancer has been steadily growing in the Czech Republic. Since the beginning of the 1980s, it has increased 4 fold. It has a higher incidence than most other European countries but it is ranked with countries with an average and decreasing mortality. Obviously, the improved detection methods do not explain the growing incidence. The highest incidence is found for papillary carcinoma (PTC), now over 80% of cases. For follicular and medullar cancers, the incidence has not increased and for anaplastic carcinoma there is a slight decrease. Women over 40 years of age constitute the highest risk group. There are a number of reasons for these trends, such as improved diagnostic techniques using ultrasound and FNAB and more radical surgery. There are also dietary/environmental factors (iodine deficiency and to a lesser extent selenium), nitrates, polychlorinated biphenyls, increased ionizing radiation, and prolonged increase in TSH. The prognosis of patients with DTC depends on the age at the time of diagnosis. A favorable prognosis also depends on timely detection.


The influence of life stage on supportive care and information needs in cancer patients: does older age matter?
The purpose of this study is to clarify the effect of older age, on supportive care needs, information satisfaction and service needs in the year following a cancer diagnosis. Primary or recurrent prostate, breast, lung or colorectal cancer patients (n = 394) were prospectively surveyed 3 and 9 months post-diagnosis using the Support Care Needs Survey (SCNS-LF59) and Information Satisfaction (ISQ) and Service Needs (SNQ) questionnaires. Two age groups were compared: ≥65 years (senior) versus ≤64 years (junior). Few differences emerged between age groups (SCNS) with the exception of psychological (p < 0.001) and sexuality (p < 0.001) domains where these were greater in the younger patients 3 months post-diagnosis. Sexuality (p < 0.001) and patient care and support (p = 0.023) needs were predicted by age (continuous); younger patients had more needs at 3 months post-diagnosis. For information satisfaction, the older group preferred doctors to make decisions (3 months p < 0.001; 9 months p = 0.008) and preferred positive information (3 months p = 0.006). For the whole group fears about cancer spreading (51 %) and returning (45 %) predominate, alongside patients' concerns about worries of those closest to them (51 %) and uncertainty about their future (42 %) at 3 months. Older patients differ on information satisfaction showing a preference for doctors to make treatment decisions. For supportive care, there were few age differences; however, the SCNS sexuality and patient care and support domains indicate greater need in younger patients around the 3-month period following diagnosis. With a few exceptions, individual rather than age-specific needs determine supportive and informational care requirements.


Maternal and offspring adiposity-related genetic variants and gestational weight gain.
Gestational weight gain (GWG) is associated with a range of health outcomes, but little is known about the factors that influence it. The objective was to test the hypothesis that maternal and fetal genetic variants that are reliably associated with adiposity are associated with GWG. We examined the association of a risk allele score by using 4 adiposity-related single nucleotide polymorphisms (SNPs; rs9939609 in FTO, rs17782313 near MC4R, rs6548238 near TMEM18, and rs10938397 near GNPDA2) with GWG in a pregnancy cohort in which women had detailed repeated assessment of GWG (median number of weight measurements: 10; interquartile range: 8, 11). The numbers included in our analyses varied between 2324 and 7563 for different variant-outcome analyses. A linear spline random-effects model was used to model weight change with gestational age and to relate genetic variants to this. This modeling confirmed 3 distinct periods of GWG: 0-18, 19-28, and ≥29 wk of gestation. Maternal risk allele score and SNPs in FTO, MC4R, and TMEM18 were positively associated with prepregnancy weight. Maternal allele score was inversely associated with GWG in the first 18 wk of pregnancy (-14.46 g/wk per allele; 95% CI: -24.75, -4.17 g/wk per allele) but was not associated with other periods of GWG. Offspring allele score and maternal and offspring individual SNPs were not associated with GWG in any period or with birth weight or postnatal weight retention. Our findings suggest that neither maternal nor fetal adiposity-related genetic variants are associated with greater GWG. The inverse association of maternal allele score with GWG in the first 18 wk requires replication.


Hesperetin prevents selenite-induced cataract in rats.
This study investigated the ability of hesperetin, a natural flavonoid, to prevent selenite-induced cataracts in a rat model. Animals were divided into four treatment groups: G1 (control group), G2 (hesperetin-treated group), G3 (selenite-induced cataract group), and G4 (hesperetin-treated selenite cataract group). Animals in the G1 and G3 groups were injected with vehicle alone, while those in the G2 and G4 groups received a subcutaneous injection of hesperetin (0.4 μg/g bodyweight on days 0, 1, and 2, corresponding to P13, P14, and P15). Sodium selenite (20 μmol/g bodyweight given 4 h after the hesperetin injection on day 0) was administered to rats in the G3 and G4 groups to induce cataract formation. Lenses were observed with slit-lamp microscopy, and filensin degradation and the decreased glutathione (GSH) and ascorbic acid levels in the lens were measured on day 6. Lenses in the G3 group showed mature central opacity, while some lenses in the G4 group lacked central opacity and had lower-grade cataracts. All lenses in the G1 and G2 groups were transparent. Expression of the 94 kDa and 50 kDa forms of filensin was significantly decreased in the lenses in the G3 group compared with those in the G1 and G2 groups. Interestingly, these forms of filensin rescued the rat lenses in the G4 group. In the G3 group lenses, the GSH and ascorbic acid levels were lower than in the control group but were normalized in the G4 group lenses. The results suggest that hesperetin can prevent selenite-induced cataract formation.


New procedures for evaluating vision functions of special populations.
Research over the last few decades has demonstrated the rapid development of vision function that occurs in infancy with near-adult levels reached before the age of 1 year. This period of rapid development coincides with the period of maximum sensitivity to insult. These facts emphasize the importance of effective screening techniques for visual disorders. Off-axis photorefraction is described as a new and effective screening technique for detection of refractive errors, media opacities, and strabismus. Separate from screening, a significant need exists for optometric vision evaluations in special populations. Normal infants, developmentally delayed or multi-handicapped children and adults, and cognitively impaired adults are examples of special populations who are difficult to examine with standard optometric techniques. New procedures for measuring visual acuity, contrast sensitivity, color vision, and stereopsis using behavioral or electrophysiological measures are described. Advantages and disadvantages of the different techniques are discussed.


Calcium Channel Blockers and Risk of Lymphedema among Breast Cancer Patients: Nested Case-Control Study.
To assess the risk of lymphedema associated with the use of calcium channel blockers (CCB) among breast cancer patients. A nested case-control study of adult female breast cancer patients receiving an antihypertensive agent was conducted using administrative claims data between 2007 and 2015. Cases were patients with lymphedema who were matched to 5 controls based on nest entry date (±180 days), age (±5 years), number of hypertensive drug classes, Charlson Comorbidity Index (CCI), thiazide exposure, and insurance type. Exposure to CCBs and covariates was identified in the 180-day period prior to event date. Conditional logistic regression was used to assess the impact of exposure among cases and controls. A total of 717 cases and 1,681 matched controls were identified. After matching on baseline characteristics, mastectomy (7.8% vs. 4.8%; P = 0.0039), exposure to radiotherapy (27.1% vs. 21.7%; P = 0.0046), taxane-based chemotherapy (11.7% vs. 7.4%; P = 0.0007), anthracycline-based chemotherapy (6.0% vs. 3.6%; P = 0.0073), CCB use (28.3% vs. 23.3%; P = 0.0087), and CCI (19.8% vs. 12.7%; P < 0.0001; score of 4 or above) were all higher in cases during the 180 days prior to the event date. In the adjusted analysis, CCB exposure was significantly associated with increased risk of lymphedema (OR = 1.320; 95% confidence interval, 1.003-1.737). CCB use was significantly associated with the development of lymphedema in breast cancer patients. CCBs should be avoided or used with caution in breast cancer patients to reduce the risk for developing lymphedema.


Regional myocardial function is not affected by severe coronary depressurization provided coronary blood flow is maintained.
It has been suggested that vasodilation distal to a stenosis may cause a profound decrease in perfusion pressure and adversely affect regional left ventricular function. This phenomenon could explain the clinical concept of reversal of regional dysfunction by coronary revascularization. To evaluate the hypothesis that regional myocardial function parallels regional coronary blood pressure in the absence of changes in coronary flow, dogs chronically instrumented with left circumflex coronary artery flow probes, cuff occluders, pressure catheters and segmental function sonomicrometers were studied. By decreasing regional coronary vascular resistance with selective intracoronary dipyridamole and controlling blood flow with a proximal coronary cuff occluder, the mean left circumflex artery pressure was reduced from 83 +/- 3 to 38 +/- 2 mm Hg while circumflex coronary blood flow was maintained constant. Regional contractile function as measured by circumflex sonomicrometers was unchanged at constant circumflex subendocardial blood flow as measured by radioactive microspheres. These findings suggest that regional contractile function is dependent on subendocardial blood flow and is independent of coronary perfusion pressure.


TGF-beta-induced apoptosis is mediated by the adapter protein Daxx that facilitates JNK activation.
Transforming growth factor-beta (TGF-beta) is a multifunctional growth factor that has a principal role in growth control through both its cytostatic effect on many different epithelial cell types and its ability to induce programmed cell death in a variety of other cell types. Here we have used a screen for proteins that interact physically with the cytoplasmic domain of the type II TGF-beta receptor to isolate the gene encoding Daxx - a protein associated with the Fas receptor that mediates activation of Jun amino-terminal kinase (JNK) and programmed cell death induced by Fas. The carboxy-terminal portion of Daxx functions as a dominant-negative inhibitor of TGF-beta-induced apoptosis in B-cell lymphomas, and antisense oligonucleotides to Daxx inhibit TGF-beta-induced apoptosis in mouse hepatocytes. Furthermore, Daxx is involved in mediating JNK activation by TGF-beta. Our findings associate Daxx directly with the TGF-beta apoptotic-signalling pathway, and make a biochemical connection between the receptors for TGF-beta and the apoptotic machinery.


Antagonistic effects of gamma interferon and steroids on tissue antigenicity.
A single injection of 10(5) U/kg of recombinant rat IFN-gamma increases the amount of tissue dendritic cells up to sixfold, and concomitantly induces the (capillary) endothelial cells to express class II MHC antigens. Both responses peak on the third day after IFN-gamma injection, and the antigen expression returns to basic levels on day 7. Simultaneous administration of 1 mg/kg/d of methylprednisolone entirely abolishes both responses. These observations demonstrate, for the first time, that IFN-gamma and steroids have antagonistic effects on class II MHC antigen presentation in tissue, and suggest that one immunosuppressive mechanism of glucocorticosteroids in organ transplantation is downregulation of graft antigenicity.


Survey on fall detection and fall prevention using wearable and external sensors.
According to nihseniorhealth.gov (a website for older adults), falling represents a great threat as people get older, and providing mechanisms to detect and prevent falls is critical to improve people's lives. Over 1.6 million U.S. adults are treated for fall-related injuries in emergency rooms every year suffering fractures, loss of independence, and even death. It is clear then, that this problem must be addressed in a prompt manner, and the use of pervasive computing plays a key role to achieve this. Fall detection (FD) and fall prevention (FP) are research areas that have been active for over a decade, and they both strive for improving people's lives through the use of pervasive computing. This paper surveys the state of the art in FD and FP systems, including qualitative comparisons among various studies. It aims to serve as a point of reference for future research on the mentioned systems. A general description of FD and FP systems is provided, including the different types of sensors used in both approaches. Challenges and current solutions are presented and described in great detail. A 3-level taxonomy associated with the risk factors of a fall is proposed. Finally, cutting edge FD and FP systems are thoroughly reviewed and qualitatively compared, in terms of design issues and other parameters.


Genetic and environmental risk factors in congenital heart disease functionally converge in protein networks driving heart development.
Congenital heart disease (CHD) occurs in ∼1% of newborns. CHD arises from many distinct etiologies, ranging from genetic or genomic variation to exposure to teratogens, which elicit diverse cell and molecular responses during cardiac development. To systematically explore the relationships between CHD risk factors and responses, we compiled and integrated comprehensive datasets from studies of CHD in humans and model organisms. We examined two alternative models of potential functional relationships between genes in these datasets: direct convergence, in which CHD risk factors significantly and directly impact the same genes and molecules and functional convergence, in which risk factors significantly impact different molecules that participate in a discrete heart development network. We observed no evidence for direct convergence. In contrast, we show that CHD risk factors functionally converge in protein networks driving the development of specific anatomical structures (e.g., outflow tract, ventricular septum, and atrial septum) that are malformed by CHD. This integrative analysis of CHD risk factors and responses suggests a complex pattern of functional interactions between genomic variation and environmental exposures that modulate critical biological systems during heart development.


Prediction of individual differences in circadian adaptation to night work among older adults: application of a mathematical model using individual sleep-wake and light exposure data.
Circadian misalignment remains a distinct challenge for night shift workers. Variability in individual sleep-wake/light-dark patterns might contribute to individual differences in circadian alignment in night shift workers. In this simulation study, we compared the predicted phase shift from a mathematical model of the effect of light on the human circadian pacemaker to the observed melatonin phase shift among individuals who completed one of four interventions during simulated night shift work. Two inputs to the model were used to simulate circadian phase: sleep-wake/light-dark patterns measured from a wrist monitor (Simulation 1) and sleep-wake/light-dark patterns measured from a wrist monitor enhanced by known light levels measured at the level of the eye during simulated night shifts (Simulation 2). The estimated phase shift from the model was within 2 hours of the observed phase shift in ~80% of night shift workers for both simulations; none of the model-predicted phase shifts was more than ~3 hours from the observed phase shift. Overall, the root-mean-square error between observed and predicted phase shifts was better for Simulation 1. The light input from the wrist monitor informed by actual light level measured at the eye performed better in the sub-group exposed to bright light during their night shifts. The findings from this simulation study suggest that using a mathematical model combined with sleep-wake and light exposure data from a wrist monitor can facilitate the design of shift work schedules to enhance circadian alignment, which is expected to improve sleep, alertness, and performance.


Risks for preterm delivery and low birth weight are independently increased by severity of maternal anaemia.
To estimate the effect of the severity of maternal anaemia on various perinatal outcomes. A cross-sectional study. Labour Ward, Muhimbili National Hospital, Dar es Salaam, Tanzania. The haemoglobin of eligible pregnant women admitted for delivery between 15 November 2002 and 15 February 2003 was measured. Data on socio-demographic characteristics, iron supplementation, malaria prophylaxis, blood transfusion during current pregnancy, and current and previous pregnancy outcomes were collected and analysed. Anaemia was classified according to the World Health Organization (WHO) standards: normal--Hb > or = 11.0 g/dl; mild--Hb 9.0-10.9 g/dl; moderate--Hb 7.0-8.9 g/dl; and severe--Hb < 7.0 g/dl. Logistic regression analysis was performed to estimate the severity of anaemia. The following outcome measures were used: preterm delivery (<37 weeks), Apgar score, stillbirth, early neonatal death, low birth weight (LBW) (<2500 g) and very low birth weight (VLBW) (<1500 g). A total of 1174 anaemic and 547 non-anaemic women were enrolled. Their median age was 24 years (range 14-46 years) and median parity was 2 (range 0-17). The prevalence of anaemia and severe anaemia was 68% and 5.8%, respectively. The risk of preterm delivery increased significantly with the severity of anaemia, with odds ratios of 1.4, 1.4 and 4.1 respectively for mild, moderate and severe anaemia. The corresponding risks for LBW and VLBW were 1.2 and 1.7, 3.8 and 1.5, and 1.9 and 4.2 respectively. The risks of preterm delivery and LBW increased in proportion to the severity of maternal anaemia.


Use of dengue NS1 antigen for early diagnosis of dengue virus infection.
Accurate and timely diagnosis of dengue virus is important for early detection of dengue virus infection. In this study, the usefulness of the dengue NS1 antigen test was evaluated as a routine, rapid diagnostic test for dengue virus infection. A total of 208 sera from patients suspected of having dengue virus infection were collected and tested for dengue antibody, dengue genome and dengue NS1 antigen. Dengue antibody test, dengue PCR test and dengue antigen test were able to detect dengue virus infection from Days 1 to 8 in 72.8, 52.8 and 44.0% of samples, respectively. Of the 208 sera tested, 69.2% (144/208) of the acute sera were positive for dengue virus infection based on IgM antibody, IgG antibody, NS1 antigen and PCR tests. Thirty-two point two percent of the samples (67/208) were found positive for dengue NS1 antigen, 38.5% (80/208) were PCR positive, 40.9% (85/208) were IgM positive and 36.1% (75/208) were IgG positive for dengue virus. The results reveal the detection rate of dengue virus infection was similar for PCR and dengue antibody (65.9%) and for NS1 antigen and dengue antibody (62.0%) combinations. Therefore, the dengue NS1 antigen test can be used to complement the current antibody test used in peripheral laboratories. Thus, the combination of the NS1 antigen and antibody tests could increase the diagnostic efficiency for early diagnosis of dengue infection.


Using variable importance measures from causal inference to rank risk factors of schistosomiasis infection in a rural setting in China.
Schistosomiasis infection, contracted through contact with contaminated water, is a global public health concern. In this paper we analyze data from a retrospective study reporting water contact and schistosomiasis infection status among 1011 individuals in rural China. We present semi-parametric methods for identifying risk factors through a comparison of three analysis approaches: a prediction-focused machine learning algorithm, a simple main-effects multivariable regression, and a semi-parametric variable importance (VI) estimate inspired by a causal population intervention parameter. The multivariable regression found only tool washing to be associated with the outcome, with a relative risk of 1.03 and a 95% confidence interval (CI) of 1.01-1.05. Three types of water contact were found to be associated with the outcome in the semi-parametric VI analysis: July water contact (VI estimate 0.16, 95% CI 0.11-0.22), water contact from tool washing (VI estimate 0.88, 95% CI 0.80-0.97), and water contact from rice planting (VI estimate 0.71, 95% CI 0.53-0.96). The July VI result, in particular, indicated a strong association with infection status - its causal interpretation implies that eliminating water contact in July would reduce the prevalence of schistosomiasis in our study population by 84%, or from 0.3 to 0.05 (95% CI 78%-89%). The July VI estimate suggests possible within-season variability in schistosomiasis infection risk, an association not detected by the regression analysis. Though there are many limitations to this study that temper the potential for causal interpretations, if a high-risk time period could be detected in something close to real time, new prevention options would be opened. Most importantly, we emphasize that traditional regression approaches are usually based on arbitrary pre-specified models, making their parameters difficult to interpret in the context of real-world applications. Our results support the practical application of analysis approaches that, in contrast, do not require arbitrary model pre-specification, estimate parameters that have simple public health interpretations, and apply inference that considers model selection as a source of variation.


Quantitative urinalysis using aggregation-induced emission bioprobes for monitoring chronic kidney disease.
Early detection and appropriate management of chronic kidney disease can reduce the progression of kidney failure and cardiovascular disease. The urine albumin to creatinine ratio (UACR) test is a standard urine test for identifying individuals at high risk of developing progressive kidney disease. In this study, IDATPE, a novel fluorescent probe with aggregation-induced emission (AIE) features, is successfully developed for creatinine detection and quantitation. An excellent correlation between fluorescent light intensity and creatinine concentration is achieved. In addition, BSPOTPE, a reported excellent AIE bioprobe for human serum albumin (HSA) quantitation, is used together with IDATPE in artificial urine for UACR testing. The mutual interference of HSA and creatinine when the bioprobes are used for quantitation is characterised, with promising results. Further improvements and potential applications in CKD quantitation are highlighted.


Endothelial dysfunction in lacunar stroke: a systematic review.
Endothelial dysfunction is thought to play an important role in the pathogenesis and progression of cerebral small-vessel disease in lacunar stroke patients. We systematically searched the literature (MEDLINE, EMBASE) for evidence of endothelial activation and dysfunction in lacunar stroke. The selected papers were assessed by a predefined checklist to estimate methodological and informative quality. The papers were categorized into subheadings concerning the different physiologic functions of the endothelium and a subheading concerning toxins for the endothelium. 29 articles were eligible for further analysis. We found 16 publications on regulation of vascular tone by the endothelium, which showed an impaired function at several time points after the stroke by means of different clinical methods (e.g. flow-mediated vasodilatation and CO2 reactivity). Nine references showed elevated levels of markers of hemostatic function of the vascular endothelium (e.g. von Willebrand factor, thrombomodulin) in acute and subsequent phases. In 4 papers, adhesion molecules (e.g. E- and P-selectin) were elevated only during the acute phase. Homocysteine, a toxin for the endothelium, was elevated in patients in 3 papers. The current literature suggests that endothelial dysfunction might be involved in the pathogenesis of lacunar stroke, especially in those patients with concomitant silent lacunar infarcts and ischemic white matter lesions. Future research on endothelial function in lacunar stroke should concentrate on long-term clinical as well as radiological follow-up in well-defined cases and combine multiple methods to evaluate endothelial function.


Bile acid retention and activation of endogenous hepatic farnesoid-X-receptor in the pathogenesis of fatty liver disease in ob/ob-mice.
The nuclear bile acid receptor FXR (farnesoid-X-receptor) has recently been implicated in the pathophysiology of non-alcoholic fatty liver disease because selective FXR-agonists improve glucose and lipid metabolism in rodent models of obesity. However, the regulation of FXR and other relevant nuclear receptors as well as their lipogenic target genes in fatty liver is still not revealed in detail. Livers were harvested from 14-week-old male ob/ob mice and wild-type controls. Serum bile acids were quantified by radioimmunoassay. mRNA and protein expression of transporters and nuclear receptors was analyzed by reverse transcriptase-polymerase chain reaction and Western blotting, whereas DNA binding to the IR-1 element was examined by electrophoretic mobility shift assay. In this study we show: (i) bile acid retention in ob/ob mice, (ii) a resulting FXR upregulation and binding to the IR-1 element in ob/ob animals and (iii) concomitant activation of the fatty acid synthase as a potential lipogenic FXR target gene in vivo. The present study suggests a potential role of hepatic bile acid retention and FXR activation in the induction of lipogenic target genes. Differences between intestinal and hepatic FXR could explain apparent contradictory information regarding its effects on fatty liver disease.


Functional xanthophyll cycle and pigment content of a kleptoplastic benthic foraminifer: Haynesina germanica.
Some shallow water benthic foraminifera are able to retain functional chloroplasts (kleptoplasts) from their food source, i.e. diatoms. Here we assessed the functionality of the kleptoplast xanthophyll cycle (XC, i.e. the main diatom short-term photo-regulation mechanism) and we surveyed Haynesina germanica kleptoplast pigment composition over time and at different light regimes. Six common diatom lipophilic pigments were detected, two chlorophylls (Chl a, Chl c) and four carotenoids (fucoxanthin and by-products, diadinoxanthin, diatoxanthin and β-carotene), the same pigment profile as the diatom species frequently isolated at the sampling site. The xanthophyll cycle (XC) was functional with kleptoplast diatoxanthin (DT) content increase with concomitant diadinoxanthin (DD) decrease after short term light exposure. DT/(DT+DD) and DT/DD ratios increased significantly in specimens exposed to low light and high light in comparison to specimens maintained in the dark. Specimens placed in very low light after the light treatments reverted to values close to the initial ones, suggesting that H. germanica XC is functional. A functional XC is an indication of H. germanica kleptoplasts capacity for short-term photo-protection from photo-oxidative damages caused by excess of light. Furthermore, the pigment survey suggests that H. germanica preserved some chloroplasts over a longer time than others and that pigment content is influenced by previous light history. Finally, the current study highlighted seasonal differences, with higher pigment contents in winter specimens (27.35 ± 1.30 ng cell-1) and lower in summer specimens (6.08 ± 1.21 ng cell-1), a quantitative and qualitative composition suggesting light acclimation to low or high light availability, according to the season.


Plasma and memory B-cell kinetics in infants following a primary schedule of CRM 197-conjugated serogroup C meningococcal polysaccharide vaccine.
The induction of persistent protective levels of pathogen-specific antibody is an important goal of immunization against childhood infections. However, antibody persistence is poor after immunization in infancy versus later in life. Serogroup C meningococci (MenC) are an important cause of bacteraemia and meningitis in children. The use of protein-polysaccharide conjugate vaccines against MenC has been associated with a significant decline in the incidence of invasive disease. However, vaccine effectiveness is negligible by more than 1 year after a three-dose priming series in infancy and corresponds to a rapid decline in antibody following an initial immune response. The cellular mechanisms underlying the generation of persistent antibody in this age group are unclear. An essential prelude to larger studies of peripheral blood B cells is an understanding of B-cell kinetics following immunization. We measured MenC- and diphtheria-specific plasma and memory B-cell kinetics in infants receiving a CRM(197) (cross-reactive material; mutant diphtheria toxoid)-conjugated MenC vaccine at 2, 3 and 4 months of age. Plasma cell responses were more delayed after the first dose when compared with the rapid appearance of plasma cells after the third dose. Memory B cells were detectable at all time-points following the third dose as opposed to the low frequency seen following a first dose. This study provides data on B-cell kinetics following a primary schedule of immunization in young infants upon which to base further studies of the underlying cellular mechanism of humoral immunity.


Localized malignant pleural sarcomatoid mesothelioma misdiagnosed as benign localized fibrous tumor.
Localized malignant pleural mesothelioma (LMPM) is a rare tumor with good prognosis by surgical resection. We report an atypical case of malignant pleural sarcomatoid mesothelioma (SM) in an asymptomatic 65-year-old woman, who had no history of exposure to asbestos. She presented with a small pleural mass without pleural effusion and was misdiagnosed as a benign localized fibrous tumor (BLFT) on pathologic examination through a surgical tumor specimen. However, seven months later, the patient returned with serious cancerous symptoms. A large recurrent tumor mass was found within the chest wall invading at the old surgical resection site. SM, a subtype of LMPM, was confirmed with histopathogy and immunohistochemisty. In conclusion, malignant pleural mesothelioma (MPM) can present with typical radiologic finding similar to a BLFT, and has a wide histopathologic presentation in biopsy specimen. A thorough pathologic investigation should be attempted even when a pleural mass resembles benign, localized, and small on radiologic studies.


Cervical intervertebral foraminal disc extrusion in dogs: clinical presentation, MRI characteristics and outcome after medical management.
The aim of the present study was to retrospectively evaluate the clinical signs, MRI characteristics, interobserver agreement and outcome after medical treatment in dogs affected by cervical intervertebral foraminal disc extrusion (CIFDE). The medical records of three referral institutions were searched for dogs diagnosed with CIFDE between 2010 and 2012. Thirteen dogs were identified with CIFDE; affected dogs often had a normal neurological examination, with cervical hyperaesthesia and lameness as the most common clinical signs. On MRI, sagittal images showed no evidence of compression of the spinal cord; CIFDE could be identified only on transverse sections in all cases. An excellent interobserver agreement was found in the localisation of the affected intervertebral disc space, and a substantial agreement was found on the detection of CIFDE versus foraminal stenosis caused by overgrowing articular processes. All but two dogs recovered completely, and they were considered free of clinical signs without analgesia within a median of 7.5 weeks (range: 2-20) after medical management was started. The remaining two dogs were surgically treated followed by complete recovery. In view of our findings, the importance of a thorough MRI investigation in dogs presenting with cervical hyperaesthesia as the sole clinical sign should be highlighted.


Plant use in Odo-Bulu and Demaro, Bale region, Ethiopia.
This paper reports on the plant use of laypeople of the Oromo in Southern Ethiopia. The Oromo in Bale had names/uses for 294 species in comparison to 230 species documented in the lower reaches of the Bale area. Only 13 species was used for veterinary purposes, or as human medicine (46). Plant medicine served mostly to treat common everyday ailments such as stomach problems and diarrhea, for wound treatment and as toothbrush-sticks, as anthelmintic, for skin infections and to treat sore muscles and. Interestingly, 9 species were used to treat spiritual ailments and to expel demons. In most cases of medicinal applications the leaves or roots were employed.Traditional plant knowledge has clearly declined in a large part of the research area. Western style health care services as provided by governments and NGOs, in particular in rural areas, seem to have contributed to a decline in traditional knowledge, in part because the local population simply regards western medicine as more effective and safer.


On the origin of the maternal age effect in trisomy 21 Down syndrome: the Oocyte Mosaicism Selection model.
We have recently documented that trisomy 21 mosaicism is common in human foetal ovaries. On the basis of this observation we propose that the maternal age effect in Down syndrome (DS) is caused by the differential behaviour of trisomy 21 in relation to disomy 21 oocytes during development from foetal life until ovulation in adulthood. In particular, we suggest that trisomy 21 oocytes, lagging behind those that are disomic, may escape the timed pruning of the seven million in foetal life to the 300-400 finally selected for ovulation. The net effect of this preferential elimination will be an accumulation of trisomy 21 oocytes in the ovarian reserve of older women. We here highlight the implications of this Oocyte Mosaicism Selection (OMS) model with respect to the prevalent view that the maternal age effect is complex, dependent on many different biological and environmental factors. We examine conclusions drawn from recent large-scale studies in families, tracing DNA markers along the length of chromosome 21q between parents and DS children, in comparison to the OMS model. We conclude that these family linkage data are equally compatible with the maternal age effect originating from the accumulation of trisomy 21 oocytes with advancing maternal age. One relatively straightforward way to get to grips with what is actually going on in this regard would be to compare incidence of trisomy 21 oocytes (and their pairing configurations) in foetal ovaries with that in oocytes at the meiosis I stage from adult women.


Autophagy-mediated turnover of dynamin-related protein 1.
Drp1 is the primary protein responsible for mitochondrial fission. Perturbations of mitochondrial morphology and increased fission are seen in neurodegeneration. While Drp1 degradation induced by Parkin overexpression can be prevented by proteasome inhibition, there are numerous links between proteasomal and autophagic processes in mitochondrial protein degradation. Here we investigated the role of autophagy in Drp1 regulation. We demonstrate that autophagy plays a major role in the control of Drp1 levels. In HEK-293T cells, inhibitors of autophagy increase total Drp1 and levels of Drp1 in the mitochondrial cellular fraction. Similarly by silencing ATG7, which is required for initiation of autophagy, there is an increased level of Drp1. Because of the role of increased Drp1 in neurodegeneration, we then examined the ability to modulate Drp1 levels in neurons by inducing autophagy. We are able to decrease Drp1 levels in a time- and dose-dependent manner with the potent neuronal autophagy inducer 10-NCP, as well as structurally related compounds. Further, 10-NCP was able increase average mitochondrial size and length verifying a functional result of Drp1 depletion in these neurons. These pharmacological and genetic approaches indicate that autophagy targets Drp1 for lysosomal degradation. Additionally these data suggest a mechanism, through Drp1 downregulation, which may partly explain the ability of autophagy to have a neuroprotective effect.


Disposition of morphine in chronically infused rats: relationship to antinociception and tolerance.
Levels of morphine in brain and other biological materials were measured fluorometrically, and relationships were drawn to tail-flick activity and to tolerance development in rats treated chronically with the narcotic by i.p. infusion. Brain morphine concentration and tail-flick latency both increased with increasing dosage over the first 3 days of the 6-day infusion regimen. There was evidence of cellular tolerance within 24 to 48 hours after the beginning of infusion, with marked tolerance by day 6. Between days 3 and 6 a dispositional tolerance, evidenced by a dramatic fall in brain morphine concentration, also became apparent. After discontinuation of the infusion, the brain morphine dropped to extremely low levels by 24 hours, but significant tolerance to antinociceptive effects remained for 72 hours. Estimation of morphine in plasma, urine, peritoneal tissues and feces suggested several possible explanations for the dispositional tolerance observed. These include increased conjugation of morphine, increased fecal elimination and increased localization in muscle or peritoneal tissues with chronic infusion at relatively high doses. The present work thus examines the pharmacokinetics of morphine in the rat in a chronic treatment model that is currently being used in a number of laboratories for the rapid induction of drug tolerance and dependence.


Analysis of memory-like natural killer cells in human cytomegalovirus-infected children undergoing αβ+T and B cell-depleted hematopoietic stem cell transplantation for hematological malignancies.
We analyzed the impact of human cytomegalovirus infection on the development of natural killer cells in 27 pediatric patients affected by hematological malignancies, who had received a HLA-haploidentical hematopoietic stem cell transplantation, depleted of both α/β+ T cells and B cells. In line with previous studies in adult recipients of umbilical cord blood transplantation, we found that human cytomegalovirus reactivation accelerated the emergence of mature natural killer cells. Thus, most children displayed a progressive expansion of a memory-like natural killer cell subset expressing NKG2C, a putative receptor for human cytomegalovirus, and CD57, a marker of terminal natural killer cell differentiation. NKG2C(+)CD57(+) natural killer cells were detectable by month 3 following hematopoietic stem cell transplantation and expanded until at least month 12. These cells were characterized by high killer Ig-like receptors (KIRs) and leukocyte inhibitory receptor 1 (LIR-1) and low Siglec-7, NKG2A and Interleukin-18Rα expression, killed tumor targets and responded to cells expressing HLA-E (a NKG2C ligand). In addition, they were poor Interferon-γ producers in response to Interleukin-12 and Interleukin-18. The impaired response to these cytokines, together with their highly differentiated profile, may reflect their skewing toward an adaptive condition specialized in controlling human cytomegalovirus. In conclusion, in pediatric patients receiving a type of allograft different from umbilical cord blood transplantation, human cytomegalovirus also induced memory-like natural killer cells, possibly contributing to controlling infections and reinforcing anti-leukemia effects.


Pre-AIDS mortality in HIV-infected individuals in England, Wales and Northern Ireland, 1982-1996.
To assess pre-AIDS mortality in HIV-infected patients in England, Wales and Northern Ireland during the period 1982-1996. Surveillance data on pre-AIDS and AIDS deaths reported to the PHLS-AIDS Centre were analysed. Pre-AIDS mortality was estimated as the proportion of pre-AIDS deaths among all deaths in HIV-infected people. Trends over time in the number of pre-AIDS and AIDS deaths were compared using Poisson regression with logarithmic link. Causes of pre-AIDS deaths were recorded. Comparisons were made between the pre-AIDS and the AIDS death groups by logistic regression for: age, location of residence at death, year of death and risk exposure. Four-hundred and sixty-eight pre-AIDS deaths and 8574 AIDS deaths were identified. Pre-AIDS mortality accounted for 5.0% of HIV-related deaths. Trends over time in the number of pre-AIDS and AIDS deaths were not significantly different (P=0.11). Reported causes of pre-AIDS death included pneumonia (92), liver disease (62), septicaemia (51), malignancies (49), suicide (45), cardiopulmonary causes (46), haemorrhage (42), overdose (24) and accidental causes (24). Factors positively associated with pre-AIDS death were injecting drug use, haemophilia and blood transfusion, residence outside the Thames regions, and death at an older age. Pre-AIDS mortality represents a substantial proportion of HIV mortality, particularly where injecting drug use is a frequent route of HIV transmission.


Pharmacokinetic and pharmacodynamic issues in the treatment of parasitic infections.
Despite increases in the incidence of many parasitic infections in recent years, the number of studies designed to improve the treatment of these infections has failed to keep pace with their huge impact on public health. Unfortunately, research and development in this field is not an economically attractive proposition for the pharmaceutical industry, and this neglect is exacerbated by the fact that many parasitic diseases have negligible profiles in countries that have the funds to research them. An absence of effective vaccines means that, for the foreseeable future, chemotherapy is likely to be the mainstay of disease management. This review describes the advances gained in our understanding of the relationship between pharmacokinetics and pharmacodynamics, with the aim of improving the way in which we use antiparasitic agents while at the same time highlighting those areas where there is an urgent need for further investigation. Unsurprisingly, much of our success has been in the chemotherapy of malaria, where the link between drug concentration and response is reasonably well characterised. For many other diseases, however, this link is poorly understood, in some cases because the mechanism of action of the drug has not been fully elucidated, or in other cases because a true pharmacodynamic endpoint may be unavailable. Overcoming these problems is critical if the clinician is to have the information necessary to enable optimal treatment of patients who may be severely ill and in need of immediate, life-saving attention.


Carer experiences of life after stroke - a qualitative analysis.
Carers' experiences of caring for a stroke survivor were explored, including reactions and changes in their lives. A phenomenological approach was taken to the collection and analysis of data. Semi-structured interviews lasting an average of 43 min were carried out with nine informal carers in their own homes. All were married to someone who had survived a stroke. An overarching theme emerged, entitled: 'lives turned upside-down'. It took time for participants to understand the long-term impacts of stroke. Carers experienced increased caring and domestic workloads alongside reduced participation and altered expectations of life. They found emotional and cognitive changes in their partners particularly distressing, and would have valued more information and help with adjusting to the increased emotional, physical and cognitive workload of caring. It is important to support carers of people who have survived a stroke in adjusting to their changed lifestyles. This may affect their quality of life as well as sustainability of caring, and requires further research.


Tumor necrosis factor-alpha promoter -308 A/G polymorphism and rheumatoid arthritis susceptibility: a metaanalysis.
Tumor necrosis factor-alpha (TNF-alpha) promoter -308 A/G polymorphism has been reported to be associated with rheumatoid arthritis (RA) with inconsistent results. We investigated whether TNF-alpha -308 A/G polymorphism confers susceptibility to RA. We conducted a random effect metaanalysis on the association of genotypes A/A (recessive effect), A/A + A/G (dominant effect), A allele, and A/A vs G/G genotypes of the TNF-alpha -308 polymorphisms with RA overall and within different ethnic populations. Fourteen studies, 10 of Europeans, 3 of Latin Americans, and one Asian, were included in this metaanalysis. An association between RA and the TNF-alpha -308 A allele was not found in the overall population (OR 1.005, 95% CI 0.715-1.412, p = 0.976). However, stratification by ethnicity indicated that the TNF-alpha A allele was significantly associated with RA in Latin Americans (OR 2.004, 95% CI 1.158-3.467, p = 0.013). Conversely, there was no association detected for the TNF-alpha A allele with RA patients from the European samples (OR 0.911, 95% CI 0.684-1.212, p = 0.520). The OR for the A/A + A/G genotype, the A/A genotypes, and the A/A vs G/G genotypes in samples overall and in each ethnic group showed a similar trend to those for the TNF-alpha A allele. This metaanalysis demonstrates that the TNF-alpha -308 A/G polymorphism may represent a significant risk factor for RA in Latin Americans, but not in Europeans.


Meta-analyses of randomized controlled trials.
A new type of research, termed meta-analysis, attempts to analyze and combine the results of previous reports. We found 86 meta-analyses of reports of randomized controlled trials in the English-language literature. We evaluated the quality of these meta-analyses, using a scoring method that considered 23 items in six major areas--study design, combinability, control of bias, statistical analysis, sensitivity analysis, and application of results. Only 24 meta-analyses (28 percent) addressed all six areas, 31 (36 percent) addressed five, 25 (29 percent) addressed four, 5 (6 percent) addressed three, and 1 (1 percent) addressed two. Of the 23 individual items, between 1 and 14 were addressed satisfactorily (mean +/- SD, 7.7 +/- 2.7). We conclude that an urgent need exists for improved methods in literature searching, quality evaluation of trials, and synthesizing of the results.


Cell-mediated delivery of brain-derived neurotrophic factor enhances dopamine levels in an MPP+ rat model of substantia nigra degeneration.
Brain-derived neurotrophic factor (BDNF) promotes the survival of fetal mesencephalic dopaminergic cells and protects dopaminergic neurons against the toxicity of MPP+ in vitro. Supranigral implantation of fibroblasts genetically engineered to secrete BDNF attenuates the loss of substantia nigra pars compacta (SNc) dopaminergic neurons associated with striatal infusion of MPP+ in the adult rat. Using this MPP+ rat model of nigral degeneration, we evaluated the neurochemical effects of supranigral, cell-mediated delivery of BDNF on substantia nigra (SN) dopamine (DA) content and turnover. Genetically engineered BDNF-secreting fibroblasts (approximately 12 ng BDNF/24 h) were implanted dorsal to the SN 7 days prior to striatal MPP+ administration. The present results demonstrate that BDNF-secreting fibroblasts, as compared to control fibroblasts, enhance SN DA levels ipsilateral as well as contralateral to the graft without altering DA turnover. This augmentation of DA levels suggests that local neurotrophic factor delivery by genetically engineered cells may provide a therapeutic strategy for preventing neuronal death or enhancing neuronal function in neurodegenerative diseases characterized by dopaminergic neuronal dysfunction, such as Parkinson's disease.


Poverty, Weight Status, and Dietary Intake among UK Adolescents.
The aims of this study were to (1) determine whether an income gradient to overweight and obesity exists in UK adolescents, and (2) examine associations between poverty, weight status, and dietary intake among adolescent girls and boys. Data is from wave six of the UK Millennium Cohort Study. Adolescent height and weight were measured. Body mass index was calculated (kg/m²) and used to classify overweight and obesity. Family income and poverty were determined using equivalised household income. Adjusted logistic and multinomial logistic regression analyses were conducted. Ten thousand seven hundred thirty-six adolescents (5425 boys) had complete data. Adolescents in the lowest income group were at greatest risk of overweight and obesity. Adolescents living in poverty were more likely to be overweight and obese, and reported more frequent consumption of sweetened drinks and fast food and less frequent consumption of fruits and vegetables (p < 0.001). The magnitude of poverty differences in weight status and dietary intake were greatest among girls. This study evidences a strong income gradient to overweight and obesity among UK adolescents. The findings of this study encourage researchers and policy makers to be equally mindful of the social determinants of health when advocating adolescent behavioural dietary interventions.


Intrinsic TGF-β2-triggered SDF-1-CXCR4 signaling axis is crucial for drug resistance and a slow-cycling state in bone marrow-disseminated tumor cells.
Dormant or slow-cycling disseminated tumor cells (DTCs) in bone marrow (BM) are resistant to conventional therapy in various cancers including head and neck squamous cell carcinoma (HNSCC), although the molecular mechanisms remain largely unknown. This study aimed to identify the intrinsic molecular mechanisms underlying drug resistance in BM-DTCs. We used in vivo selection of the human HNSCC cell line HEp3, which mimics non-proliferative BM-DTCs in mice, to establish BM-DTC-derived (BM-HEp3) and lung metastases-derived (Lu-HEp3) sublines. Both sublines had higher migration activity and shortened survival in a murine xenograft model compared with parental (P-HEp3) cells. Slow-cycling BM-HEp3 cells had intrinsically enhanced cisplatin resistance compared with Lu-HEp3 cells, which also manifested this resistance but proliferated rapidly. The drug resistance and slow-cycling state of BM-HEp3 cells depended on enhanced positive feedback of the signaling axis of stromal cell-derived factor-1 (SDF-1)-C-X-C chemokine receptor-4 (CXCR4) via their overexpression. Interestingly, BM-DTCs highly expressed transforming growth factor-beta 2 (TGF-β2) to maintain SDF-1-CXCR4 overexpression. Inhibition of SDF-1-CXCR4 signaling by down-regulating TGF-β2 fully reversed the drug resistance of BM-HEp3 cells via reactivation of cell proliferation. These data suggest that the intrinsic TGF-β2-triggered SDF-1-CXCR4 signaling axis is crucial for drug resistance dependent on a slow-cycling state in BM-DTCs.


Activity and recovery profiles of state-of-origin and national rugby league match-play.
State-of-Origin is the highest standard of rugby league competition played anywhere in the world. This study investigated the activity profiles of State-of-Origin and compared them against regular National Rugby League (NRL) fixture matches. Video footage from State-of-Origin and NRL matches were coded for activity and recovery cycles. Time when the ball was continuously in play was considered activity, whereas any stoppages during matches were considered recovery. Ball-in-play periods in matches of different playing standards were analyzed by comparing State-of-Origin matches, NRL matches (with representative players available), and NRL matches (with representative players unavailable). The mean, maximum, and total ball-in-play time of State-of-Origin matches were longer than NRL matches (effect size [ES] ≥ 0.75) with and without the availability of representative players. State-of-Origin matches were associated with a greater proportion (ES ≥ 1.54) of long duration (46-300 seconds) ball-in-play periods, and a smaller proportion (ES ≥ 1.69) of short duration (<45 seconds) ball-in-play periods than NRL matches when representative players were both available and unavailable for selection. When representative players were available for club selection, NRL matches were associated with a smaller proportion of short duration ball-in-play periods (ES = 1.14) and a larger proportion of long duration ball-in-play periods (ES = 0.89), compared with NRL matches when representative players were unavailable. The results of this study provide empirical support for the higher playing intensity of State-of-Origin matches in comparison with regular NRL fixture matches. Furthermore, these findings demonstrate the lower quality of NRL matches during the State-of-Origin period, when representative players are unavailable for selection for their club team. From a practical perspective, these results quantify the difference in activity profiles between State-of-Origin and NRL competitions and demonstrate the need to prepare rugby league players to perform prolonged passages of high-intensity exercise during match-play.


Letrozole-induced necrotising leukocytoclastic small vessel vasculitis: First report of a case in the UK.
Letrozole, an aromatase inhibitor, is a commonly used neo-adjuvant drug to treat hormone-sensitive breast cancer. There have been a few cases of aromatase inhibitor induced vasculitis but the first case of letrozole-induced vasculitis was reported from Switzerland in 2014 (Digklia et al.) [1]. We report the case of a 72-year-old woman with a small breast cancer. She was started on pre-operative letrozole (2.5mg/d) whilst awaiting surgery. Ten days later she presented with burning pain and purpuric skin lesions which progressed to extensive ischaemic superficial necrosis of the lower limb skin, resolving over 3-4 months after local and systemic steroids. Histologically, it showed leucocytoclasis with evidence of eosinophilia consistent with a diagnosis of cutaneous leukocytoclastic small vessel vasculitis. The initial clinical presentation was severe burning pain around the ankles and a spreading violaceous rash. Letrozole was stopped. Wide local excision (lumpectomy) and sentinel node biopsy were postponed because of the accompanying pneumonitis and gastrointestinal upset, and were carried out 3.5 months later. Fortunately, the tumour size did not increase, but appeared to reduce, and axillary lymph nodes remained negative, i.e., this patient's cancer outcome does not seem to have been jeopardized. Leukocytoclastic vasculitis is a hypersensitivity reaction that is usually self-resolving, though our case needed systemic steroid treatment. Letrozole is a commonly used drug in clinical practice and prescribers should be aware of this rare side effect, which in our case delayed treatment without any apparent harm and possibly reduced tumour size.


Opinion dynamics on an adaptive random network.
We revisit the classical model for voter dynamics in a two-party system with two basic modifications. In contrast to the original voter model studied in regular lattices, we implement the opinion formation process in a random network of agents in which interactions are no longer restricted by geographical distance. In addition, we incorporate the rapidly changing nature of the interpersonal relations in the model. At each time step, agents can update their relationships. This update is determined by their own opinion, and by their preference to make connections with individuals sharing the same opinion, or rather with opponents. In this way, the network is built in an adaptive manner, in the sense that its structure is correlated and evolves with the dynamics of the agents. The simplicity of the model allows us to examine several issues analytically. We establish criteria to determine whether consensus or polarization will be the outcome of the dynamics and on what time scales these states will be reached. In finite systems consensus is typical, while in infinite systems a disordered metastable state can emerge and persist for infinitely long time before consensus is reached.


Does mechanical damage on soybean induces the production of flavonoids?
The response of plants to grazing includes the production of chemical defense compounds such as proteases inhibitors and secondary metabolites as flavonoids, which makes them less palatable to feeding and negatively affecting the physiology of insects. The aim of this study was to evaluate the phytochemical response of soybean cultivars (Glycine max (L.) Merrill) resistant (IAC-17, IAC-24) and susceptible (IAC-P1) to insects after mechanical damage. These cultivars were mechanically injured, and after 24 hours samples of these plants were analyzed by HPLC to identify and quantify flavonoids. The flavonoids daidzein, quercetin, and rutin were quantified, with the highest concentration of daidzin in soybean cultivars after mechanical damage. Rutin was biosynthesized by IAC-24. The cultivars IAC-PL1, IAC-17, and IAC-24 did not show a flavonoid response to mechanical damage. The soybean cultivars are not dependent on mechanical damage to produce flavonoids.


Cervico-thoracic or lumbar sympathectomy for neuropathic pain and complex regional pain syndrome.
This review is an update on 'Sympathectomy for neuropathic pain' originally published in Issue 2, 2003. The concept that many neuropathic pain syndromes (traditionally this definition would include complex regional pain syndromes (CRPS)) are "sympathetically maintained pains" has historically led to treatments that interrupt the sympathetic nervous system. Chemical sympathectomies use alcohol or phenol injections to destroy ganglia of the sympathetic chain, while surgical ablation is performed by open removal or electrocoagulation of the sympathetic chain, or minimally invasive procedures using thermal or laser interruption. To review the evidence from randomised, double blind, controlled trials on the efficacy and safety of chemical and surgical sympathectomy for neuropathic pain. Sympathectomy could be compared with placebo (sham) or other active treatment. We searched MEDLINE, EMBASE and The Cochrane Library to May 2010. We screened references in the retrieved articles and literature reviews, and contacted experts in the field of neuropathic pain. Randomised, double blind, placebo or active controlled studies assessing the effects of sympathectomy for neuropathic pain and CRPS. Two review authors independently assessed trial quality and validity, and extracted data. No pooled analysis of data was possible. Only one study satisfied our inclusion criteria, comparing percutaneous radiofrequency thermal lumbar sympathectomy with lumbar sympathetic neurolysis using phenol in 20 participants with CRPS. There was no comparison of sympathectomy versus sham or placebo. No dichotomous pain outcomes were reported. Average baseline scores of 8-9/10 on several pain scales fell to about 4/10 initially (1 day) and remained at 3-5/10 over four months. There were no significant differences between groups, except for "unpleasant sensation", which was higher with radiofrequency ablation. One participant in the phenol group experienced postsympathectomy neuralgia, while two in the radiofrequency group and one in the phenol group complained of paresthaesia during needle positioning. All participants had soreness at the injection site. The practice of surgical and chemical sympathectomy for neuropathic pain and CRPS is based on very little high quality evidence. Sympathectomy should be used cautiously in clinical practice, in carefully selected patients, and probably only after failure of other treatment options.