Intestinal flora differences between patients with ulcerative colitis of different ethnic groups in China.
To determine the differences in intestinal flora between Uygur and Han patients with ulcerative colitis (UC).Microbial diversity and structural composition of fecal bacteria from patients with UC and their matched healthy spouses or first-degree relatives were analyzed using high-throughput sequencing technology.The fecal microbial diversity and abundance index of Uygur patients with UC (UUC) were significantly lower compared with the Uygur normal control group, while there was no significant difference between the Han UC patients (HUC) and the Han normal control group (HN). Compared with their respective control groups, Uygur UC patients and Han UC patients had a different main composition of human intestinal flora (P < .05). The abundance of Burkholderia, Caballeronia, Paraburkholderia in the UUC group were higher compared with the HUC group, while Faecalibacterium, Bifidobacterium, and Blautia in the HUC group were higher than those in the UUC group (P < .05). Veillonella in the UUC group was higher than that in the Uygur normal control group group, while Subdoligranulum and Ruminococcaceae_UCG-002 were significantly lower (P < .05). Prevotella_9 in the HUC group was significantly higher than that in HN group, while Blautia, Anaerostipes, and [Eubacterium]_hallii_group were significantly lower. Moreover, the top 6 species in order of importance were Christensenellaceae_R_7_group, Ruminococcae_ucg_005, Ruminococcae_ucg_010, Ruminococcae_ucg_013, Haemophilus, and Ezakiella.The difference in intestinal microflora structure may be one of the reasons for the clinical heterogeneity between Uygur and Han patients with UC. Christensenellaceae_R_7_group, Ruminococcae_ucg_005, Ruminococcae_ucg_010, Ruminococcae_ucg_013, Haemophilus, and Ezakiella could be used as potential biomarkers for predicting UC.


Metastasis-associated protein 1/histone deacetylase 4-nucleosome remodeling and deacetylase complex regulates phosphatase and tensin homolog gene expression and function.
Metastasis-associated protein 1 (MTA1) is widely overexpressed in human cancers and is associated with malignant phenotypic changes contributing to morbidity in the associated diseases. Here we discovered for the first time that MTA1, a master chromatin modifier, transcriptionally represses the expression of phosphatase and tensin homolog (PTEN), a tumor suppressor gene, by recruiting class II histone deacetylase 4 (HDAC4) along with the transcription factor Yin-Yang 1 (YY1) onto the PTEN promoter. We also found evidence of an inverse correlation between the expression levels of MTA1 and PTEN in physiologically relevant breast cancer microarray datasets. We found that MTA1 up-regulation leads to a decreased expression of PTEN protein and stimulation of PI3K as well as phosphorylation of its signaling targets. Accordingly, selective down-regulation of MTA1 in breast cancer cells increases PTEN expression and inhibits stimulation of the PI3K/AKT signaling. Collectively, these findings provide a mechanistic role for MTA1 in transcriptional repression of PTEN, leading to modulation of the resulting signaling pathways.


[The histological expression of prostate-specific antigen and its clinical significance in patients with prostate cancer].
A total of 58 cases with prostatic diseases including benign hypertrophy (BPH) (n = 10) and adenocarcinoma (n = 48) were studied as to prostate-specific antigen (PA) with indirect enzyme immunohistochemistry. The expression of PA in the prostate, as well as the localization of PA in the tissue, was also studied in regard to cell differentiations, clinical stages, serum PA levels, with or without endocrine therapy, and prognosis of prostate cancer. Strong staining of PA was noted in epithelial cells of the gland, particularly on the ductal cavity, except for patients in the poorly differentiated carcinoma group. The overall positive rate for expression of PA was 100% in BPH and 73% (35/48) in prostate cancer. When prostate cancer was classified by cell differentiation, the positive rate was 100% (17/17) in the patients with well, 83% (10/12) moderately, and 42% (8/19) poorly differentiated carcinoma. When divided by clinical stages, the positive rate was 100% (1/1 and 9/9) in stages A and B each, 69% (9/13) in stage C, and 65% (17/26) in stage D. Of 33 cases whose serum PA values were determined, the histochemistry was positive in 67% of 12 patients with normal serum PA levels and in 86% of 21 in the elevated group. The prior to endocrine therapy group showed the presence of PA in 22 of 27 cases (82%) and a positive rate of 62% (13/21) was observed in the group during the treatment.(ABSTRACT TRUNCATED AT 250 WORDS)


Nature and Specificity of Gestural Disorder in Children with Developmental Coordination Disorder: A Multiple Case Study.
Aim: Praxis assessment in children with developmental coordination disorder (DCD) is usually based on tests of adult apraxia, by comparing across types of gestures and input modalities. However, the cognitive models of adult praxis processing are rarely used in a comprehensive and critical interpretation. These models generally involve two systems: a conceptual system and a production system. Heterogeneity of deficits is consistently reported in DCD, involving other cognitive skills such as executive or visual-perceptual and visuospatial functions. Surprisingly, few researches examined the impact of these functions in gestural production. Our study aimed at discussing the nature and specificity of the gestural deficit in DCD using a multiple case study approach. Method: Tasks were selected and adapted from protocols proposed in adult apraxia, in order to enable a comprehensive assessment of gestures. This included conceptual tasks (knowledge about tool functions and actions; recognition of gestures), representational (transitive, intransitive), and non-representational gestures (imitation of meaningless postures). We realized an additional assessment of constructional abilities and other cognitive domains (executive functions, visual-perceptual and visuospatial functions). Data from 27 patients diagnosed with DCD were collected. Neuropsychological profiles were classified using an inferential clinical analysis based on the modified t-test, by comparison with 100 typically developing children divided into five age groups (from 7 to 13 years old). Results: Among the 27 DCD patients, we first classified profiles that are characterized by impairment in tasks assessing perceptual visual or visuospatial skills (n = 8). Patients with a weakness in executive functions (n = 6) were then identified, followed by those with an impaired performance in conceptual knowledge tasks (n = 4). Among the nine remaining patients, six could be classified as having a visual spatial/visual constructional dyspraxia. Gestural production deficits were variable between and within profiles. Discussion: This study confirmed the heterogeneity of gestural production deficit among children with a diagnosis of DCD, at both intra- and inter-individual levels. The contribution of other cognitive deficits in most of the profiles allows discussing the specificity of gestural difficulties. This argues in favor of the necessity to distinguish gestural problems with other deficits made apparent through gesture.


A 'two-point' bound zinc porphyrin-zinc phthalocyanine-fullerene supramolecular triad for sequential energy and electron transfer.
A novel supramolecular triad composed of a zinc porphyrin-zinc phthalocyanine dyad and fullerenes has been assembled using a 'two-point' axial binding approach, and occurrence of efficient photoinduced energy transfer followed by electron transfer is demonstrated.


Rice black-streaked dwarf virus Genome in China: Diversification, Phylogeny, and Selection.
Rice black-streaked dwarf virus (RBSDV), a Fijivirus, causes maize rough dwarf disease and rice black-streaked dwarf disease in the summer maize-growing regions of the Yellow and Huai rivers, respectively, in China. Nevertheless, the diversification and selection of the entire genome from S1 to S10 have not been illuminated. Molecular variation, evolution, conserved regions, and other genomic properties were analyzed in 21 RBSDV isolates from maize (Zea mays L.) and rice (Oryza sativa) hosts sampled from nine geographic locations in China. Low codon adaptation index values ranging from 0.1878 to 0.2918 indicated a low degree of codon-usage bias and low potential expression for all 13 RBSDV open reading frames (ORFs). ORF9-2 showed a stronger effect of codon usage bias than did other ORFs, as the majority of points for this ORF lay close to the standard curve in the Nc plot (the effective number of codons [Nc] versus the frequency of G+C at synonymous third-base positions [GC3]). A 9-bp deletion mutation was detected in the RBSDV genome in the 3' UTR of S8. Nucleotide diversity analysis indicated that the structural proteins of RBSDV, such as S2 and S4, were all more conserved than nonstructural proteins such as S9. Nucleotide diversity (π) was highest among S9 sequences (0.0656), and was significantly higher than among S4 sequences (0.0225, P < 0.01). The number of conserved regions among the 10 segments varied substantially. The highest number of conserved regions (5) was found in S5, whereas no conserved regions were identified in S9. Nucleotide diversity and the number of conserved regions were independent of the lengths of segments. Nucleotide diversity was also not correlated with the number of conserved regions in segments. Ten recombination events in 21 isolates were found in seven segments with breakpoint positions in UTRs, intergenic spacer regions, and gene coding regions. The number of recombination events was also independent of the lengths of segments. RBSDV isolates from China could be phylogenetically classified into two groups using either 10 segment sequences or the concatenated sequence of S1 through S10, regardless of host or geographical location. The phylogenetic tree generated from pairwise nucleotide identities of individual RBSDV segments such as S9 and S3, with nucleotide identity values of 93.74% and 95.86%, respectively, is similar to the tree constructed from the concatenated sequences of the entire RBSDV genome. The 13 RBSDV ORFs were under negative and purifying selection (Ka/Ks < 1). ORF5-2 was under the greatest selection pressure; however, ORF2, which encodes the core protein of RBSDV, was under the lowest selection pressure.


Ghost mycobacteria on Gram stain.
The Gram stain is a key tool in diagnostic microbiology. Its usefulness with respect to mycobacteria is undefined. The neutrality of mycobacteria other than Mycobacterium tuberculosis on Gram staining of various clinical specimens is described.


In vitro recombination and inverted terminal repeat binding activities of the Mcmar1 transposase.
The Mcmar1 mariner element (MLE) presents some intriguing features with two large, perfectly conserved, 355 bp inverted terminal repeats (ITRs) containing two 28 bp direct repeats (DRs). The presence of a complete ORF in Mcmar1 makes it possible to explore the transposition of this unusual MLE. Mcmar1 transposase (MCMAR1) was purified, and in vitro transposition assays showed that it is able to promote ITR-dependent DNA cleavages and recombination events, which correspond to plasmid fusions and transpositions with imprecise ends. Further analyses indicated that MCMAR1 is able to interact with the 355 bp ITR through two DRs: the EDR (external DR) is a high-affinity binding site for MCMAR1, whereas the IDR (internal DR) is a low-affinity binding site. The main complex detected within the EDR contained a transposase dimer and only one DNA molecule. We hypothesize that the inability of MCMAR1 to promote precise in vitro transposition events could be due to mutations in its ORF sequence or to the specific features of transposase binding to the ITR. Indeed, the ITR region spanning from EDR to IDR resembles a MITE and could be bent by specific host factors. This suggests that the assembly of the transposition complex is more complex than that of those involved in the mobility of the Mos1 and Himar1 mariner elements.


Validity of a behavioural measure of heat stress and a skin tent test for dehydration in working horses and donkeys.
Dehydration and heat stress are serious welfare issues for equids working in developing countries. There is a lack of any standardised method or validated interpretation of the skin tent test in horses and donkeys. Owners of dehydrated and heat-stressed animals often depend on veterinary examination for identification of these conditions, leading to delays in treatment and unnecessary reliance on external sources to effect welfare improvement. To validate a standardised skin tent test for dehydration and a behavioural measure of heat stress in working equids; and to examine the effect of heat stress and dehydration on tripping and staggering behaviour. The study was carried out on 130 working horses and donkeys in Pakistan. Associations between skin tent and blood parameters (packed cell volume [PCV], serum total protein [TP], serum osmolality), clinical parameters, resting and drinking behaviour were examined. Heat stress behaviour (increased respiratory rate and depth, head nodding, flared nostrils, apathy) was observed in conjunction with rectal temperature. Tripping and staggering were assessed using a simple obstacle course. In both species, heat stress behaviour was significantly associated with increased rectal temperature (P<0.001). A positive skin tent test was not significantly associated with PCV or TP, although in donkeys it was significantly associated with lower serum osmolality (P<0.001). More animals age >15 years had a positive skin tent than those in younger age groups (P = 0.037). Very thin horses were more likely to have a positive skin tent than those in thin or moderate condition (P = 0.028). There was no significant correlation between skin tent and tripping or staggering in either species. Heat stress behaviour is related to increased body temperature in working horses and donkeys. Owners may use this to make judgements regarding rest and cooling, precluding the need to seek veterinary attention. The skin tent test for dehydration used in this study did not show a significant relationship with PCV or TP. However, the use of blood parameters to validate the skin tent test may be confounded by anaemia, hypoproteinaemia or electrolyte depletion. Alternative methods are needed to confirm or refute the validity of the skin tent test in working equids.


TGF-beta signalling in bovine mammary gland involution and a comparative assessment of MAC-T and BME-UV1 cells as in vitro models for its study.
The goal of the dairy industry is ultimately to increase lactation persistency, which is the length of time during which peak milk yield is sustained. Lactation persistency is determined by the balance of cell apoptosis and cell proliferation; when the balance is skewed toward the latter, this results in greater persistency. Thus, we can potentially increase milk production in dairy cows through manipulating apoptogenic and antiproliferative cellular signaling that occurs in the bovine mammary gland. Transforming growth factor beta 1 (TGFβ1) is an antiproliferative and apoptogenic cytokine that is upregulated during bovine mammary gland involution. Here, we discuss possible applications of TGFβ1 signaling for the purposes of increasing lactation persistency. We also compare the features of mammary alveolar cells expressing SV-40 large T antigen (MAC-T) and bovine mammary epithelial cells-clone UV1 (BME-UV1) cells, two extensively used bovine mammary epithelial cell lines, to assess their appropriateness for the study of TGFβ1 signaling. TGFβ1 induces apoptosis and arrests cell growth in BME-UV1 cells, and this was reported to involve suppression of the somatotropic axis. Conversely, there is no proof that exogenous TGFβ1 induces apoptosis of MAC-T cells. In addition to TGFβ1's different effects on apoptosis in these cell lines, hormones and growth factors have distinct effects on TGFβ1 secretion and synthesis in MAC-T and BME-UV1 cells as well. MAC-T and BME-UV1 cells may behave differently in response to TGFβ1 due to their contrasting phenotypes; MAC-T cells have a profile indicative of both myoepithelial and luminal populations, while the BME-UV1 cells exclusively contain a luminal-like profile. Depending on the nature of the research question, the use of these cell lines as models to study TGFβ1 signaling should be carefully tailored to the questions asked.


From solution phase to "on-column" chemistry: trichloroacetimidate-based glycosylation promoted by perchloric acid-silica.
[reaction: see text] Activation of ester-protected glycosyl trichloroacetimidate donors by perchloric acid immobilized on silica afforded 1,2-trans disaccharides in 60-90% yields. Applying this approach to one-pot sequential glycosylation resulted in efficient syntheses of the N-linked glycan trimannoside and Le(X) and Le(A) trisaccharides in very good yield (76%, 62%, and 59% yields, respectively). Solution phase reactions were also translated to a solid phase format; priming the top of a standard silica chromatography column with perchloric acid immobilized on silica facilitated "on-column" glycosylation with subsequent "in situ" purification of products. Coupling yields from this approach were comparable to those obtained from the corresponding solution-phase disaccharide couplings. A series of glycosylated amino acids were also synthesized in high yield with use of the on-column approach.


Complement C5a Receptor 1 Exacerbates the Pathophysiology of N. meningitidis Sepsis and Is a Potential Target for Disease Treatment.
Sepsis caused by Neisseria meningitidis (meningococcus) is a rapidly progressing, life-threatening disease. Because its initial symptoms are rather unspecific, medical attention is often sought too late, i.e., when the systemic inflammatory response is already unleashed. This in turn limits the success of antibiotic treatment. The complement system is generally accepted as the most important innate immune determinant against invasive meningococcal disease since it protects the host through the bactericidal membrane attack complex. However, complement activation concomitantly liberates the C5a peptide, and it remains unclear whether this potent anaphylatoxin contributes to protection and/or drives the rapidly progressing immunopathogenesis associated with meningococcal disease. Here, we dissected the specific contribution of C5a receptor 1 (C5aR1), the canonical receptor for C5a, using a mouse model of meningococcal sepsis. Mice lacking C3 or C5 displayed susceptibility that was enhanced by >1,000-fold or 100-fold, respectively, consistent with the contribution of these components to protection. In clear contrast, C5ar1-/- mice resisted invasive meningococcal infection and cleared N. meningitidis more rapidly than wild-type (WT) animals. This favorable outcome stemmed from an ameliorated inflammatory cytokine response to N. meningitidis in C5ar1-/- mice in both in vivo and ex vivo whole-blood infections. In addition, inhibition of C5aR1 signaling without interference with the complement bactericidal activity reduced the inflammatory response also in human whole blood. Enticingly, pharmacologic C5aR1 blockade enhanced mouse survival and lowered meningococcal burden even when the treatment was administered after sepsis induction. Together, our findings demonstrate that C5aR1 drives the pathophysiology associated with meningococcal sepsis and provides a promising target for adjunctive therapy.IMPORTANCE The devastating consequences of N. meningitidis sepsis arise due to the rapidly arising and self-propagating inflammatory response that mobilizes antibacterial defenses but also drives the immunopathology associated with meningococcemia. The complement cascade provides innate broad-spectrum protection against infection by directly damaging the envelope of pathogenic microbes through the membrane attack complex and triggers an inflammatory response via the C5a peptide and its receptor C5aR1 aimed at mobilizing cellular effectors of immunity. Here, we consider the potential of separating the bactericidal activities of the complement cascade from its immune activating function to improve outcome of N. meningitidis sepsis. Our findings demonstrate that the specific genetic or pharmacological disruption of C5aR1 rapidly ameliorates disease by suppressing the pathogenic inflammatory response and, surprisingly, allows faster clearance of the bacterial infection. This outcome provides a clear demonstration of the therapeutic benefit of the use of C5aR1-specific inhibitors to improve the outcome of invasive meningococcal disease.


Estimating Infection Risks and the Global Burden of Diarrheal Disease Attributable to Intermittent Water Supply Using QMRA.
Intermittent water supply (IWS) is prevalent throughout low and middle-income countries. IWS is associated with increased microbial contamination and potentially elevated risk of waterborne illness. We used existing data sets to estimate the population exposed to IWS, assess the probability of infection using quantitative microbial risk assessment, and calculate the subsequent burden of diarrheal disease attributable to consuming fecally contaminated tap water from an IWS. We used reference pathogens Campylobacter, Cryptosporidium, and rotavirus as conservative risk proxies for infections via bacteria, protozoa, and viruses, respectively. Results indicate that the median daily risk of infection is an estimated 1 in 23 500 for Campylobacter, 1 in 5 050 000 for Cryptosporidium, and 1 in 118 000 for rotavirus. Based on these risks, IWS may account for 17.2 million infections causing 4.52 million cases of diarrhea, 109 000 diarrheal DALYs, and 1560 deaths each year. The burden of diarrheal disease associated with IWS likely exceeds the WHO health-based normative guideline for drinking water of 10-6 DALYs per person per year. Our results underscore the importance water safety management in water supplies and the potential benefits of point-of-use treatment to mitigate risks.


Antithrombotic therapy in carotid artery stenosis: an update.
Carotid stenosis is generally associated with high risks of stroke and vascular events. In asymptomatic and symptomatic patients, with or without revascularization, optimal managements of carotid artery stenosis require the use of medications or lifestyle modifications (stopping smoking and monitoring hypertension, hyperlipidemia, and diabetes) to control the processes associated with atheroma to reduce the risk of embolic events. Moreover, antiplatelet therapy should be considered. There is little evidence that antiplatelet therapy is beneficial in preventing stroke or the progression of stenosis in asymptomatic patients, whereas, evidence of a benefit from antiplatelet therapy for secondary prevention of recurrent stroke in symptomatic patients with carotid atherosclerosis is more robust. Also, in patients undergoing carotid endarterectomy, perioperative antithrombotic therapy should include aspirin, while the addition of clopidogrel should be decided case-by-case. Furthermore, perioperative antithrombotic therapy in patients undergoing carotid stenting should consist a combination of aspirin plus clopidogrel.


Marketing a Healthy Mind, Body, and Soul: An Analysis of How African American Men View the Church as a Social Marketer and Health Promoter of Colorectal Cancer Risk and Prevention.
The Centers for Disease Control and Prevention ranks colorectal cancer (CRC) as the third most commonly diagnosed cancer among men in the United States; African American (AA) men are at even greater risk. The present study was from a larger study that investigates the church's role as a social marketer of CRC risk and prevention messages, and whether religiously targeted and tailored health promotion materials will influence screening outcome. We used an integrated theoretical approach to explore participants' perceptions of CRC risk and prevention and how promotion messages should be developed and socially marketed by the church. Six focus groups were conducted with men from predominately AA churches in the Midwest. Themes from focus group discussions showed participants lacked knowledge about CRC, feared cancer diagnosis, and feared the procedure for screening. Roles of masculinity and the mistrust of physicians were also emergent themes. Participants did perceive the church as a trusted marketer of CRC but believed that promotional materials should be cosponsored and codeveloped by reputable health organizations. Employing the church as a social marketer of CRC screening promotion materials may be useful in guiding health promotions and addressing barriers that are distinct among African American men.


Effect of Vitamin D Receptor Activation on the AGE/RAGE System and Myeloperoxidase in Chronic Kidney Disease Patients.
Vitamin D receptor (VDR) activation has been reported to increase circulating levels of the advanced glycation end products (AGE) and their decoy receptor (RAGE). However, until now, the effect of VDR activation on AGE and RAGE has not been tested in the setting of a randomized, double-blind clinical trial. We have therefore analyzed the effect of VDR activation by paricalcitol on pentosidine, S100A12/ENRAGE, and RAGE and on established biomarkers of oxidative stress like myeloperoxidase in CKD patients in the PENNY trial. At baseline, human S100A12/ENRAGE, RAGE, and myeloperoxidase, but not pentosidine, were intercorrelated, and the association between S100A12/ENRAGE and myeloperoxidase (r = 0.71, P < 0.001) was the strongest among these correlations. Paricalcitol failed to modify biomarkers of the AGE/RAGE system and myeloperoxidase in unadjusted and adjusted analyses by the generalized linear model (GLM). No effect modification by other risk factors was registered. Paricalcitol does not modify biomarkers of the AGE/RAGE system and myeloperoxidase in CKD patients. The apparent increase in RAGE levels by VDR activation reported in previous uncontrolled studies is most likely due to confounding factors rather than to VDR activation per se. This trial is registered with NCT01680198.


RNA-Seq analysis of salinity stress-responsive transcriptome in the liver of spotted sea bass (Lateolabrax maculatus).
Salinity is one of the most prominent abiotic factors, which greatly influence reproduction, development, growth, physiological and metabolic activities of fishes. Spotted sea bass (Lateolabrax maculatus), as a euryhaline marine teleost, has extraordinary ability to deal with a wide range of salinity changes. However, this species is devoid of genomic resources, and no study has been conducted at the transcriptomic level to determine genes responsible for salinity regulation, which impedes the understanding of the fundamental mechanism conferring tolerance to salinity fluctuations. Liver, as the major metabolic organ, is the key source supplying energy for iono- and osmoregulation in fish, however, little attention has been paid to its salinity-related functions but which should not be ignored. In this study, we perform RNA-Seq analysis to identify genes involved in salinity adaptation and osmoregulation in liver of spotted sea bass, generating from the fishes exposed to low and high salinity water (5 vs 30ppt). After de novo assembly, annotation and differential gene expression analysis, a total of 455 genes were differentially expressed, including 184 up-regulated and 271 down-regulated transcripts in low salinity-acclimated fish group compared with that in high salinity-acclimated group. A number of genes with a potential role in salinity adaptation for spotted sea bass were classified into five functional categories based on the gene ontology (GO) and enrichment analysis, which include genes involved in metabolites and ion transporters, energy metabolism, signal transduction, immune response and structure reorganization. The candidate genes identified in L. maculates liver provide valuable information to explore new pathways related to fish salinity and osmotic regulation. Besides, the transcriptomic sequencing data supplies significant resources for identification of novel genes and further studying biological questions in spotted sea bass.


Neuromuscular blockade in cardiac surgery: an update for clinicians.
There have been great advancements in cardiac surgery over the last two decades; the widespread use of off-pump aortocoronary bypass surgery, minimally invasive cardiac surgery, and robotic surgery have also changed the face of cardiac anaesthesia. The concept of "Fast-track anaesthesia" demands the use of nondepolarising neuromuscular blocking drugs with short duration of action, combining the ability to provide (if necessary) sufficiently profound neuromuscular blockade during surgery and immediate re-establishment of normal neuromuscular transmission at the end of surgery. Postoperative residual muscle paralysis is one of the major hurdles for immediate or early extubation after cardiac surgery. Nondepolarising neuromuscular blocking drugs for cardiac surgery should therefore be easy to titrate, of rapid onset and short duration of action with a pathway of elimination independent from hepatic or renal dysfunction, and should equally not affect haemodynamic stability. The difference between repetitive bolus application and continuous infusion is outlined in this review, with the pharmacodynamic and pharmacokinetic characteristics of vecuronium, pancuronium, rocuronium, and cisatracurium. Kinemyography and acceleromyography are the most important currently used neuromuscular monitoring methods. Whereas monitoring at the adductor pollicis muscle is appropriate at the end of surgery, monitoring of the corrugator supercilii muscle better reflects neuromuscular blockade at more central, profound muscles, such as the diaphragm, larynx, or thoraco-abdominal muscles. In conclusion, cisatracurium or rocuronium is recommended for neuromuscular blockade in modern cardiac surgery.


Ratio of systolic blood pressure to left ventricular end-diastolic pressure at the time of primary percutaneous coronary intervention predicts in-hospital mortality in patients with ST-elevation myocardial infarction.
To determine the ability of simple hemodynamic parameters obtained at the time of cardiac catheterization to predict in-hospital mortality following ST-elevation myocardial infarction (STEMI). Hemodynamic parameters measured at the time of primary percutaneous coronary intervention (PPCI) could potentially identify high-risk patients who would benefit from aggressive hemodynamic support in the Cardiac Catheterization laboratory. This is a retrospective single-center study of 219 consecutive patients with STEMI. Left ventricular end-diastolic pressure (LVEDP), systolic blood pressure (SBP), and aortic diastolic blood pressure were obtained after successful revascularization. The prognostic ability of LVEDP, pulse pressure, and SBP/LVEDP ratio were compared to major mortality risk scores. Patients had a mean age of 60 ±14 years, were predominantly white (73%), male (64%), with anterior wall infarcts in 39%. Comorbidities included diabetes mellitus (27%), heart failure (9%), and chronic kidney disease (7%). In-hospital mortality was 9%. Patients with SBP/LVEDP ≤ 4 had increased risk of in-hospital death (32% vs. 5.3%, P < 0.0001), intra-aortic balloon pump (IABP) usage (51.6% vs. 9.6%, P < 0.0001) and combined endpoint of death or IABP usage (58.1% vs. 13.3%, P < 0.0001) compared to patients with SBP/LVEDP > 4. The area under curve (AUC) for SBP/LVEDP ratio for in-hospital mortality (0.69) was more predictive than LVEDP (0.61, P = 0.04) or pulse pressure (0.55, P = 0.02) but similar to Shock Index (ratio of heart rate to SBP) and Modified Shock Index (ratio of HR to mean arterial pressure). An SBP/LVEDP ratio ≤ 4 identified a group of STEMI patients at high risk of in-hospital death. © 2017 Wiley Periodicals, Inc.


Effectiveness of pulse dose methyl prednisolone in management of COVID 19: A systematic review and meta-analysis of observational studies.
Till date, only systemic corticosteroids have demonstrated definite mortality benefit in management of COVID 19 in various studies. Still certain questions regarding the appropriate dose, duration and timing of corticosteroids remain unanswered. For this reason, the study was planned to determine the efficacy and safety of the pulse dose methyl prednisolone in management of COVID 19 from the publicly available evidence. PubMed, the Cochrane library, ClinicalTrials.gov and medRxiv were searched for articles reporting the use of pulse dose methyl prednisolone in COVID 19 from inception till 31st May, 2021. Odds ratios (ORs) were calculated for estimation of pooled effect by using random effect model and heterogeneity was checked by using I2 statistics. Twelve studies (11 observational and 1 RCT) were included in the systematic review. A total of 3110 patients from 9 studies were included in the meta-analysis. Though the use of pulse dose methyl prednisolone demonstrated statistically significant mortality benefit in comparison to usual care (OR=0.71, 95% CI: 0.51 to 0.97, [P=0.03]), (I2= 21%) with calculated Number needed to treat (NNT) of 23.5, there was no statistically significant difference between the use of pulse dose and low dose corticosteroid (OR=0.66, 95% CI: 0.44 to 1.01, [(P=0.05]), (I2= 25%) and the NNT is 23.5. Incidence of adverse events were similar across all the groups. The grade of evidence for primary outcome was of moderate certainty. This meta-analysis concurs with the previous reports regarding the use of corticosteroid in COVID 19 in comparison to usual care. However, for both the primary and secondary outcome, the study did not find any statistically significant difference between the use of pulse dose methyl prednisolone and low dose corticosteroid to treat COVID 19 patients.


The concomitant intramyocardial bridging in the left coronary artery and anomalous origin of the right coronary artery--evaluation in ECG-gated multi-slice computed tomography (MSCT).
The anomalous origin and course of coronary vessels are rare and in some cases may lead to the symptoms of heart ischaemia. The paper presents the case of a 63-year-old patient with angina pectoris evaluated in ECG-gated multi-slice CT and coronarography in whom the concomitant ectopic origin of the recessive right coronary artery from the left sinus of Valsalva and intramyocardial bridging in the left anterior descendens artery were observed.


Neutral effect of prolonged transdermal hormone therapy on liver function of postmenopausal women with chronic active hepatitis.
To test whether transdermal hormone therapy can be safely administered to postmenopausal women with chronic viral hepatitis B and/or C. Eighty-one postmenopausal women with chronic viral hepatitis B and/or C and with severe vasomotor symptoms were treated for 5 years with transdermal estradiol (50 microg/day) continuously and with transdermal norethisterone (250 microg/day) for 14 days of every 28-day cycle. Another 95 women with viral chronic hepatitis but without climacteric symptoms were used as controls. Liver enzymes (glutamic-oxalacetic transaminase, glutamic-pyruvic transaminase, gamma-glutamine-transferase, and alkaline phosphatase) were measured every year. At baseline, liver enzymes were similar in the two groups, with the exception of gamma-GT, which was slightly higher in untreated women (P < 0.01). Liver enzymes did not significantly vary with time in hormone-treated and untreated women. No significant difference was observed between the two groups. Transdermal estradiol and norethisterone can be safely administered for a prolonged period to postmenopausal women with chronic viral B and/or C hepatitis.


Avian influenza outbreaks in chickens, Bangladesh.
To determine the epidemiology of outbreaks of avian influenza A virus (subtypes H5N1, H9N2) in chickens in Bangladesh, we conducted surveys and examined virus isolates. The outbreak began in backyard chickens. Probable sources of infection included egg trays and vehicles from local live bird markets and larger live bird markets.


[About odontomas].
The AA., after to have passed in review etiopathogenetic interpretations of odontomas and symptomatology, report 12 cases, from Odontostomatologic Clinic of Cagliari, dwelling on one of them especially, where the two epithelial and connective components, made evident microscopically, let foresee probable reductions either connective eithen epithelial component.


Is the TAM receptor Axl a receptor for lymphocytic choriomeningitis virus?
A recent publication indicated that overexpression of Axl, a cellular receptor that negatively regulates Toll-like receptor signaling, enhanced the entry of viruses pseudotyped with the glycoprotein of lymphocytic choriomeningitis virus (LCMV) in vitro. In testing the biological relevance of these observations, we found differences in neither viral kinetics between LCMV infections of Axl(-/-) and wild-type mice nor T-cell responses prior to spontaneous viral clearance. Thus, Axl is not required for productive LCMV infection of mice.


THE ANALYST'S RELOCATION: ANALYSIS TERMINABLE, INTERMINABLE, AND DISLOCATED.
The analyst's relocation is relatively neglected in the literature. Yet relocation is profoundly unsettling, striking at the psychoanalytic contract in a way that illness or even severe countertransference disturbances do not, and this unsettling aspect of resettling can disturb analytic functioning. The few previous papers about relocation focus on how to best understand and manage "reality" intrusions in terms of the nature and status of the transference relationship. In this paper, an engagement with object relational ideas is the prism through which to examine the dislocations of relocation and the potential disruptions of thinking caused by the vicissitudes of moving.


Scaffold-Free Strategy Using a PEG-Dextran Aqueous Two-Phase-System for Corneal Tissue Repair.
Forming thin tissue constructs with minimal extracellular matrix surrounding them is important for tissue engineering applications. Here, we explore and optimize a strategy that enables rapid fabrication of scaffold-free corneal tissue constructs using the liquid-liquid interface of an aqueous two-phase system (ATPS) that is based on biocompatible polymers, dextran and polyethylene glycol. Intact tissue-like constructs, made of corneal epithelial or endothelial cells, can be formed on the interface between the two liquid phases of ATPS within hours and subsequently collected simply by removing the liquid phases. The formed corneal cell constructs express essential physiological markers and have preserved viability and proliferative ability in vitro. The corneal epithelial cell constructs are also able to re-epithelialize the corneal epithelial wound in vitro. The results suggest the promise of our reported strategy in corneal repair.


The role of extended-release amantadine for the treatment of dyskinesia in Parkinson's disease patients.
Levodopa is the most efficacious treatment for Parkinson's disease (PD). Long-term treatment with levodopa is limited due to dyskinesia. Dyskinesia in PD can be socially and functionally disabling. Extended-release amantadine (amantadine ER) is the first approved medication for the treatment of dyskinesia. When it is given at bedtime, it reaches plasma concentration approximately twice the level achieved by amantadine immediate release. Amantadine ER reduces the severity and duration of dyskinesia during the day, reduces OFF time and increases ON time without troublesome dyskinesia. The most common side effects are hallucination, dizziness, orthostatic hypotension and pedal edema. This review discusses the safety and efficacy of amantadine ER in dyskinesia in PD patients.


Cardiac MRI Findings in Patients Clinically Referred for Evaluation of Post-Acute Sequelae of SARS-CoV-2 Infection.
Persistent or recurrent cardiovascular symptoms have been identified as one of the hallmarks of long-COVID or post-acute sequelae of SARS-CoV-2 infection (PASC). The purpose of this study was to determine the prevalence and extent of cardiac abnormalities in patients referred for cardiac MRI due to clinical evidence of PASC. To investigate this, two tertiary care hospitals identified all patients who were referred for cardiac MRI under the suspicion of PASC in a 2-year period and retrospectively included them in this study. Patients with previously known cardiac diseases were excluded. This resulted in a total cohort of 129 patients (63, 51% female; age 41 ± 16 years). The majority of patients (57%) showed normal cardiac results. No patient had active myocarditis or an acute myocardial infarction. However, 30% of patients had evidence of non-ischemic myocardial fibrosis, which exceeds the prevalence in the normal adult population and suggests that a possible history of myocarditis might explain persistent symptoms in the PASC setting.


Skeletal Muscle and Lymphocyte Mitochondrial Dysfunctions in Septic Shock Trigger ICU-Acquired Weakness and Sepsis-Induced Immunoparalysis.
Fundamental events driving the pathological processes of septic shock-induced multiorgan failure (MOF) at the cellular and subcellular levels remain debated. Emerging data implicate mitochondrial dysfunction as a critical factor in the pathogenesis of sepsis-associated MOF. If macrocirculatory and microcirculatory dysfunctions undoubtedly participate in organ dysfunction at the early stage of septic shock, an intrinsic bioenergetic failure, sometimes called "cytopathic hypoxia," perpetuates cellular dysfunction. Short-term failure of vital organs immediately threatens patient survival but long-term recovery is also severely hindered by persistent dysfunction of organs traditionally described as nonvital, such as skeletal muscle and peripheral blood mononuclear cells (PBMCs). In this review, we will stress how and why a persistent mitochondrial dysfunction in skeletal muscles and PBMC could impair survival in patients who overcome the first acute phase of their septic episode. First, muscle wasting protracts weaning from mechanical ventilation, increases the risk of mechanical ventilator-associated pneumonia, and creates a state of ICU-acquired muscle weakness, compelling the patient to bed. Second, failure of the immune system ("immunoparalysis") translates into its inability to clear infectious foci and predisposes the patient to recurrent nosocomial infections. We will finally emphasize how mitochondrial-targeted therapies could represent a realistic strategy to promote long-term recovery after sepsis.


Oats, more than just a whole grain: an introduction.
In May 2012, an oats workshop was held in New York to convene a group of international experts to discuss the implications and applications of oats relative to human health. These diverse experts represented disciplines including, but not limited to, epidemiology, food regulation, nutrition and food science, grain breeding and plant genetics, food processing, medicine and public-health policy. This ensuing series addresses three important aspects pertinent to oats: a brief overview of the dynamics of oats; the spectrum of established and emerging research in agriculture and health; and the options and opportunities for future applications of oats that extend beyond dietary fibre. Oats have many unique chemical properties, potential health benefits, agricultural challenges and nutrition-policy opportunities – but global production of oats appears to be falling. This is occurring despite contemporary research in the development of drought and infestation resistance and climate-adaptive cultivars and assessments of oats' unique components (such as dietary fibre, lipids, β-glucan and avenanthramides) that may contribute to health benefits. This suggests that oats represent a promising grain in the whole-grains landscape. New insights have been created into benefits beyond cardiovascular health. Modern milling and processing technologies have been developed to retain the nutritive value and functional properties of oats and to assure a consistent foundation for global health policies.


Association between chromosome abnormities and prenatal diagnosis indicators screening in the second trimester of pregnancy.
This study aimed to explore the prenatal indicators in the second trimester of pregnancy and their association with chromosome abnormities (CA) to guide decisions toward invasive diagnostic procedures. Pregnant women who underwent prenatal screening and underwent amniocentesis in the second trimester in our Hospital between June 2017 and February 2019 were included in this retrospective cohort study. The reason for amniocentesis in prenatal screening and diagnoses was extracted from the charts. Finally, 3449 pregnant women were included. Of them, 181 were with CA confirmed by amniocentesis (i.e., the CA group), while 3268 were without CA (i.e., the non-CA group). Compared with the women in the non-CA group, those in the CA group were more likely to be older (30 [27,32] vs 29 [26,31], P < .001), had higher gestational weeks (20 [19,23] vs 19 [18,23], P = .008), an increased risk of advanced maternal age (AMA) (9.4% vs 2.2%, P < .001), had an increased risk of NIPT (IRN) (5.1% vs 1.9%, P < .001), had higher rates of a parental chromosome abnormality (PCA) (1.8% vs 0.9%, P = .002), and had increased risk of trisomy 21 (IRT21) (63.0% vs 45.3%, P < .001). AMA (OR = 4.22, 95% CI: 2.35-7.58, P < .001; AUC = 0.536), IRN (OR = 10.62, 95% CI: 6.66-16.94, P < .001; AUC = 0.589), PCA (OR = 4.77, 95% CI: 2.01-11.32, P < .001; AUC = 0.584), and IRT21 (OR = 0.67, 95% CI: 0.47-0.89, P = .008; AUC = 0.515) were independently associated with CA. AMA, IRN, IRT21, and PCA during the second trimester were independently associated with CA, but their predictive values for CA were relatively low. Combining those indicators may improve the predictive value.


[A case of locally advanced residual gastric cancer treated with combined resection of multiple adjacent organs].
A 60-year-old man was diagnosed as having type 3 advanced gastric cancer in the gastric antrum and multiple liver metastases( S2, S3, S4, and S7)( cT3[ SS] N0M0H1, Stage IV). The patient received combined neoadjuvant chemotherapy with S-1 and cisplatin( CDDP). S-1( 80 mg/body/day) was administered orally for 3 weeks followed by 2 drug-free weeks as a course, and CDDP (60 mg/m2) was administered by intravenous infusion on day 8. The gastric tumor reduced in size and the liver metastases improved after 5 courses of treatment. Distal gastrectomy, D2 lymph node dissection, and partial liver resection( 4 sites) were performed. S-1 alone was continued as adjuvant chemotherapy; no recurrence was detected in 2 years and 2 months after surgery. Although there is insufficient evidence to support the benefit of surgical resection in patients with advanced gastric cancer with liver metastases, chemotherapy combined with surgical resection would improve the survival time without deterioration of quality of life of these patients. This case suggests that neoadjuvant chemotherapy is effective against advanced gastric cancer even with multiple liver metastases.


Comparing pregnancy, childbirth, and neonatal outcomes in women with different phenotypes of polycystic ovary syndrome and healthy women: a prospective cohort study.
The aim of this study was to compare pregnancy, childbirth, and neonatal outcomes in women with different phenotypes of polycystic ovary syndrome (PCOS) with healthy women. A prospective cohort study from the beginning to the end of pregnancy for 41 pregnant women with PCOS (case) and 49 healthy pregnant women (control) was completed. Based on the presence or absence of menstrual dysfunction (M), hyperandrogenism (HA), and polycystic ovaries (PCO) on ultrasound, the PCOS (case) group were divided into three phenotypes (HA + PCO (n = 22), M + PCO (n = 9), HA + M+PCO (n = 10). Pre-eclampsia, gestational diabetes, and lower birth weight among newborns were significantly higher in the PCOS case group compared to the control group especially in the phenotype HA + M+PCO (p < .05). High BMI (β = 2.40; p=.03) was the strongest predictor of pre-eclampsia in patients with PCOS. High androgen levels (free androgen index) (β = 13.71, 3.02; p < .05), was the strongest predictor of developing diabetes during pregnancy and reduced birth weight baby, respectively.These results suggest that PCOS, particularly in phenotype HA + M+PCO (p < .05), is a risk factor for adverse pregnancy and neonatal outcomes including gestational diabetes, pre-eclampsia, and reduced weight babies.


Dryness increases predation risk in efts: support for an amphibian decline hypothesis.
One hypothesis for amphibian declines is that increased dryness attributed to global climate change exposes amphibians to greater biotic threat and, consequently, greater mortality. But, little is known about behavioral responses of terrestrial amphibians to dry conditions alone or in combination with biotic threats. We used field observations and laboratory experiments to test the response of efts (terrestrial juveniles) of the eastern red-spotted newt, Notophthalmus viridescens, to separate and combined desiccation and predation risks. When only at risk of desiccation, efts moved into shade, traveled down slope, decreased activity, and adopted water-conserving postures. Efts also significantly reduced the rate of water loss by huddling and were attracted to chemical cues from conspecific efts but not from conspecific adults. Thus, efts have a variety of behaviors that reduce the risk of dehydration associated with climate change. When faced only with a predation risk, represented by adult and eft newt tissue extracts (alarm chemicals), efts reduced their activity and avoided alarm cues from both sources. When exposed to combined desiccation and predation risks, efts were less active than when exposed to either risk separately and avoided adult tissue extracts, but not eft extracts. These results suggest that under dry conditions, conspecific tissue extracts contain both attractive (huddling) and repulsive (predator-related) chemical components that induce offsetting behavioral responses. This is the first study to demonstrate moisture-dependent responses to conspecific rinses and alarm substances, underscoring the importance of considering environmental moisture and animal hydration in studies examining responses to conspecific odors and/or alarm chemicals. These results support the hypothesis that elevated dehydration risk may compromise anti-predator behavior and exacerbate amphibian population declines.


Water Activity Regulates the Q(A)(-) to Q(B) electron transfer in photosynthetic reaction centers from Rhodobacter sphaeroides.
We report on the effects of water activity and surrounding viscosity on electron transfer reactions taking place within a membrane protein: the reaction center (RC) from the photosynthetic bacterium Rhodobacter sphaeroides. We measured the kinetics of charge recombination between the primary photoxidized donor (P(+)) and the reduced quinone acceptors. Water activity (aW) and viscosity (eta) have been tuned by changing the concentration of cosolutes (trehalose, sucrose, glucose, and glycerol) and the temperature. The temperature dependence of the rate of charge recombination between the reduced primary quinone, Q(A)(-), and P(+) was found to be unaffected by the presence of cosolutes. At variance, the kinetics of charge recombination between the reduced secondary quinone (Q(B)(-)) and P(+) was found to be severely influenced by the presence of cosolutes and by the temperature. Results collected over a wide eta-range (2 orders of magnitude) demonstrate that the rate of P(+)Q(B)(-) recombination is uncorrelated to the solution viscosity. The kinetics of P(+)Q(B)(-) recombination depends on the P(+)Q(A)(-)Q(B) <--> P(+)Q(A)Q(B)(-) equilibrium constant. Accordingly, the dependence of the interquinone electron transfer equilibrium constant on T and aW has been explained by assuming that the transfer of one electron from Q(A)(-) to Q(B) is associated with the release of about three water molecules by the RC. This implies that the interquinone electron transfer involves at least two RC substates differing in the stoichiometry of interacting water molecules.


Novosphingobium lubricantis sp. nov., isolated from a coolant lubricant emulsion.
A yellow-pigmented, Gram-stain-negative, rod-shaped, non-spore-forming bacterium (strain KSS165-70T) was isolated from a coolant lubricant emulsion. The 16S rRNA gene sequence analysis of strain KSS165-70T showed high sequence similarity to the type strains of Novosphingobium subterraneum (98.1 %), Novosphingobium lentum (97.9 %) and Novosphingobium taihuense (97.8 %). Sequence similarities to type strains of all other Novosphingobium species were below 97.5 %. Ubiquinone Q-10 was detected as the major respiratory quinone. The predominant fatty acid C18 : 1ω7c and the typical 2-hydroxy fatty acid C14 : 0 2-OH were detected. The polar lipid profile contained the major lipids diphosphatidylglycerol, phosphatedylethanolamine, sphingoglycolipid, phosphatidylcholine and two unidentified phospholipids. The polyamine pattern contained the major compound spermidine. Characterization by 16S rRNA gene sequence analysis, physiological parameters, pigment analysis, and ubiquinone, polar lipid and fatty acid composition revealed that strain KSS165-70T represents a new species of the genus Novosphingobium. For this reason, we propose the name Novosphingobium lubricantis sp. nov. with the type strain KSS165-70T (=CIP 111490T=CCM 8814T).


Culture isolation and partial characterization of a Babesia sp. from a North American elk (Cervus elaphus).
Three North American yearling elk (Cervus elaphus) died with clinical symptoms suggestive of babesiosis. Babesia sp. organisms similar in morphology to B. odocoilei of white-tailed deer (Odocoileus virginianus) were observed in Giemsa-stained blood films from one of the elk. Continuous cultures of the parasite were established. Antiserum raised against the elk Babesia sp. isolate was compared to B. odocoilei specific antiserum in an immunofluorescent antibody assay; we found evidence of differences in reactivity to several Babesia spp. isolated from wildlife and domestic ruminants. Cultured parasites from the elk were not infective to either intact or splenectomized Bos taurus steers.


Severe tomato allergy (Lycopersicon esculentum).
Although tomatoes are a commonly consumed food, severe allergic reactions to tomatoes are unusual or rarely reported. Previously reported allergic manifestations to tomato include urticaria/angioedema, dermatitis, oral allergy syndrome, rhinitis, and abdominal pain. The aim of this study was to report two patients with significant immediate hypersensitivity reactions to tomato and characterize the responsible allergen. We reviewed the history and documentation of tomato-specific immunoglobulin E (IgE) of two patients with adverse symptoms after ingesting tomato. Fresh tomato extracts prepared from the skin, seeds, and flesh of red, ripe tomatoes were evaluated for total protein content and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) was performed to characterize the tomato protein. IgE enzyme-linked immunosorbent assay (ELISA) using the patients' serum against the various tomato extracts was accomplished and IgE immunoblot was performed. Percutaneous skin tests or radioallergosorbent tests (RASTs) were positive to tomato in both patients. Both adults experienced laryngeal edema and one had anaphylaxis. Similar total protein contents were found in each of the tomato extracts and gel electrophoresis revealed similar protein profile for skin and seed extracts with protein bands discernible at molecular weights of 21, 33, and 43 kDa. One patient reacted specifically to a 43-kDa protein band on IgE immunoblot. The two cases show that severe allergic reactions to tomato occur in adults and one is associated with IgE binding to a 43-kDa protein.


The Effect of a Virtual Reality-Based Intervention Program on Cognition in Older Adults with Mild Cognitive Impairment: A Randomized Control Trial.
This study aimed to investigate the association between a virtual reality (VR) intervention program and cognitive, brain and physical functions in high-risk older adults. In a randomized controlled trial, we enrolled 68 individuals with mild cognitive impairment (MCI). The MCI diagnosis was based on medical evaluations through a clinical interview conducted by a dementia specialist. Cognitive assessments were performed by neuropsychologists according to standardized methods, including the Mini-Mental State Examination (MMSE) and frontal cognitive function: trail making test (TMT) A & B, and symbol digit substitute test (SDST). Resting state electroencephalogram (EEG) was measured in eyes open and eyes closed conditions for 5 minutes each, with a 19-channel wireless EEG device. The VR intervention program (3 times/week, 100 min each session) comprised four types of VR game-based content to improve the attention, memory and processing speed. Analysis of the subjects for group-time interactions revealed that the intervention group exhibited a significantly improved executive function and brain function at the resting state. Additionally, gait speed and mobility were also significantly improved between and after the follow-up. The VR-based training program improved cognitive and physical function in patients with MCI relative to controls. Encouraging patients to perform VR and game-based training may be beneficial to prevent cognitive decline.


Electrostatic Variation of Haemagglutinin as a Hallmark of the Evolution of Avian Influenza Viruses.
Avian influenza virus is a zoonotic agent that significantly impacts public health and the poultry industry. Monitoring viral evolution and spread is crucial for surveillance and tracing programmes, which are currently based on serological or DNA sequencing-phylogenetics analysis. However, virus-host interactions, antigenic drift and spreading of viral clades strongly depend on variation in the surface features of capsid proteins. We report here that in silico comparative structural analysis of haemagglutinin can reveal relevant evolutionary fingerprints, particularly when integrated with sequence-based analyses. Phylogenetic analyses of H9 viral strains from wild birds and poultry, performed with different methods, reliably led to clustering of viruses into five main groups. Subsequent comparison of structural features showed congruence between such clustering and surface electrostatic fingerprints. These latter fingerprints relate group-specific variations in electrostatic charges and isocontours to well-known haemagglutinin sites involved in the modulation of immune escape and host specificity. This work suggests that the integration of structural and sequence comparisons may enhance investigations of trends and relevant mechanisms in viral evolution.


Role of bone morphogenetic proteins in sprouting angiogenesis: differential BMP receptor-dependent signaling pathways balance stalk vs. tip cell competence.
Before the onset of sprouting angiogenesis, the endothelium is prepatterned for the positioning of tip and stalk cells. Both cell identities are not static, as endothelial cells (ECs) constantly compete for the tip cell position in a dynamic fashion. Here, we show that both bone morphogenetic protein 2 (BMP2) and BMP6 are proangiogenic in vitro and ex vivo and that the BMP type I receptors, activin receptor-like kinase 3 (ALK3) and ALK2, play crucial and distinct roles in this process. BMP2 activates the expression of tip cell-associated genes, such as delta-like ligand 4 (DLL4) and kinase insert domain receptor (KDR), and p38-heat shock protein 27 (HSP27)-dependent cell migration, thereby generating tip cell competence. Whereas BMP6 also triggers collective cell migration via the p38-HSP27 signaling axis, BMP6 induces in addition SMAD1/5 signaling, thereby promoting the expression of stalk cell-associated genes, such as hairy and enhancer of split 1 (HES1) and fms-like tyrosine kinase 1 (FLT1). Specifically, ALK3 is required for sprouting from HUVEC spheroids, whereas ALK2 represses sprout formation. We demonstrate that expression levels and respective complex formation of BMP type I receptors in ECs determine stalk vs. tip cell identity, thus contributing to endothelial plasticity during sprouting angiogenesis. As antiangiogenic monotherapies that target the VEGF or ALK1 pathways have not fulfilled efficacy objectives in clinical trials, the selective targeting of the ALK2/3 pathways may be an attractive new approach.-Benn, A., Hiepen, C., Osterland, M., Schütte, C., Zwijsen, A., Knaus, P. Role of bone morphogenetic proteins in sprouting angiogenesis: differential BMP receptor-dependent signaling pathways balance stalk vs. tip cell competence.


Sugar glues for broken neurons.
Proteoglycans (PGs) regulate diverse functions in the central nervous system (CNS) by interacting with a number of growth factors, matrix proteins, and cell surface molecules. Heparan sulfate (HS) and chondroitin sulfate (CS) are two major glycosaminoglycans present in the PGs of the CNS. The functionality of these PGs is to a large extent dictated by the fine sulfation patterns present on their glycosaminoglycan (GAG) chains. In the past 15 years, there has been a significant expansion in our knowledge on the role of HS and CS chains in various neurological processes, such as neuronal growth, regeneration, plasticity, and pathfinding. However, defining the relation between distinct sulfation patterns of the GAGs and their functionality has thus far been difficult. With the emergence of novel tools for the synthesis of defined GAG structures, and techniques for their characterization, we are now in a better position to explore the structure-function relation of GAGs in the context of their sulfation patterns. In this review, we discuss the importance of GAGs on CNS development, injury, and disorders with an emphasis on their sulfation patterns. Finally, we outline several GAG-based therapeutic strategies to exploit GAG chains for ameliorating various CNS disorders.


Reactions of difunctional electrophiles with functionalized aryllithium compounds: remarkable chemoselectivity by flash chemistry.
Flash chemistry using flow microreactors enables highly chemoselective reactions of difunctional electrophiles with functionalized aryllithium compounds by virtue of extremely fast micromixing. The approach serves as a powerful method for protecting-group-free synthesis using organolithium compounds and opens a new possibility in the synthesis of polyfunctional organic molecules.


Phenotypic and functional stability of leukocytes from human peripheral blood samples: considerations for the design of immunological studies.
Human peripheral blood mononuclear cells (PBMCs) are extensively used for research of immune cell functions, identification of biomarkers and development of diagnostics and therapeutics for human diseases, among others. The assumption that "old blood samples" are not appropriate for isolation of PBMCs for functional assays has been a dogma in the scientific community. However, partial data on the impact of time after phlebotomy on the quality and stability of human PBMCs preparations impairs the design of studies in which time-controlled blood sampling is challenging such as field studies involving multiple sampling centers/sites. In this study, we evaluated the effect of time after phlebotomy over a 24 h time course, on the stability of human blood leukocytes used for immunological analyses. Blood samples from eight healthy adult volunteers were obtained and divided into four aliquots, each of which was left in gentle agitation at room temperature (24 °C) for 2 h (control), 7 h, 12 h and 24 h post phlebotomy. All samples at each time point were independently processed for quantification of mononuclear cell subpopulations, cellular viability, gene expression and cytokine secretion. A 24 h time delay in blood sample processing did not affect the viability of PBMCs. However, a significantly lower frequency of CD3+ T cells (p < 0.05) and increased LPS-induced CXCL10 secretion were observed at 12 h post-phlebotomy. Alterations in TNFα, CCL8, CCR2 and CXCL10 gene expression were found as early as 7 h after blood sample procurement. These data reveal previously unrecognized early time-points for sample processing control, and provide an assay-specific time reference for the design of studies that involve immunological analyses of human blood samples.


[Antagonistic activity of novel green microalgae strain].
Screening of novel microalgae strains for the presence of pronounced antagonistic (antibacterial) activity against opportunistic bacteria. 11 pure cultures of green unicellular algae isolated from fresh and salt basins of Orenburg region were studied for the presence of antagonistic activity against 4 test-strains of opportunistic bacteria by a photometric method. The effect of water extracts of microalgae Astermonas gracilis on the speed of self-purification of brine from Escherichia coli as well as antibacterial activity of peloid were evaluated under co-cultivation conditions. Pure cultures of green unicellular algae Scenedesmus obliquus (Turpin) Kütz, Scenedesmus magnus Meyen var. magnus, Pediastru duplex Meyen var. duplex, Chlorella vulgaris Bory, Monoraphidium arcuatum (Korschikov) Hindak (=Ankistrodesmus arcuatus Korschikov), Dictyosphaerium sp. had the most pronounced antagonistic activit against opportunistic bacteria. Water extract ofA. gracilis microalgae accelerated brine self-purification fro E. coli due to antibacterial effect. Peloid containing extracts of microorganism cells had a pronounced antibacterial effect against opportunistic bacteria. Antagonistic substances localized inside cells of microalgae increased the speed of allochthonic microorganism elimination that is one of the mechanisms of self-purification of a basin and antibacterial effect of peloid. The novel green microalgae strains studied due to the presence of pronounced antagonistic activity may have a wide practical application.


Root growth-promoting activity of unsaturated oligomeric uronates from alginate on carrot and rice plants.
The root elongation activity of unsaturated oligomeric uronates from alginate on carrot and rice plants was investigated. Unsaturated oligomeric uronates were prepared by digesting polymannuronate (PM) and polyguluronate (PG) with an alginate lyase purified from Pseudoalteromonas sp. strain No. 272. The root elongation activity was measured by elongation in length of carrot- and rice-excised root incubated in the B5-medium containing 0.8% agar in the dark. PM and PG showed no activity, but the enzymatic digestion mixtures of PG had promoting activity on roots of both plants at a final concentration of 0.5 mg/ml. The maximum activity was obtained at 0.75 mg/ml. The dependence of activity on degree of polymerization of the uronates was tested and the pentamer was most active, but the mechanism of the action of unsaturated uronates on the cells remains to be solved.


Insights into Concomitant Atrial Fibrillation and Chronic Kidney Disease.
Chronic kidney disease (CKD) shows a high prevalence and is characterized by progressive and irreversible loss of renal function. It is also associated with a high risk of cardiovascular disease. The CKD population often suffers from atrial fibrillation (AF), which is associated with cardiovascular and all-cause mortality. There is a pernicious bidirectional relationship between CKD and AF: renal dysfunction can help promote AF initiation and maintenance, while unmanageable AF often accelerates kidney function deterioration. Therefore, it is necessary to determine the interactive mechanisms between CKD and AF for optimal management of patients. However, due to renal function impairment and changes in the pharmacokinetics of anticoagulants, it is still elusive to formulate a normative therapeutic schedule for the AF population concomitant with CKD especially those with end-stage kidney failure. This review describes the possible molecular mechanisms linking CKD to AF and existing therapeutic options.


Macrophage targeted N-(2-hydroxypropyl)methacrylamide conjugates for magnetic resonance imaging.
This study describes the synthesis, characterization and in vitro evaluation of targetable N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-gadolinium (Gd) chelates for enhanced magnetic resonance imaging (MRI) of macrophages. Copolymers of HPMA, methacryloylglycylglycyl-mannosamine (MA-GG-ManN), aminopropylmethacrylamide-benzyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (APMA-DOTA), and 5-(3-(methacryloylaminopropyl)thioureidyl) fluorescein (MA-AP-FITC) were synthesized and characterized. Gd was chelated to the polymeric precursors. The conjugates were characterized for gadolinium content by inductively coupled plasma optical emission spectrometry (ICP-OES) and T1 relaxivity (r1) at room temperature and 1.5 T. The effect of ManN content on mannose receptor mediated uptake of THP-1 human macrophages was evaluated as a function of time and temperature. The polymer conjugates showed relaxivities in the range of 21.8-24.9 s(-1) mM(-1) Gd. Relaxivities of the conjugates per mM Gd were up to 7 times higher than that of a commercially available MR contrast agent Gd-DOTA. Significantly (p < 0.042) higher uptake was observed for targeted conjugates compared to nontargeted conjugates. The uptake of polymeric conjugates was time and concentration dependent and appears to be mannose receptor mediated. The increased relaxivity coupled with the ability to target these carriers to cells containing ManN receptors shows promise for the application of these agents in clinical MR imaging of macrophage mediated malignancies.


Dosimetric optimization of a conical breast brachytherapy applicator for improved skin dose sparing.
Both the AccuBoost D-shaped and round applicators have been dosimetrically characterized and clinically used to treat patients with breast cancer. While the round applicators provide conformal dose coverage, under certain clinical circumstances the breast skin dose may be higher than preferred. The purpose of this study was to modify the round applicators to minimize skin dose while not substantially affecting dose uniformity within the target volume and reducing the treatment time. In order to irradiate the intended volume while sparing critical structures such as the skin, the current round applicator design has been augmented through the addition of an internal truncated cone (i.e., frustum) shield. Monte Carlo methods and clinical constraints were used to design the optimal cone applicator. With the cone applicator now defined as the entire assembly including the surrounding tungsten-alloy shell holding the HDR 192Ir source catheter, the applicator height was reduced to diminish the treatment time while minimizing skin dose. Monte Carlo simulation results were validated using both radiochromic film and ionization chamber measurements based on established techniques. The optimal cone applicators diminished the maximum skin dose by 15%-32% (based on the applicator diameter and breast separation) with the tumor dose reduced by less than 3% for a constant exposure time. Furthermore, reduction in applicator height diminished the treatment time by up to 30%. Radiochromic film and ionization chamber dosimetric results in phantom agreed with Monte Carlo simulation results typically within 3%. Larger differences were outside the treatment volume in low dose regions or associated with differences between the measurement and Monte Carlo simulation environments. A new radiotherapy treatment device was developed and dosimetrically characterized. This set of applicators significantly reduces the skin dose and treatment time while retaining uniform target dose.


Targeted delivery of siRNA by nonviral vectors: lessons learned from recent advances.
siRNA is a potential therapeutic candidate for treating genetic and acquired diseases, including cancer, that cannot be easily cured by conventional drugs. The limiting step for siRNA-based therapy is the delivery of the oligonucleotide into target cells by systemic administration. Several strategies, including chemical modification and nanoparticle formulation, have been developed to improve the delivery of siRNA into a variety of target tissues. In this review, significant advances in the field over the past year are highlighted and key findings and technologies are discussed. First, the elucidation of the liver-targeting mechanism of lipid-conjugated siRNA, which may lead to further optimization of conjugates, is presented. The development of different materials and formulations to overcome delivery barriers and enhance RNAi efficiency is also presented, in addition to strategies to manage siRNA immunotoxicity (eg, chemical modification). Finally, remaining challenges and future perspectives in the field are discussed.


[The indications for the curative radiotherapy of non-small-cell bronchial carcinoma. Reflections from a clinical viewpoint].
To find out the indications for treatment and selection criteria of patients who will profit from curative radiotherapy. A literature review and own data concerning the lymphogenous metastatic pathways and incidence of involvement of loco-regional lymph nodes are used to define the biological treatment volume of a curative irradiation. A retrospective analysis of 266 patients with non-small-cell lung cancer (NSCLC) was performed. The metastatic pathway of the lymphogenous spread was analysed based on pretherapy CT scan as well as clinical examination. Only carefully selected patients under similar selection criteria as for curative surgery are suitable to undergo a curative radiotherapy. The biological treatment volume for curative irradiation has to include the primary with a margin, the ipsilateral hilar nodes as well as the whole mediastinum including the subcarinal lymph nodes, but not the contralateral hilar and supraclavicular lymph nodes. The survival rate of patients with N3 nodal stage are 0%. A 3-step concept for curative radiotherapy until 70 Gy is proposed. A limited number of patients with NSCLC, carefully selected as for surgery, are suitable to undergo a curative radiotherapy with 70 Gy. This will enable to demonstrate a curative value of radiotherapy.


Stem cell transplantation and mesenchymal cells to treat autoimmune diseases.
Since the start of the international stem cell transplantation project in 1997, over 2000 patients have received a haematopoietic stem cell transplant (HSCT), mostly autologous, as treatment for a severe autoimmune disease, the majority being multiple sclerosis (MS), systemic sclerosis (SSc) and Crohn's disease. There was an overall 85% 5-year survival and 43% progression-free survival. Around 30% of patients in all disease subgroups had a complete response, often durable despite full immune reconstitution. In many cases, e.g. systemic sclerosis, morphological improvement such as reduction of skin collagen and normalization of microvasculature was documented, beyond any predicted known effects of intense immunosuppression alone. It is hoped that the results of the three running large prospective randomized controlled trials will allow modification of the protocols to reduce the high transplant-related mortality which relates to regimen intensity, age of patient, and comorbidity. Mesenchymal stromal cells (MSC), often incorrectly called stem cells, have been the intense focus of in vitro studies and animal models of rheumatic and other diseases over more than a decade. Despite multiple plausible mechanisms of action and a plethora of positive in vivo animal studies, few randomised controlled clinical trials have demonstrated meaningful clinical benefit in any condition so far. This could be due to confusion in cell product terminology, complexity of clinical study design and execution or agreement on meaningful outcome measures. Within the rheumatic diseases, SLE and rheumatoid arthritis (RA) have received most attention. Uncontrolled multiple trial data from over 300 SLE patients have been published from one centre suggesting a positive outcome; one single centre comparative study in 172 RA was positive. In addition, small numbers of patients with Crohn's disease, multiple sclerosis, primary Sjögren's disease, polymyositis/dermatomyositis and type II diabetes mellitus have received MSC therapeutically. The possible reasons for this apparent mismatch between expectation and clinical reality will be discussed.


Profiling serum antibodies to Mycobacterium tuberculosis proteins in rhesus monkeys with nontuberculous Mycobacteria.
Recent evidence indicates that the prevalence of diseases caused by nontuberculous mycobacteria (NTM) has been increasing in both human and animals. In this study, antibody profiles of NTM in rhesus monkeys (Macaca mulatta) were determined and compared with those of monkeys infected with Mycobacterium tuberculosis complex (MTBC). Antibodies against 10 M. tuberculosis proteins, purified protein derivative (PPD), and mammalian old tuberculin (MOT) were detected in 14 monkeys naturally infected with NTM by indirect ELISA. Sera from 10 monkeys infected with MTBC and 10 healthy monkeys were set as controls. All antigens showed high serological reactivities to MTBC infections and low reactivities in healthy monkeys. NTM infections showed strong antibody responses to MOT and PPD; moderate antibody responses to 16kDa, U1, MPT64L, 14kDa, and TB16.3; and low antibody responses to 38kDa, Ag85b, CFP10, ESAT-6, and CFP10-ESAT-6. According to the criteria of MTBC, only CFP10, ESAT-6, and CFP10-ESAT-6 showed negative antibody responses in all NTM infections. Taken together, these results suggest that positive results of a PPD/MOT-based ELISA in combination with results of antibodies to M. tuberculosis-specific antigens, such as CFP10 and ESAT-6, could discriminate NTM and MTBC infections. Two positive results indicate an MTBC infection, and a negative result for an M. tuberculosis-specific antigen may preliminarily predict an NTM infection.


Concurrent endobronchial carcinoid tumor and sarcoidosis.
Sarcoidosis is an inflammatory disease of unknown cause which is characterized by the presence of noncaseating granulomas. The association of sarcoidosis with malignancy has been an issue and remains controversial. We herein report endobronchial carcinoid tumor in a patient with sarcoidosis diagnosed by nasal mucosal biopsy, excisional biopsy of cervical lymph nodes and mediastinal lymph node dissection.


[Unstable angina: from physiopathology to therapeutics].
Unstable angina is a term which encompasses several clinical syndromes (crescendo angina, angina de novo, resting angina, postinfarction angina), intermediary between stable angina and myocardial infarction. The results of coronary angioscopy have allowed differentiation of accelerated effort angina which seems related to ulceration of an atheromatous plaque from resting angina, more commonly associated with intraluminal thrombosis. The diagnosis of unstable angina is clinical and justifies immediate hospital admission to a coronary care unit because of the risk of myocardial infarction and/or sudden death. Medical management comprises triple anti-ischemic therapy (nitrate derivatives, betablockers, calcium antagonists), anticoagulants and platelet antiagregants. Randomised therapeutic trials versus placebo have shown that this treatment decreases the incidence of refractory angina and myocardial infarction. Several studies are under way to assess the role of thrombolytic therapy in unstable angina. When unstable angina is refractory to maximal medical therapy, emergency coronary angiography should be performed. However the outcome is usually favourable and coronary angiography can be performed several days after the acute event. The coronary lesion responsible for unstable angina is often "complex", an eccentric, irregular, severe stenosis or appearances of thrombosis. Whenever possible, depending on the coronary lesion, myocardial revascularisation by coronary angioplasty or aorto-coronary bypass should be proposed. Surgical treatment has been shown to be more effective (symptomatic relief, improved survival) than medical therapy in patients with triple vessel disease. However, the results of studies comparing medical or surgical treatment with coronary angioplasty are not yet available.


Causal interaction in high frequency turbulence at the biosphere-atmosphere interface: Structure-function coupling.
At the biosphere-atmosphere interface, nonlinear interdependencies among components of an ecohydrological complex system can be inferred using multivariate high frequency time series observations. Information flow among these interacting variables allows us to represent the causal dependencies in the form of a directed acyclic graph (DAG). We use high frequency multivariate data at 10 Hz from an eddy covariance instrument located at 25 m above agricultural land in the Midwestern US to quantify the evolutionary dynamics of this complex system using a sequence of DAGs by examining the structural dependency of information flow and the associated functional response. We investigate whether functional differences correspond to structural differences or if there are no functional variations despite the structural differences. We base our analysis on the hypothesis that causal dependencies are instigated through information flow, and the resulting interactions sustain the dynamics and its functionality. To test our hypothesis, we build upon causal structure analysis in the companion paper to characterize the information flow in similarly clustered DAGs from 3-min non-overlapping contiguous windows in the observational data. We characterize functionality as the nature of interactions as discerned through redundant, unique, and synergistic components of information flow. Through this analysis, we find that in turbulence at the biosphere-atmosphere interface, the variables that control the dynamic character of the atmosphere as well as the thermodynamics are driven by non-local conditions, while the scalar transport associated with CO2 and H2O is mainly driven by short-term local conditions.


Expansion and characterization of regulatory T cell populations from Korean kidney transplant recipients.
The development of immunosuppressants has enabled remarkable progress in kidney transplantation (KT). However, current immunosuppressants cannot induce immune tolerance, and their nonspecific immunosuppressive effects result in many adverse effects. Regulatory T cells (Tregs) play crucial roles in controlling all specific immune responses. This study evaluated the distribution of Tregs and their effects on kidney allograft function in Korean KT recipients. We enrolled 113 KT recipients with stable graft function. The differentiation and expansion of Tregs were examined by flow cytometry to compare the Tregs subpopulations. Among the 113 patients, 73 (64.6%) were males, and the mean follow-up period from KT to Tregs collection was 147.5 + 111.3 months. Patients receiving lower doses of cyclosporine had higher proportions of Tregs than those with higher doses of cyclosporine (36.3 + 21.6 vs 17.0 + 12.7, P = .010, respectively). Patients taking cyclosporine tended to have higher Tregs numbers than those taking tacrolimus (94.7 + 158.1 vs 49.3 + 69.4, P = .095, respectively). However, no significant association was observed between Tregs and allograft dysfunction in the cox proportional hazard model. Tregs counts may be associated with the type and dose of immunosuppressants. However, no significant relationship was found between Tregs and kidney allograft function in stable KT recipients.


CalbindinD28k- and parvalbumin-immunoreactive neurons form complementary sublaminae in the rat superior colliculus.
By using light microscopic immunocytochemistry and computer analysis, we have mapped the distributions of two calcium-binding proteins (CaBPs), calbindinD28k (CB) and parvalbumin (PV), in the rat superior colliculus (SC). The patterns of CaBP expression were complementary. A band of heavily labeled, medium-sized CB-immunoreactive cells (CB-cells) was centered in the optic layer (OL), whereas PV-immunoreactive cells (PV-cells) were found predominantly in the intermediate gray layer (IGL), where they were clustered within patches of PV-labeled fibers. The superficial gray layer (SGL) could be divided into two sublaminae. CB-cells were found mostly in the dorsal half of the SGL, whereas PV-cells were scattered throughout the ventral SGL and the dorsal OL. Most of the CaBP-immunoreactive cells in the SGL were small bipolar cells with vertically oriented dendrites; however, there were also some PV-cells with horizontally oriented dendrites. Quantitative analysis of the CaBP distributions reinforced our observations that these cells are distributed in complementary tiers that are not restricted to the traditional laminae. The size and shape of some of these tiers were determined from a three-dimensional reconstruction of serial sections. The complementarity of the CaBP-immunoreactive tiers was also confirmed by fluorescence microscopy of double-labeled sections, in which few if any double-labeled neurons were observed. Complementary tiers of CB-cells and PV-cells have been observed previously in the SC of the cat. The present results demonstrate them in another species and further suggest that there are functional sublaminae in the SC that can be distinguished by CaBP content.


Conservative Management of Horizontal Root Fracture - A Case Series.
Root fracture has been defined as a fracture involving dentin, cementum, pulp and periodontal ligament. Depending on the level of the fracture line various treatment modalities may be employed by the clinician to promote healing. The following case reports highlight how changes in technique allow for conservative management of horizontal root fractures at different levels. This approach allows the patient to retain their natural dentition at an affordable cost and provide a viable alternative to the use of more invasive and expensive alternatives. These patients presented with complaints of pain and mobility in upper front tooth region following trauma. Diagnosis was confirmed on the basis of intra-oral periapical radiographs following which non-surgical root canal treatment was performed.


Bilateral maxillary fused primary incisors accompanied by succedaneous supernumerary teeth: report of a case.
A rare case of fusion between maxillary primary central incisors and supplemental teeth occurring bilaterally, accompanied by succedaneous supernumerary teeth, is presented. The patient was an 8.5-year-old Japanese boy. Intraoral examination revealed fusion of left and right maxillary primary central incisors to supplemental teeth, which had labial and lingual grooves. The maxillary primary lateral incisors were present. Radiographs showed that the fused teeth had separate roots, pulp chambers and root canals. There were two impacted supernumerary teeth and eruption of the permanent maxillary central incisors was delayed. Treatment was performed and the fused primary teeth and the impacted supernumerary teeth were extracted. After 6 months observation, surgical exposure of the two crowns of the permanent maxillary central incisors was performed. The teeth began to erupt and have since been kept under observation.


Preclinical to phase II amyloid beta (Aβ) peptide modulators under investigation for Alzheimer's disease.
Alzheimer disease (AD) is the most common form of dementia and its incidence is increasing at an alarming rate all over the world. The pathophysiology of AD is characterized by chronic, progressive neurodegeneration which involves early synaptotoxicity. One of the most obvious pathological feature of AD is the accumulation of amyloid-β (Aβ) in the brain. Since current treatment options only provide symptomatic help and Aβ is thought to underlie early synaptic pathology, Aβ reduction or modulation in the brain may be a promising therapeutic strategy in preventing and /or reversing AD-related dysfunction. Areas covered: This paper outlines and evaluates the current landscape of preclinical and clinical studies focusing on modulating Aβ pathophysiology. Data and analysis for this review were procured from PubMed, clinicaltrials.gov and Alzforum. Expert opinion: According to current knowledge, reducing Aβ production offers numerous treatment options. However, targeting the initial steps by pharmacological interference with secretases is challenging due to the emergence of various side effects. The most promising approach seems to be the prevention of early Aβ oligomerization. Combination approaches targeting both Aβ and tau would seem to be another promising strategy that could have beneficial effects through the course of the disease.


Efficient and robust quantum Monte Carlo estimate of the total and spin electron densities at nuclei.
The computational performance of two different variational quantum Monte Carlo estimators for both the electron and spin densities on top of nuclei are tested on a set of atomic systems containing also third-row species. Complications due to an unbounded variance present for both estimators are circumvented using appropriate sampling strategies. Our extension of a recently proposed estimator [Phys. Rev. A 69, 022701 (2004)] to deal with heavy fermionic systems appears to provide improved computational efficiency, at least an order of magnitude, with respect to alternative literature approaches for our test set. Given the importance of an adequate sampling of the core region in computing the electron density at a nucleus, a further reduction in the overall simulation cost is obtained by employing accelerated sampling algorithms.


Temporal relationship between the onset of daily gonadotrophin surges and of puberty in female golden hamsters.
Daily rhythms of LH and FSH release commence on day 16 or 17 of age in the prepubertal female golden hamster, 2-3 weeks before regular 4-day oestrous cycles begin. We tested the hypothesis that the daily surges of gonadotrophin regulate, at least in part, rate of sexual maturation and, hence, age at puberty. We predict that an advance or a delay in the initiation of the daily rhythm should result in a corresponding advance or delay in the day of puberty. In the first test, the onset of daily gonadotrophin surges was advanced by gonadotrophin-releasing hormone (GnRH) injections; in the second test, the onset was delayed by daily injection of phenobarbital sodium (PB). The day of the first of at least three consecutive post-ovulatory vaginal discharges was used as an index of the age at puberty. Gonadotrophin-releasing hormone (50 ng/0.1 ml saline per animal) was injected at 16.30 h on days 8-17 of age. These injections initiated a daily mid-afternoon surge of LH about 8 days before the onset of the daily rhythm of gonadotrophins in saline-injected controls and the day of first vaginal discharge was advanced by 4 days compared with saline-injected controls (32.0 +/- 1.8 days vs 36.3 +/- 1.0 days; P less than 0.001). Phenobarbital sodium (100 mg/kg body wt), injected at 13.30 h from 16 to 25 days of age, blocked daily surges of gonadotrophin observed in controls by day 18.(ABSTRACT TRUNCATED AT 250 WORDS)


Inheritance of intersex disorders.
Intersex disorders result from abnormalities of the sex chromosomes, gonads, internal and external genitalia, sex hormones and gender role. This article reviews the literature on intersex disorders, outlining the characteristics and mode of inheritance, if known, of each. For appropriate and effective management and counselling of patients and their families, physicians must have a good knowledge of the development of the genital tract and of the interaction between genetic sex and environmental influences.


Preclinical activities of Cassia tora Linn against aging-related diseases.
Globally, an aging population is increasing, and aging is a natural physiological process and a major risk factor for all age-related diseases. It seriously threatens personal health and imposes a great economic burden. Therefore, there is a growing scientific interest in strategies for well-aging with prevention and treatment of age-related diseases. The seed, root, stem or leaves of Cassia tora Linn. are useful for anti-bacteria, anti-hyperlipidemia and anti-obesity due to its pharmacological activities such as anti-inflammation and anti-oxidant both in vitro and in vivo. Nevertheless, no clinical trials have been attempted so far, therefore here we would like to understand the current preclinical activities for aging-related disease models including cataract, metabolic dysfunction and neurodegeneration, then discuss their preparation for clinical trials and perspectives.


Organic-inorganic nanocomposites via directly grafting conjugated polymers onto quantum dots.
Nanocomposites of poly(3-hexylthiophene)-cadmium selenide (P3HT-CdSe) were synthesized by directly grafting vinyl-terminated P3HT onto [(4-bromophenyl)methyl]dioctylphosphine oxide (DOPO-Br)-functionalized CdSe quantum dot (QD) surfaces via a mild palladium-catalyzed Heck coupling, thereby dispensing with the need for ligand exchange chemistry. The resulting P3HT-CdSe nanocomposites possess a well-defined interface, thus significantly promoting the dispersion of CdSe within the P3HT matrix and facilitating the electronic interaction between these two components. The photophysical properties of nanocomposites were found to differ from the conventional composites in which P3HT and CdSe QDs were physically mixed. Solid-state emission spectra of nanocomposites suggested the charge transfer from P3HT to CdSe QDs, while the energy transfer from 3.5 nm CdSe QD to P3HT was implicated in the P3HT/CdSe composites. A faster decay in lifetime further confirmed the occurrence of charge transfer in P3HT-CdSe nanocomposites.


Skeletal anatomy of the pectoral fin in mudskipper species from terrestrial and aquatic habitats.
Mudskippers are a group of amphibious fishes in the family Oxudercidae, whose species inhabit a range of habitats from mostly aquatic to mostly terrestrial. Most of our understanding about habitat preference comes from natural history observations, particularly where they are collected (i.e., low intertidal vs. high intertidal regions). Mudskippers have undergone several morphological changes to accommodate a terrestrial life, including major changes to the pectoral and pelvic girdles. These changes result in a novel crutching gait, which mudskippers use to move over land. Though the appendicular morphology and crutching gait of mudskippers have been described in some species, few studies have compared skeletal structures across the family. In our study, we use microcomputed tomography (µCT) scans to compare the skeletal anatomy of 16 species of aquatic and terrestrial mudskippers. Linear discriminant analysis is used to analyze measurements obtained through geometric morphometrics (landmarks). We found bone structures of the pectoral region in the terrestrial group were significantly longer and wider than those in the aquatic group. Furthermore, a significant difference in anatomy is shown between terrestrial and aquatic genera with both axial and appendicular elements contributing to the separation between groups. This work describes the differences in skeletal morphology associated with terrestriality in mudskippers and provides valuable insights into specific anatomical characteristics contributing to their adaptation to novel environments.


CLONE SPECIFIC SEGREGATION IN THE SEA ANEMONE ANTHOPLEURA-ELEGANTISSIMA.
The anemones in a single continuous aggregation of the sea anemone Anthopleura elegantissima are observed to resemble each other in two obvious ways: (1) all have the same color pattern, and (2) all individuals having developed gonads are of the same sex. Furthermore, while sustained contact between individuals within an aggregation is very common, contact between individuals from different aggregations has been found to initiate an intraspecific aggressive response resulting in the separation of these individuals (Francis, 1973). These animals are known to reproduce asexually by longitudinal fission, and it is therefore concluded that the aggregations must each be comprised of anemones from a single clone. It seems to me improbable that anything other than genetic identity could account for aggregations of up to thousands of individuals of the same sex, having the same color patterns and showing mutual tolerance for contact with each other and for no other members of the species. Even among anemones within a single clone, the presence of gonads containing gametes is shown to be related to size. Anemones smaller than 0.2 g dry wt consistently lack developed gonads, while some proportion of those over 0.2 g have gonads with gametes. In the field, adjacent clonal groups are observed to remain separated from each other. In the laboratory a mixed group of anemones will reaggregate into isolated uniclonal groups, implying that clone specific segregation is actively accomplished by the anemones. Living in aggregations has a number of potential advantages for the anemones such as reducing their effective surface area and thereby reducing water loss and the battering effects of wave action, excluding interspecific competition for space by promoting effective blanketing of an area, and allowing for cooperation in the capture and holding of larger prey. The function for the anemones of clone specific segregation and separation is not yet clear (see Francis, 1973), however the phenomenon is not without parallel since some other coelenterates as well as some bryozoans have also been observed to respond differently to contact with a genetically identical conspecific than to contact with other conspecifics.