Does insulin have a role in hypertension?
There is a growing body of evidence linking insulin resistance and hyperinsulinaemia with hypertension. Vascular delivery of insulin and glucose to the striated muscle may be rate-limiting for them to exercise their effects. We therefore studied the effects of experimentally induced hypertension (renovascular and DOCA-salt) on muscle uptake of [(3)H]-deoxyglucose ([(3)H]-DOG)(non-metabolized glucose analog). In both models of induced hypertension uptake of [(3)H]-DOG was compared with the corresponding normotensive controls. Spontaneously hypertensive rats (SHR), however, had a reduced [(3)H]-DOG muscle uptake relative to normotensive WKY rats. To clarify a pro-hypertensive role on insulin it was administered by means of a sustained release subcutaneous implant to normotensive rats for 2 months and we could not detect hypertension in the resting state, though a transient hypertensive response to acute saline loading was present. On the other hand, young SHR made hyperinsulinaemic by the same method had an accelerated development of hypertension relative to control SHR. Thus it is not hypertension as such but the genetic susceptibility that is associated with insulin effects on blood pressure. In human hypertension we evaluated exercise (a maneuver known to improve insulin-sensitivity and reduce blood pressure) in non-obese essential hypertensive subjects. Three months of exercise training was associated with improved glucose tolerance and insulin clearance rate, but had no effect on 24-h ambulatory blood pressure. Thus, in essential hypertension insulin does not contribute significantly to the maintenance of hypertension. Taken together, our data indicate that hypertension does not cause insulin resistance and that exogenous hyperinsulinaemia does not produce hypertension in normotensive rats. However, in genetically determined hypertension insulin may play a role in its development.


Scaling up discovery of hidden diversity in fungi: impacts of barcoding approaches.
The fungal kingdom is a hyperdiverse group of multicellular eukaryotes with profound impacts on human society and ecosystem function. The challenge of documenting and describing fungal diversity is exacerbated by their typically cryptic nature, their ability to produce seemingly unrelated morphologies from a single individual and their similarity in appearance to distantly related taxa. This multiplicity of hurdles resulted in the early adoption of DNA-based comparisons to study fungal diversity, including linking curated DNA sequence data to expertly identified voucher specimens. DNA-barcoding approaches in fungi were first applied in specimen-based studies for identification and discovery of taxonomic diversity, but are now widely deployed for community characterization based on sequencing of environmental samples. Collectively, fungal barcoding approaches have yielded important advances across biological scales and research applications, from taxonomic, ecological, industrial and health perspectives. A major outstanding issue is the growing problem of 'sequences without names' that are somewhat uncoupled from the traditional framework of fungal classification based on morphology and preserved specimens. This review summarizes some of the most significant impacts of fungal barcoding, its limitations, and progress towards the challenge of effective utilization of the exponentially growing volume of data gathered from high-throughput sequencing technologies.This article is part of the themed issue 'From DNA barcodes to biomes'.


Dexamethasone-induced hepatomegaly and steatosis in larval zebrafish.
Fish hepatobiliary syndrome, characterized by hepatomegaly and fatty liver, has been frequently reported in many cultured fish species and has caused a dramatic economic loss in China. Glucocorticoids are thought to be important non-nutritional factors for hepatomegaly and fatty liver development. In the present study, a dexamethasone-induced zebrafish model of fatty liver and hepatomegaly was established, and the role of glucocorticoid receptor (GR) in the development of hepatomegaly and fatty liver was investigated using developing zebrafish. Exposure of larval zebrafish at 5 days post fertilization (dpf) to dexamethasone for 24 hr caused significant increases of liver size and number of fish with hepatic steatosis at 6 dpf. The increase of liver size caused by dexamethasone was significantly reversed by treatment with RU486, a GR antagonist, and by gene knock-down with a morpholino against the GR. The dexamethasone-induced hepatic steatosis was also inhibited by treatment with RU486. Overall, the results highlight larval zebrafish as a useful model for stress-induced liver failure.


Family education and support for families at psychosocial risk in Europe: Evidence from a survey of international experts.
There is overwhelming consensus among policy makers, academics, and professionals about the need to support families in their childrearing tasks. Consequently, European countries have been encouraged to develop family support interventions aimed at guaranteeing children's rights, targeting particularly those children in situations of psychosocial risk. While a certain amount of evidence exists regarding how family support is generally delivered in certain European countries, with a particular focus on parenting initiatives, this paper aims to take existing evidence one step further by providing an updated review focusing on two core components of the Council of Europe's Recommendation on Positive Parenting: families at psychosocial risk as the target population, and family education and support initiatives as the delivery format. The scope of the study was therefore broad, in both geographical and conceptual terms. An online survey was conducted with experts from 19 European countries to gather information regarding how they perceive family education and support initiatives for families at psychosocial risk. Both quantitative and qualitative data were analysed by computing frequencies/percentages and by following a thematic synthesis method, respectively. The results revealed both similarities and disparities as regards provider profiles, intervention characteristics, and quality standards. Practical implications are discussed, such as the need to diversify initiatives for at-risk families in accordance with the tenets of progressive universalism, the ongoing need for an evidence-based, pluralistic approach to programmes, and the skills and qualifications required in the family support workforce. This study constitutes a first step towards building a common family support framework at a European level, which would encompass family support and parenting policies aimed at families at psychosocial risk.


The genomics of land plant chloroplasts: Gene content and alteration of genomic information by RNA editing.
The entire nucleotide sequence of the chloroplast genome has been determined from 12 land plants. The gene content and arrangement are relatively uniform from species to species, and the genome contains an average of 111 identified gene species (except Epifagus). Chloroplast genes can be classified into three main categories: Genes for the photosynthetic apparatus, those for the transcription/translation system, and those related to biosyntheses. The genes encoding components of the photosynthesis apparatus have been identified by protein chemical analyses from higher plants, Chlamydomonas and cyanobacteria, and then by chloroplast transformation techniques using tobacco and Chlamydomonas. The genes for subunits of RNA polymerases and of ribosomes were initially deduced similarity to those in E. coli, and later confirmed by protein analyses. Coding information is often modified at the level of transcripts by RNA editing (mostly C-U changes), resulting in amino acid substitutions and creation of novel reading frames. Perspectives of chloroplast genomics are discussed.


Disrupting the Btk Pathway Suppresses COPD-Like Lung Alterations in Atherosclerosis Prone ApoE-/- Mice Following Regular Exposure to Cigarette Smoke.
Chronic obstructive pulmonary disease (COPD) is associated with severe chronic inflammation that promotes irreversible tissue destruction. Moreover, the most broadly accepted cause of COPD is exposure to cigarette smoke. There is no effective cure and significantly, the mechanism behind the development and progression of this disease remains unknown. Our laboratory has demonstrated that Bruton's tyrosine kinase (Btk) is a critical regulator of pro-inflammatory processes in the lungs and that Btk controls expression of matrix metalloproteinase-9 (MMP-9) in the alveolar compartment. For this study apolipoprotein E null (ApoE-/-) mice were exposed to SHS to facilitate study in a COPD/atherosclerosis comorbidity model. We applied two types of treatments, animals received either a pharmacological inhibitor of Btk or MMP-9 specific siRNA to minimize MMP-9 expression in endothelial cells or neutrophils. We have shown that these treatments had a protective effect in the lung. We have noted a decrease in alveolar changes related to SHS induced inflammation in treated animals. In summary, we are presenting a novel concept in the field of COPD, i.e., that Btk may be a new drug target for this disease. Moreover, cell specific targeting of MMP-9 may also benefit patients affected by this disease.


Review article: Thiazolidinediones and heart failure.
DM is an independent risk factor for the development of HF and its presence confers an adverse prognosis for those already diagnosed with HF.TZDs are potent insulin-sensitisers associated with a number of beneficial cardiovascular effects. However,TZDs increase renal sodium and water reabsorption, leading to fluid retention and overt signs of HF in patients with diabetes. Rosiglitazone has also been associated with an increased risk of myocardial infarction and cardiovascular mortality. However, pioglitazone may have macrovascular benefits. The majority of data on the cardiovascular safety of TZDs are based on non-cardovascular outcome trials and meta-analyses. Concerns regarding the risk of HF and cardiovascular safety of TZDs have led to restrictions on their use in patients with HF. This review addresses the latest evidence for HF with each of the TZD drugs currently available and reflects on the current guidelines regarding their prescription in at-risk patients.


Effect of butylated hydroxytoluene and butylated hydroxyanisole on the mutagenicity of 3,2'-dimethyl-4-aminobiphenyl.
This study was undertaken to investigate the possible antimutagenic effects of butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) on 3,2'-dimethyl-4-aminobiphenyl (DMAB)-induced mutagenicity, using the Ames Salmonella/mammalian microsome system. The addition of 100-250 micrograms of BHT or 25-500 micrograms of BHA/plate was found to inhibit DMAB-induced mutagenicity in Salmonella strains TA 98 and TA 100. In TA 100, the mutagenicity was further inhibited with the addition of S9 prepared from the livers of rats fed a 0.6% BHT diet as compared to S9 from the animals fed a diet containing no BHT.


Impact of illumination spectrum and eye pigmentation on image quality from a fundus camera using transscleral illumination.
The use of the transscleral illumination approach has the potential to simplify the optical design of fundus cameras. In particular, this approach could allow the use of smaller and cheaper cameras that are easier to use by non-specialists, thereby facilitating a wider spread of eye disease screening programs. Our aim was to investigate the suitability of transscleral illumination in a fundus camera system. In particular, we explored the impact of the illumination spectrum and the eye pigmentation on the quality of the image. These factors have never been systematically investigated before in the literature on transscleral illumination. A fundus camera was constructed using transscleral illumination. We studied the influence of eye pigmentation and choice of illumination spectra on the image quality for a group of 10 individuals with varied skin pigmentation, ranging from pale white (North-European) to darkest brown (African). The influence of the light source spectrum on the image quality was assessed using wavelength filters. There was a difference of a factor of 100 in the signal level of retinal images between individuals with low and high skin pigmentation. The image contrast was highest using illumination wavelengths of 500 to 600 nm. The illumination level can be adjusted to obtain high-quality images for highly pigmented eyes while keeping the system eye-safe. We have demonstrated that a fundus camera with transscleral illumination can provide high-quality images. However, the variations observed in scleral and retinal pigmentation in a practical setting require a system that must be able to adapt illumination and/or exposure to the individual patient.


Memories of parental rearing practices and personality features.
Relationships between own memories of parental rearing practices and adult personality features were examined. Two hundred healthy volunteers, 86 males and 114 females, completed the Own Memories of Child-Rearing Experiences ( EMBU ), the Eysenck Personality Questionnaire ( EPQ ) and the Lazare - Klerman - Armor Trait Scale ( LKAS ). Relations between two sets of variables were examined by means of Pearson product moment correlation coefficient, and Bonferroni inequalities were applied for each family of hypotheses. For the male sample all correlations were not significant. For females there were several significant correlations. The most consistent finding was that the experience of negative parental rearing factors was associated with pathological features in the personality. About one half of the significant correlations were found between female hysterical scores and EMBU father. The findings support the general assumption that females with hysterical traits have complicated relations to their fathers, which may indicate fixation in the Oedipal stage.


Theory-practice integration in selected clinical situations.
The current changes in health care systems challenge knowledgeable, mature and independent practitioners to integrate theoretical content with practice. The aim of this study was to investigate the problems of integrating theory with practice in selected clinical nursing situations. The study focused on rendering of family planning services to clients as a component of Community Nursing Science. Structured observation schedules were used to observe the theoretical content of the curriculum as well as the practical application of what has been taught in the clinical area. The findings of the study revealed that there was a need for an integrated holistic curriculum, which would address the needs of the community. It was concluded that a problem-based and community-based curriculum, intersectoral collaboration between college and hospital managements and student involvement in all processes of teaching and learning would improve the integration of theory and practice. There also appeared to be a need for tutors to be more involved in clinical teaching and accompaniment.


Effects of external pH variations on brain presynaptic sodium and calcium channels; repercussion on the evoked release of amino acid neurotransmitters.
The effects of external pH (pHout) variations on the Na+ and on the Ca2+ dependent fractions of the evoked amino acid neurotransmitter release were separately investigated, using GABA as a model transmitter. In [3H]GABA loaded mouse brain synaptosomes, the external acidification (pHout 6.0) markedly decreased the Na+ dependent fraction of [3H]GABA release evoked by veratridine (10 microM) in the absence of external Ca2+, as well as the Ca2+ dependent fraction of [3H]GABA release evoked by high (20 mM) K+ in the absence of external Na+. The depolarization-induced elevation of [Na(i)] (monitored in synaptosomes loaded with the Na+ indicator dye, SBFI) and the depolarization-induced elevation of [Ca(i)] (monitored in synaptosomes loaded with the Ca2+ indicator dye fura-2) were also markedly decreased at pHout 6. On the contrary, the external alkalinization (pHout 8) facilitated all the above responses. A slight increase of the baseline release of the [3H]GABA was observed when pHout was changed from 7.4 to 8. This effect was only observed in the presence of Ca2+. pHout changes from 7.4 to 6 or to 7 did not modify the baseline release of the transmitter. All the effects of pHout variations on [3H]GABA release were independent on the presence of HCO3-. It is concluded that external H+ regulate amino acid neurotransmitter release by their actions on presynaptic Na+ channels, as well as on presynaptic Ca2+ channels.


[Epidemiology, pathogenesis and therapy of diabetic retinopathy and maculopathy].
Diabetic retinopathy is the most prevalent microvascular complication of diabetes mellitus and affects the majority of patients who have suffered diabetes for at least 20 years. Due to the lack of specific symptoms screening of patients is required for early retinal lesions to be detected. Chronic hyperglycemia plays a predominant role in the pathogenesis of the disease. A common denominator of hyperglycemic vascular injury is the increased production of mitochondrial reactive oxygen species, leading to the activation of protein kinase C, of the aldose reductase pathway, and to the increased formation of advanced glycation end products, with the well-described deleterious effects on the microvasculature. Moreover, hypertension and factors such as puberty and pregnancy can worsen retinopathy. Effective screening and therapy can prevent blindness. A distinction is made between proliferative and non-proliferative diabetic retinopathy and diabetic macula oedema. The professional associations of ophthalmologists and internists have drawn up guidelines for the necessary examinations, for therapy and the appropriate intervals between check-ups. Laser photocoagulation can halt further loss of vision, in particular in cases of proliferative diabetic retinopathy and diabetic macula oedema. Vitrectomy is an operative procedure that can bring about a functional improvement even for patients in advanced stages.


First record of the genus Gomesius (Hemiptera: Heteroptera: Reduviidae: Emesinae) from India, with description of a new species.
Gomesius indicus sp. nov. (Hemiptera: Heteroptera: Reduviidae: Emesinae: Leistarchini), collected in Goa State, India, is described. This is the first record of the genus Gomesius Distant, 1903, from India.


Comprehensive Evaluation of Anterior Corneal Change in Asphericity Calculated by the Tangential Radius of Curvature after LASIK.
To evaluate the change in the anterior corneal asphericity (ΔQ) comprehensively calculated using the tangential radius (rt ) after LASIK. Forty-two right eyes were evaluated using the Orbscan II corneal topographer. The pre- and postoperative Q-values of the flat principal semimeridians calculated by the sagittal radius were compared to those by the tangential radius. The Q-value of each semimeridian in the horizontal region was calculated by rt . Fourier fitting was used to model the 360-semimeridional variation of Q-values and to fit the Q-values in the vertical region before and after surgery. There were significant differences in Q-values between the two methods before (P < 0.001) and after surgery (P = 0.003). A significant increase in postoperative Q-value was detected compared to preoperative Q-value (P < 0.001) calculated by rt . The 360-semimeridional variation of the Q-values was well fitted with a third- and fourth-degree Fourier function before and after surgery. The ΔQ-value distribution presented double valley variation, with the amount of ΔQ being lowest in the near-vertical regions and highest in the near-horizontal regions. Calculating the Q-value with rt combined with Fourier fitting, we evaluated 360 ΔQ-values' variation of semimeridians of the entire anterior corneal surface and then displayed true and complete anterior corneal shape after LASIK.


[Effect of globular adiponectin on proliferation, migration and tube formation of ovarian microvascular endothelial cells].
To analyze the effect of globular adiponectin on angiogenesis of ovarian microvascular endothelial cells (OMECs). Mouse OMECs were isolated and purified by density gradient centrifugation with Percoll and identified by immunofluorescence analysis of follicle-stimulating hormone receptor (FSHR), luteinizing hormone receptor (LHR), and endothelial cell marker von Willebrand factor (vWF). The capillary-like tube formation of OMECs was determined by vascular endothelial growth factor A (VEGFA) treatment in Matrigel matrix. OMECs treated with recombinant globular adiponectin protein were examined for cell proliferation with MTS assay and cell migration with scratch wound healing assay, and capillary-like tube formation was tested in Matrigel matrix. Western blotting was performed to detect the effect of globular adiponectin on AMPK phosphorylation. The signals of LHR and vWF, but not that of FSHR, were detected in the isolated cells. VEGFA treatment of the cells induced capillary-like tube formation, indicating their properties of ovarian-specific endothelial cells. Treatment with 1 and 3 µg/mL of recombinant globular adiponectin significantly increased the number of OMECs by (158.72∓14.50) % and (186.50∓4.20)% (P<0.01) and resulted in scratch wound closure rates of (49.43∓3.43)% (P<0.05) and (69.67∓1.2) % (P<0.01) respectively. The cells treated with 3 µg/mL globular adiponectin formed a capillary-tube length 6.63∓0.66 folds greater than that formed by the control cells (P<0.01). Treatment of the cells with 3 µg/mL globular adiponectin for 15 and 30 min resulted in pAMPK/AMPK ratios of 0.86∓0.08 and 0.66∓0.13, respectively significantly higher than that in the control cells (0.13∓0.12, P<0.01). Compound C obviously suppressed the tube formation and AMPK phosphorylation induced by globular adiponectin. Globular adiponectin promotes angiogenesis of OMECs through activation of the AMPK signal pathway.


High-throughput generation of an activation-tagged mutant library for functional genomic analyses in tobacco.
Tobacco (Nicotiana tabacum L.) is an ideal model system for molecular biological and genetic studies. In this study, activation tagging was used to generate approximately 100,000 transgenic tobacco plants. Southern blot analysis indicated that there were 1.6 T-DNA inserts per line on average in our transformed population. The phenotypes observed include abnormalities in leaf and flower morphology, plant height, flowering time, branching, and fertility. Among 6,000 plants in the T0 generation, 57 displayed obvious phenotypes. Among 4,105 lines in the T1 generation, 311 displayed abnormal phenotypes. Fusion primer and nested integrated PCR was used to identify 963 independent genomic loci of T-DNA insertion sites in 1,257 T1 lines. The distribution of T-DNA insertions was non-uniform and correlated well with the predicted gene density along each chromosome. The insertions were biased toward genic regions and noncoding regions within 5 kb of a gene. Fifteen plants that showed the same phenotype as their parent with a dominant pattern in the T2 generation were chosen randomly to detect the expression levels of genes adjacent to the T-DNA integration sites by semi-quantitative RT-PCR. Fifteen candidate genes were identified. Activation was observed in 7 out of the 15 adjacent genes, including one that was located 13.1 kb away from the enhancer sequence. The activation-tagged population described in this paper will be a highly valuable resource for tobacco functional genomics research using both forward and reverse genetic approaches.


Haemophilus aphrophilus bleb infection after a mitomycin trabeculectomy.
Haemophilus aphrophilus is a rare cause of ocular infection. It has been reported once as a cause of late-onset endophthalmitis in a patient with an inadvertent bleb after cataract surgery. We present a case of Haemophilus aphrophilus bleb infection after a mitomycin trabeculectomy. A 56-year-old woman presented with a bleb infection 10 weeks after a mitomycin C augmented trabeculectomy at a University tertiary referral practice of one of the authors (GET). The causative organism was Haemophilus aphrophilus, identified by the Toronto Public Health Laboratory, Ontario, Canada. The bleb infection resolved following topical, subconjunctival and intravenous antibiotic therapy. A formal bleb revision was required to repair a persistent bleb leak. Patients who have had trabeculectomies augmented with mitomycin C may be predisposed to bleb infection with unusual organisms. Prompt diagnosis and treatment is necessary to control the infection. Increased awareness and communication with laboratory personnel may increase the isolation of this fastidious organism.


Fate and function of anti-CD3/CD28-activated T cells following adoptive transfer: IL-2 promotes development of anti-tumor memory T cells in vivo.
Adoptive immunotherapy with T cells activated through CD3 alone requires exogenous IL-2 for T-cell function and survival after transfer, but the in vivo cytokine requirement of T cells activated through CD3 and CD28 is unknown. We hypothesized that CD3/CD28-activated T cells, unlike those activated through CD3 alone, might develop into long-lived memory T cells, either with or without systemic IL-2. We used MHC class I-restricted TCR transgenic T cells from the OT-1 mouse, specific for the surrogate tumor Ag ovalbumin (OVA), to assess the trafficking kinetics, antigenic responsiveness and anti-tumor efficacy of dual-activated T cells in vivo as a function of IL-2 administration. At days 7, 14, and 28 after transfer, lymph node cells and splenocytes were examined for donor cell persistence and antigenic responsiveness by FACS and ELISA, respectively. In IL-2-treated mice, donor CD8+ T cells persisted and developed a memory phenotype, based on CD44 and Ly6c expression at day 28, while mice given no IL-2 had fewer donor cells at all time points. OVA-specific release of IFN-gamma was higher from lymphocytes of IL-2-treated mice compared with no-IL-2 mice (P<0.02 at all time points). In mice challenged with an OVA-bearing subline of the AML leukemia model C1498, IL-2 did not confer added protection from tumor challenge at 1 or 2 weeks after adoptive transfer, but gave improved survival at 4 weeks post-transfer. We conclude that exogenous IL-2 is not required for anti-tumor activity of CD3/CD28-activated CD8+ cells early after adoptive transfer, but promotes T-cell persistence that confers disease protection at more remote times.


The statistical properties of RCTs and a proposal for shrinkage.
We abstract the concept of a randomized controlled trial as a triple (β,b,s) , where β is the primary efficacy parameter, b the estimate, and s the standard error ( s>0 ). If the parameter β is either a difference of means, a log odds ratio or a log hazard ratio, then it is reasonable to assume that b is unbiased and normally distributed. This then allows us to estimate the joint distribution of the z-value z=b/s and the signal-to-noise ratio SNR=β/s from a sample of pairs (bi,si) . We have collected 23 551 such pairs from the Cochrane database. We note that there are many statistical quantities that depend on (β,b,s) only through the pair (z,SNR) . We start by determining the estimated distribution of the achieved power. In particular, we estimate the median achieved power to be only 13%. We also consider the exaggeration ratio which is the factor by which the magnitude of β is overestimated. We find that if the estimate is just significant at the 5% level, we would expect it to overestimate the true effect by a factor of 1.7. This exaggeration is sometimes referred to as the winner's curse and it is undoubtedly to a considerable extent responsible for disappointing replication results. For this reason, we believe it is important to shrink the unbiased estimator, and we propose a method for doing so. We show that our shrinkage estimator successfully addresses the exaggeration. As an example, we re-analyze the ANDROMEDA-SHOCK trial.


Triterpenes from Cynomorium songaricium--analysis of HCV protease inhibitory activity, quantification, and content change under the influence of heating.
Inhibitory activity of the three major triterpenes from the stems of Cynomorium songaricum--ursolic acid, acetyl ursolic acid, and malonyl ursolic acid hemiester--and their related compounds were tested for their inhibitory activity on HCV protease; malonyl ursolic acid hemiester was the most potent. A HPLC-PAD (photo diode array detector)-MS method was established to quantify the contents of each triterpene in C. songaricum. Using this method, the effect heating had on the contents was also investigated. It was found that among the three triterpenes, the content of malonyl ursolic acid hemiester decreased most quickly during the heating process.


Progressive hypoventilation due to mixed CD8+ and CD4+ lymphocytic polymyositis following tremelimumab - durvalumab treatment.
The combination of CTLA-4 and PD-L1 inhibitors has a manageable adverse effect profile, although rare immune-related adverse events (irAE) can occur. We describe an autoimmune polymyositis following a partial response to combination tremelimumab and durvalumab for the treatment of recurrent lung adenocarcinoma. Radiography revealed significant reduction in all metastases; however, the patient developed progressive neuromuscular hypoventilation due to lymphocytic destruction of the diaphragmatic musculature. Serologic testing revealed a low level of de novo circulating antibodies against striated muscle fiber. Immunohistochemistry revealed type II muscle fiber atrophy with a mixed CD8+ and CD4+ lymphocyte infiltrate, indicative of inflammatory myopathy. This case supports the hypothesis that muscle tissue is a target for lymphocytic infiltration in immune checkpoint inhibitor-associated polymyositis. Further insights into the autoimmune mechanism of PM will hopefully contribute to the prevention and treatment of this phenomenon.


Transcription-translation coupling: Recent advances and future perspectives.
The flow of genetic information from the chromosome to protein in all living organisms consists of two steps: (1) copying information coded in DNA into an mRNA intermediate via transcription by RNA polymerase, followed by (2) translation of this mRNA into a polypeptide by the ribosome. Unlike eukaryotes, where transcription and translation are separated by a nuclear envelope, in bacterial cells, these two processes occur within the same compartment. This means that a pioneering ribosome starts translation on nascent mRNA that is still being actively transcribed by RNA polymerase. This tethering via mRNA is referred to as 'coupling' of transcription and translation (CTT). CTT raises many questions regarding physical interactions and potential mutual regulation between these large (ribosome is ~2.5 MDa and RNA polymerase is 0.5 MDa) and powerful molecular machines. Accordingly, we will discuss some recently discovered structural and functional aspects of CTT.


Neuroanatomical and histochemical evidence for the presence of common lateral line and inner ear efferents and of efferents to the basilar papilla in a frog, Xenopus laevis.
The claimed absence of efferents to the basilar papilla in frogs was reexamined in Xenopus laevis with the use of acetylcholinesterase (AChE) histochemistry. We also tested the presence of common lateral line and inner ear efferents by employing neuroanatomical tract tracing techniques. Our data show some AChE-positive fibers to the basilar papilla and all other sensory epithelia of the inner ear in larval and postmetamorphic frogs. Labeling of anterior lateral line and inner ear fibers with different fluorescing dextran amines resulted in a few double labeled efferent cells in the brainstem. Examination of the branching patterns of anterior lateral line efferents revealed collaterals to the inner ear, predominantly to the saccule and the lagena. In addition, two animals showed common efferents between the anterior lateral line and the basilar papilla. In derived anurans, such as ranids, which reportedly lack efferents to the basilar papilla, the basilar papillary afferents have a peripheral course that differs from that in salamanders and Xenopus. If such efferents are, indeed, absent, we propose that changed cues for pathway selection may have enabled only the afferents, and not the efferents, to reach the basilar papilla in derived frogs.


Consistent coarse-graining strategy for polymer solutions in the thermal crossover from good to θ solvent.
We extend our previously developed coarse-graining strategy for linear polymers with a tunable number n of effective atoms (blobs) per chain [G. D'Adamo et al., J. Chem. Phys. 137, 024901 (2012)] to polymer systems in thermal crossover between the good-solvent and the θ regimes. We consider the thermal crossover in the region in which tricritical effects can be neglected, i.e., not too close to the θ point, for a wide range of chain volume fractions Φ = c∕c* (c* is the overlap concentration), up to Φ ≈ 30. Scaling crossover functions for global properties of the solution are obtained by Monte Carlo simulations of the Domb-Joyce model with suitably rescaled on-site repulsion. They provide the input data to develop a minimal coarse-grained model with four blobs per chain (tetramer model). As in the good-solvent case, the coarse-grained model potentials are derived at zero density, thus avoiding the inconsistencies related to the use of state-dependent potentials. We find that the coarse-grained model reproduces the properties of the underlying, full-monomer system up to some reduced density Φ which increases when lowering the temperature towards the θ state. Close to the lower-temperature crossover boundary, the tetramer model is accurate at least up to Φ ~/= 10, while near the good-solvent regime reasonably accurate results are obtained up to Φ ~/= 2. The density region in which the coarse-grained model is predictive can be enlarged by developing coarse-grained models with more blobs per chain. We extend the strategy used in the good-solvent case to the crossover regime. This requires a proper treatment of the length rescalings as before, but also a proper temperature redefinition as the number of blobs is increased. The case n = 10 is investigated in detail. We obtain the potentials for such finer-grained model starting from the tetramer ones. Comparison with full-monomer results shows that the density region in which accurate predictions can be obtained is significantly wider than that corresponding to the tetramer case.


Frequency of amount and axis of astigmatism in subjects of Rawalpindi, Pakistan.
To assess the frequency of amount and axis of astigmatism with respect to age and gender. The prospective, observational study was carried out from September 2009 to January 2010 at Armed Forces Institute of Ophthalmology, Rawalpindi. Patients from 5-70 years of age were included from both genders with no previous history of eye abnormality, surgery or eye pathology. An auto refractor-keratometre was used for measurement. Descriptive statistics were used to analyse data on SPSS 15. Among the total 288 patients, with-the-rule astigmatism (n = 21; 55%) had greater frequency in the 26-35 years sub-group. In terms of gender, 88 (48%); against-the-rule in 81 (44%); and oblique astigmatism in 14 (7.6%). In females, with-the-rule astigmatism was found in 52 (50%); against-the-rule in 36 (34.2%); and oblique in 17 (16%). The frequency of astigmatism > or = 0.25 ranged from 0.8% (n = 1) to 74% (n = 28) across all age groups. The amount of astigmatism which was noted to be the most common and prominent in the sample was < 1D. The amount and axis of astigmatism varied within the age sub-groups and within the gender.


Urine-derived compound evokes membrane responses in mouse vomeronasal receptor neurons.
Sensory neurons of the vomeronasal organ (VNO) are thought to detect species-specific chemical signals important for reproductive function. The electrical properties of VNO neurons have begun to be characterized in a variety of species; however, the response of VNO neurons to possible physiological ligands has not yet been reported. One physiological effector, dehydro-exo-brevicomin (DHB), is found in the urine of intact male mice and affects the estrous cycle of female mice. In the present study, dissociated VNO neurons were voltage- or current-clamped and their response to DHB was determined. Approximately 26% of VNO neurons responded to DHB with an outward current at negative holding potentials; the current reversed at approximately +4 mV. Application of DHB in current-clamp mode produced membrane hyperpolarization and/or a reduction in the firing of action potentials. Because membrane conductance was shown to be decreased during application of DHB, the results suggest that the outward current associated with DHB application is a reflection of a reduction in inward current caused by closing an ion channel. This study provides the first evidence that a compound found in male urine directly affects VNO neurons.


Radioimmunoassay for salmon pancreatic somatostatin-25.
A specific and sensitive radioimmunoassay (RIA) for the measurement of plasma levels of somatostatin-25 (SS-25) in salmon was developed using antisera raised against coho salmon (Oncorhynchus kisutch) SS-25. Somatostatin-25 was iodinated by the chloramine-T method and repurified on Sephadex G-25. The RIA was performed using a double antibody (goat anti-rabbit gammaglobulin as second antibody) method under disequilibrium conditions. Plasma from several salmonids (coho, chinook, rainbow trout, brook trout, arctic char, lake trout, and whitefish) as well as plasma from some nonsalmonids (sucker, bluegill) cross-reacted with the antisera; serial dilutions of plasma from rainbow trout, brook trout, chinook salmon, and coho salmon were parallel to the SS-25 standard curve. Plasma from catfish showed negligible cross-reactivity. None of the mammalian somatostatins (somatostatin-14, somatostatin-28). U II, or other pancreatic hormones (insulin, glucagon) tested showed significant cross-reactivity with the antibody in the assay system. The lowest detectable level of SS-25 was 5 pg/tube; especially reproducible results were obtained in the range of 0.15-1.20 ng/ml, which appears to be the normal range of SS-25 circulating in the plasma of salmonids. Intra- and interassay coefficients of variation were 5.7 and 12.6%, respectively. Injection of glucose into chinook salmon resulted in an elevation of plasma SS-25 titers within 30 min and was coincident with hyperglycemia.


Does Smartphone Use Affect a Subsequent Swimming Training Session? Preliminary Results in Amateur Triathletes.
To date, the literature has failed to individuate a clear motivation for the performance decrement after a mental fatigue-inducing task. This study aimed to evaluate biomechanical and perceptual variables during a swimming training session in different mental fatigue states. Seven amateur triathletes watched a documentary, utilized a smartphone, or performed an AX-CPT for 45 min randomly on three different days. After, they performed a 15-min warm-up followed by 6 × 200 m at constant pre-set speed plus one 200 m at maximal effort. The mental fatigue status was assessed by the visual analog scale (VAS) and short-Stroop task results before, post-mental task, and post-swimming session. The biomechanical and motor coordination variables during swimming were assessed using five IMU sensors and video analysis. The heart rate and rate of perceived exertion were monitored during the task. No differences in biomechanical and perceptual variables were found between and within conditions. Higher mental fatigue was found only in the AX-CPT condition at post task by VAS. In this preliminary study, no changes in swimming biomechanics were highlighted by mental fatigue, but the warm-up performed may have counteracted its negative effects. Further studies are recommended.


Refined X-ray structures of haloalkane dehalogenase at pH 6.2 and pH 8.2 and implications for the reaction mechanism.
The crystal structure of haloalkane dehalogenase from Xanthobacter autotrophicus GJ10 has been refined at 1.9 A resolution at two different pH values, the pH of crystallization (pH 6.2) and the pH of optimal activity (pH 8.2), to final R-factors of 16.8% and 16.4%, respectively. Both models show good stereochemical quality. Two non-glycine residues have main-chain torsion angles that are located outside the "allowed" regions in a Ramachandran plot. One of them is the nucleophilic residue Asp124, which, together with the two other active site residues His289 and Asp260, is situated in an internal, predominantly hydrophobic cavity. The other residue, Asn148, helps stabilize the conformations of two of these active-site residues, Asp124 and Asp260. Comparison of the models at pH 6.2 and pH 8.2 revealed one major structural difference. At pH 6.2, a salt-bridge is present between the N epsilon 2 atom of His289 and the O delta 1 atom of Asp124, while at pH 8.2, this salt-bridge is absent, indicating that the N epsilon 2 atom of the histidine residue is mostly deprotonated at the pH of optimum activity. This is in agreement with the putative reaction mechanism in which the O delta 1 atom of Asp124 performs a nucleophilic attack on the substrate, resulting in an intermediate ester. This ester is subsequently cleaved by a hydrolytic water molecule. The high-resolution data sets clearly show the exact position of this water molecule. It is in an ideal position for donating a proton to the N epsilon 2 atom of His289 and subsequently cleaving the covalently bound intermediate ester, releasing the alcohol product. Detailed investigation of both refined models showed a number of unusual structural features. Four out of 11 helices contain an internal proline residue other than in the first turn. Two other alpha-helices have adopted in their central part a 3(10) conformation. A novel four-residue turn between a helix and a strand, the alpha beta 4 turn, is located at the site of the bend in the central eight-stranded beta-sheet of the dehalogenase structure.


A Pheromone Antagonist Regulates Optimal Mating Time in the Moth Helicoverpa armigera.
Many insect species use multi-component sex pheromones to discriminate among potential mating partners [1-5]. In moths, pheromone blends tend to be dominated by one or two major components, but behavioral responses are frequently optimized by the inclusion of less abundant minor components [6]. An increasing number of studies have shown that female insects use these chemicals to convey their mating availability to males, who can assess the maturity of females and thus decide when to mate [7, 8]. However, little is known about the biological mechanisms that enable males to assess female reproductive status. In this study, we found that females of Helicoverpa armigera avoid nonoptimal mating by inhibiting males with pheromone antagonist cis-11-Hexadecenol (Z11-16:OH). We also show that this antagonist-mediated optimization of mating time ensures maximum fecundity. To further investigate molecular aspects of this phenomenon, we used the CRISPR/Cas9 system to knock out odorant receptor 16 (OR16), the only pheromone receptor tuned to Z11-16:OH. In mutant males, electrophysiological and behavioral responses to Z11-16:OH were abolished. Inability to detect Z11-16:OH prompted the males to mate with immature females, which resulted in significantly reduced viability of eggs. In conclusion, our study demonstrates that the sensitivity of OR16 to Z11-16:OH regulates optimal mating time and thus ensures maximum fecundity. These results may suggest novel strategies to disrupt pest insect mating.


Antigen-specific suppression of type II collagen-induced arthritis by collagen-coupled spleen cells.
The induction of arthritis in Wistar-Lewis rats was suppressed by i.v. injections of spleen cells coupled to native type II collagen, beginning 14 days before intradermal injection of native type II collagen in incomplete Freund's adjuvant and continuing at 7-day intervals for the next 3 weeks. Cells coupled to native type I collagen or to denatured type II collagen were ineffectual, suggesting antigen-relevant cells were required for suppression. The phenomenon appeared to be mediated by a humoral effector mechanism; IgG antibody titers but not hemagglutinating antibody titers or delayed-type hypersensitivity to collagen were decreased by the injection of type II collagen-coupled cells. These data demonstrate the potential of antigen-specific immunotherapy for autoimmune disease.


Sonography and color Doppler imaging of Budd-Chiari syndrome of membranous obstruction of the inferior vena cava.
We examined 18 patients with Budd-Chiari syndrome (membranous obstruction of the hepatic IVC). IVC obstruction was detected by sonography in 17 cases (94%). The causes were a web in 10 cases and a fibrous cord in four cases. In three cases, the cause was unspecified. Obliteration of the hepatic veins or intrahepatic collateral vessels or both was delineated in 16 cases (89%). With seven cases of color Doppler imaging, there was no detectable color or Doppler signal within the IVC, and the direction of hepatic venous blood flow through intravenous communications was fairly well demonstrated in all cases. In four cases of follow-up color Doppler imaging, the patency of the IVC was well demonstrated. Sonography is useful in detecting obstruction of the hepatic IVC and in demonstrating the hepatic venous obstruction and intrahepatic collateral vessels. Color Doppler sonography is useful in demonstrating the direction of blood flow through interconnecting vessels and in evaluating the patency of the IVC after treatment.


Fröhlich systems in cellular physiology.
Electromagnetic fields are usually absent in the picture of processes taking place in living cells which is dominated by biochemistry, molecular genetics and microscopic morphology. Yet experimental and theoretical studies suggest that this omission is not justified. At the end of 1960's H. Fröhlich elaborated a semi-phenomenological model of polar oscillating units that are metabolically driven, exchange energy with the cell's internal heat reservoir, and store part of the energy in excited vibrational modes in such way, that mode with the lowest frequency becomes highly excited, while the higher-order modes remain near thermal equilibrium. This affords energy-hungry chemical reactions to take place while the rest of the cell is not exposed to heat stress. At present, part of the cytoskeleton - microtubules - are deemed to fulfil the role of oscillating units. The paper provides an introduction to the Fröhlich ideas for readers with background in medicine and biology in that it avoids mathematical formulas and relies on figures to convey information about the basic properties of the model. The essential features of the Fröhlich model - most notably the energy condensation - are demonstrated on ensemble encompassing three coupled vibration modes that can be exactly described using original diagrammatic method.


The combined use of artemether, sulfadoxine and pyrimethamine in the treatment of uncomplicated falciparum malaria.
29 male patients (14 from Taunggyi, 6 from Rangoon and 9 from Tharrawaddy in Burma) were treated simultaneously with 200 mg artemether (Single intramuscular dose), 1500 mg sulfadoxine and 75 mg [corrected] pyrimethamine (orally). The mean parasite clearance time was 106.7 +/- 48.7 h. Side effects were few and self-limiting. 13 of 29 patients had recrudescences before day 28; as all the patients were living in towns, reinfection was unlikely. This parasite clearance time was longer than that in patients treated with artemether alone (600 mg total dose), and the recrudescence rate was higher. This drug combination is not recommended for patients in areas where sulfadoxine/pyrimethamine resistance is already established.


Probing New Long-Range Interactions by Isotope Shift Spectroscopy.
We explore a method to probe new long- and intermediate-range interactions using precision atomic isotope shift spectroscopy. We develop a formalism to interpret linear King plots as bounds on new physics with minimal theory inputs. We focus only on bounding the new physics contributions that can be calculated independently of the standard model nuclear effects. We apply our method to existing Ca^{+} data and project its sensitivity to conjectured new bosons with spin-independent couplings to the electron and the neutron using narrow transitions in other atoms and ions, specifically, Sr and Yb. Future measurements are expected to improve the relative precision by 5 orders of magnitude, and they can potentially lead to an unprecedented sensitivity for bosons within the 0.3 to 10 MeV mass range.


Virtual-Lattice Based Intrusion Detection Algorithm over Actuator-Assisted Underwater Wireless Sensor Networks.
Due to the lack of a physical line of defense, intrusion detection becomes one of the key issues in applications of underwater wireless sensor networks (UWSNs), especially when the confidentiality has prime importance. However, the resource-constrained property of UWSNs such as sparse deployment and energy constraint makes intrusion detection a challenging issue. This paper considers a virtual-lattice-based approach to the intrusion detection problem in UWSNs. Different from most existing works, the UWSNs consist of two kinds of nodes, i.e., sensor nodes (SNs), which cannot move autonomously, and actuator nodes (ANs), which can move autonomously according to the performance requirement. With the cooperation of SNs and ANs, the intruder detection probability is defined. Then, a virtual lattice-based monitor (VLM) algorithm is proposed to detect the intruder. In order to reduce the redundancy of communication links and improve detection probability, an optimal and coordinative lattice-based monitor patrolling (OCLMP) algorithm is further provided for UWSNs, wherein an equal price search strategy is given for ANs to find the shortest patrolling path. Under VLM and OCLMP algorithms, the detection probabilities are calculated, while the topology connectivity can be guaranteed. Finally, simulation results are presented to show that the proposed method in this paper can improve the detection accuracy and save the energy consumption compared with the conventional methods.


Experience with phosphorus removal and sludge handling and disposal in Flanders.
The way excess sludge must be disposed of is a key factor in the choice of the appropriate phosphorus removal technique at municipal wastewater treatment plants. In Europe the ongoing trend of tightening the sludge spreading rules called for a serious reduction of its agricultural utilisation and the expansion of the (co-)incineration disposal route, which led to a shift towards more sophisticated sludge handling techniques. This paper illustrates the impact of different sludge handling techniques on the performance of chemical and enhanced biological phosphorus removal at municipal WWTPs. The main conclusion is that although enhanced biological phosphorus removal is particularly sensitive to the problem of return liquors from sludge treatment processes indirect dewatering and anaerobic stabilisation cannot be discarded altogether when considering its implementation.


Water or sediment? Partitioning the role of water column and sediment chemistry as drivers of macroinvertebrate communities in an austral South African stream.
Water pollution is a critical management issue, with many rivers and streams draining urban areas being polluted by the disposal of untreated solid waste and wastewater discharge, storm water and agricultural runoff. This has implications for biodiversity, and many rivers in the developing world are now considered compromised. We investigated benthic macroinvertebrate community structure and composition in relation to physico-chemical conditions of the water column and sediments. The study was conducted in an Austral catchment subject to both urban and agricultural pollutants in two different seasons. We assessed whether sediment characteristics were more important drivers of macroinvertebrate community composition than water column characteristics. We expected clear differences in macroinvertebrate community composition and in the associated community metrics due to distinct flow conditions between the two seasons. A combination of multivariate analyses (canonical correspondence analysis (CCA)) and biological indicator analysis were used to examine these patterns. Chironomidae was the most abundant family (>60%) in the upper mainstem river and stream sites. Stream sites were positively associated with CCA axis 2, being characterised by high turbidity and lower pH, salinity, phosphate concentration, channel width and canopy cover. Canopy cover, channel width, substrate embeddedness, phosphate concentration, pH, salinity and turbidity all had a significant effect on macroinvertebrate community composition. Using CCA variation partitioning, water quality was, however, a better predictor of benthic macroinvertebrate composition than sediment chemical conditions. Furthermore, our results suggest that seasonality had little effect on structuring benthic macroinvertebrate communities in this south-eastern zone of South Africa, despite clear changes in sediment chemistry. This likely reflects the relative lack of major variability in water chemistry compared to sediment chemistry between seasons and the relatively muted variability in precipitation between seasons than the more classic Austral temperate climates.


Impairment of renal function after islet transplant alone or islet-after-kidney transplantation using a sirolimus/tacrolimus-based immunosuppressive regimen.
The immunosuppressive (IS) regimen based on sirolimus/low-dose tacrolimus is considered a major determinant of success of the Edmonton protocol. This regimen is generally considered safe or even protective for the kidney. Herein, we analyzed the impact of the sirolimus/low-dose tacrolimus combination on kidney function. The medical charts of islet transplant recipients with at least 6 months follow up were reviewed. There were five islet-after-kidney and five islet transplantation alone patients. Serum creatinin, albuminuria, metabolic control markers and graft function were analyzed. Impairment of kidney function was observed in six of 10 patients. Neither metabolic markers nor IS drugs levels were significantly associated with the decrease of kidney function. Although a specific etiology was not identified, some subsets of patients presented a higher risk for decline of kidney function. Low creatinin clearance, albuminuria and long-established kidney graft were associated with poorer outcome.


Vagococcus proximus sp. nov. and Vagococcus intermedius sp. nov., originating from modified atmosphere packaged broiler meat.
During our studies on spoilage microbiomes of modified atmosphere packaged broiler meat, we isolated three strains (PNs007T, STAA11T and STAA25) of unknown identity. In this present polyphasic taxonomy study, including genome-based analyses, we discovered that these isolates represent two novel species belonging to the genus Vagococcus. In all phylogenetic analyses, PNs007T was positioned very close to Vagococcus fessus but both the average nucleotide identity (ANI; 89.5 %) and digital DNA-DNA hybridization (dDDH; 38.3 %) values distinguished it as a novel vagococcal species. STAA11T and STAA25 were genetically highly similar (16S rRNA, ANI and dDDH 100 %). The phylogenetic position of STAA11T was adjacent to but out of the cluster containing V. fessus, Vagococcus coleopterorum and PNs007T. According to the ANI (76.2-76.4 %) and dDDH (<22.6 %) values it also represented a novel vagococcal species. Phenotypic characteristics and chemotaxonomic properties of both novel species were typical for vagococci and they contained C16 : 0 (25.5-30.1 %) and C18 : 1 ω9c (67.3-73.0 %) as the major cellular fatty acids. The streptomycin-resistant genotype of STAA11T and STAA25 allowing the growth on streptomycin thallous acetate actidione medium was considered to result from a modification in codon 104 of the rpsL gene leading to P104A substitution. The ability of STAA11T and STAA25 to produce ammonia from arginine separated them from PNs007T, which did not show arginine deiminase activity. We propose the names Vagococcus proximus sp. nov. (type strain PNs007T=DSM 115185T=CCUG 76696T) and Vagococcus intermedius sp. nov. (type strain STAA11T=DSM 115183T=CCUG 76697T) for these novel species.


End stage renal disease in Brunei Darussalam - report from the first Brunei Dialysis Transplant Registry (BDTR).
The Brunei Dialysis and Transplant Registry (BDTR) was established in 2011 to collect data from patients undergoing renal replacement therapy (RRT) in Brunei Darussalam. The chief aims of the registry are to obtain general demographic data for RRT patients and to determine disease burden attributable to End Stage Renal Disease (ESRD). The registry population comprises of all ESRD patients treated in Brunei Darussalam. Data domains include general demographic data, medical history, ESRD etiological causes, laboratory investigations, dialysis treatment and outcomes. There were 545 prevalent RRT patients in Brunei at the end of 2011. The incidence and prevalence of ESRD were 265 and 1250 per million population. Hemodialysis (HD), Peritoneal Dialysis (PD) and Transplant comprised of 83%, 11% and 6% of the RRT population, respectively. Diabetes mellitus accounted for 57% of all new incident cases. The mean serum hemoglobin, phosphate, calcium and iPTH were 11.0 ± 1.6 g/dL, 1.9 ± 0.5 mmol/L, 2.3 ± 0.2 mmol/L and 202.5 ± 323.4 ng/mL. Dialysis adequacy for HD and PD were 65.1 (urea reduction ratio) and 2.0 ± 0.3 (Kt/v). 71 % of all prevalent HD had functioning AV fistulae and the peritonitis incidence was one in 24.5 patient-month/episode. The first BDTR has identified some deficiencies in the renal services in Brunei. However, it signals an important milestone for the establishment of benchmarked renal practice in the country. We hoped to maintain and improve our registry for years to come and will strive to align our standards to acceptable international practice.


Lineage specification in innate lymphocytes.
Innate lymphoid cells (ILCs) are immune cells that lack specific antigen receptors but possess similar effector functions as T cells. Concordantly, ILCs express many transcription factors known to be important for T cell effector function. ILCs develop from lymphoid progenitors in fetal liver and adult bone marrow. However, the identification of ILC progenitor (ILCP) and other precursors in peripheral tissues raises the question of whether ILC development might occur at extramedullary sites. We discuss central and local generation in maintaining ILC abundance at peripheral sites.


COPD exacerbations.
Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the United States. It's estimated that more than 13 million U.S. adults have COPD, and as many as 24 million have evidence of impaired lung function, suggesting that COPD is underdiagnosed. Even when patients receive optimal COPD therapy, they periodically experience exacerbations, which reduce lung function and quality of life, increase risk of death from COPD, and account for the majority of costs related to COPD treatment. This article, the second in a two-part series on COPD, outlines current guidelines and evidence-based recommendations for identifying, assessing, and managing COPD exacerbations (the first article in the series, "An Evidence-Based Approach to COPD," March 2012, focused on the management of stable COPD in the outpatient setting).


Job Satisfaction of Teachers of Students who are Deaf or Hard of Hearing.
The pressure that educators are experiencing to educate more students, with more challenges, to higher levels of learning than any time in the past is significantly changing their working conditions. The purpose of this study was to examine the perceptions of a national sample of teachers of students who are deaf or hard of hearing to ascertain their overall job satisfaction as well as to identify the specific factors that positively and negatively affect their ability to do their jobs well. In addition, responses of different subsets of teachers (e.g., itinerant, elementary, and secondary) were compared. Responses from 495 deaf educators are reported. Collectively, 89% of participants stated that they were satisfied to very satisfied with their overall job. Specific aspects of the job that respondents indicated that they were most satisfied or most dissatisfied with are presented and suggestions for addressing some of the identified challenges as well as recommendations for future research are provided.


Stem-loop oligonucleotides as tools for labelling double-stranded DNA.
We report on a sequence-specific double-stranded DNA labelling strategy in which a stem-loop triplex forming oligonucleotide (TFO) is able to encircle its DNA target. Ligation of this TFO to either a short hairpin oligonucleotide or a long double-stranded DNA fragment leads to the formation of a topological complex. This process requires the hybridization of both extremities of the TFO to each other on a few base pairs. The effects of different factors on the formation of these complexes have been investigated. Efficient complex formation was observed using both GT or TC TFOs. The stem-loop structure enhances the specificity of the complex. The topologically linked TFO remains associated with its target even under conditions that do not favour triple-helix formation. This approach is sufficiently sensitive for detection of a 20-bp target sequence at the subfemtomolar level. This study provides new insights into the mechanics and properties of stem-loop TFOs and their complexes with double-stranded DNA targets. It emphasizes the interest of such molecules in the development of new tools for the specific labelling of short DNA sequences.


Evidence of a d- to s-wave pairing symmetry transition in the electron-doped cuprate superconductor Pr(2-x)CexCuO4.
We present point contact spectroscopy (PCS) data for junctions between a normal metal and the electron-doped cuprate superconductor Pr(2-x)CexCuO4 (PCCO). For the underdoped compositions of this cuprate ( x approximately 0.13) we observe a peak in the conductance-voltage characteristics of the point contact junctions. The shape and magnitude of this peak suggest the presence of Andreev bound states at the surface of underdoped PCCO which is evidence for a d-wave pairing symmetry. For overdoped PCCO ( x approximately 0.17) the PCS data do not show any evidence of Andreev bound states at the surface suggesting an s-wave pairing symmetry.


[Bowel dysfunctional microflora: clinical significance and prospects for its therapy].
Due to the application of complex drugs as well as synergistic action of drugs with a different mechanism of their activity, it is quite possible to restore the eubiosis of bowels. The up-to-date correction of biocenosis is an essential principle of the microecological approach to the maintenance of health in individuals and the entire population.


Ru-Catalyzed Chemoselective Olefin Migration Reaction of Cyclic Allylic Acetals to Enol Acetals.
A Ru-catalyzed olefin migration reaction of chiral cyclic allylic acetal is reported. The reaction generates cyclic enol acetal in a highly chemoselective manner. A variety of O,O- and N,O-acetals participated in the reaction with conservation of the stereochemical integrity of the acetal moiety. The utility of the reaction was demonstrated by the short and protective group-free syntheses of (L)-deoxyribonucleoside and β-amicetose glycoside.


Universal external RNA controls for microbial gene expression analysis using microarray and qRT-PCR.
Gene expression analysis provides significant insight to understand regulatory mechanisms of biology, yet acquisition and reproduction of quality data, as well as data confirmation and verification remain challenging due to a lack of proper quality controls across different assay platforms. We present a set of six universal external RNA quality controls for microbial mRNA expression analysis that can be applied to both DNA oligo microarray and real-time qRT-PCR including using SYBR Green and TaqMan probe-based chemistry. This set of controls was applied for Saccharomyces cerevisiae and Pseudomonas fluorescens Pf-5 microarray assays and qRT-PCR for yeast gene expression analysis. Highly fitted linear relationships between detected signal intensity and mRNA input were described. Valid mRNA detection range, from 10 to 7000 pg and from 100 fg to 1000 pg were defined for microarray and qRT-PCR assay, respectively. Quantitative estimation of mRNA abundance was tested using randomly selected yeast ORF including function unknown genes using the same source of samples by the two assay platforms. Estimates of mRNA abundance by the two methods were similar and highly correlated in an overlapping detection range from 10 to 1000 pg. The universal external RNA controls provide a means to compare microbial gene expression data derived from different experiments and different platforms for verification and confirmation. Such quality controls ensure reliability and reproducibility of gene expression data, and provide unbiased normalization reference for validation, quantification, and estimate of variation of gene expression experiments. Application of these controls also improves efficiency and facilitates high throughput applications of gene expression analysis using the qRT-PCR assay.


Taking a critical stance towards mixed methods research: A cross-disciplinary qualitative secondary analysis of researchers' views.
Recent growth and institutionalization in the field of mixed methods research has provided fertile ground for a wide range of thoughtful criticism of how this research approach has been developed and conceptualized by some members of the mixed methods community. This criticism reflects the increasing maturity of the field as well as the different theoretical perspectives and methodological practices of researchers in different disciplines. While debates addressing these criticisms are likely to lead to valuable insights, no empirical studies have been carried out to date that have investigated researchers' critical views on the development and conceptualization of mixed methods research. This study examines the criticisms of the mixed methods field raised by a cross-national sample of researchers in education, nursing, psychology, and sociology. We carried out a secondary analysis of semi-structured interviews with 42 researchers and identified 11 different criticisms, which we classified in four domains: essence of mixed methods, philosophy, procedures, and politics. The criticisms related to the procedures domain were equally distributed among the four disciplines, while those related to the essence, philosophy and politics domains were more common among sociologists. Based on our findings, we argue that the divergence of views on foundational issues in this field reflects researchers' affiliation to different communities of practice, each having its own principles, values, and interests. We suggest that a greater awareness of this divergence of perspectives could help researchers establish effective collaboration and anticipate potential challenges when working with researchers having different methodological approaches.


Personalized medicine for neonates born prematurely.
In clinical practice, the guidelines used for premature neonates are mainly based on gestational age. In the literature the use of the gestational-age guidelines is heavily debated and regarded as an oversimplification of a complex situation. Three systematic reviews showing the results of long-term outcome of premature neonates are used in this article to illustrate that gestational age alone does not adequately predict outcome. For this reason, we propose to focus more on individual risk factors than on gestational age alone, as we believe personalized medicine is the only way to improve morbidity.


The DFF40/CAD endonuclease and its role in apoptosis.
The sequential generation of large-scale DNA fragments followed by internucleosomal chromatin fragmentation is a biochemical hallmark of apoptosis. One of the nucleases primarily responsible for genomic DNA fragmentation during apoptosis is called DNA Fragmentation Factor 40 (DFF40) or Caspase-activated DNase (CAD). DFF40/CAD is a magnesium-dependent endonuclease specific for double stranded DNA that generates double strand breaks with 3'-hydroxyl ends. DFF40/CAD is activated by caspase-3 that cuts the nuclease's inhibitor DFF45/ICAD. The nuclease preferentially attacks chromatin in the internucleosomal linker DNA. However, the nuclease hypersensitive sites can be detected and DFF40/CAD is potentially involved in large-scale DNA fragmentation as well. DFF40/CAD-mediated DNA fragmentation triggers chromatin condensation that is another hallmark of apoptosis.


Sirtuin 1 is a potential therapeutic candidate gene for fetal growth restriction via insulin-like 4.
Insufficient placental development causes various obstetric complications, including fetal growth restriction (FGR). The Sirtuin 1 (SIRT1) and insulin-like 4 (INSL4) protein-coding genes have been demonstrated to play an important role in placental development. However, no treatment for FGR is available due to placental dysfunction. Therefore, this study aimed to examine the potential of the SIRT1-INSL4 axis as a treatment candidate for FGR caused by insufficient placental development. Twenty patients were enrolled, including 10 with FGR and 10 full-term controls. FGR and control placental samples were collected. Quantitative real-time polymerase chain reaction, immunohistochemical analysis, and western blotting were used to analyze INSL4 and SIRT1 expression. An in-vitro loss-of-function approach with the human choriocarcinoma cell line BeWo was applied for functional analyses of SIRT1 in placental development. BeWo cells were differentiated into syncytiotrophoblasts by silencing SIRT1 using small interfering RNA. SIRT1 activator was added during differentiation of SIRT1-knockdown BeWo cells into syncytiotrophoblasts. The FGR samples had lower INSL4 and SIRT1 mRNA and protein expression levels than the control samples. Immunohistochemistry showed that both SIRT1 and INSL4 were expressed mainly in syncytiotrophoblasts. In-vitro analyses showed that SIRT1 knockdown decreased INSL4 expression; however, SIRT1 activator restored SIRT1 expression in SIRT1-silenced BeWo cells. SIRT1 and INSL4 are downregulated in the placenta of FGR, and INSL4 is regulated by SIRT1. These findings indicate that the SIRT1-INSL4 axis may be a potential therapeutic target for FGR.


Mutations of 15 short tandem repeat loci in Chinese population.
To explore the mutations of 15 short tandem repeat (STR) loci in PlowerPlex16 System which are world-widely used in parentage testing. Mutations of 15 STR loci in PlowerPlex16 System were investigated in 1921 parentage testing cases from Chinese population. In 1921 parentage cases, seventy cases (3.644%) were found to have mutations. Among these were one case with double mutations (D21S11 and PentaD) and another case with two different mutations (D7S820 and D16S539) in two children. The total number of mutated STR loci observed was 72 over 3764 meiosis with a mutation rate of 0.128% +/- 0.1104% x 10(-3). The highest mutation rate was 0.292% at vWA and D21S11. No mutation was observed at TH01 or at TPOX. The mutated alleles coming from father were five times more than those from mother. The majority (98.611%) of mutated alleles were the results of one-step mutation. The ratio of one-step gain versus loss was 1.826:1. There was only one multiple-step mutation with a double-repeat gain observed at PentaD locus. In the PlowerPlex16 System, nine loci, namely D8S1179, Penta D, D13S317, D16S539, D7S820, D5S818, D3S1358, TH01 and TPOX, have lower mutation rates and are more suitable for parentage testing. Mutation of STR is relatively common and often makes parentage testing more complicated. Selecting stable STR locus with low mutation rate is more important in parentage testing.


Delta sleep instability in children with chronic arthritis.
The objective of the present study was to evaluate the expression of a cyclic alternating pattern (CAP) in slow wave sleep (SWS) in children with the well-defined chronic syndrome juvenile idiopathic arthritis (JIA). Twelve patients (9-17 years of age), 7 girls, with JIA were compared to matched controls by age, pubertal stage and gender. After one night of habituation in the sleep laboratory, sleep measurements were obtained by standard polysomnography with conventional sleep scoring and additional CAP analyses. The sleep parameters of the JIA and control groups were similar for sleep efficiency (91.1 +/- 6.7 vs 95.8 +/- 4.0), sleep stage in minutes: stage 1 (16.8 +/- 8.5 vs 17.8 +/- 4.0), stage 2 (251.9 +/- 41 vs 262.8 +/- 38.1), stage 3 (17.0 +/- 6.0 vs 15.1 +/- 5.7), stage 4 (61.0 +/- 21.7 vs 77.1 +/- 20.4), and rapid eye movement sleep (82.0 +/- 27.6 vs 99.0 +/- 23.9), respectively. JIA patients presented nocturnal disrupted sleep, with an increase in short awakenings, but CAP analyses showed that sleep disruption was present even during SWS, showing an increase in the overall CAP rate (P < 0.01). Overall CAP rate during non-rapid eye movement sleep was significantly higher in pediatric patients who were in chronic pain. This is the first study of CAP in pediatric patients with chronic arthritis showing that CAP analyses can be a powerful tool for the investigation of disturbance of SWS in children, based on sleep EEG visual analysis.


Gaucher's disease: unexpected diagnosis in three patients over seventy years old.
Gaucher's disease is usually diagnosed in the first or second decade of life with the appearance of bone pains, splenomegaly and hemorrhagic manifestations due to thrombocytopenia. When the hematological parameters are preserved and the enlarged spleen not evident until late in life, patients are rarely identified as having Gaucher's disease and the diagnosis is based only on the presence of Gaucher's cells in bone marrow. We present here three cases of elderly patients aged 81, 73 and 72 years in whom the disease was a surprise finding of bone marrow examination.


The UGT1A1*28 genotype and the toxicity of low-dose irinotecan in patients with advanced lung cancer.
The association between the UGT1A1*28 genotype and the severe toxicity of low-dose irinotecan has been controversial, and few studies have examined this association in patients with lung cancer. The aim of this study was to assess the association between the UGT1A1*28 genotype and the severe toxicity of low-dose irinotecan in Japanese patients with lung cancer. From December 2005 through July 2008, 53 Japanese patients with advanced lung cancer who underwent chemotherapy that included low-dose irinotecan (50 or 60 mg/m2) as a single agent or in combination chemotherapy were retrospectively analyzed. Genomic DNA was extracted from peripheral blood. Genotypes for the UGT1A1*28 were denoted as wild-type for 6/6, heterozygous for 6/7, or homozygous for 7/7 depending on the number of TA repeats found in each allele. Of the 53 patients, 42 (79.2%) were wild-type, 9 (17.0%) were heterozygous, and 2 (3.7%) were homozygous for the UGT1A1*28 genotype. The UGT1A1*28 genotype was not associated with grade 3 or 4 neutropenia, thrombocytopia, diarrhea, or febrile neutropenia. The frequency of dose reduction of irinotecan did not differ between wild-type and heterozygous or homozygous for the UGT1A1*28 genotype. In addition, there were no significant differences in response rates and survival between wild-type and heterozygous or homozygous for the UGT1A1*28 genotype. In conclusion, the UGT1A1*28 genotype did not predict the severe toxicity of low-dose irinotecan in patients with lung cancer. Therefore, low-dose irinotecan could be administered without reducing starting dose in patients with UGT1A1*28 genotype.


Purification of PEGylated nanoparticles using tangential flow filtration (TFF).
A tangential flow filtration system was evaluated to purify PEGylated nanoparticles. Two widely used surfactants, PVA and sodium cholate were efficiently removed from an empty nanoparticles suspension using the proposed system. During drug loading, surfactant (PVA) was observed to be entrapped within the core of the nanoparticle to a higher extent, hence was purified at a comparatively slower rate. The presence of dextran sulfate enhanced the drug loading but also resulted in reduced purification rate; this was described by the hypothesis of PVA inclusion within the core of the nanoparticles. Practically, it was possible to correlate the slow purification rate of PVA to its reduced filtration flow during the purification of the empty and loaded nanoparticles containing dextran sulfate. Indirectly, this system was capable of revealing the influence of an excipient and drug on the nanoparticle surface.


Introduction to a special section on the supervisee's perspective of reflective supervision/consultation.
The definition and implementation of reflective supervision/consultation (RS/C) in the infant early childhood mental health field (IECMH) has largely been driven by expert supervisors, researchers, and leaders in the field. The voice of the frontline practitioner, the most likely recipient of RS/C has had less prominence in the scholarly discourse, leaving unclear supervisees' perspectives on the meaning and value of RS/C. This special section addresses supervisees' experiences with RS/C across five studies. In the first two papers, researchers examined supervisees' perspectives on essential components of RS/C and perceived impacts of RS/C on their work. In paper 3, researchers report on perceived associations between RS/C and professionals' well-being. The fourth paper addresses experiences in RS/C and professionals' use of reflective practices. Finally, researchers in the fifth paper present the psychometric properties of an observational tool that focuses on the interaction between supervisors and supervisees. Collectively, the studies promote understanding about supervisees' perspectives and experiences that may benefit future research studies aimed at investigating the role of RS/C in well-being and practice and provide information for program administrators considering the inclusion of RS/C in professional development efforts.


[Hemorrhagic dengue without hemorrhaging: a novel diagnostic category?].
Compare the clinical course of Dengue Fever (DF) and Dengue Hemorrhagic Fever (DHF). Cross-sectional study among seropositive cases reported by the Northern Veracruz District IMSS Office in 2004. We analyzed the epidemiology, symptomology, clinical findings and disease progression. We calculated frequencies, proportions and averages. Clinical data and disease progression were compared. We studied 404 patients, divided into three groups: 75 with CD, 120 DHF and 212 cases with no hemorrhagic data although displaying Dengue with Thrombocytopenia (DwT). General symptoms were much less common among Dengue cases. Abdominal pain, hepatomegaly and splenomegaly were more frequent among patients with DHF. Fluid leakage and hemorrhaging were observed in 75% and 46%, respectively, of the latter group. The history of prior infection was proportional. All patients presenting DHF showed thrombocytopenia, though only 3% showed hemoconcentration. The mean value for hematocrit was low (p=0.02) and the platelet count greater (p<0.001) among Dengue cases. Hemoglobin concentration showed no difference. The average time between disease onset and appearance of thrombocytopenia was similar in DHF cases (4.3+/- 1.6 days) and Dengue with Thrombocytopenia (4.3+/-1.6); even though, contrary to these, in the first group fluid leakage (3.7+/-1.8) and hemorrhaging (3.4+/-1.7) were previously identified. Our results confirm the presence of cases showing atypical disease course, without external hemorrhaging data but showing significant thrombocytopenia that may go unnoticed and worsen disease progression.


Are golden jackals (Canis aureus) definitive hosts for Angiostrongylus vasorum?
Angiostrongylosis caused by Angiostrongylus vasorum is an emerging disease in Europe. Recent reports have shown that, besides the red fox (Vulpes vulpes) recognized as the main definitive host and reservoir for the parasite, the role of the definitive host can be taken by a range of mammals. We considered that, due to the rapid large-scale expansion of its populations in Europe, the golden jackal (Canis aureus) could assume an important role in the epidemiology of the disease. The aim of the investigations was to explore the role of the golden jackal as the definitive host for A. vasorum. Sixty-three golden jackals, legally hunted in lowlands around the Danube River in Serbia recognized as the core area of the species' distribution in Europe, were subjected to patho-morphological and parasitological examination. The adult forms of A. vasorum were detected in the pulmonary arteries in six golden jackals with gross lesions manifested in the lungs. The finding of first stage larvae (L1) of A. vasorum in microscopic smears of the lung tissue altered by infection, which was consistent with the presence of adult parasites and manifestation of gross lesions in the lungs, confirms the successful reproduction of the parasite in the golden jackal. Migration of L1 from the blood vessels to the airways was confirmed by histopathology and, subsequently, their shedding was demonstrated by the Baermann method. The results support the hypothesis that the golden jackal acts as a suitable definitive host for A. vasorum. As a definitive host with a large-scale expansion of its populations in Europe, the golden jackal may be an important part of the parasite's host repertoire by spreading the parasite into previously non-endemic areas and by being an additional definitive host in endemic areas of vulpine angiostrongylosis.


Default network activity is a sensitive and specific biomarker of memory in multiple sclerosis.
Patients with multiple sclerosis (MS) suffer memory impairment but the link between MS-related neuroanatomical changes (brain atrophy) and memory is relatively weak. The purpose of this study was to use functional magnetic resonance imaging (fMRI) to investigate task-induced default network (DN) deactivation as a neurophysiologic biomarker of memory functioning in MS. Twenty-eight MS patients underwent high-resolution MRIs to measure brain atrophy (third ventricle width, cerebral gray matter, cerebral white matter, parenchymal fraction, and thalamic, caudate, hippocampal, and amygdala volumes), and fMRI blood oxygen level dependent (BOLD) signal to measure DN deactivation during sustained attention relative to rest. Neuropsychological assessment of episodic memory was performed on a separate day. We used hierarchical regression to predict memory, with age, education, and depression in step one, brain atrophy within step two, DN activity within step three, and the interaction between brain atrophy and DN activity in step four. Brain atrophy predicted worse memory but DN activity independently predicted memory over-and-above measurements of brain atrophy (R (2)=0.108), with greater DN activity (lesser deactivation) linked to better memory. A significant brain atrophy by DN activity interaction indicated a stronger relationship between memory and DN activity among patients with more advanced disease, at which point higher DN activity protects patients from disease/atrophy-related memory impairment. To establish specificity, we showed no relationship between DN activity and non-memory cognition, and no relationship between non-DN brain activity and memory. Maintenance of DN activity during sustained attention was supported as a sensitive and specific neurophysiologic biomarker of episodic memory functioning in MS, even when controlling for neuroanatomical changes (brain atrophy).


Posterior longitudinal ligament suturation after lumbar discectomy provides postoperative a large intradural area: First report.
Stability and flexibility of the spine are provided by the posterior longitudinal ligament (PLL). It plays a key role in the pathogenesis of lumbar disc herniation (LDH) by preventing disc protrusion. The effect of the suturing of the PLL on the intradural area was investigated. The patients were included in whom lumbar microdiscectomy was performed between January 2021 and July 1, 2022. The patients were randomly divided into two groups as PLLs were sutured and unsutured. Forty-six (23 males and 23 females) patients were included. The PLLs were sutured in 22 patients (Group 1) and not sutured in 24 patients (Group 2). The levels, sides of LDHs, and ages and gender of patients were also analyzed in both groups, which were not statistically significant. Preoperative mean spinal intradural areas were 77.29 mm2 for the PLL unsutured group and 85.40 mm2 for the PLL sutured group (Groups 1 and 2). For patients in Groups 1 and 2, the postoperative mean spinal intradural areas grew to 134.73 mm2 and 96.12 mm2, respectively. The difference in preoperative mean spinal intradural regions between the two groups was not statistically significant; however, Group 1 showed a substantial difference (sutured PLL patients). This study first time indicates that suturing PLL has a protective and supportive role in patients who were operated on for LDH.


Sequential XylS-CTD binding to the Pm promoter induces DNA bending prior to activation.
XylS protein, a member of the AraC family of transcriptional regulators, comprises a C-terminal domain (CTD) involved in DNA binding and an N-terminal domain required for effector binding and protein dimerization. In the absence of benzoate effectors, the N-terminal domain behaves as an intramolecular repressor of the DNA binding domain. To date, the poor solubility properties of the full-length protein have restricted XylS analysis to genetic approaches in vivo. To characterize the molecular consequences of XylS binding to its operator, we used a recombinant XylS-CTD variant devoid of the N-terminal domain. The resulting protein was soluble and monomeric in solution and activated transcription from its cognate promoter in an effector-independent manner. XylS binding sites in the Pm promoter present an intrinsic curvature of 35 degrees centered at position -42 within the proximal site. Gel retardation and DNase footprint analysis showed XylS-CTD binding to Pm occurred sequentially: first a XylS-CTD monomer binds to the proximal site overlapping the RNA polymerase binding sequence to form complex I. This first event increased Pm bending to 50 degrees and was followed by the binding of the second monomer, which further increased the observed global curvature to 98 degrees. This generated a concomitant shift in the bending center to a region centered at position -51 when the two sites were occupied (complex II). We propose a model in which DNA structure and binding sequences strongly influence XylS binding events previous to transcription activation.


Biogeochemical signals from deep microbial life in terrestrial crust.
In contrast to the deep subseafloor biosphere, a volumetrically vast and stable habitat for microbial life in the terrestrial crust remains poorly explored. For the long-term sustainability of a crustal biome, high-energy fluxes derived from hydrothermal circulation and water radiolysis in uranium-enriched rocks are seemingly essential. However, the crustal habitability depending on a low supply of energy is unknown. We present multi-isotopic evidence of microbially mediated sulfate reduction in a granitic aquifer, a representative of the terrestrial crust habitat. Deep meteoric groundwater was collected from underground boreholes drilled into Cretaceous Toki granite (central Japan). A large sulfur isotopic fractionation of 20-60‰ diagnostic to microbial sulfate reduction is associated with the investigated groundwater containing sulfate below 0.2 mM. In contrast, a small carbon isotopic fractionation (<30‰) is not indicative of methanogenesis. Except for 2011, the concentrations of H2 ranged mostly from 1 to 5 nM, which is also consistent with an aquifer where a terminal electron accepting process is dominantly controlled by ongoing sulfate reduction. High isotopic ratios of mantle-derived 3He relative to radiogenic 4He in groundwater and the flux of H2 along adjacent faults suggest that, in addition to low concentrations of organic matter (<70 µM), H2 from deeper sources might partly fuel metabolic activities. Our results demonstrate that the deep biosphere in the terrestrial crust is metabolically active and playing a crucial role in the formation of reducing groundwater even under low-energy fluxes.


[Pathophysiology of depression].
Neurobiological findings of depression are reviewed in this paper. Modern neurobiological methods have revealed pathophysiological mechanism associated with depression. Monoamine hypothesis, which was advocated in the 1950's, emphasizes that the deficiency of monoamine neurotransmitters bring about depressive symptoms. This theory played an important role in promoting the development of new antidepressants, but some inconsistent findings were pointed out concerning this theory. Neuroendocrine studies have revealed the hypothalamic-pituitary-adrenal (HPA) axis dysfunctions in depressive patients, and increased activity of HPA axis are considered as state marker of depression. Morphological changes of hippocampus, polymorphism of serotonin transporter gene, and down regulation of neurotrophin are also discussed in this review.


Dental caries in urban and rural areas in Mozambique.
The purpose of this study was to assess the level of dental caries among 11-13 year old children and adults in urban and rural areas in Mozambique. The survey comprised a total of 575 schoolchildren from 5 areas in the Maputo Province, and 239 adults from 2 of the areas. There was a gradual increase in caries prevalence among the children from 23 per cent in the most distant rural area to 65 per cent in the urban centre, with a corresponding increase in DMFT from 0.5 to 2.1. In adults from a rural village there was an increase in caries prevalence and experience with age from 69 per cent with a DMFT of 3.7 at the age of 25-34 years, to 94 per cent and a DMFT of 7.9 at 45-54 years. In the urban group aged 25-34 years, there was a caries prevalence of 93 per cent and an average DMFT of 8.1, with no further increase in caries level with age. It was concluded that there was a sociogeographic variation in caries levels strongly associated with the degree of exposure to markets, and that a recent increase in exposure to cariogenic factors had occurred in urban areas.


[Better quality of thrombotest in family practice. Results from the NOKLUS survey 1993-97].
The Norwegian centre for external quality assurance of primary health care laboratories (Norwegian abbreviation: NOKLUS) was established in 1992. In 1997 about 1,800 practices participated in NOKLUS' quality assurance schemes, and 576 of these participated in the PT survey. Participation is voluntary and free of charge. The interlaboratory variation (CV%) was 17.7% in 1993 and 13.3% in 1997, and the percentage of results classified as "poor" has decreased from 7-8% in 1993 to 4% in 1997. These data indicate that participation in the scheme has led to a widespread improvement in laboratory performance. Norwegian primary health care practices now seem to analyse PT just as accurately as the Norwegian hospital laboratories. Logistic regression showed that the two most important factors for ensuring quality analysis were having a medical laboratory technician perform the PT analyses, and using an analyzer rather than a manual procedure.


The endogenous fatty acid amide, palmitoylethanolamide, has anti-allodynic and anti-hyperalgesic effects in a murine model of neuropathic pain: involvement of CB(1), TRPV1 and PPARgamma receptors and neurotrophic factors.
Palmitoylethanolamide (PEA) is an endogenous lipid that is thought to be involved in endogenous protective mechanisms activated as a result of stimulation of inflammatory response. In spite of the well demonstrated anti-inflammatory properties of PEA, its involvement in controlling pain pathways still remains poorly characterized. On this basis, we tested the efficacy of PEA in vivo against a peculiar persistent pain, such as neuropathic one. PEA was administered i.p. to mice with chronic constriction injury of sciatic nerve (CCI) once a day for one week starting the day after the lesion. This therapeutic regimen evoked a relief of both thermal hyperalgesia and mechanical allodynia in neuropathic mice. Various selective receptor antagonists were used in order to clarify the relative contribution of cannabinoid, vanilloid and peroxisome proliferator-activated receptor to PEA-induced effects. The results indicated that CB(1), PPARgamma and TRPV1 receptors mediated the antinociception induced by PEA, suggesting that the most likely mechanism might be the so-called "entourage effect" due to the PEA-induced inhibition of the enzyme catalyzing the endocannabinoid anandamide (AEA) degradation that leads to an enhancement of its tissue levels thus increasing its analgesic action. In addition, the hypothesis that PEA might act through the modulation of local mast cells degranulation is sustained by our findings showing that PEA significantly reduced the production of many mediators such as TNFalpha and neurotrophic factors, like NGF. The findings presented here, in addition to prove the beneficial effects of PEA in chronic pain, identify new potential targets for analgesic medicine.


Immune mediated liver failure.
Liver failure is a clinical syndrome of various etiologies, manifesting as jaundice, encephalopathy, coagulopathy and circulatory dysfunction, which result in subsequent multiorgan failure. Clinically, liver failure is classified into four categories: acute, subacute, acute-on-chronic and chronic liver failure. Massive hepatocyte death is considered to be the core event in the development of liver failure, which occurs when the extent of hepatocyte death is beyond the liver regenerative capacity. Direct damage and immune-mediated liver injury are two major factors involved in this process. Increasing evidence has suggested the essential role of immune-mediated liver injury in the pathogenesis of liver failure. Here, we review the evolved concepts concerning the mechanisms of immune-mediated liver injury in liver failure from human and animal studies. Both innate and adaptive immunity, especially the interaction of various immune cells and molecules as well as death receptor signaling system are discussed. In addition, we highlight the concept of "immune coagulation", which has been shown to be related to the disease progression and liver injury exacerbation in HBV related acute-on-chronic liver failure.


[Contribution of allergen immunotherapy using Phostal in the treatment of seasonal allergic rhinitis (two years of use)].
Allergen immunotherapy consists in the administration of the appropriate allergen to which the patient is hypersensitive. The objective is to induce immunological tolerance of the organism. In the present study, the effect of the administration of Phostal on the occurrence of seasonal symptoms of pollinosis in a group of 35 outpatients was observed during two years. The substance was administered according to the regular dosage schedule, all year round. The results of the study have demonstrated a significant effect of the product on the decrease in the occurrence of observed objective symptoms of the disease, starting already from the first year of treatment. This is in correlation with changes in the spirometric functions, selected laboratory parameters and results of the prick tests in the treated group in comparison to the control group.


Improved traffic safety at work zones through animation-based variable message signs.
Work zones are established to provide a safe environment for all road users and road workers. However, based on the statistics, they can be considered as crash prone zones due to changes in the road alignments and the posted speed limits. In this driving simulator study, we aimed at investigating the safety impacts of a newly proposed system composed of graphical and animation-based variable message signs (VMSs) in the state of Qatar. The proposed VMS condition was compared with a control condition that was designed following the Qatar Work Zone Traffic Management Guide. A total of seventy subjects were invited to participate in the experiment voluntarily. Study results showed that in the VMS condition, drivers reduced their traveling speeds in advanced compared to the control condition. Drivers' traveling speed in the VMS condition was significantly reduced by 6.3 and 11.1 km/h on the leftmost and the second leftmost lanes, respectively. Next, the results uncovered that the proposed system motivated drivers to initiate early lane changing maneuvers, i.e., 150 m earlier than the control condition. Finally, the VMS condition was effective in stimulating drivers to keep larger headways with a merging vehicle. In sum, the proposed VMS system outperformed the control condition in terms of speed reduction, early merging, and higher headways between the through and the merging vehicle.