Risk assessment of 'Candidatus Liberibacter solanacearum' transmission by the psyllids Bactericera trigonica and B. tremblayi from Apiaceae crops to potato.
Candidatus Liberibacter solanacearum (Lso) is bacterium transmitted by psyllids to Solanaceae and Apiaceae plants. So far, Lso is found in Europe affecting Apiaceae. In the Mediterranean region, Bactericera trigonica is the only known vector of Lso, but the leek-onion psyllid Bactericera tremblayi is another widespread psyllid and potential vector of Lso. Commonly, carrot, leek and potato are cultivated in the same zones and it is uncertain if these psyllid species are able to transmit Lso to potato plants. Here, we assessed the transmission of Lso by B. trigonica and B. tremblayi to potato plants. B. trigonica showed preference to ingest from the phloem, settle and oviposit on carrot and celery but not on potato. This was correlated with high Lso transmission rates to both carrot (80%) and celery (70%) but very low to potato (≤3%). B. tremblayi preferred leek over carrot and potato, the latter being the less preferred host. B. tremblayi readily ingested from the phloem of infected carrots but failed to transmit Lso from carrot to carrot. Our study shows that the risk of Lso transmission from Apiaceae to potato by B. trigonica is very low, and that B. tremblayi is not a likely vector of Lso.


From inflammation to gastric cancer: Role of Helicobacter pylori.
Gastric cancer is a multifactorial disease and a leading cause of mortality and the risk factors for this include environmental factors and factors that influence host-pathogen interaction and complex interplay between these factors. Gastric adenocarcinomas are of two types, namely intestinal and diffuse type, and Helicobacter pylori (H. pylori) infection has been suspected of being causally linked to the initiation of chronic active gastritis, which leads to adenocarcinoma of the intestinal type. Even though most individuals with H. pylori infection do not show any clinical symptoms, long-term infection leads to inflammation of gastric epithelium and approximately 10% of infected patients develop peptic ulcers and 1-3% of patients develop gastric adenocarcinoma. Among the several mechanisms involved in tumorigenesis, CagA and peptidoglycan of H. pylori, which enter the infected gastric epithelial cells play an important role by triggering oncogenic pathways. Inflammation induced by H. pylori in gastric epithelium, which involves the cyclooxygenase-2/prostaglandin E2 pathway and IL-1β, is also an important factor that triggers chronic active gastritis and adenocarcinoma. H. pylori infection induced oxidative stress and dysregulated E-cadherin/β-catenin/p120 interactions and function also play a critical role in tumorigenesis. Environmental and dietary factors, in particular salt intake, are known to modify the pathogenesis induced by H. pylori. Gastric cancer induced by H. pylori appears to involve several mechanisms, making this mode of tumorigenesis a highly complicated process. Nevertheless, there are many events in this tumorigenesis that remain to be clarified and investigated.


Multi-Biosignal Analysis for Epileptic Seizure Monitoring.
Persons who suffer from intractable seizures are safer if attended when seizures strike. Consequently, there is a need for wearable devices capable of detecting both convulsive and nonconvulsive seizures in everyday life. We have developed a three-stage seizure detection methodology based on 339 h of data (26 seizures) collected from 10 patients in an epilepsy monitoring unit. Our intent is to develop a wearable system that will detect seizures, alert a caregiver and record the time of seizure in an electronic diary for the patient's physician. Stage I looks for concurrent activity in heart rate, arterial oxygenation and electrodermal activity, all of which can be monitored by a wrist-worn device and which in combination produce a very low false positive rate. Stage II looks for a specific pattern created by these three biosignals. For the patients whose seizures cannot be detected by Stage II, Stage III detects seizures using limited-channel electroencephalogram (EEG) monitoring with at most three electrodes. Out of 10 patients, Stage I recognized all 11 seizures from seven patients, Stage II detected all 10 seizures from six patients and Stage III detected all of the seizures of two out of the three patients it analyzed.


Effect of actor depression on observer attributions: existence and impact of negative attributions toward the depressed.
This experiment examined whether others explain the successes and failures of depressed versus nondepressed people differently and how these attributions are related to affective and behavioral reactions to a request for psychological help. Ss reported attributions about the success and failure experiences of hypothetical depressed and nondepressed people. Ss also responded to a hypothetical request for psychological help by indicating their attributions, affective reactions, willingness to help, and desire for future social contact. As hypothesized, Ss displayed more negative attributions toward depressed people. Replicating prior research, Ss responded to the depressive's request for help with mixed emotional and behavioral reactions. Path analyses revealed that attributions influenced affective reactions, which influenced willingness to help; but a more complex pattern emerged from the analysis of desire for future social contact. Results are discussed in terms of the interpersonal impact and possible causes of negative attributions about the experiences of depressed people.


Nitric oxide modulates cardiac performance in the heart of Anguilla anguilla.
Nothing is known about the effects of nitric oxide (NO) on cardiac performance in fish. Using an in vitro working heart preparation that generates physiological values of output pressure, cardiac output and ventricular work and power, we assessed the effects of NO on the cardiac performance of the eel Anguilla anguilla. We examined basal cardiac performance (at constant preload, afterload and heart rate), the effects of cholinergic stimulation and the Frank-Starling response (preload-induced increases in cardiac output at constant afterload and heart rate). The NO synthase (NOS) inhibitors NG-monomethyl-L-arginine (L-NMMA) and L-N5(1-iminoethyl)ornithine (L-NIO), the guanylate cyclase inhibitor 1H-(1,2,4)oxadiazolo-(4,3-a)quinoxalin-1-one (ODQ) and Triton X-100, a detergent that damages the endocardial endothelium, all increased stroke volume (VS) and stroke work (WS). In contrast, the endogenous NOS substrate L-arginine, tested before and after treatment with haemoglobin, the NO donor 3-morpholinosydnonimine, tested with and without the superoxide scavenger superoxide dismutase, and the stable cGMP analogue 8-bromoguanosine 3',5'-cyclic monophosphate (8-Br-cGMP) decreased VS and WS. Acetylcholine chloride produced a biphasic effect. At nanomolar concentrations, in 34 % of the preparations, it induced a NO-cGMP-dependent positive inotropism that required the integrity of the endocardial endothelium. Pretreatment with Triton X-100 or with NO-cGMP pathway inhibitors (L-NMMA, L-NIO, NG-nitro-l-arginine methyl ester, Methylene Blue and ODQ) abolished the positive effect of acetylcholine. In contrast, at micromolar concentrations, acetylcholine produced a negative effect that involved neither the endocardial endothelium nor the NO-cGMP pathway. Pre-treatment with L-arginine (10(-6 )mol x l(-1)) was without effect, whereas L-NIO (10(-5 )mol x l(-1)) significantly reduced the Frank-Starling response. Taken together, these three experimental approaches provide evidence that NO modulates cardiac performance in the eel heart.


Potassium channels: watching a voltage-sensor tilt and twist.
The fourth transmembrane helix (S4) is the primary voltage-sensor of voltage-gated ion channels. Recent studies have used fluorescence resonance energy transfer as a spectroscopic ruler to determine the nature and magnitude of the voltage-induced movement of S4 that leads to channel opening.


Cognitive performance in older women relative to ApoE-epsilon4 genotype and aerobic fitness.
Apolipoprotein E (ApoE) genotype and aerobic fitness are each associated with cognitive performance in older adults. However, their potentially interactive effects on cognitive performance have not been examined. The primary purpose of this study was to determine whether ApoE genotype and aerobic fitness interact to uniquely impact memory performance and executive functioning. A secondary purpose was to examine the interactive effects on other measures of cognition to provide a more comprehensive assessment of cognitive abilities across a broad range of functions. Community-dwelling, cognitively normal older women (N = 90) provided blood samples to allow for assessment of ApoE genotype, completed cognitive tests, and performed a maximal aerobic fitness test. Primary outcome variables were the auditory verbal learning test (AVLT), the complex figures test (CFT), and the Wisconsin card-sorting task (WCST). Secondary outcome variables were the block design test and the paced auditory serial addition task (PASAT). Regression analyses indicated that aerobic fitness was associated with significantly better performance on measures of the AVLT, the CFT, and the PASAT for the ApoE-epsilon4 homozygotes. The preliminary findings from this study support the possibility that aerobic fitness is positively associated with the memory performance of those individuals at most genetic risk for Alzheimer disease.


Recognition of sequence-information in synthetic copolymer chains by a conformationally-constrained tweezer molecule.
A novel type of tweezer molecule containing electron-rich 2-pyrenyloxy arms has been designed to exploit intramolecular hydrogen bonding in stabilising a preferred conformation for supramolecular complexation to complementary sequences in aromatic copolyimides. This tweezer-conformation is demonstrated by single-crystal X-ray analyses of the tweezer molecule itself and of its complex with an aromatic diimide model-compound. In terms of its ability to bind selectively to polyimide chains, the new tweezer molecule shows very high sensitivity to sequence effects. Thus, even low concentrations of tweezer relative to diimide units (< 2.5 mol %) are sufficient to produce dramatic, sequence-related splittings of the pyromellitimide proton NMR resonances. These induced resonance-shifts arise from ring-current shielding of pyromellitimide protons by the pyrenyloxy arms of the tweezer-molecule, and the magnitude of such shielding is a function of the tweezer-binding constant for any particular monomer sequence. Recognition of both short-range and long-range sequences is observed, the latter arising from cumulative ring-current shielding of diimide protons by tweezer molecules binding at multiple adjacent sites on the copolymer chain.


Complement C5 in experimental autoimmune encephalomyelitis (EAE) facilitates remyelination and prevents gliosis.
Activation of the classical complement system is known to play a central role in autoimmune demyelination. We have analyzed the role of complement component C5 in experimental autoimmune encephalomyelitis (EAE) using C5-deficient (C5-d) and C5-sufficient (C5-s) mice. Both groups of mice displayed early onset EAE, a short recovery phase, and similar stable chronic courses. However, in contrast to the clinical similarities, marked differences were apparent by histopathology. During acute EAE in C5-d, a delay in inflammatory cell infiltration and tissue damage was observed along with restricted lesion areas, which in C5-s mice were more extensive and diffuse. More striking were the differences in chronic lesions. In C5-d mice, inflammatory demyelination and Wallerian degeneration were followed by axonal depletion and severe gliosis, while in C5-s, the same initial signs were followed by axonal sparing and extensive remyelination. In C5-d, immunohistochemistry and Western blotting showed an increase in glial fibrillary acidic protein and a decrease in neurofilament protein, proteolipid protein, and several pro-inflammatory markers. These results in the EAE model indicate that absence of C5 resulted in fiber loss and extensive scarring, whereas presence of C5-favored axonal survival and more efficient remyelination.


The role of heparan sulfate in host macrophage infection by Leishmania species.
The leishmaniases are a group of neglected tropical diseases caused by parasites from the Leishmania genus. More than 20 Leishmania species are responsible for human disease, causing a broad spectrum of symptoms ranging from cutaneous lesions to a fatal visceral infection. There is no single safe and effective approach to treat these diseases and resistance to current anti-leishmanial drugs is emerging. New drug targets need to be identified and validated to generate novel treatments. Host heparan sulfates (HSs) are abundant, heterogeneous polysaccharides displayed on proteoglycans that bind various ligands, including cell surface proteins expressed on Leishmania promastigote and amastigote parasites. The fine chemical structure of HS is formed by a plethora of specific enzymes during biosynthesis, with various positions (N-, 2-O-, 6-O- and 3-O-) on the carbon sugar backbone modified with sulfate groups. Post-biosynthesis mechanisms can further modify the sulfation pattern or size of the polysaccharide, altering ligand affinity to moderate biological functions. Chemically modified heparins used to mimic the heterogeneous nature of HS influence the affinity of different Leishmania species, demonstrating the importance of specific HS chemical sequences in parasite interaction. However, the endogenous structures of host HSs that might interact with Leishmania parasites during host invasion have not been elucidated, nor has the role of HSs in host-parasite biology. Decoding the structure of HSs on target host cells will increase understanding of HS/parasite interactions in leishmaniasis, potentiating identification of new opportunities for the development of novel treatments.


PolySearch2: a significantly improved text-mining system for discovering associations between human diseases, genes, drugs, metabolites, toxins and more.
PolySearch2 (http://polysearch.ca) is an online text-mining system for identifying relationships between biomedical entities such as human diseases, genes, SNPs, proteins, drugs, metabolites, toxins, metabolic pathways, organs, tissues, subcellular organelles, positive health effects, negative health effects, drug actions, Gene Ontology terms, MeSH terms, ICD-10 medical codes, biological taxonomies and chemical taxonomies. PolySearch2 supports a generalized 'Given X, find all associated Ys' query, where X and Y can be selected from the aforementioned biomedical entities. An example query might be: 'Find all diseases associated with Bisphenol A'. To find its answers, PolySearch2 searches for associations against comprehensive collections of free-text collections, including local versions of MEDLINE abstracts, PubMed Central full-text articles, Wikipedia full-text articles and US Patent application abstracts. PolySearch2 also searches 14 widely used, text-rich biological databases such as UniProt, DrugBank and Human Metabolome Database to improve its accuracy and coverage. PolySearch2 maintains an extensive thesaurus of biological terms and exploits the latest search engine technology to rapidly retrieve relevant articles and databases records. PolySearch2 also generates, ranks and annotates associative candidates and present results with relevancy statistics and highlighted key sentences to facilitate user interpretation.


Differentiation of pathogenic from nonpathogenic Entamoeba histolytica by restriction fragment analysis of a single gene amplified in vitro.
We previously reported the identification of homologous cDNA clones derived from a pathogenic isolate and a nonpathogenic isolate of Entamoeba histolytica, which had been designated cEh-P1 and cEh-NP1, respectively. Sequence analysis of both clones had revealed 10% nucleic acid substitutions, which were dispersed over the entire sequence. This genetic difference had been found to be conserved between all four pathogenic and all five nonpathogenic laboratory strains of E. histolytica tested. On the basis of nucleic acid substitutions, we have now developed a sensitive assay to distinguish pathogenic from nonpathogenic forms of E. histolytica by using fresh clinical isolates. Comparing the sequence of cEh-P1 and cEh-NP1, we identified a 482-bp segment that contained identical 5' and 3' ends but differed in internal cleavage sites for restriction endonucleases. By using oligonucleotide primers corresponding to the 5' and 3' ends of this segment, the corresponding gene was amplified by the polymerase chain reaction. Endonuclease digestion of the amplified DNA yielded restriction fragments that are characteristic for pathogenic and nonpathogenic forms. This assay allows the detection and classification of fewer than 10 amoebae within a few hours. The differentiation of 48 isolates into pathogenic and nonpathogenic strains by using this method corresponded to the clinical status of the infected individuals and to the classification obtained by isoenzyme determination. The results further support the concept that pathogenic and nonpathogenic strains of E. histolytica constitute distinct subspecies.


The nature of words in human protolanguages: it's not a holophrastic-atomic meanings dichotomy.
There is an ongoing debate as to whether the words in early presyntactic forms of human language had simple atomic meanings like modern words, or whether they were holophrastic. Simulations were conducted using an iterated learning model in which the agents were able to associate words with meanings, but in which they were not able to use syntactic rules to combine words into phrases or sentences. In some of these simulations words emerged that had neither holophrastic nor atomic meanings, demonstrating the possibility of protolanguages intermediate between these two extremes. Further simulations show how increases in cognitive or articulatory capacity would have produced changes in the type of words that was dominant in protolanguages. It is likely that at some point in time humans spoke a protolanguage in which most words had neither holophrastic nor atomic meanings.


Rent1, a trans-effector of nonsense-mediated mRNA decay, is essential for mammalian embryonic viability.
The ability to detect and degrade transcripts that lack full coding potential is ubiquitous but non-essential in lower eukaryotes, leaving in question the evolutionary basis for complete maintenance of this function. One hypothesis holds that nonsense-mediated RNA decay (NMD) protects the organism by preventing the translation of truncated peptides with dominant negative or deleterious gain-of-function potential. All organisms studied to date that are competent for NMD express a structural homolog of Saccharomyces cerevisiae Upf1p. We have now explored the consequences of loss of NMD function in vertebrates through targeted disruption of the Rent1 gene in murine embryonic stem cells which encodes a mammalian ortholog of Upf1p. Mice heterozygous for the targeted allele showed no apparent phenotypic abnormalities but homozygosity was never observed, demonstrating that Rent1 is essential for embryonic viability. Homozygous targeted embryos show complete loss of NMD and are viable in the pre-implantation period, but resorb shortly after implantation. Furthermore, Rent1(-/-) blastocysts isolated at 3.5 days post-coitum undergo apoptosis in culture following a brief phase of cellular expansion. These data suggest that NMD is essential for mammalian cellular viability and support a critical role for the pathway in the regulated expression of selected physiologic transcripts.


Data sharing practices in randomized trials of addiction interventions.
Transparent, open scientific research practices aim to improve the validity and reproducibility of research findings. A key component of open science is the public sharing of data and metadata that constitute the basis for research findings. We conducted a 6 year cross-sectional investigation of the rates and methods of data sharing in 15 high-impact addiction journals that publish clinical trials. We extracted trial characteristics and whether the trial data were shared publicly in any form. We conducted a sensitivity analysis of only trials with public funding sources. In the included journals, zero (0/394, 0.0%) RCTs shared their data publicly. The large majority (315/394, 79.9%) of included trials received funding from public sources. Eight journals had data sharing policies and published 299 of the included trials (75.9%). Our finding has significant implications for the addiction research community. These implications are broad, ranging from possibly slowed scientific advancement to noncompliance with obligations to the public whose tax dollars funded a large majority of the included RCTs. To improve the rates of data sharing, we recommend studying incentive systems, while simultaneously working to cultivate a data sharing system that emphasizes scientific, rather than author, accuracy.


Casticin induces apoptosis and G0/G1 cell cycle arrest in gallbladder cancer cells.
Casticin, the flavonoid extracted from Vitex rotundifolia L, exerts various biological effects, including anti-inflammatory and anti-cancer activity. The aim of this study is to investigate the effects and mechanisms of casticin in human gallbladder cancer cells. Human NOZ and SGC996 cells were used to perform the experiments. CCK-8 assay and colony formation assay were performed to evaluate cell viability. Cell cycle analyses and annexin V/PI staining assay for apoptosis were measured using flow cytometry. Western blot analysis was used to evaluate the changes in protein expression, and the effect of casticin treatment in vivo was experimented with xenografted tumors. In this study, we found that casticin significantly inhibited gallbladder cancer cell proliferation in a dose- and time-dependent manner. Casticin also induced G0/G1 arrest and mitochondrial-related apoptosis by upregulating Bax, cleaved caspase-3, cleaved caspase-9 and cleaved poly ADP-ribose polymerase expression, and by downregulating Bcl-2 expression. Moreover, casticin induced cycle arrest and apoptosis by upregulating p27 and downregulating cyclinD1/cyclin-dependent kinase4 and phosphorylated protein kinase B. In vivo, casticin inhibited tumor growth. Casticin induces G0/G1 arrest and apoptosis in gallbladder cancer, suggesting that casticin might represent a novel and effective agent against gallbladder cancer.


Cigarette smoke condensate-induced oxidative DNA damage and its removal in human cervical cancer cells.
Exposure to cigarette smoke is well documented to increase oxidative stress and could account for higher risk of cervical cancer in smokers. Cervical pre-cancerous lesions that are initiated by human papillomavirus (HPV) infection generally regress in the absence of known risk factors such as smoking. 8-oxodeoxyguanosine (8-oxodG) is a highly mutagenic oxidative DNA lesion that is formed by the oxidation of deoxyguanosine. In the present study, we examined: a) the effect of cigarette smoke condensate (CSC) on 8-oxodG formation in and its removal from HPV-transfected (ECT1/E6 E7), HPV-positive (CaSki) and HPV-negative (C33A) human cervical cancer cells, and b) the cell cycle progression and apoptosis in CSC-treated ECT1/E6 E7 cells. CSC induced 8-oxodG in a dose- (p=0.03) and time (p=0.002)-dependent fashion in ECT1/E6 E7 cells as determined by flow cytometry. A 2.4-fold higher level of 8-oxodG was observed in HPV-positive compared with HPV-negative cells. However, 8-oxodG lesions were almost completely removed 72 h post-exposure in all cell lines as determined by ImageStream analysis. This observation correlates with the 2- and 5-fold increase in the p53 levels in ECT1/E6 E7 and CaSki cells with no significant change in C33A cells. We conclude that: a) cigarette smoke constituents induce oxidative stress with higher burden in HPV-positive cervical cancer cells and b) the significant increase observed in p53 levels in wild-type cervical cells (ECT1/E6 E7 and CaSki) may be attributed to the p53-dependent DNA repair pathway while a p53-independent pathway in C33A cells cannot be ruled out.


Control of NFAT Isoform Activation and NFAT-Dependent Gene Expression through Two Coincident and Spatially Segregated Intracellular Ca2+ Signals.
Excitation-transcription coupling, linking stimulation at the cell surface to changes in nuclear gene expression, is conserved throughout eukaryotes. How closely related coexpressed transcription factors are differentially activated remains unclear. Here, we show that two Ca2+-dependent transcription factor isoforms, NFAT1 and NFAT4, require distinct sub-cellular InsP3 and Ca2+ signals for physiologically sustained activation. NFAT1 is stimulated by sub-plasmalemmal Ca2+ microdomains, whereas NFAT4 additionally requires Ca2+ mobilization from the inner nuclear envelope by nuclear InsP3 receptors. NFAT1 is rephosphorylated (deactivated) more slowly than NFAT4 in both cytoplasm and nucleus, enabling a more prolonged activation phase. Oscillations in cytoplasmic Ca2+, long considered the physiological form of Ca2+ signaling, play no role in activating either NFAT protein. Instead, effective sustained physiological activation of NFAT4 is tightly linked to oscillations in nuclear Ca2+. Our results show how gene expression can be controlled by coincident yet geographically distinct Ca2+ signals, generated by a freely diffusible InsP3 message.


Myocarditis in Duchenne Muscular Dystrophy After Changing Steroids.
Cardiac dysfunction is a leading cause of morbidity and mortality in Duchenne muscular dystrophy (DMD). This case highlights the importance of steroids in treating cardiac complications of DMD and the dangers of discontinuing or switching between steroid classes. To recognize the presentation of acute myocardial inflammation, or dystrophinitis, in DMD, which presents as myocarditis and to treat the myocardial inflammation and dilated cardiomyopathy associated with DMD through guideline-directed medical therapy, steroids, and serial surveillance for cardiac dysfunction. A case report of an 18-year-old patient with DMD and with steroid withdrawal-induced myocarditis followed up for 3 years to observe for cardiac function recovery and the natural history of cardiomyopathy in DMD, who was hospitalized in the cardiac care unit and followed up between November 3, 2016, and March 27, 2017. Switching from deflazacort to underdosed prednisone for 7 days. Increased myocardial inflammation, edema, and fibrosis after stopping deflazacort abruptly. An 18-year-old male patient with DMD presented to the emergency department with acute-onset chest pain. Ischemic changes were present on electrocardiogram, and elevated cardiac enzymes were detected. Depressed cardiac function and potential evidence of inflammation were seen on cardiac magnetic resonance (CMR) imaging, characterized by elevated T2 values and late gadolinium enhancement. These findings were all consistent with acute myocarditis but without a viral prodrome. Several days prior to presentation, the patient's deflazacort was abruptly discontinued and converted to an equivalent dose of prednisone. After restarting deflazacort, his symptoms improved, and subsequent CMR showed resolution of myocardial edema and improved left ventricular function. This case highlights adverse effects associated with changing between corticosteroid classes in DMD cardiomyopathy and also demonstrates the utility of CMR in detecting myocardial inflammation and monitoring response to treatment.


Clinical outcome of transthoracic esophagectomy with thoracic duct resection: Number of dissected lymph node and distribution of lymph node metastasis around the thoracic duct.
The number of dissected lymph nodes (LNs), surgical outcomes, and postoperative recurrence-free survival (RFS) were compared between thoracic duct (TD)-preserved and TD-resected groups. The distribution of metastasis in LNs around TD (TDLN) was reviewed. Transthoracic esophagectomy (TTE) with TD resection for esophageal cancer patients has been one of the standard procedures. Because the adipose tissue surrounding the TD contains LNs, TD resection might be necessary for radical LN dissection. However, few studies have investigated the oncological outcome of TTE with TD resection. Two hundred fifty-six consecutive patients who underwent TTE between 2004 and 2015 were retrospectively reviewed and classified into TD-preserved or TD-resected groups. The number of dissected LNs for each LN station and surgical outcomes were compared. RFS was analyzed in 155 patients who underwent TTE before December 2012. Since 2013, the TDLN number was prospectively examined, independent of the regional LNs (n = 72). Of these, the TDLN number for each location (TDLN-Ut/Mt/Lt) was investigated and the correlation between TDLN metastasis and clinicopathological factors was analyzed. The TD was preserved in 89 patients and resected in 167 patients. Patients with TD resection showed significant advanced stage. There was no significant difference in the incidence of postoperative complications, including pneumonia, anastomotic leakage, and chylothorax. The number of dissected mediastinal LNs was significantly increased in the TD-resected group. The 5-year RFS rate of cStage I patients was 67.3% in the TD-preserved group against 90.3% in the TD-resected group, showing a tendency towards RFS extension that did not quite reach statistical significance (P = 0.055). The mean TDLN-Ut/Mt/Lt numbers were 0.89/0.56/0.44, respectively. Eight of 72 (11%) patients displayed TDLN metastasis. Metastatic TDLNs were observed on the same or cranial level of the primary lesion in 7 of 8 patients. Transthoracic esophagectomy with TD resection could increase the number of dissected mediastinal LNs without increase of postoperative complication. TDLN metastasis was observed in patients with advanced disease. A prospective trial, investigating the survival between TD-preserved and TD-resected groups, should be conducted to clarify if TD should be resected in TTE.


Serum neuron-specific enolase levels from the same patients differ between laboratories: assessment of a prospective post-cardiac arrest cohort.
In comatose post-cardiac arrest patients, a serum neuron-specific enolase (NSE) level of >33 μg/L within 72 h was identified as a reliable marker for poor outcome in a large Dutch study (PROPAC), and this level was subsequently adopted in an American Academy of Neurology practice parameter. Later studies reported that NSE >33 μg/L is not a reliable predictor of poor prognosis. To test whether different clinical laboratories contribute to this variability, we compared NSE levels from the laboratory used in the PROPAC study (DLM-Nijmegen) with those of our hospital's laboratory (ARUP) using paired blood samples. We prospectively enrolled cardiac arrest patients who remained comatose after resuscitation. During the first 3 days, paired blood samples for serum NSE were drawn at a median of 10 min apart. After standard preparation for each lab, one sample was sent to ARUP laboratories and the other to DLM-Nijmegen. Fifty-four paired serum samples from 33 patients were included. Although the serum NSE measurements correlated well between laboratories (R = 0.91), the results from ARUP were approximately 30% lower than those from DLM-Nijmegen. Therapeutic hypothermia did not affect this relationship. Two patients had favorable outcomes after hypothermia despite NSE levels measured by DLM-Nijmegen as >33 μg/L. Absolute serum NSE levels of comatose cardiac arrest patients differ between laboratories. Any specific absolute cut-off levels proposed to prognosticate poor outcome should not be used without detailed data on how neurologic outcomes correspond to a particular laboratory's method, and even then only in conjunction with other prognostic variables.


Population dynamics and potential of fisheries stock enhancement: practical theory for assessment and policy analysis.
The population dynamics of fisheries stock enhancement, and its potential for generating benefits over and above those obtainable from optimal exploitation of wild stocks alone are poorly understood and highly controversial. I review pertinent knowledge of fish population biology, and extend the dynamic pool theory of fishing to stock enhancement by unpacking recruitment, incorporating regulation in the recruited stock, and accounting for biological differences between wild and hatchery fish. I then analyse the dynamics of stock enhancement and its potential role in fisheries management, using the candidate stock of North Sea sole as an example and considering economic as well as biological criteria. Enhancement through release of recruits or advanced juveniles is predicted to increase total yield and stock abundance, but reduce abundance of the naturally recruited stock component through compensatory responses or overfishing. Economic feasibility of enhancement is subject to strong constraints, including trade-offs between the costs of fishing and hatchery releases. Costs of hatchery fish strongly influence optimal policy, which may range from no enhancement at high cost to high levels of stocking and fishing effort at low cost. Release of genetically maladapted fish reduces the effectiveness of enhancement, and is most detrimental overall if fitness of hatchery fish is only moderately compromised. As a temporary measure for the rebuilding of depleted stocks, enhancement cannot substitute for effort limitation, and is advantageous as an auxiliary measure only if the population has been reduced to a very low proportion of its unexploited biomass. Quantitative analysis of population dynamics is central to the responsible use of stock enhancement in fisheries management, and the necessary tools are available.


An extract of neem leaves reduces anxiety without causing motor side effects in an experimental model.
Anxiety modulation often requires pharmaceutical intervention, and though effective in the short-term, benzodiazepines may cause impaired motor function. As a potential alternative, anxiety-modulating effects of a neem leaf (Azadirachta indica, A Juss) extract were investigated using ethological analysis of rat behaviour on an elevated X maze and compared with diazepam treatment. Sexually immature female Sprague-Dawley rats received 0.07 or 7 mg/kg neem leaf steroidal extract, a sham injection, a 1% DMSO/saline vehicle, 2 mg/kg diazepam or no treatment one hour prior to a recorded five-minute exploration of the elevated X maze. Neem matched diazepam in anxiety reduction as both treatments caused a decrease in per cent protected stretched-attend postures (PPSAP). Neem treatment had no effect on closed arm entries or total rears, distinguishing it pharmacologically from diazepam which resulted in a predictable decrease in those locomotor measures. Whereas both neem and diazepam reduced anxiety in complex ethological behavioural indices, only neem produced anxiolysis without motor deficiency.


SeqFold: genome-scale reconstruction of RNA secondary structure integrating high-throughput sequencing data.
We present an integrative approach, SeqFold, that combines high-throughput RNA structure profiling data with computational prediction for genome-scale reconstruction of RNA secondary structures. SeqFold transforms experimental RNA structure information into a structure preference profile (SPP) and uses it to select stable RNA structure candidates representing the structure ensemble. Under a high-dimensional classification framework, SeqFold efficiently matches a given SPP to the most likely cluster of structures sampled from the Boltzmann-weighted ensemble. SeqFold is able to incorporate diverse types of RNA structure profiling data, including parallel analysis of RNA structure (PARS), selective 2'-hydroxyl acylation analyzed by primer extension sequencing (SHAPE-Seq), fragmentation sequencing (FragSeq) data generated by deep sequencing, and conventional SHAPE data. Using the known structures of a wide range of mRNAs and noncoding RNAs as benchmarks, we demonstrate that SeqFold outperforms or matches existing approaches in accuracy and is more robust to noise in experimental data. Application of SeqFold to reconstruct the secondary structures of the yeast transcriptome reveals the diverse impact of RNA secondary structure on gene regulation, including translation efficiency, transcription initiation, and protein-RNA interactions. SeqFold can be easily adapted to incorporate any new types of high-throughput RNA structure profiling data and is widely applicable to analyze RNA structures in any transcriptome.


Whole genome sequencing for lung cancer.
Lung cancer is a leading cause of cancer related morbidity and mortality globally, and carries a dismal prognosis. Improved understanding of the biology of cancer is required to improve patient outcomes. Next-generation sequencing (NGS) is a powerful tool for whole genome characterisation, enabling comprehensive examination of somatic mutations that drive oncogenesis. Most NGS methods are based on polymerase chain reaction (PCR) amplification of platform-specific DNA fragment libraries, which are then sequenced. These techniques are well suited to high-throughput sequencing and are able to detect the full spectrum of genomic changes present in cancer. However, they require considerable investments in time, laboratory infrastructure, computational analysis and bioinformatic support. Next-generation sequencing has been applied to studies of the whole genome, exome, transcriptome and epigenome, and is changing the paradigm of lung cancer research and patient care. The results of this new technology will transform current knowledge of oncogenic pathways and provide molecular targets of use in the diagnosis and treatment of cancer. Somatic mutations in lung cancer have already been identified by NGS, and large scale genomic studies are underway. Personalised treatment strategies will improve care for those likely to benefit from available therapies, while sparing others the expense and morbidity of futile intervention. Organisational, computational and bioinformatic challenges of NGS are driving technological advances as well as raising ethical issues relating to informed consent and data release. Differentiation between driver and passenger mutations requires careful interpretation of sequencing data. Challenges in the interpretation of results arise from the types of specimens used for DNA extraction, sample processing techniques and tumour content. Tumour heterogeneity can reduce power to detect mutations implicated in oncogenesis. Next-generation sequencing will facilitate investigation of the biological and clinical implications of such variation. These techniques can now be applied to single cells and free circulating DNA, and possibly in the future to DNA obtained from body fluids and from subpopulations of tumour. As costs reduce, and speed and processing accuracy increase, NGS technology will become increasingly accessible to researchers and clinicians, with the ultimate goal of improving the care of patients with lung cancer.


Impaired imagery for upper limbs.
The brain processes associated with mental imagery have long been a matter of debate. Neuroimaging and neuropsychological studies have yielded diverging evidence of mental transformation activating the right hemisphere, the left hemisphere, or both. Here, using a mirror/normal discrimination task with rotated body parts (BPs) and external objects (EOs), we describe the case of a patient who developed a selective deficit in mental imagery of such BPs due to left posterior parietal brain damage. In addition, the patient's deficit predominated for pictures of right arms (i.e., arms corresponding to the patient's imagined contralesional arm) and was further characterised by an inability to distinguish between anatomically possible and impossible arm positions. This neuropsychological deficit was corroborated by neuroimaging evidence revealing the absence of activation in the left parietal lobe for the mental rotation of body parts as shown in healthy participants. In contrast, his behavioural performance and brain activation for EOs were similar to those of healthy participants. These data suggest that mental imagery of BPs and EOs relies on different cognitive and neural mechanisms and indicate that the left posterior parietal lobe is a necessary structure for mental transformations of human BPs.


Chikungunya virus and Aedes mosquitoes: saliva is infectious as soon as two days after oral infection.
Aedes aegypti and Aedes albopictus are potential vectors of chikungunya virus (CHIKV). The recent CHIKV outbreaks were caused by a new variant characterized by a mutation in the E1 glycoprotein gene (E1-226V) which has favored a better transmissibility by Ae. albopictus. As Ae. albopictus tends to replace Ae. aegypti in many regions, one question remained: is Ae. albopictus as efficient as Ae. aegypti to transmit the variant E1-226V of CHIKV? We infected orally both species with the variant E1-226V and estimated the infection, the viral dissemination, and the transmission rate by real time RT-PCR. Additionally, we used an in vitro assay to determine the amount of virus delivered by mosquitoes in their saliva. We found that Ae. aegypti as well as Ae. albopictus ensured a high replication of the virus which underwent an efficient dissemination as detectable in the salivary glands at day 2 post-infection (pi). Infectious CHIKV particles were delivered by salivary glands from day 2 with a maximum at day 6 pi for Ae. albopictus (10(3.3) PFU) and day 7 pi for Ae. aegypti (10(2.5) PFU). Ae. albopictus is slightly more efficient than Ae. aegypti to transmit the variant E1-226V of CHIKV. These results will help to design an efficient vector control to limit transmission as soon as the first human cases are diagnosed.


Decidual Bleeding as a Cause of Spontaneous Hemoperitoneum in Pregnancy and Risk of Preterm Birth.
Spontaneous hemoperitoneum in pregnancy (SHiP) is a rare, life-threatening event, particularly relevant to women with endometriosis or deciduosis. To determine the type of lesions leading to SHiP, a literature search was conducted among all published SHiP cases. From a total of 1,339 publications, information on pathological findings at the bleeding site with histological data was found in 24 case reports (16 pregnant, 8 postpartum). Among pregnant women (81% primigravida), 75% had a diagnosis of endometriosis and 25% of deciduosis. Among postpartum women (38% primiparous), 63% had a diagnosis of deciduosis and 25% of endometriosis. In all cases except one, decidual cells, with or without glandular structures, were present at the bleeding site. Decidual vessels were described in 7 cases and all exhibited vascular changes, including distension of the lumen, medial disorganization, or loss of vascular integrity. These vessels were significantly different from arteries seen in the secretory endometrium, showing that structural modifications take place during the initial stage of the remodelling of placental bed spiral arteries. During pregnancy, a link seems to exist between ectopic decidualization, particularly that occurring in endometriotic foci, and occurrence of SHiP. In addition, subclinical decidual bleeding may be a potential risk factor for preterm labour.


Structure of the immature Zika virus at 9 Å resolution.
The current Zika virus (ZIKV) epidemic is characterized by severe pathogenicity in both children and adults. Sequence changes in ZIKV since its first isolation are apparent when pre-epidemic strains are compared with those causing the current epidemic. However, the residues that are responsible for ZIKV pathogenicity are largely unknown. Here we report the cryo-electron microscopy (cryo-EM) structure of the immature ZIKV at 9-Å resolution. The cryo-EM map was fitted with the crystal structures of the precursor membrane and envelope glycoproteins and was shown to be similar to the structures of other known immature flaviviruses. However, the immature ZIKV contains a partially ordered capsid protein shell that is less prominent in other immature flaviviruses. Furthermore, six amino acids near the interface between pr domains at the top of the spikes were found to be different between the pre-epidemic and epidemic ZIKV, possibly influencing the composition and structure of the resulting viruses.


Interactive effects of KIBRA and CLSTN2 polymorphisms on episodic memory in old-age unipolar depression.
The KIBRA (rs17070145) C-allele and the CLSTN2 (rs6439886) T-allele have both been associated with poorer episodic memory performance. Given that episodic memory is affected in depression, we hypothesized that the combination of these risk alleles would be particularly detrimental to episodic memory performance in depressed persons. In the population-based SNAC-K study, 2170 participants (≥ 60 years) without dementia (DSM-IV criteria) and antidepressant pharmacotherapy were clinically examined and diagnosed following ICD-10 criteria for unipolar depression, and genotyped for KIBRA and CLSTN2. Participants were categorized according to unipolar depression status (yes, no) and genotype combinations (KIBRA: CC, any T; CLSTN2: TT, any C). Critically, a three-way interaction effect showed that the CC/TT genotype combination was associated with poorer episodic recall and recognition performance only in depressed elderly persons, with depressed CC/TT carriers consistently performing at the lowest level. This finding supports the view that effects of genetic polymorphisms on cognitive functioning may be most easily disclosed at suboptimal levels of cognitive ability, such as in old-age depression.


What causes a neuron to spike?
The computation performed by a neuron can be formulated as a combination of dimensional reduction in stimulus space and the nonlinearity inherent in a spiking output. White noise stimulus and reverse correlation (the spike-triggered average and spike-triggered covariance) are often used in experimental neuroscience to "ask" neurons which dimensions in stimulus space they are sensitive to and to characterize the nonlinearity of the response. In this article, we apply reverse correlation to the simplest model neuron with temporal dynamics-the leaky integrate-and-fire model-and find that for even this simple case, standard techniques do not recover the known neural computation. To overcome this, we develop novel reverse-correlation techniques by selectively analyzing only "isolated" spikes and taking explicit account of the extended silences that precede these isolated spikes. We discuss the implications of our methods to the characterization of neural adaptation. Although these methods are developed in the context of the leaky integrate-and-fire model, our findings are relevant for the analysis of spike trains from real neurons.


MR "microscopy" of the rat thorax.
High resolution images can be obtained from anywhere in the body of small animals with magnetic resonance combined with cardiac gating and scan synchronous ventilation. We used these methods to examine the intrathoracic anatomy of the rat. Anesthetized rats were intubated and ventilated in synchrony with imaging acquisition. Images were obtained in a 1 m bore, 1.5 T system fitted with a 28 cm diameter high field gradient coil and a 5 cm radio-frequency coil. We used cardiac gated, three-dimensional spin warp acquisitions. Eight contiguous slices (2.5 mm thick) were obtained simultaneously. In addition to visualizing major vessels and cardiac chambers, cardiac valves and papillary muscles were clearly demonstrated. Major pulmonary vessels and peripheral parenchyma were also seen. These results demonstrate MR "microscopy" can be used to image all major cardiopulmonary structures in the rat with respect to selected times of the cardiac cycle. This capability for noninvasive "microscopy" opens new avenues for cardiopulmonary research using well characterized rodent models.


An aphasia database on the internet: a model for computer-assisted analysis in aphasiology.
A web-based software model was developed as an example for data mining in aphasiology. It is used for educating medical and engineering students. It is based upon a database of 254 aphasic patients which contains the diagnosis of the aphasia type, profiles of an aphasia test battery (Aachen Aphasia Test), and some further clinical information. In addition, the cerebral lesion profiles of 147 of these cases were standardized by transferring the coordinates of the lesions to a 3D reference brain based upon the ACPC coordinate system. Two artificial neural networks were used to perform a classification of the aphasia type. First, a coarse classification was achieved by using an assessment of spontaneous speech of the patient which produced correct results in 87% of the test cases. Data analysis tools were used to select four features of the 30 available test features to yield a more accurate diagnosis. This classifier produced correct results in 92% of the test cases. The neural network approach is similar to grouping performed in group studies, while the nearest-neighbor method shows a design more similar to case studies. It finds the neurolinguistic and the lesion data of patients whose AAT profiles are most similar to the user's input. This way lesion profiles can be compared to each other interindividually. The Aphasia Diagnoser is available on the Web address http://fuzzy.iau.dtu.dk/aphasia.nsf and thus should facilitate a discussion about the reliability and possibilities of data-mining techniques in aphasiology.


Chronic pain syndromes after ischemic stroke: PRoFESS trial.
Chronic pain syndromes are reported to be common after stroke, but most previous epidemiological studies have generally included small cohorts of patients with relatively short-term follow-up. In a large cohort with ischemic stroke (Prevention Regimen for Effectively avoiding Second Stroke [PRoFESS] trial), we determined the prevalence, risk factors, and clinical consequence of new poststroke pain syndromes. Within the PRoFESS trial (mean follow-up 2.5 years), a standardized chronic pain questionnaire was administered (at the penultimate follow-up visit) to all participants who reported chronic pain since their stroke and did not have a history of chronic pain before their index stroke. Multivariable logistic regression analyses were used to determine risk factors for poststroke pain (and pain subtypes), and the association between poststroke pain and cognitive (≥ 3 reduction in Mini-Mental State Examination score) and functional decline (≥ 1 increase in m-Rankin). In total, 15 754 participants were included; of which 1665 participants (10.6%) reported new chronic poststroke pain, and included 431 participants (2.7%) with central poststroke pain, 238 (1.5%) with peripheral neuropathic pain, 208 (1.3%) with pain from spasticity, and 136 participants (0.9%) with pain from shoulder subluxation. More than 1 pain subtype was reported in 86 participants (0.6%). Predictors of poststroke pain included increased stroke severity, female sex, alcohol intake, statin use, depressive symptoms, diabetes mellitus, antithrombotic regimen, and peripheral vascular disease. A new chronic pain syndrome was associated with greater dependence (odds ratio, 2.16; 95% confidence interval, 1.82-2.56). Peripheral neuropathy and pain from spasticity/shoulder subluxation were associated with cognitive decline. Chronic pain syndromes are common after ischemic stroke and are associated with increased functional dependence and cognitive decline.


Variable impact on mortality of AIDS-defining events diagnosed during combination antiretroviral therapy: not all AIDS-defining conditions are created equal.
The extent to which mortality differs following individual acquired immunodeficiency syndrome (AIDS)-defining events (ADEs) has not been assessed among patients initiating combination antiretroviral therapy. We analyzed data from 31,620 patients with no prior ADEs who started combination antiretroviral therapy. Cox proportional hazards models were used to estimate mortality hazard ratios for each ADE that occurred in >50 patients, after stratification by cohort and adjustment for sex, HIV transmission group, number of antiretroviral drugs initiated, regimen, age, date of starting combination antiretroviral therapy, and CD4+ cell count and HIV RNA load at initiation of combination antiretroviral therapy. ADEs that occurred in <50 patients were grouped together to form a "rare ADEs" category. During a median follow-up period of 43 months (interquartile range, 19-70 months), 2880 ADEs were diagnosed in 2262 patients; 1146 patients died. The most common ADEs were esophageal candidiasis (in 360 patients), Pneumocystis jiroveci pneumonia (320 patients), and Kaposi sarcoma (308 patients). The greatest mortality hazard ratio was associated with non-Hodgkin's lymphoma (hazard ratio, 17.59; 95% confidence interval, 13.84-22.35) and progressive multifocal leukoencephalopathy (hazard ratio, 10.0; 95% confidence interval, 6.70-14.92). Three groups of ADEs were identified on the basis of the ranked hazard ratios with bootstrapped confidence intervals: severe (non-Hodgkin's lymphoma and progressive multifocal leukoencephalopathy [hazard ratio, 7.26; 95% confidence interval, 5.55-9.48]), moderate (cryptococcosis, cerebral toxoplasmosis, AIDS dementia complex, disseminated Mycobacterium avium complex, and rare ADEs [hazard ratio, 2.35; 95% confidence interval, 1.76-3.13]), and mild (all other ADEs [hazard ratio, 1.47; 95% confidence interval, 1.08-2.00]). In the combination antiretroviral therapy era, mortality rates subsequent to an ADE depend on the specific diagnosis. The proposed classification of ADEs may be useful in clinical end point trials, prognostic studies, and patient management.


Factor structure and utility of the Behavior Rating Inventory of Executive Function-Preschool Version.
Executive function (EF) is a domain general cognitive construct associated with a number of important developmental outcomes. The Behavior Rating Inventory of Executive Function-Preschool version (BRIEF-P) is intended to assess 5 distinct components of EF in preschool age children. In this study, a series of factor analyses was conducted with teacher-reported EF of 2,367 preschool students to assess the structure of the BRIEF-P, and the predictive relations between the resulting factors and children's academic abilities and behavioral self-regulation were assessed to test the construct and convergent validity of the BRIEF-P scores. Results yielded mixed findings concerning the structure of the BRIEF-P and validity of its resultant scores. Results of the factor analyses indicated that the items of the BRIEF-P did not map onto factors in the way that would be expected based on its item-to-subscale mapping. The best solutions were a 4-factor and a bifactor model. The 4-factor solution revealed substantial correlations between factors, and although the bifactor solution identified a General Self-Regulation factor that explained variance in responses across items, this general factor did not account for all of the overlap among specific factors. Analyses of the relations for the factors from the correlated-factors and the bifactor models indicated that the majority of the factors had limited convergent validity with academic ability or with a measure of behavior self-regulation. Overall, these findings call into question the validity of aspects of BRIEF-P. (PsycINFO Database Record


Prefrontal cortex activity associated with source monitoring in a working memory task.
Using functional magnetic resonance imaging (fMRI), we investigated prefrontal cortex (PFC) activity during remembering specific source information (format, location judgments) versus remembering that could be based on undifferentiated information, such as familiarity (old/new recognition [ON], recency judgments). A working memory (WM) paradigm with an immediate test yielded greater activation in the lateral PFC for format and location source memory (SM) tasks than ON recognition; this SM-related activity was left lateralized. The same regions of PFC were recruited in Experiment 2 when information was tested immediately and after a filled delay. Substituting recency for location judgments (Experiment 3) resulted in an overall shift in task context that produced greater right PFC activity associated with ON and recency tasks compared to the format task, in addition to left SM-related activity. These data extend to WM previous findings from long-term memory (LTM) indicating that the left and right PFC may be differentially involved in memory attributions depending on the specificity of information evaluated. The findings also provide evidence for the continuity of evaluative processes recruited in WM and LTM.


Priming is key to effective incorporation of image-guided thermal ablation into immunotherapy protocols.
Focal therapies play an important role in the treatment of cancers where palliation is desired, local control is needed, or surgical resection is not feasible. Pairing immunotherapy with such focal treatments is particularly attractive; however, there is emerging evidence that focal therapy can have a positive or negative impact on the efficacy of immunotherapy. Thermal ablation is an appealing modality to pair with such protocols, as tumors can be rapidly debulked (cell death occurring within minutes to hours), tumor antigens can be released locally, and treatment can be conducted and repeated without the concerns of radiation-based therapies. In a syngeneic model of epithelial cancer, we found that 7 days of immunotherapy (TLR9 agonist and checkpoint blockade), prior to thermal ablation, reduced macrophages and myeloid-derived suppressor cells and enhanced IFN-γ-producing CD8+ T cells, the M1 macrophage fraction, and PD-L1 expression on CD45+ cells. Continued treatment with immunotherapy alone or with immunotherapy combined with ablation (primed ablation) then resulted in a complete response in 80% of treated mice at day 90, and primed ablation expanded CD8+ T cells as compared with all control groups. When the tumor burden was increased by implantation of 3 orthotopic tumors, successive primed ablation of 2 discrete lesions resulted in survival of 60% of treated mice as compared with 25% of mice treated with immunotherapy alone. Alternatively, when immunotherapy was begun immediately after thermal ablation, the abscopal effect was diminished and none of the mice within the cohort exhibited a complete response. In summary, we found that immunotherapy begun before ablation can be curative and can enhance efficacy in the presence of a high tumor burden. Two mechanisms have potential to impact the efficacy of immunotherapy when begun immediately after thermal ablation: mechanical changes in the tumor microenvironment and inflammatory-mediated changes in immune phenotype.


High levels of glucose induce apoptosis in cardiomyocyte via epigenetic regulation of the insulin-like growth factor receptor.
Diabetic hyperglycemia result in cardiovascular complications, but the mechanisms by which high levels of glucose (HG) cause diabetic cardiomyopathy are not known. We investigate whether HG-induced repression of insulin-like growth factor 1 receptor (IGF-1R) mediated by epigenetic modifications is one potential mechanism. We found that HG resulted in decreased IGF-1 receptor (IGF-1R) mRNA levels, and IGF-1R protein when compared with H9C2 rat cardiomyocyte cells incubated in normal glucose. HG also induced apoptosis of H9C2 cells. The effects of HG on reduced expression of IGF-1R and increased apoptosis were blocked by silencing p53 with small interference RNA but not by non-targeting scrambled siRNA. Moreover, HG negatively regulated IGF-1R promoter activity as determined by ChIP analysis, which was dependent on p53 since siRNA-p53 attenuated the effects of HG on IGF-1R promoter activity. HG also increased the association of p53 with histone deacetylase 1 (HDAC1), and decreased the association of acetylated histone-4 with the IGF-1R promoter. Furthermore, HDAC inhibitor relieved the repression of IGF-1R following HG state. These results suggest that HG-induced repression of IGF-1R is mediated by the association of p53 with the IGF-1R promoter, and by the subsequent enhanced recruitment of chromatin-modifying proteins, such as HDAC1, to the IGF-1R promoter-p53 complex. In conclusion, our data demonstrate that HG decreases expression of IGF-1R and decreases the association of acetylated histone-4 with the IGF-1R promoter. These studies may help delineate the complex pathways regulating diabetic cardiomyopathy, and have implications for the development of novel therapeutic strategies to prevent diabetic cardiomyopathy by epigenetic regulation of IGF-1R.


Characterization of endogenous sodium channel gene expressed in Chinese hamster ovary cells.
Chinese hamster ovary (CHO-K1) cells were observed to display transient inward Na+ currents of average amplitude (-92 +/- 20 pA), which activated at voltages more than -40 mV, and peak inward currents were observed at potentials equal to or more than +10 mV. Inward Na+ currents in these cells were eliminated after treatment with 500 or 50 nM tetrodotoxin (TTX), whereas 5 nM TTX resulted in 64 +/- 10% inhibition of Na+ current. Using DNA primers designed to bind to the rat brain IIA Na+ channel subtype, we amplified specific polymerase chain reaction (PCR) fragments from CHO-K1 poly-(A)+RNA. The cloning and sequencing of two of these fragments confirmed the presence of an endogenously expressed Na+ channel gene in these cells, which we have termed cho 1. Comparison of the DNA sequence of cho 1 PCR fragments with other known Na+ channel genes indicated a high degree of homology with rat brain Na+ channel subtypes. Northern blots using riboprobes generated from the cho 1 PCR fragments revealed the presence of a specific 9-kb mRNA in these cells. The molecular and electrophysiological data suggest that the cho 1 Na+ channel gene from CHO-K1 cells is closely related to brain-type Na+ channels.


Antibacterial activity of a DNA topoisomerase I inhibitor versus fluoroquinolones in Streptococcus pneumoniae.
The DNA topoisomerase complement of Streptococcus pneumoniae is constituted by two type II enzymes (topoisomerase IV and gyrase), and a single type I enzyme (topoisomerase I). These enzymes maintain the DNA topology, which is essential for replication and transcription. While fluoroquinolones target the type II enzymes, seconeolitsine, a new antimicrobial agent, targets topoisomerase I. We compared for the first time the in vitro effect of inhibition of topoisomerase I by seconeolitsine and of the type II topoisomerases by the fluoroquinolones levofloxacin and moxifloxacin. We used three isogenic non-encapsulated strains and five non-vaccine serotypes isolates belonging to two circulating pneumococcal clones, ST638 (2 strains) and ST1569V (3 strains). Each group contained strains with diverse susceptibility to fluoroquinolones. Minimal inhibitory concentrations, killing curves and postantibiotic effects were determined. Seconeolitsine demonstrated the fastest and highest bactericidal activity against planktonic bacteria and biofilms. When fluoroquinolone-susceptible planktonic bacteria were considered, seconeolitsine induced postantibiotic effects (1.00-1.87 h) similar than levofloxacin (1.00-2.22 h), but longer than moxifloxacin (0.39-1.71 h). The same effect was observed in sessile bacteria forming biofilms. Seconeolitsine induced postantibiotic effects (0.84-2.31 h) that were similar to those of levofloxacin (0.99-3.32 h) but longer than those of moxifloxacin (0.89-1.91 h). The greatest effect was observed in the viability and adherence of bacteria in the postantibiotic phase. Seconeolitsine greatly reduced the thickness of the biofilms formed in comparison with fluoroquinolones: 2.91 ± 0.43 μm (seconeolitsine), 7.18 ± 0.58 μm (levofloxacin), 17.08 ± 1.02 μm (moxifloxacin). When fluoroquinolone-resistant bacteria were considered, postantibiotic effects induced by levofloxacin and moxifloxacin, but not by seconeolitsine, were shorter, decreasing up to 5-fold (levofloxacin) or 2-fold (moxifloxacin) in planktonic cells, and up to 1.7 (levofloxacin) or 1.4-fold (moxifloxacin) during biofilm formation. Therefore, topoisomerase I inhibitors could be an alternative for the treatment of pneumococcal diseases, including those caused by fluoroquinolone-resistant isolates.


Resistant starch: promise for improving human health.
Ongoing research to develop digestion-resistant starch for human health promotion integrates the disciplines of starch chemistry, agronomy, analytical chemistry, food science, nutrition, pathology, and microbiology. The objectives of this research include identifying components of starch structure that confer digestion resistance, developing novel plants and starches, and modifying foods to incorporate these starches. Furthermore, recent and ongoing studies address the impact of digestion-resistant starches on the prevention and control of chronic human diseases, including diabetes, colon cancer, and obesity. This review provides a transdisciplinary overview of this field, including a description of types of resistant starches; factors in plants that affect digestion resistance; methods for starch analysis; challenges in developing food products with resistant starches; mammalian intestinal and gut bacterial metabolism; potential effects on gut microbiota; and impacts and mechanisms for the prevention and control of colon cancer, diabetes, and obesity. Although this has been an active area of research and considerable progress has been made, many questions regarding how to best use digestion-resistant starches in human diets for disease prevention must be answered before the full potential of resistant starches can be realized.


The precuneus and hippocampus contribute to individual differences in the unfolding of spatial representations during episodic autobiographical memory.
Spatial information is a central aspect of episodic autobiographical memory (EAM). Space-based theories of memory, including cognitive map and scene construction models, posit that spatial reinstatement is a required process during early event recall. Spatial information can be represented from both allocentric (third-person) and egocentric (first-person) perspectives during EAM, with egocentric perspectives being important for mental imagery and supported by the precuneus. Individuals differ in their tendency to rely on allocentric or egocentric information, and in general, the subjective experience of remembering in EAM differs greatly across individuals. Here we examined individual differences in spatial aspects of EAM, how such differences influence the vividness and temporal order of recollection, and their anatomical correlates. We cued healthy young participants (n =63) with personally familiar locations and non-locations. We examined how cue type affects (i) retrieval dynamics and (ii) phenomenological aspects of remembering, and related behavioural performance to regional brain volumes (n =42). Participants tended to spontaneously recall spatial information early during recollection, even in the absence of spatial cues, and individuals with a stronger tendency to recall space first also displayed faster reaction times. Across participants, place-cued memories were re-experienced more vividly and were richer in detail than those cued by objects, but not more than those cued by familiar persons. Volumetric differences were associated with behavioural performance such that egocentric remembering was positively associated with precuneus volume. Hippocampal CA2/CA3 volumes were associated with the tendency to recall place-cued memories less effortfully. Consistent with scene construction theories, this study suggests that spatial information is reinstated early and contributes to the efficiency and phenomenology of EAM. However, early recall of spatial information is not universal and other routes to recall exist, challenging some aspects of these models. Variability among participants highlights the importance of an individual differences approach to studying EAM.


Laser photocoagulation for proliferative diabetic retinopathy.
Diabetic retinopathy is a complication of diabetes in which high blood sugar levels damage the blood vessels in the retina. Sometimes new blood vessels grow in the retina, and these can have harmful effects; this is known as proliferative diabetic retinopathy. Laser photocoagulation is an intervention that is commonly used to treat diabetic retinopathy, in which light energy is applied to the retina with the aim of stopping the growth and development of new blood vessels, and thereby preserving vision. To assess the effects of laser photocoagulation for diabetic retinopathy compared to no treatment or deferred treatment. We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (2014, Issue 5), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to June 2014), EMBASE (January 1980 to June 2014), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 3 June 2014. We included randomised controlled trials (RCTs) where people (or eyes) with diabetic retinopathy were randomly allocated to laser photocoagulation or no treatment or deferred treatment. We excluded trials of lasers that are no longer in routine use. Our primary outcome was the proportion of people who lost 15 or more letters (3 lines) of best-corrected visual acuity (BCVA) as measured on a logMAR chart at 12 months. We also looked at longer-term follow-up of the primary outcome at two to five years. Secondary outcomes included mean best corrected distance visual acuity, severe visual loss, mean near visual acuity, progression of diabetic retinopathy, quality of life, pain, loss of driving licence, vitreous haemorrhage and retinal detachment. We used standard methods as expected by the Cochrane Collaboration. Two review authors selected studies and extracted data. We identified a large number of trials of laser photocoagulation of diabetic retinopathy (n = 83) but only five of these studies were eligible for inclusion in the review, i.e. they compared laser photocoagulation with currently available lasers to no (or deferred) treatment. Three studies were conducted in the USA, one study in the UK and one study in Japan. A total of 4786 people (9503 eyes) were included in these studies. The majority of participants in four of these trials were people with proliferative diabetic retinopathy; one trial recruited mainly people with non-proliferative retinopathy. Four of the studies evaluated panretinal photocoagulation with argon laser and one study investigated selective photocoagulation of non-perfusion areas. Three studies compared laser treatment to no treatment and two studies compared laser treatment to deferred laser treatment. All studies were at risk of performance bias because the treatment and control were different and no study attempted to produce a sham treatment. Three studies were considered to be at risk of attrition bias.At 12 months there was little difference between eyes that received laser photocoagulation and those allocated to no treatment (or deferred treatment), in terms of loss of 15 or more letters of visual acuity (risk ratio (RR) 0.99, 95% confidence interval (CI) 0.89 to 1.11; 8926 eyes; 2 RCTs, low quality evidence). Longer term follow-up did not show a consistent pattern, but one study found a 20% reduction in risk of loss of 15 or more letters of visual acuity at five years with laser treatment. Treatment with laser reduced the risk of severe visual loss by over 50% at 12 months (RR 0.46, 95% CI 0.24 to 0.86; 9276 eyes; 4 RCTs, moderate quality evidence). There was a beneficial effect on progression of diabetic retinopathy with treated eyes experiencing a 50% reduction in risk of progression of diabetic retinopathy (RR 0.49, 95% CI 0.37 to 0.64; 8331 eyes; 4 RCTs, low quality evidence) and a similar reduction in risk of vitreous haemorrhage (RR 0.56, 95% CI 0.37 to 0.85; 224 eyes; 2 RCTs, low quality evidence).None of the studies reported near visual acuity or patient-relevant outcomes such as quality of life, pain, loss of driving licence or adverse effects such as retinal detachment.We did not plan any subgroup analyses, but there was a difference in baseline risk in participants with non-proliferative retinopathy compared to those with proliferative retinopathy. With the small number of included studies we could not do a formal subgroup analysis comparing effect in proliferative and non-proliferative retinopathy. This review provides evidence that laser photocoagulation is beneficial in treating proliferative diabetic retinopathy. We judged the evidence to be moderate or low, depending on the outcome. This is partly related to reporting of trials conducted many years ago, after which panretinal photocoagulation has become the mainstay of treatment of proliferative diabetic retinopathy.Future Cochrane Reviews on variations in the laser treatment protocol are planned. Future research on laser photocoagulation should investigate the combination of laser photocoagulation with newer treatments such as anti-vascular endothelial growth factors (anti-VEGFs).


A systematic review of missed opportunities for improving tuberculosis and HIV/AIDS control in Sub-saharan Africa: what is still missed by health experts?
In sub-Saharan Africa, HIV/AIDS and tuberculosis are major public health problems. In 2010, 64% of the 34 million of people infected with HIV were reported to be living in sub-Saharan Africa. Only 41% of eligible HIV-positive people had access to antiretroviral therapy (ART). Regarding tuberculosis, in 2010, the region had 12% of the world's population but reported 26% of the 8.8 million incident cases and 254000 tuberculosis-related deaths. This paper aims to review missed opportunities for improving HIV/AIDS and tuberculosis prevention and care. We conducted a systematic review in PubMed using the terms 'missed'(Title) AND 'opportunities'(Title). We included systematic review and original research articles done in sub-Saharan Africa on missed opportunities in HIV/AIDS and/or tuberculosis care. Missed opportunities for improving HIV/AIDS and/or tuberculosis care can be classified into five categories: i) patient and community; ii) health professional; iii) health facility; iv) local health system; and v) vertical programme (HIV/AIDS and/or tuberculosis control programmes). None of the reviewed studies identified any missed opportunities related to health system strengthening. Opportunities that are missed hamper tuberculosis and/or HIV/AIDS care in sub-Saharan Africa where health systems remain weak. What is still missing in the analysis of health experts is the acknowledgement that opportunities that are missed to strengthen health systems also undermine tuberculosis and HIV/AIDS prevention and care. Studying why these opportunities are missed will help to understand the rationales behind the missed opportunities, and customize adequate strategies to seize them and for effective diseases control.


Angiogenesis and vasculogenesis in the corpus luteum in vitro.
Despite standardized cultivation conditions different morphological forms of vascular development and different angiogenic potency were detected in endothelial cells of the corpus luteum in vitro. The aim of the present study was a comparative investigation of these luteal endothelial cell cultures by light and electron microscopy as well as immunocytochemistry including the use of endothelial and endothelial progenitor markers (CD34, VEGF-R2 and CD31). Screening of cellular proliferation in endothelial cells from regressing corpus luteum (ECreg) showed that vascular development in vitro followed the steps of the angiogenic cascade which starts with a linear alignment of cells, followed by circular side-by-side arrangement. In contrast endothelial cells from developing corpus luteum (ECdev) showed highly active cells and in vitro vascular development was initiated by specific cell groups, so-called "Vascular Initiation Points" (VIP). These cells showed intense proliferation, built typical cellular clusters reminiscent of de novo vasculogenesis and organized into capillary-like tubes with an internal lumen as shown by electron microscopy.


Prevalence of antibodies to type a influenza virus in wild avian species using two serologic assays.
Serologic testing to detect antibodies to avian influenza (AI) virus has been an underused tool for the study of these viruses in wild bird populations, which traditionally has relied on virus isolation and reverse transcriptase-polymerase chain reaction (RT-PCR). In a preliminary study, a recently developed commercial blocking enzyme-linked immunosorbent assay (bELISA) had sensitivity and specificity estimates of 82% and 100%, respectively, for detection of antibodies to AI virus in multiple wild bird species after experimental infection. To further evaluate the efficacy of this commercial bELISA and the agar gel immunodiffusion (AGID) test for AI virus antibody detection in wild birds, we tested 2,249 serum samples collected from 62 wild bird species, representing 10 taxonomic orders. Overall, the bELISA detected 25.4% positive samples, whereas the AGID test detected 14.8%. At the species level, the bELISA detected as many or more positive serum samples than the AGID in all 62 avian species. The majority of positive samples, detected by both assays, were from species that use aquatic habitats, with the highest prevalence from species in the orders Anseriformes and Charadriiformes. Conversely, antibodies to AI virus were rarely detected in the terrestrial species. The serologic data yielded by both assays are consistent with the known epidemiology of AI virus in wild birds and published reports of host range based on virus isolation and RT-PCR. The results of this research are also consistent with the aforementioned study, which evaluated the performance of the bELISA and AGID test on experimental samples. Collectively, the data from these two studies indicate that the bELISA is a more sensitive serologic assay than the AGID test for detecting prior exposure to AI virus in wild birds. Based on these results, the bELISA is a reliable species-independent assay with potentially valuable applications for wild bird AI surveillance.


Case report: ultrasound-guided continuous thoracic paravertebral block for outpatient acute pain management of multilevel unilateral rib fractures.
A 61-year-old man with multiple unilateral rib fractures (T3-T8) gained the ability to breathe deeply and to ambulate after ultrasound-guided continuous thoracic paravertebral block and was discharged home after being observed for 15 hours after the block. The ultrasound guidance was helpful in determining the site of rib fractures and the optimal level for catheter placement. This report also discusses the management of analgesia using continuous paravertebral block in an outpatient with trauma.


Structural connectivity abnormality in children with acute mild traumatic brain injury using graph theoretical analysis.
The traumatic biomechanical forces associated with mild traumatic brain injury (mTBI) typically impart diffuse, as opposed to focal, brain injury potentially disrupting the structural connectivity between neural networks. Graph theoretical analysis using diffusion tensor imaging was used to assess injury-related differences in structural connectivity between 23 children (age 11-16 years) with mTBI and 20 age-matched children with isolated orthopedic injuries (OI) scanned within 96 h postinjury. The distribution of hub regions and the associations between alterations in regional network measures and symptom burden, as assessed by the postconcussion symptom scale score (PCSS), were also examined. In comparison to the OI group, the mTBI group was found to have significantly higher small-worldness (P < 0.0001), higher normalized clustering coefficients (P < 0.0001), higher normalized characteristic path length (P = 0.007), higher modularity (P = 0.0005), and lower global efficiency (P < 0.0001). A series of hub regions in the mTBI group were found to have significant alterations in regional network measures including nodal degree, nodal clustering coefficient, and nodal between-ness centrality. Correlation analysis showed that PCSS total score acquired at the time of imaging was significantly associated with the nodal degree of two hubs, the superior frontal gyrus at orbital section and the middle frontal gyrus. These findings provide new evidence of acute white matter alteration at both global and regional network level following mTBI in children furthering our understanding of underlying mechanisms of acute neurological insult associated with mTBI.


A prospective study of the effects of ultralow volume (ULV) aerial application of malathion on epidemic Plasmodium falciparum malaria. III. Ecologic aspects.
The effects of aerial ultralow volume (ULV) malathion on selected species of nontarget animals in Haiti are reported. Mortality of certain groups of insects such as bees, flies, beetles, and butterflies was observed immediately following spray application. Minor fish mortality occurred only in shallow water exposed to direct spray. The brain acetylcholine esterase levels of living fish, tree lizards, birds and bats collected from treated areas were not significantly reduced. No ill or dead animals, besides the few fish, were seen even when maximum exposure occurred. Only minor changes in the feeding behavior of some insectivorous birds were observed. The relative bird density decreased substantially for only one species during the study, and other factors besides treatment were considered to be the reasons for the decline. Aerial applications of ULV malathion at dosages sufficient to dramatically reduce anopheline populations did not significantly affect nontarget vertebrates in this tropical environment.


Examination of the factor structure of the Disabilities of the Arm, Shoulder, and Hand questionnaire.
The Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire is a global scale evaluating the impact of upper-extremity disorders. We sought to validate or challenge the unidimensional factor structure of the DASH. Secondary analysis was performed on data collected from outpatient clinics. Factor analysis was performed in two steps, exploratory factor analysis (EFA) followed by confirmatory factor analysis (CFA). To provide further support for unidimensionality, fit statistics were calculated using the Andrich Rasch rating-scale model. EFA revealed three potential factors (eigenvalues = 18.40, 1.56, and 1.54). CFA was performed fitting a three-factor model. Tucker-Lewis Index (.99) and standardized root mean square residual (.05) values indicated good fit. Comparative fit index (.89) and root mean square error of approximation (.13) did not. When divided into three constructs, only one item misfit. More research is needed to determine situations in which division of the DASH may enhance interpretability.


Fast, automated measurement of nematode swimming (thrashing) without morphometry.
The "thrashing assay", in which nematodes are placed in liquid and the frequency of lateral swimming ("thrashing") movements estimated, is a well-established method for measuring motility in the genetic model organism Caenorhabditis elegans as well as in parasitic nematodes. It is used as an index of the effects of drugs, chemicals or mutations on motility and has proved useful in identifying mutants affecting behaviour. However, the method is laborious, subject to experimenter error, and therefore does not permit high-throughput applications. Existing automation methods usually involve analysis of worm shape, but this is computationally demanding and error-prone. Here we present a novel, robust and rapid method of automatically counting the thrashing frequency of worms that avoids morphometry but nonetheless gives a direct measure of thrashing frequency. Our method uses principal components analysis to remove the background, followed by computation of a covariance matrix of the remaining image frames from which the interval between statistically-similar frames is estimated. We tested the performance of our covariance method in measuring thrashing rates of worms using mutations that affect motility and found that it accurately substituted for laborious, manual measurements over a wide range of thrashing rates. The algorithm used also enabled us to determine a dose-dependent inhibition of thrashing frequency by the anthelmintic drug, levamisole, illustrating the suitability of the system for assaying the effects of drugs and chemicals on motility. Furthermore, the algorithm successfully measured the actions of levamisole on a parasitic nematode, Haemonchus contortus, which undergoes complex contorted shapes whilst swimming, without alterations in the code or of any parameters, indicating that it is applicable to different nematode species, including parasitic nematodes. Our method is capable of analyzing a 30 s movie in less than 30 s and can therefore be deployed in rapid screens. We demonstrate that a covariance-based method yields a fast, reliable, automated measurement of C. elegans motility which can replace the far more time-consuming, manual method. The absence of a morphometry step means that the method can be applied to any nematode that swims in liquid and, together with its speed, this simplicity lends itself to deployment in large-scale chemical and genetic screens.


Striatal grey matter increase in patients suffering from fibromyalgia--a voxel-based morphometry study.
Fibromyalgia (FM), among other chronic pain syndromes, such as chronic tension type headache and atypical face pain, is classified as a so-called dysfunctional pain syndrome. Patients with fibromyalgia suffer from widespread, "deep" muscle pain and often report concomitant depressive episodes, fatigue and cognitive deficits. Clear evidence for structural abnormalities within the muscles or soft tissue of fibromyalgia patients is lacking. There is growing evidence that clinical pain in fibromyalgia has to be understood in terms of pathological activity of central structures involved in nociception. We applied MR-imaging and voxel-based morphometry, to determine whether fibromyalgia is associated with altered local brain morphology. We investigated 20 patients with the diagnosis of primary fibromyalgia and 22 healthy controls. VBM revealed a conspicuous pattern of altered brain morphology in the right superior temporal gyrus (decrease in grey matter), the left posterior thalamus (decrease in grey matter), in the left orbitofrontal cortex (increase in grey matter), left cerebellum (increase in grey matter) and in the striatum bilaterally (increase in grey matter). Our data suggest that fibromyalgia is associated with structural changes in the CNS of patients suffering from this chronic pain disorder. They might reflect either a consequence of chronic nociceptive input or they might be causative to the pathogenesis of fibromyalgia. The affected areas are known to be both, part of the somatosensory system and part of the motor system.


Modeling the spread of methicillin-resistant Staphylococcus aureus (MRSA) outbreaks throughout the hospitals in Orange County, California.
Since hospitals in a region often share patients, an outbreak of methicillin-resistant Staphylococcus aureus (MRSA) infection in one hospital could affect other hospitals. Using extensive data collected from Orange County (OC), California, we developed a detailed agent-based model to represent patient movement among all OC hospitals. Experiments simulated MRSA outbreaks in various wards, institutions, and regions. Sensitivity analysis varied lengths of stay, intraward transmission coefficients (β), MRSA loss rate, probability of patient transfer or readmission, and time to readmission. Each simulated outbreak eventually affected all of the hospitals in the network, with effects depending on the outbreak size and location. Increasing MRSA prevalence at a single hospital (from 5% to 15%) resulted in a 2.9% average increase in relative prevalence at all other hospitals (ranging from no effect to 46.4%). Single-hospital intensive care unit outbreaks (modeled increase from 5% to 15%) caused a 1.4% average relative increase in all other OC hospitals (ranging from no effect to 12.7%). MRSA outbreaks may rarely be confined to a single hospital but instead may affect all of the hospitals in a region. This suggests that prevention and control strategies and policies should account for the interconnectedness of health care facilities.


Wound-induced cell proliferation during animal regeneration.
Many animal species are capable of replacing missing tissues that are lost upon injury or amputation through the process of regeneration. Although the extent of regeneration is variable across animals, that is, some animals can regenerate any missing cell type whereas some can only regenerate certain organs or tissues, regulated cell proliferation underlies the formation of new tissues in most systems. Notably, many species display an increase in proliferation within hours or days upon wounding. While different cell types proliferate in response to wounding in various animal taxa, comparative molecular data are beginning to point to shared wound-induced mechanisms that regulate cell division during regeneration. Here, we synthesize current insights about early molecular pathways of regeneration from diverse model and emerging systems by considering these species in their evolutionary contexts. Despite the great diversity of mechanisms underlying injury-induced cell proliferation across animals, and sometimes even in the same species, similar pathways for proliferation have been implicated in distantly related species (e.g., small diffusible molecules, signaling from apoptotic cells, growth factor signaling, mTOR and Hippo signaling, and Wnt and Bmp pathways). Studies that explicitly interrogate molecular and cellular regenerative mechanisms in understudied animal phyla will reveal the extent to which early pathways in the process of regeneration are conserved or independently evolved. This article is categorized under: Comparative Development and Evolution > Body Plan Evolution Adult Stem Cells, Tissue Renewal, and Regeneration > Regeneration Comparative Development and Evolution > Model Systems.


Filanesib in combination with pomalidomide and dexamethasone in refractory MM patients: safety and efficacy, and association with alpha 1-acid glycoprotein (AAG) levels. Phase Ib/II Pomdefil clinical trial conducted by the Spanish MM group.
This phase I/II trial evaluated the combination of the kinesin spindle protein inhibitor filanesib with pomalidomide and dexamethasone in relapsed or refractory multiple myeloma (RRMM) patients. Forty-seven RRMM patients with a median of three prior lines (2-8) and 94% refractory to lenalidomide were included: 14 in phase I and 33 in phase II. The recommended dose was 1·25 mg/m2 of filanesib on days 1, 2, 15, 16, with pomalidomide 4 mg on days 1-21 and dexamethasone 40 mg weekly. The defined threshold for success was achieved, with 18 out of 31 patients obtaining at least minor response (MR) in the phase II. In the global population, 51% of patients achieved at least partial response (PR) and 60% ≥MR, resulting in a median progression-free survival (mPFS) of seven months and overall survival (OS) of 19 months. The main toxicity was haematological. Importantly, patients with low serum levels of alpha 1-acid glycoprotein (AAG) at baseline (<800 mg/l) had a superior response (overall response rate of 62% vs. 17%; P = 0·04), which also translated into a longer mPFS (9 vs. 2 months; P = 0·014). In summary, filanesib with pomalidomide and dexamethasone is active in RRMM although with significant haematological toxicity. Most importantly, high levels of AAG can identify patients unlikely to respond to this strategy. Trial registration: clinicaltrials.gov identifier: NCT02384083.


Single crystal X- and Q-band EPR spectroscopy of a binuclear Mn(2)(III,IV) complex relevant to the oxygen-evolving complex of photosystem II.
The anisotropic g and hyperfine tensors of the Mn di-micro-oxo complex, [Mn(2)(III,IV)O(2)(phen)(4)](PF(6))(3).CH(3)CN, were derived by single-crystal EPR measurements at X- and Q-band frequencies. This is the first simulation of EPR parameters from single-crystal EPR spectra for multinuclear Mn complexes, which are of importance in several metalloenzymes; one of them is the oxygen-evolving complex in photosystem II (PS II). Single-crystal [Mn(2)(III,IV)O(2)(phen)(4)](PF(6))(3).CH(3)CN EPR spectra showed distinct resolved (55)Mn hyperfine lines in all crystal orientations, unlike single-crystal EPR spectra of other Mn(2)(III,IV) di-micro-oxo bridged complexes. We measured the EPR spectra in the crystal ab- and bc-planes, and from these spectra we obtained the EPR spectra of the complex along the unique a-, b-, and c-axes of the crystal. The crystal orientation was determined by X-ray diffraction and single-crystal EXAFS (Extended X-ray Absorption Fine Structure) measurements. In this complex, the three crystallographic axes, a, b, and c, are parallel or nearly parallel to the principal molecular axes of Mn(2)(III,IV)O(2)(phen)(4) as shown in the crystallographic data by Stebler et al. (Inorg. Chem. 1986, 25, 4743). This direct relation together with the resolved hyperfine lines significantly simplified the simulation of single-crystal spectra in the three principal directions due to the reduction of free parameters and, thus, allowed us to define the magnetic g and A tensors of the molecule with a high degree of reliability. These parameters were subsequently used to generate the solution EPR spectra at both X- and Q-bands with excellent agreement. The anisotropic g and hyperfine tensors determined by the simulation of the X- and Q-band single-crystal and solution EPR spectra are as follows: g(x) = 1.9887, g(y) = 1.9957, g(z) = 1.9775, and hyperfine coupling constants are A(III)(x) = |171| G, A(III)(y) = |176| G, A(III)(z) = |129| G, A(IV)(x) = |77| G, A(IV)(y) = |74| G, A(IV)(z) = |80| G.


Speciation and reactivity of Cisplatin in river water and seawater.
The adsorption of the cytostatic anticancer drug, cisplatin (cis-PtCl(2)(NH(3))(2)), has been studied after its addition to suspensions of estuarine sediment in river water and seawater. After a 16 h reaction period, adsorption was significantly greater in river water (sediment-water distribution coefficient, K(D), of 400 mL g(-1)) than that in seawater (K(D) approximately 150 mL g(-1)) because of the ready aquation of cisplatin to the more reactive monoaquacisplatin (cis-PtCl(OH(2))(NH(3))(2)(+)) at low chloride ion concentrations. Adsorption in river water was enhanced (K(D) approximately 2000 mL g(-1)) by a 24 h period of preincubation in the aqueous phase in which aquation proceeded further. The effects of pH on adsorption were relatively small, presumably because protonation-deprotonation of the particle surface was accompanied by near-equivalent shifts in the charge of hydrolysis products of aquated cisplatin. Kinetic experiments revealed a period of slow protracted uptake (up to about 60 h), followed by gradual desorption in both river water and seawater. Results were interpreted in terms of the formation of monoaquacisplatin, its adsorption to the particle surface, and the subsequent desorption of undefined, unreactive species. Kinetic data were modeled with a sequence of pseudofirst-order reactions and fits were obtained with forward and reverse rate constants for aquation of 1.79 x 10(-5) and 1.84 x 10(-5) s(-1) in river water and 5.50 x 10(-6) and 5.84 x 10(-6) s(-1) in seawater, and adsorption and desorption rate constants of 1.75 x 10(-5) and 0.20 x 10(-5) s(-1) in river water and 0.98 x 10(-5) and 2.8 x 10(-5) s(-1) in seawater. Environmental conditions favoring the retention of cisplatin and its degradation products are low chloride ion concentrations, high turbidities, and long residence or transit times; dispersion of the drug is favored in saline, coastal waters.


Text chat as a tool for referential questioning in Asperger syndrome.
This article reports a study in which referential communication in 11 individuals with Asperger syndrome (AS) and 11 controls was compared between text chat and telephone, using a route-solving task. Participants deduced routes by asking closed questions, and the dependent variables were (a) accuracy in working out the route, (b) number of questions posed (turns taken), and (c) time taken to complete the task. Generally, individuals with AS were equally competent in solving the task in both media but less efficient than the typically developing comparison group. Individuals with AS who had higher measured executive ability adopted a similar approach to the comparison group, asking about landmarks on the map to deduce the route taken. In contrast, AS participants with lower executive ability used an inefficient left/right questioning strategy, which occupied more time, required more conversational turns, and was associated with a higher rate of error. Individuals with AS, who also have problems of executive functioning, may have difficulty communicating with others to use a route-solving task.