Obligatory consultation of an independent physician on euthanasia requests in the Netherlands: what influences the SCEN physicians judgment of the legal requirements of due care?
In the Netherlands, euthanasia is allowed if physicians adhere to legal requirements. Consultation of an independent physician is one of the requirements. SCEN (Support and Consultation on Euthanasia in the Netherlands) physicians have been trained to provide such consultations. To study why euthanasia requests are sometimes judged not to meet requirements of due care and to find out which characteristics are associated with the SCEN physicians' judgments. During 5 years (2006, 2008-2011) standardized registration forms were used for data-collection. We used multilevel logistic regression analysis to assess the associations of characteristics and SCEN physicians' judgments. We analyzed 1631 euthanasia requests, involving 415 SCEN physicians. Patient characteristics that were associated with a lower likelihood to meet due care requirements were: being tired with life, depression and not wanting to be a burden. Physical suffering and higher patient age were related to greater chances of meeting the requirements. There was no clear association between SCEN physicians' characteristics and their judgment. Psychological suffering involves a greater chance that SCEN physicians judge that requirements of due care are not met. The association between SCEN physician characteristics and the judgment of euthanasia requests is limited, suggesting uniformity in their judgment.


Transfusional Mansonella perstans microfilariasis.
Mansonella perstans filariasis is widely distributed across the center of Africa and equatorial America. We describe a case of post-transfusional M. perstans microfilariasis in a young child, affected with severe Plasmodium falciparum malaria, admitted in Goundi Hospital in South of Chad. A decrease of M. perstans microfilariasis in the patient's blood was observed, with no subsequent development of either clinical symptoms or eosinophilia. We suggest that, in endemic areas, transfused M. perstans microfilariae may be cleared from the blood over relatively short periods of time. It is likely that only adult worms are responsible for symptoms and eosinophilia, whereas microfilariae in the bloodstream are unable to give clinical manifestations.


Advances in analysis of microbial metabolic fluxes via (13)C isotopic labeling.
Metabolic flux analysis via (13)C labeling ((13)C MFA) quantitatively tracks metabolic pathway activity and determines overall enzymatic function in cells. Three core techniques are necessary for (13)C MFA: (1) a steady state cell culture in a defined medium with labeled-carbon substrates; (2) precise measurements of the labeling pattern of targeted metabolites; and (3) evaluation of the data sets obtained from mass spectrometry measurements with a computer model to calculate the metabolic fluxes. In this review, we summarize recent advances in the (13)C-flux analysis technologies, including mini-bioreactor usage for tracer experiments, isotopomer analysis of metabolites via high resolution mass spectrometry (such as GC-MS, LC-MS, or FT-ICR), high performance and large-scale isotopomer modeling programs for flux analysis, and the integration of fluxomics with other functional genomics studies. It will be shown that there is a significant value for (13)C-based metabolic flux analysis in many biological research fields.


Development of a receptor-based inhibitory penta-unit-conjugated peptide to enhance anthrax toxin neutralization.
Anthrax toxin is a key virulence factor for Bacillus anthracis. The cell-binding component of anthrax toxin, protective antigen (PA), mediates the entry of the toxin into cells by first binding to the extracellular von Willebrand factor A (VWA) domain of the cellular anthrax toxin receptor (ATR). Herein, we targeted the VWA domain of the cellular receptor to develop a more effective antitoxin agent for neutralization of anthrax toxin. We selected ATR-binding peptides by using a phage display: among these, we identified two novel peptides binding to the ATR with high affinity and specificity, and that neutralized anthrax toxicity in cells. Furthermore, to enhance the functional efficiency of the probes, the peptides were modified and conjugated to three polyvalent probe backbones: a 17 amino-acid-based cyclic form penta-unit, poly-d-lysine (PDL), or the M13 bacteriophage. One of the functionally modified polyvalent peptide probes, the penta-unit-conjugated probe (PUCP) produced the most potent neutralization of anthrax toxin, with half-maximal inhibitory concentration (IC50) of 20 nM. The PUCP disrupted anthrax toxin binding to its receptor and reduced endocytosis of anthrax toxin. This peptide-based approach may, therefore, represent a promising strategy to combat anthrax toxicosis and other bacterial diseases and may be efficient for disease treatment.


How QOF is shaping primary care review consultations: a longitudinal qualitative study.
Long-term conditions (LTCs) are increasingly important determinants of quality of life and healthcare costs in populations worldwide. The Chronic Care Model and the NHS and Social Care Long Term Conditions Model highlight the use of consultations where patients are invited to attend a consultation with a primary care clinician (practice nurse or GP) to complete a review of the management of the LTC. We report a qualitative study in which we focus on the ways in which QOF (Quality and Outcomes Framework) shapes routine review consultations, and highlight the tensions exposed between patient-centred consulting and QOF-informed LTC management. A longitudinal qualitative study. We audio-recorded consultations of primary care practitioners with patients with LTCs. We then interviewed both patients and practitioners using tape-assisted recall. Patient participants were followed for three months during which the research team made weekly contact and invited them to complete weekly logs about their health service use. A second interview at three months was conducted with patients. Analysis of the data sets used an integrative framework approach. Practitioners view consultations as a means of 'surveillance' of patients. Patients present themselves, often passively, to the practitioner for scrutiny, but leave the consultation with unmet biomedical, informational and emotional needs. Patients perceived review consultations as insignificant and irrelevant to the daily management of their LTC and future healthcare needs. Two deviant cases, where the requirements of the 'review' were subsumed to meet the patient's needs, focused on cancer and bereavement. Routine review consultations in primary care focus on the biomedical agenda set by QOF where the practitioner is the expert, and the patient agenda unheard. Review consultations shape patients' expectations of future care and socialize patients into becoming passive subjects of 'surveillance'. Patient needs outside the narrow protocol of the review are made invisible by the process of review except in extreme cases such as anticipating death and bereavement. We suggest how these constraints might be overcome.


The position of neoadjuvant chemotherapy within the treatment of ovarian cancer.
It is clear that primary debulking remains the standard of care within the treatment of advanced ovarian cancer (International Federation of Gynaecology and Obstetrics, FIGO, stage III and IV). Debulking surgery should be performed by a gynaecologic oncologist without any residual tumour load, or so called optimal debulking'. Over the last decades, interest in the use of neoadjuvant chemotherapy together with an interval debulking has increased. Open laparoscopy is probably the most valuable tool for evaluating the operability primarily or at the time of interval debulking surgery. Neoadjuvant therapy can be used for patients that are primarily suboptimally debulked due to an extensive tumor load. In this situation, based on the randomized EORTC-GCG trial, interval debulking by an experienced surgeon improves survival in some patients who did not undergo optimal primary debulking surgery. Based on the GOG 152 data, interval debulking surgery does not seem to be indicated in patients who underwent primarily a maximal surgical effort by a gynecological oncologist. Neoadjuvant chemotherapy can also be used as an alternative to primary debulking. In retrospective analyses neoadjuvant chemotherapy followed by interval debulking surgery does not seem to worsen prognosis compared to primary debulking surgery followed by chemotherapy. However, we will have to wait for the results of future randomized trials to know whether neoadjuvant chemotherapy followed by interval debulking surgery is a good alternative to primary debulking surgery in stage IIIc and IV patients.


Centenary of Lewy bodies (1912-2012).
During the years from 1908 until 1923, Lewy was the first to detail the pathological anatomy of Parkinson's disease, leading to his seminal contribution in 1912 describing the neuronal eosinophilic cytoplasmatic concentric inclusion bodies in the brainstem, later accomplished by more systematic investigations in 1923 (Lewy in Lewandowsky's Handbuch der Neurologie, 3. Band: Spez. Neurologie II. Springer, Berlin, pp 920-933, 1912). With the exception of a minority of cases and those that displayed postencephalitic Parkinsonism, Lewy was not able to confirm the significance of the substantia nigra. The findings of Tretiakoff in 1919 (significance of the substantia nigra in PD and coining of the term 'Corps de Lewy') have been underestimated or ignored for a long time. In a historical review on basal ganglia diseases from 1942, Lewy stressed the histological abnormalities of the basal ganglia and their diffuse distribution but not expressly the inclusion bodies, which in his former studies were unique in PD. For Lewy this finding was not a characteristic of the disease. Subsequent to his expulsion from Nazi-Germany in 1933, Lewy never resumed his research on PD. At the time of Lewy's death in 1950, the era of the Lewy bodies, Lewy-body-disease and the identification of atypical Parkinson syndrome cases had not even begun and followed much later.


Modeling discrete combinatorial systems as alphabetic bipartite networks: theory and applications.
Genes and human languages are discrete combinatorial systems (DCSs), in which the basic building blocks are finite sets of elementary units: nucleotides or codons in a DNA sequence, and letters or words in a language. Different combinations of these finite units give rise to potentially infinite numbers of genes or sentences. This type of DCSs can be represented as an alphabetic bipartite network (ABN) where there are two kinds of nodes, one type represents the elementary units while the other type represents their combinations. Here, we extend and generalize recent analytical findings for ABNs derived in [Peruani, Europhys. Lett. 79, 28001 (2007)] and empirically investigate two real world systems in terms of ABNs, the codon gene and the phoneme-language network. The one-mode projections onto the elementary basic units are also studied theoretically as well as in real world ABNs. We propose the use of ABNs as a means for inferring the mechanisms underlying the growth of real world DCSs.


A sero-epidemiological study of arboviral fevers in Djibouti, Horn of Africa.
Arboviral infections have repeatedly been reported in the republic of Djibouti, consistent with the fact that essential vectors for arboviral diseases are endemic in the region. However, there is a limited recent information regarding arbovirus circulation, and the associated risk predictors to human exposure are largely unknown. We performed, from November 2010 to February 2011 in the Djibouti city general population, a cross-sectional ELISA and sero-neutralisation-based sero-epidemiological analysis nested in a household cohort, which investigated the arboviral infection prevalence and risk factors, stratified by their vectors of transmission. Antibodies to dengue virus (21.8%) were the most frequent. Determinants of infection identified by multivariate analysis pointed to sociological and environmental exposure to the bite of Aedes mosquitoes. The population was broadly naïve against Chikungunya (2.6%) with risk factors mostly shared with dengue. The detection of limited virus circulation was followed by a significant Chikungunya outbreak a few months after our study. Antibodies to West Nile virus were infrequent (0.6%), but the distribution of cases faithfully followed previous mapping of infected Culex mosquitoes. The seroprevalence of Rift valley fever virus was 2.2%, and non-arboviral transmission was suggested. Finally, the study indicated the circulation of Toscana-related viruses (3.7%), and a limited number of cases suggested infection by tick-borne encephalitis or Alkhumra related viruses, which deserve further investigations to identify the viruses and vectors implicated. Overall, most of the arboviral cases' predictors were statistically best described by the individuals' housing space and neighborhood environmental characteristics, which correlated with the ecological actors of their respective transmission vectors' survival in the local niche. This study has demonstrated autochthonous arboviral circulations in the republic of Djibouti, and provides an epidemiological inventory, with useful findings for risk mapping and future prevention and control programs.


Abrocitinib for the treatment of atopic dermatitis.
Abrocitinib is an oral small molecule which selectively inhibits JAK1, modulating multiple cytokine pathways involved in atopic dermatitis. Both abrocitinib 200 mg and 100 mg reached efficacy results comparable to dupilumab and superior to placebo. Abrocitinib 200 mg was superior to dupilumab in some trials, consistently providing a faster response and itch relief from week 2 to 26. Continuous abrocitinib 200 mg is the most effective at controlling this disease, but with an induction-maintenance approach with abrocitinib 200 mg followed by 100 mg, over 55% of patients did not flare for 40 weeks. Abrocitinib common adverse effects are nonserious. A self-limited dose-related decrease in platelet counts was consistently observed, without clinical repercussion. Abrocitinib demonstrated high efficacy and a favorable safety profile.


Region specific changes in nonapeptide levels during client fish interactions with allopatric and sympatric cleaner fish.
Social relationships are crucially dependent on individual ability to learn and remember ecologically relevant cues. However, the way animals recognize cues before engaging in any social interaction and how their response is regulated by brain neuromodulators remains unclear. We examined the putative involvement of arginine vasotocin (AVT) and isotocin (IT), acting at different brain regions, during fish decision-making in the context of cooperation, by trying to identify how fish distinguish and recognize the value of other social partners or species. We hypothesized that the behavioural responses of cleaner fish clients to different social contexts would be underlain by changes in brain AVT and IT levels. We have found that changes in AVT at the level of forebrain and optic tectum are linked with a response to allopatric cleaners (novel or unfamiliar stimuli) while those at cerebellum are associated with the willingness to be cleaned (in response to sympatric cleaners). On the other hand, higher brain IT levels that were solely found in the diencephalon, also in response to allopatric cleaners. Our results are the first to implicate these nonapeptides, AVT in particular, in the assessment of social cues which enable fish to engage in mutualistic activities.


Computational and experimental simulations of the haemodynamics at cuffed arterial bypass graft anastomoses.
The development of intimal hyperplasia at arterial bypass graft anastomoses is a major factor responsible for graft failure. A revised surgical technique, involving the incorporation of a small section of vein (vein cuff) into the distal anastomosis of polytetrafluoroethylene (PTFE) grafts, alters the distribution of intimal hyperplasia and improves graft performance. Numerical and in vitro flow visualization experiments have been conducted to identify the flow behaviour in the cuffed bypass model and to determine whether the improved performance of the cuffed system can be accounted for by haemodynamic factors. The flowfield at the cuffed anastomosis is characterized by an expansive recirculation. Separation occurs at the graft heel, and at the cuff toe as the blood enters the recipient artery. Wall shear stresses in the vicinity of the cuff heel are low, but high shear stresses and large spatial gradients in the shearing force act for a time on the artery floor. In the conventional model, a less disturbed flow prevails while the gradients of shear stress on the floor are smaller. Aspects of the anastomotic haemodynamics are worsened when the cuff is employed. The superior patency rates of cuffed bypasses may not be explained purely on the basis of local haemodynamic factors.


Oxidative stress, hepcidin and nesfatin-I status in childhood iron and vitamin B12 deficiency anemias.
Anemia is a disease that is long and often repetitive and can result in a great burden to the national economy. The most frequent nutritional deficiency anemias in children are related with iron and vitamin B12 deficiencies. The aim of this study was to determine the oxidative stress, hepcidin, and nesfatin-I levels in childhood iron and vitamin B12 deficiency anemias. The study had 3 groups of 15 children, iron anemia deficiency group, vitamin B12 deficiency group and a control group. The TBARS and nesfatin-I levels were significantly higher in the iron and vitamin B12 deficiency groups and the total antioxidant levels were significantly lower when compared to the control group. In contrast, the plasma hepcidin levels were significantly lower in the iron deficiency group (p < 0.01) when compared to the control group; however, no significant differences were observed in the vitamin B12 deficiency group. Plasma homocysteine levels were significantly higher in the vitamin B12 deficiency group when compared to the control group (p < 0.001), but no differences were determined between the iron deficiency and control groups. Our results showed that there are high levels of oxidative stress in childhood iron and vitamin B12 deficiency anemias, and we propose that plasma hepcidin and homocycteine levels may be useful in the differential diagnosis of childhood nutritional deficiency anemias. Nesfatin-1 hormone levels were identified for the first time in childhood iron deficiency and vitamin B12 deficiency anemias within this study and this hormone may also be useful in the differential diagnosis of anemias.


A national study on weight classes among children in Greenland at school entry.
To estimate the proportion of gender-specific thinness, overweight and obesity among children born in 2005 at school entry in Greenland and to compare figures between the capital, Nuuk, with the rest of Greenland. A cross-sectional study based on data from Electronic Medical Records (EMR). All children born in 2005 with permanent address in Greenland at the time of data extraction with a registered weight and height in EMR from January 1st 2011 to January 31st 2013 were included in the study. Information about height without shoes and weight in light indoor clothing was obtained. Body Mass Index (BMI) was calculated. Participants were categorized into age and gender-specific weight classes based on the International Obesity Task Force (IOTF) cut-offs for child overweight, obesity and thinness. A total of 842 children born in 2005 were identified. Of those, 72% (N=607, 308 boys and 299 girls) had a recorded weight and height in the study period. In total, 74.6% (71.2-78.1) were categorized as of normal weight. The proportion of children with overweight was 15.8% (12.9-18.7) while 6.8% (4.8-8.8) were obese. In all, 2.9% were categorized as thin. The proportion of overweight among boys (12.7%) was lower (p=0.031) than among girls (19.1%), and boys in Nuuk had a lower median BMI compared to the rest of Greenland. No differences in distribution of age and gender-specific overweight and obesity were observed between the capital and the rest of Greenland. Nearly 1 quarter of Greenlandic children are overweight or obese at school entry. No differences were observed between Nuuk and the rest of Greenland. Information about weight and height is available in the EMR for the majority of all children at school entry in Greenland. Continuous monitoring of the proportion of overweight and obesity among children using data from the EMR in Greenland is recommended.


Retinal Shape-Based Classification of Retinal Detachment and Posterior Vitreous Detachment Eyes.
Retinal detachment is a sight-threatening emergency, with more than half of those affected suffering permanent visual impairment. A diagnostic test to identify eyes at risk before vision is threatened would enable exploration of prophylactic treatment. This report presents the use of irregularities in retinal shape, quantified from optical coherence tomography (OCT) images, as a biomarker for retinal detachment. OCT images were taken from posterior and mid-peripheral retina of 264 individuals [97 after a posterior vitreous detachment (PVD), 99 after vitrectomy for retinal detachment and 68 after laser for a retinal tear]. Diagnoses were taken from history, examination and OCT. Retinal irregularity was quantified in the frequency domain, and the distribution of irregularity across the regions of the eye was explored to identify features exhibiting the greatest difference between retinal detachment and PVD eyes. Two of these features plus axial length were used to train a quadratic discriminant analysis classifier. Classifier performance was assessed by its sensitivity and specificity in identifying retinal detachment eyes and visualised with a receiver operating characteristic (ROC) curve. Validation set specificity was 84% (44/52 PVD eyes correctly labelled) and sensitivity 35% (23/64 retinal detachment eyes identified, p = 0.02). Area under the ROC curve was 0.75 (95% confidence intervals 0.58-0.85). Retinal detachment eyes were significantly more irregular than PVD eyes in the superior retina (0.70 mm versus 0.49 mm, p < 0.05) and supero-temporal retina (1.12 mm versus 0.80 mm, p < 0.05). Lower sensitivity (16/68, 24%) was seen for eyes with a retinal tear without detachment, that were intermediate in size between retinal detachment and PVD eyes. Axial length on its own was a poor classifier. Neither irregularity nor classification were affected by surgery for retinal detachment or the development of PVD. The classifier identified 1/3 of retinal detachment eyes in this sample. In future work, these features can be evaluated as a test for retinal detachment prior to PVD.


Fixing healthcare from the inside: teaching residents to heal broken delivery processes as they heal sick patients.
There is a marked gap between the potential of medical science to treat illness and injury and the performance of the health care system in which hard-working, intelligent, well-trained people put that science to work. Care is available to too few, and costs and risks of injury are too high. This is avoidable. Experience in Boston, Pittsburgh, Salt Lake City, Seattle, and elsewhere indicates that quality can be raised-while risks and costs are dramatically reduced-by applying lessons from the highest-performing industrial organizations to designing, operating, and improving health care processes. What are these lessons? Improve sick processes with the same approaches used to treat patients. Specify "normal." When problems in quality, safety, efficiency, responsiveness, and the like occur, quickly determine exactly what is abnormal and determine what might be causing them. Develop a "treatment plan"-process changes that will eliminate or counteract the causal factors. Run the process (or a facsimile) with a modified, watching for gaps between actual and expected outcomes. When gaps occur, do a new work-up, diagnosis, treatment plan, and test. Lessons in designing, operating, and improving processes can be taught just as medical expertise is developed. Teach basic frameworks didactically; then, provide hands-on experience in applying those principles to real problems. Start with simple well-bounded situations that can be practiced frequently, with rapid feedback and close mentoring before advancing to more complex, less well bounded situations that occur less frequently and provide less immediate feedback between action and outcome. Incorporate development of process improvement skills into residency training so that deepening expertise within specialties is complemented by greater skill at integrating functional knowledge into well-integrated care processes.


Differences in the Binding Affinity of an HIV-1 V2 Apex-Specific Antibody for the SIVsmm/mac Envelope Glycoprotein Uncouple Antibody-Dependent Cellular Cytotoxicity from Neutralization.
As a consequence of their independent evolutionary origins in apes and Old World monkeys, human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency viruses of the SIVsmm/mac lineage express phylogenetically and antigenically distinct envelope glycoproteins. Thus, HIV-1 Env-specific antibodies do not typically cross-react with the Env proteins of SIVsmm/mac isolates. Here we show that PGT145, a broadly neutralizing antibody to a quaternary epitope at the V2 apex of HIV-1 Env, directs the lysis of SIVsmm/mac-infected cells by antibody-dependent cellular cytotoxicity (ADCC) but does not neutralize SIVsmm/mac infectivity. Amino acid substitutions in the V2 loop of SIVmac239 corresponding to the epitope for PGT145 in HIV-1 Env modulate sensitivity to this antibody. Whereas a substitution in a conserved N-linked glycosylation site (N171Q) eliminates sensitivity to ADCC, a lysine-to-serine substitution in this region (K180S) increases ADCC and renders the virus susceptible to neutralization. These differences in function correlate with an increase in the affinity of PGT145 binding to Env on the surface of virus-infected cells and to soluble Env trimers. To our knowledge, this represents the first instance of an HIV-1 Env-specific antibody that cross-reacts with SIVsmm/mac Env and illustrates how differences in antibody binding affinity for Env can differentiate sensitivity to ADCC from neutralization.IMPORTANCE Here we show that PGT145, a potent broadly neutralizing antibody to HIV-1, directs the lysis of SIV-infected cells by antibody-dependent cellular cytotoxicity but does not neutralize SIV infectivity. This represents the first instance of cross-reactivity of an HIV-1 Env-specific antibody with SIVsmm/mac Env and reveals that antibody binding affinity can differentiate sensitivity to ADCC from neutralization.


Neurtrophil degranulation in cadmium-chloride-induced acute lung inflammation.
Lobar intrabronchial instillation of cadmium chloride (200 micrograms/ml) in saline causes a reproducible acute pulmonary inflammation in dogs. The influx of inflammatory neutrophils from the circulation into the alveolar spaces reaches a maximum approximately 16 hours after the cadmium chloride treatment in the treated lobe, while the controlateral lung appears normal. Morphometric quantitation of peroxidase-positive (azurophilic) granules in the inflammatory neutrophils shows a 74% loss of these granules, with little or no loss of the peroxidase-negative (specific) granules. These data are in good agreement with the measured loss of intracellular elastase, an enzyme known to be localized in the azurophilic granules. The results suggest that degranulation of azurophilic granules may occur selectively during this chemically induced acute inflammation.


Stability and crystal structures of His88 mutant human transthyretins.
Destabilization of human transthyretin (TTR) has been implicated in its misfolding and aggregation. A previous study on the neutron crystal structure of TTR suggested that a large hydrogen bond network around H88 which includes water molecules is significantly involved in the stability of wild-type TTR (WT-TTR). Here, we demonstrate that the H88R mutant associated with amyloid cardiomyopathy is substantially destabilized compared with WT-TTR. In order to clarify the role of H88 and the hydrogen bond network in the stability of TTR, we determined the thermodynamic stability and the crystal structure of H88 mutants (H88A, H88F, H88Y, and H88S). Our results suggest that in some cases TTR is destabilized due to alterations in bound water molecules as well as structural changes in TTR itself.


Sensorineural hearing loss in children and adults with Williams syndrome.
Williams syndrome (WS) is a genetic neurodevelopmental disorder, most often accompanied by mild-to-moderate mental retardation. Individuals with WS show unique communication strengths and impairments that are challenging to treat in community, educational, and vocational settings. Many issues regarding characteristics of auditory sensitivity in WS remain to be resolved. Our purpose was to obtain behavioral (screening and pure-tone audiometry) and objective (distortion product otoacoustic emission-DPOAE) measures of auditory system function from a group of 27 individuals with WS, 6-48 years of age. These measures were gathered both at an international professional conference (n = 19) and in a clinic setting (n = 8). In the behavioral screening conditions, 16/19 (84%) of the individuals failed the hearing screening; and in the behavioral diagnostic hearing condition, 6/8 (75%) demonstrated sensorineural hearing loss (SNHL) and 1/8 demonstrated a hearing loss of undetermined type. In the objective DPOAE testing, 19/25 (76%) had DPOAE absolute amplitudes below the 5th percentile for ears with normal hearing [Gorga et al. (1997); Ear Hear 18(6):440-455]. We report SNHL in 14/18 (78%) of school-age children with WS. Post hoc analyses revealed a significant effect for age, suggesting a pattern of progressive hearing loss. An effect size analysis indicated a clinically meaningful difference in the hearing sensitivity between school-aged children and adults in the high frequencies (4,000 and 8,000 Hz). Similar hearing loss phenotype was observed in patients with familial nonsyndromic supravalvular aortic stenosis (SVAS), suggesting that molecular defects in the elastin gene in the pathogenesis of SNHL in WS. This study highlights the importance of early and regular hearing testing for WS patients and suggests that elastin may have a previously unappreciated function in maintaining hearing sensitivity.


Separation of killing and tumorigenic effects of an alkylating agent in mice defective in two of the DNA repair genes.
Alkylation of DNA at the O6-position of guanine is one of the most critical events leading to mutation, cancer, and cell death. The enzyme O6-methylguanine-DNA methyltransferase repairs O6-methylguanine as well as a minor methylated base, O4-methylthymine, in DNA. Mouse lines deficient in the methyltransferase (MGMT) gene are hypersensitive to both the killing and to the tumorigenic effects of alkylating agents. We now show that these dual effects of an alkylating agent can be dissociated by introduction of an additional defect in mismatch repair. Mice with mutations in both alleles of the MGMT gene and one of the mismatch repair genes, MLH1, are as resistant to methylnitrosourea (MNU) as are wild-type mice, in terms of survival, but do have numerous tumors after receiving MNU. In contrast to MGMT-/- MLH1(+/+) mice with decrease in size of the thymus and hypocellular bone marrow after MNU administration, no conspicuous change was found in MGMT-/- MLH1(-/-) mice treated in the same manner. Thus, killing and tumorigenic effects of an alkylating agent can be dissociated by preventing mismatch repair pathways.


Interaction between glutathione S-transferase variants, maternal smoking and childhood wheezing changes with age.
Maternal smoking increases the risk of respiratory symptoms in children. Glutathione S-transferases (GSTs) detoxify xenobiotics from tobacco smoke, and functional polymorphism in GST gene(s) could predispose children to the detrimental effects of maternal smoking. Our objective was to investigate interactions between GST variants and maternal smoking in relation to the development of wheezing during childhood and whether any such interaction changes with time. In a population-based birth cohort, we assessed maternal smoking and current wheeze at five time points during the first 11 yr of life. DNA was genotyped for GSTP1, GSTM1 and GSTT1 (n = 807). Longitudinal analyses were performed using generalized estimating equations. During early childhood, children whose mothers smoked were more likely to wheeze, with the strongest association observed at age 3 yr (p = 0.006). In a longitudinal model, children with GSTP1 AA and AG genotypes had significantly higher risk of wheeze compared with GG homozygotes. We observed a significant interaction between GSTP1 and maternal smoking where the risk of infantile wheezing was significantly increased in AA homozygotes, but only if their mothers smoked (OR 2.59, [1.08-6.21], p(int) = 0.03). Furthermore, amongst AA carriers, there was a significant interaction between child's age and maternal smoking, with the effect of maternal smoking on the risk of wheeze significantly diminishing with age (p(int) = 0.05); no such findings were observed for GSTM1 and GSTT1. Children with AA genotype for GSTP1 are at increased risk of early-life wheezing if their mothers smoke, but the effect of maternal smoking on wheezing diminishes with time.


Nomenclatural and taxonomic notes on three South-East Asian species of Amata (Lepidoptera: Erebidae: Arctiinae: Syntomini).
The taxonomy and nomenclature of three South-East Asian species of Amata all named leopoldi is clarified. Leopoldina leopoldi Hering, 1934 syn. n., is synonymized with Amata sperbius (Fabricius, 1787), Syntomis leopoldi Hering, 1934 is transferred to Amata as Amata leopoldi (Hering, 1934) comb. n. and Syntomis leopoldi Tams, 1935 is renamed as Amata tamsi nom. n., due to its primary homonymy with Syntomis leopoldi Hering, 1934. A synonymic list of the three species is provided, together with a colour plate of the holotypes and other relevant specimens.


Sensitive detection of cadmium ions based on a quantum-dot-mediated fluorescent visualization sensor.
A sensitive ratiometric fluorescent sensor for detecting cadmium ions (Cd2+) was constructed based on carbon quantum dots (CQDs)/CdTe quantum dots (CdTe QDs). Red fluorescence (from CdTe QDs) played the role of the signal response and blue fluorescence (from CQDs) served as a reference probe without a color change. The fluorescent sensor showed high selectivity and sensitivity to Cd2+ with a limit of detection (LOD) of 0.018 μM and a range from 0.1 μM to 23 μM. The proposed method was successfully applied to the determination of Cd2+ in real rice samples. In addition, a fluorescent sensor integrated with a smartphone platform was further designed for the visualized and quantitative detection of Cd2+. This work might extend the range of visualization analysis strategies and provide new insights into the rapid quantitative, portable and sensitive detection of Cd2+ in real-time and on-site applications.


Iron-Induced Respiration Promotes Antibiotic Resistance in Actinomycete Bacteria.
The bacterial response to antibiotics eliciting resistance is one of the key challenges in global health. Despite many attempts to understand intrinsic antibiotic resistance, many of the underlying mechanisms still remain elusive. In this study, we found that iron supplementation promoted antibiotic resistance in Streptomyces coelicolor. Iron-promoted resistance occurred specifically against bactericidal antibiotics, irrespective of the primary target of antibiotics. Transcriptome profiling revealed that some genes in the central metabolism and respiration were upregulated under iron-replete conditions. Iron supported the growth of S. coelicolor even under anaerobic conditions. In the presence of potassium cyanide, which reduces aerobic respiration of cells, iron still promoted respiration and antibiotic resistance. This suggests the involvement of a KCN-insensitive type of respiration in the iron effect. This phenomenon was also observed in another actinobacterium, Mycobacterium smegmatis. Taken together, these findings provide insight into a bacterial resistance strategy that mitigates the activity of bactericidal antibiotics whose efficacy accompanies oxidative damage by switching the respiration mode. IMPORTANCE A widely investigated mode of antibiotic resistance occurs via mutations and/or by horizontal acquisition of resistance genes. In addition to this acquired resistance, most bacteria exhibit intrinsic resistance as an inducible and adaptive response to different classes of antibiotics. Increasing attention has been paid recently to intrinsic resistance mechanisms because this may provide novel therapeutic targets that help rejuvenate the efficacy of the current antibiotic regimen. In this study, we demonstrate that iron promotes the intrinsic resistance of aerobic actinomycetes Streptomyces coelicolor and Mycobacterium smegmatis against bactericidal antibiotics. A surprising role of iron to increase respiration, especially in a mode of using less oxygen, appears a fitting strategy to cope with bactericidal antibiotics known to kill bacteria through oxidative damage. This provides new insights into developing antimicrobial treatments based on the availability of iron and oxygen.


Neuromagnetic abnormality of motor cortical activation and phases of headache attacks in childhood migraine.
The cerebral cortex serves a primary role in the pathogenesis of migraine. This aberrant brain activation in migraine can be noninvasively detected with magnetoencephalography (MEG). The objective of this study was to investigate the differences in motor cortical activation between attacks (ictal) and pain free intervals (interictal) in children and adolescents with migraine using both low- and high-frequency neuromagnetic signals. Thirty subjects with an acute migraine and 30 subjects with a history of migraine, while pain free, were compared to age- and gender-matched controls using MEG. Motor cortical activation was elicited by a standardized, validated finger-tapping task. Low-frequency brain activation (1~50 Hz) was analyzed with waveform measurements and high-frequency oscillations (65-150 Hz) were analyzed with wavelet-based beamforming. MEG waveforms showed that the ictal latency of low-frequency brain activation was significantly delayed as compared with controls, while the interictal latency of brain activation was similar to that of controls. The ictal amplitude of low-frequency brain activation was significantly increased as compared with controls, while the interictal amplitude of brain activation was similar to that of controls. The ictal source power of high-frequency oscillations was significantly stronger than that of the controls, while the interictal source power of high-frequency oscillations was significantly weaker than that of controls. The results suggest that aberrant low-frequency brain activation in migraine during a headache attack returned to normal interictally. However, high-frequency oscillations changed from ictal hyper-activation to interictal hypo-activation. Noninvasive assessment of cortical abnormality in migraine with MEG opens a new window for developing novel therapeutic strategies for childhood migraine by maintaining a balanced cortical excitability.


Immunoblot analysis of salivary allergens in 10 mosquito species with worldwide distribution and the human IgE responses to these allergens.
Most people develop skin reactions to mosquito bites, however, little is known about mosquito salivary allergens and the IgE responses to them. We sought to identify these allergens and the specific IgE responses they elicit. Saliva or salivary gland extracts were prepared from 10 mosquito species, including seven species with worldwide distribution: Aedes (Ae.) aegypti, Ae. vexans, Ae. albopictus, Ae. togoi, Ae. triseriatus, Culex (Cx.) quinquefasciatus, Cx. pipiens, Cx. tarsalis, Anopheles (An.) sinensis, and Culiseta (Cs.) inornata. Proteins from these preparations were separated by sodium dodecylsulfate-polyacrylamide gel electrophoresis and transferred to nitrocellulose membranes, which were immunoblotted by sequential incubations with human serum, monoclonal anti-human IgE, and enzyme-conjugated goat anti-mouse IgG. Salivary allergens were analyzed by using a pooled serum from subjects allergic to mosquitos. Individual IgE responses to each allergen were evaluated in 12 subjects allergic to mosquitos living in Canada, the United States, and China, as well as in five subjects not allergic to mosquito bites. To study species-shared allergens, the membranes were immunoblotted with two rabbit antibodies specific to recombinant mosquito salivary proteins. Three to sixteen salivary allergens with molecular masses ranging from 16 to 95 kd were found in each species. Both species-shared and species-specific allergens were identified by molecular masses, binding to the two rabbit antibodies, and individual IgE responses to species indigenous to and absent from the regions where the subjects lived. Salivary allergens, especially from Ae. aegypti, Ae. vexans, and Ae. albopictus, elicited higher IgE responses in subjects allergic to mosquitos than in nonallergic subjects. Species-shared and species-specific allergens that cause IgE responses in subjects allergic to mosquitos are immunologically identified. Species-shared allergens are the most important for potential use in diagnosis and immunotherapy.


Ergonomic stressors and upper extremity musculoskeletal disorders in automobile manufacturing: a one year follow up study.
To estimate the one year cumulative incidence and persistence of upper extremity (UE) soft tissue disorders, in a fixed cohort of automotive manufacturing workers, and to quantify their associations with ergonomic exposures. At baseline and at follow up, cases of UE musculoskeletal disorders were determined by interviewer administered questionnaire and standardised physical examination of the upper extremities. The interview obtained new data on psychosocial strain and updated the medical and work histories. An index of exposure to ergonomic stressors, obtained at baseline interview, was the primary independent variable. Cumulative incidence and persistence of UE disorders (defined both by symptoms and by physical examination plus symptoms) were analysed in relation to baseline ergonomic exposures, adjusting for other covariates. The incidence of new disorders was modelled using multivariate proportional hazards regression among workers who were not cases in the first year and the prevalence on both occasions was modelled by repeated measures analysis. A total of 820 workers (69% of eligible cohort members) was examined. Follow up varied slightly by department group but not by baseline exposure level or other characteristics. Among the non-cases at baseline, the cumulative incidence of UE disorders was 14% by symptoms and 12% by symptoms plus examination findings. These rates increased with index of physical exposures primarily among subjects who had the same jobs at follow up as at baseline. Increased exposure during follow up increased risk of incidence. The persistence of UE disorders from baseline to follow up examination was nearly 60% and somewhat associated with baseline exposure score. These longitudinal results confirm the previous cross sectional associations of UE musculoskeletal disorders with exposure to combined ergonomic stressors. The exposure-response relation was similar for incident cases defined by symptoms alone and those confirmed by physical examination.


Effect of partial sodium replacement on physicochemical parameters of smoked sea bass during storage.
The objective of this work was to study the effect of partial sodium replacement by potassium and packaging conditions on the physicochemical properties of smoked sea bass during cold storage. Sea bass fillets were salted with 100% NaCl (Na samples) or with 50% NaCl-50% KCl (Na:K samples), smoked, packaged under three different conditions (air, vacuum and modified atmosphere) and stored at 4 °C for 42 days. Physicochemical parameters, color and texture were periodically determined in the raw material and in smoked samples during cold storage. The smoking process led to a reduction in moisture, pH and a(w) values, and an increase in water holding capacity, ash and mineral contents. Smoked fish exhibited significant differences in color and texture as compared to fresh fish. The type of packaging had an effect on the pH, water holding capacity and texture. Samples in air exhibited the highest pH values and water holding capacity in these samples gradually decreased during storage. Textural parameters decreased during storage in samples packaged in vacuum and modified atmosphere. The pH of Na samples was initially higher than in Na:K samples, and this difference remained over the rest of the study. The type of salt did not affect the texture or other physicochemical parameters.


Heparin affin regulatory peptide modulates the endogenous anticoagulant activity of heparin and heparan sulphate mimetics.
Pleiotrophin, also known as heparin affin regulatory peptide (HARP), is a growth factor expressed in various tissues and cell lines. In this work, HARP was tested for its capacity to modulate the anticoagulant activity of heparin and heparan sulphate mimetics (OTR4120). We used both in vitro and in vivo assays. HARP was found to be differently effective for neutralization of the anticoagulant activity of the mimetic heparan sulphate (OTR4120) and heparin in purified system and human plasma. HARP was shown to compete with both antithrombin and thrombin for binding to heparin and to OTR4120, respectively. In the presence of OTR4120, the V(max) was constant and the calculated maximum velocity was 1.56 U/min; the thrombin Km value (0.011 nM) was affected by HARP concentrations. The Km (HARP) value was 0.085 nM, which is consistent with high affinity of HARP to OTR4120. Under the same conditions, initial velocity patterns for antithrombin-heparin were determined in the presence or in the absence of HARP. The antithrombin value Km (0.022 nM) was affected by HARP (0.077 nM). HARP exhibits efficacy equivalent to or greater than protamine. Interestingly, intraperitoneally administered HARP decreased the anticoagulant activity of heparin and of OTR4120 in mice. Taken together, these data provide the first evidence for a physiological role of HARP in the modulation of anticoagulant activity of heparin and heparin-like material.


Identification and comprehensive analysis of super-enhancer related genes involved in epithelial-to-mesenchymal transition in lung adenocarcinoma.
Lung adenocarcinoma is a disease with a high mortality rate, and its mechanism is still unclear. Super-enhancers play an important role in gene expression and also affect the occurrence and development of lung adenocarcinoma, so more and more people pay attention to them. In order to explore the influence of super-enhancer related genes on tumor development, we identified super-enhancer regulated genes related to Epithelial-to-mesenchymal transition (EMT). By analyzing the single-cell sequencing data and the TCGA database of lung adenocarcinoma, we suggest that the up-regulation of TMSB10 in lung adenocarcinoma and its association with poor prognosis may be due to the regulation of super-enhancers during tumor cell metastasis. Using the TCGA lung adenocarcinoma data set, the samples were divided into TMSB10 high-expression group and low-expression group, and it was found that there were significant differences in immune infiltration between the high-expression group and the low-expression group. We parted 513 samples into eight TMSB10-related molecular subtypes using differentially expressed genes of high and low TMSB10 expression groups. We concentrated on four molecular subtypes with the most significant clusters, each with its own characteristics in terms of Immune cell infiltration, prognosis, or pathological stages. In order to predict the four molecular subtypes, we established a prediction model using random forest, and the external test results showed that the prediction accuracy of the model was 0.87. This study may provide potential help for the study of the mechanism of metastasis and invasion of lung adenocarcinoma cells and personalized treatment of lung adenocarcinoma.


Experiences of miscarriage: the voice of parents and health professionals.
The death of a child in the intrauterine stage has legal, psychological, spiritual, and health-related connotations that condition the woman's experience. To understand better the processes set in motion around early pregnancy loss, this ethnographic study explores the experiences of miscarriage in a group of 15 women. The following themes are analyzed: Experience of losing the child, spirituality, health care, and the need to physically recognize the child. The study shows that the need women have to honor the child who did not live may be conditioned by the perception of an uncertain loss and by the absence of a place to honor him/her. Attitudes among professionals are revealed that could be perceived as gender-related abuse. The care of women places emphasis on physical aspects, underlining the lack of comprehensive care during the grieving process.


Doppler ultrasonographic evaluation of blood flow in the superior mesenteric artery in celiac patients and in healthy controls in fasting conditions and after saccharose ingestion.
We studied, by means of Doppler ultrasonography, the blood flow in the superior mesenteric artery in 12 untreated patients with celiac disease (nontropical sprue) and in 15 healthy controls; peak systolic velocity, end diastolic velocity, mean velocity, flow volume, and resistive index were measured in the fasting state and at regular intervals after ingestion of 0.5 liter of water containing 50 g of saccharose. Under fasting conditions, celiac patients showed peak systolic velocity, end diastolic velocity, mean velocity, and flow volume values significantly higher than those of normal subjects, whereas resistive index was significantly lower. After saccharose ingestion these parameters showed greater variations in normal subjects than in celiac patients. Fasting end diastolic velocity turned out to be the best parameter to distinguish celiac patients from healthy subjects. Doppler ultrasonography of the superior mesenteric artery could discriminate between normal subjects and celiac patients with overt disease. However, these data need further confirmation given the limited sample that we studied; moreover, the capability of this technique in distinguishing nontropical sprue from other gastrointestinal diseases that cause increasing splanchnic flow remains to be ascertained.


Hydrotris(triazolyl)borate complexes as functional models for Cu nitrite reductase: the electronic influence of distal nitrogens.
Hydrotris(triazolyl)borate (Ttz) ligands form CuNO(x) (x = 2, 3) complexes for structural and functional models of copper nitrite reductase. These complexes have distinct properties relative to complexes of hydrotris(pyrazolyl)borate (Tp) and neutral tridentate N-donor ligands. The electron paramagnetic resonance spectra of five-coordinate copper complexes show rare nitrogen superhyperfine couplings with the Ttz ligand, indicating strong σ donation. The copper(I) nitrite complex [PPN](+)[(Ttz(tBu,Me))Cu(I)NO(2)](-) has been synthesized and characterized and allows for the stoichiometric reduction of NO(2)(-) to NO with H(+) addition. Anionic Cu(I) nitrite complexes are unusual and are stabilized here for the first time because Ttz is a good π acceptor.


Effects of Topical 1% Sodium Hyaluronate and Hydroxypropyl Methylcellulose in Treatment of Corneal Epithelial Defects.
We aimed to compare the therapeutic effects of topical 1% sodium hyaluronate (Healon) or hydroxypropyl methylcellulose (HPMC) for the treatment of alkali-induced epithelial corneal defects. An alkali burn was produced in 30 corneas of 30 New Zealand White rabbits, using a 7.5-mm-diameter trephine. The rabbits were randomly divided into three groups. Four times a day, one group was treated with 1% sodium hyaluronate, one with HPMC, and one (the control group) with physiologic saline. During the treatment period, the size of the epithelial defect was observed every day, up to day 17, using a slit-lamp biomicroscope (with fluorescein). Sodium hyaluronate significantly accelerated the wound healing process compared with saline and increased the healing rate to an even greater extent compared with HPMC. Sodium hyaluronate, but not HPMC, is an effective wound-healing adjuvant for alkali-induced corneal epithelial defects.


Control of intracellular pH during regulatory volume decrease in HL-60 cells.
Intracellular pH (pHi) homeostasis was investigated in human promyelocytic leukemic HL-60 cells as they undergo regulatory volume decrease (RVD) in hypotonic media to determine how well pHi is regulated and which transport systems are involved. Cells suspended in hypotonic (50-60% of isotonic) media undergo a small (< 0.2 pH units), but significant (P < 0.05), intracellular acidification within 5 min. However, after 30 min of RVD, pHi is not significantly different from the initial pHi in 20 mM HCO3- medium and is significantly higher in HCO3(-)-free medium. Experiments performed in media with or without 150 microM 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid and HCO3- demonstrate that the anion exchanger (AE) mediates a net Cl- influx, with compensating HCO3- efflux, during RVD. To determine which transport systems are involved in counteracting this tendency toward acidification, we measured transport rates and examined the effect of transport system inhibitors on pHi. We found that inhibition of Na+/H+ exchange (NHE) with 12.5 microM ethylisoproplamiloride (EIPA) causes pHi to fall significantly by the end of 30 min of RVD. As assessed by EIPA-sensitive 22Na+ uptake measurements, NHE, largely dormant under resting isotonic conditions, becomes significantly activated by the end of 30 min of RVD, despite recovery of pHi and cell volume to near-normal levels. Thus a shift in the normal pHi dependence and/or volume dependence of NHE activity must occur during RVD under hypotonic conditions. In contrast, H(+)-monocarboxylate cotransport appears to play only a supportive role in pH regulation during RVD, as indicated by lack of stimulation of [14C]lactate efflux during RVD.


Glutathione transferases sequester toxic dinitrosyl-iron complexes in cells. A protection mechanism against excess nitric oxide.
It is now well established that exposure of cells and tissues to nitric oxide leads to the formation of a dinitrosyl-iron complex bound to intracellular proteins, but little is known about how the complex is formed, the identity of the proteins, and the physiological role of this process. By using EPR spectroscopy and enzyme activity measurements to study the mechanism in hepatocytes, we here identify the complex as a dinitrosyl-diglutathionyl-iron complex (DNDGIC) bound to Alpha class glutathione S-transferases (GSTs) with extraordinary high affinity (K(D) = 10(-10) m). This complex is formed spontaneously through NO-mediated extraction of iron from ferritin and transferrin, in a reaction that requires only glutathione. In hepatocytes, DNDGIC may reach concentrations of 0.19 mm, apparently entirely bound to Alpha class GSTs, present in the cytosol at a concentration of about 0.3 mm. Surprisingly, about 20% of the dinitrosyl-glutathionyl-iron complex-GST is found to be associated with subcellular components, mainly the nucleus, as demonstrated in the accompanying paper (Stella, L., Pallottini, V., Moreno, S., Leoni, S., De Maria, F., Turella, P., Federici, G., Fabrini, R., Dawood, K. F., Lo Bello, M., Pedersen, J. Z., and Ricci, G. (2007) J. Biol. Chem. 282, 6372-6379). DNDGIC is a potent irreversible inhibitor of glutathione reductase, but the strong complex-GST interaction ensures full protection of glutathione reductase activity in the cells, and in vitro experiments show that damage to the reductase only occurs when the DNDGIC concentration exceeds the binding capacity of the intracellular GST pool. Because Pi class GSTs may exert a similar role in other cell types, we suggest that specific sequestering of DNDGIC by GSTs is a physiological protective mechanism operating in conditions of excessive levels of nitric oxide.


Myeloid differentiation antigens identify leukemic cell subpopulations with different cell cycle characteristics.
In order to assess the proliferative capacity of leukemic subpopulations and to know whether it can be related to the stage of maturation, the expression of two surface antigens identifying distinct steps of leukocyte differentiation (CD15 and CD34) was studied by flow cytometry in correlation with DNA content in 16 cases of acute myeloid leukemia (AML). The surface markers were studied by indirect immunofluorescence, using the monoclonal antibodies VIMD5 (anti-CD15) and MY10 (anti-CD34). The percentage of cells stained by each antibody and the intensity of staining were heterogeneous. Double-staining showed that a small percentage of cells coexpressed both antigens. A correlation was found between the percentage of cells stained by MY10 and the percentage of cells in S + G2 + M in the whole population (p less than 0.05). The percentage of cells in S + G2 + M was significantly higher in MY10-positive than in MY10-negative cells (p less than 0.005), and also higher in VIMD5-positive than in VIMD5-negative cells (p less than 0.005). In the 14 cases expressing both antigens, the percentage of cells in S + G2 + M was higher in VIMD5-positive than in MY10-positive cells (p less than 0.05), whereas there was no difference between VIMD5-negative and MY10-negative cells. It is concluded that the phenotype heterogeneity observed in leukemic cell populations is associated with differences in proliferative capacities. The subset of leukemic cells with the more mature phenotype (CD15-positive) has the highest proliferative activity.


The expanding indications for virtual histology intravascular ultrasound for plaque analysis prior to carotid stenting.
Complications of carotid artery stenting (CAS), including stroke, remain relatively high when compared with carotid endarterectomy (CEA). Current selection criteria for patients undergoing CAS are based predominately on surgical risk related to other comorbidities. Little attention is given to the morphology of the atherosclerotic plaque, although studies have shown that extensive variability exists which confers certain risks for plaque vulnerability. Virtual Histology intravascular ultrasound (VH IVUS) offers a unique method of assessing plaque morphology prior to CAS. Herein, the authors review the concepts of atherosclerotic plaque morphology and discuss the background of VH IVUS and illustrate its use in the carotid system. With selection of the appropriate patient and the appropriate plaque, more favorable outcomes of CAS may be achieved which will solidify its place as a frontline treatment of carotid vascular disease.


Pattern of interleukin 6 gene expression in vivo suggests a role for this cytokine in angiogenesis.
Interleukin 6 (IL-6) is a cytokine that acts on various cell types. Here we show that IL-6 mRNA is produced in vivo in two self-limiting physiologic angiogenic processes: (i) the formation of the vascular system accompanying development of ovarian follicles and (ii) the formation of a capillary network in the maternal decidua following embryonic implantation. In situ and RNA blot hybridization analyses detected transient expression of IL-6 mRNA in gonadotropin-primed hyperstimulated ovaries, with maximal mRNA levels coinciding with the period of formation of a capillary network around follicles. Expression of IL-6 mRNA was detected in the vasculature extending from the ovarian medulla to the forming capillary sheath in the thecal layer of individual growing follicles. No expression was detected in more-developed preovulatory follicles once angiogenesis had been completed. IL-6 mRNA was also detected in the uterus of pregnant mice 9.5 days postcoitum, and there was no appreciable IL-6 mRNA at later stages of embryonic development. Expression in the uterus was confined to cords of endothelial cells in the process of formation of an anastomosing network that traversed the maternal decidua towards the developing embryo. The expression of IL-6 mRNA in two independent physiological angiogenic processes and the transient nature of its expression in endothelial cells suggest a role for IL-6 in angiogenesis.


Moderate hypoxia induces β-cell dysfunction with HIF-1-independent gene expression changes.
Pancreatic β-cell failure is central to the development and progression of type 2 diabetes. We recently demonstrated that β-cells become hypoxic under high glucose conditions due to increased oxygen consumption and that the pancreatic islets of diabetic mice but not those of control mice are moderately hypoxic. However, the impact of moderate hypoxia on β-cell number and function is unknown. In the present study, moderate hypoxia induced a hypoxic response in MIN6 cells, as evidenced by increased levels of HIF-1α protein and target genes. Under these conditions, a selective downregulation of Mafa, Pdx1, Slc2a2, Ndufa5, Kcnj11, Ins1, Wfs1, Foxa2, and Neurod1, which play important roles in β-cells, was also observed in both MIN6 cells and isolated pancreatic islets. Consistent with the altered expression of these genes, abnormal insulin secretion was detected in hypoxic MIN6 cells. Most of the hypoxia-induced gene downregulation in MIN6 cells was not affected by the suppression of HIF-1α, suggesting a HIF-1-independent mechanism. Moderate hypoxia also induced apoptosis in MIN6 cells. These results suggest that hypoxia is a novel stressor of β-cells and that hypoxic stress may play a role in the deterioration of β-cell function.


Association of TCF7L2 Variants in Type 2 Diabetes Mellitus with Hypertriglyceridemia - A Case-Control Study.
Type 2 Diabetes Mellitus (T2DM) is a chronic metabolic condition involving various genetic and environmental factors leading to impaired insulin secretion, resulting in hyperglycemia. The transcription factor 7-like 2 (TCF7L2) gene is an element of the Wnt signaling pathway that plays an important role in glucose and lipid metabolism. The aim of this study is to evaluate the association of TCF7L2 rs7903146 and rs12255372 polymorphisms in T2DM with hypertriglyceridemia. We investigated the effect of rs7903146 and rs12255372 on T2DM with high triglyceride (TG) levels in 60 patients and 20 controls. The anthropometric measurements and biochemical tests were assessed. Peripheral blood samples were collected, and genomic DNA was extracted. The genotyping of TCF7L2 polymorphisms was carried out using polymerase chain reaction (PCR)-based direct sequencing and allele-specific PCR methods. The T2DM patients and controls were compared by means of the t-test, Chi-square test, odds ratio (OR), and 95% confidence interval (CI) using Epi Info v7. The HbA1c was found to be 9.7 ± 2.1 and 5.4 ± 0.5% in patients and controls, respectively. The average TG levels (P < 0.005) in patients were 205.2 ± 145.7 and 106.4 ± 27.4mg/dl in controls. Significant evidence of association was found in T2DM patients having high TG levels with rs7903146 CT/TT (OR: 4.89; P = 0.0105) and rs12255372 GT/TT (OR: 5.23; P = 0.0101) genotypes when compared to controls. The results of this study show that TCF7L2 rs7903146 CT/TT and rs12255372 GT/TT genotypes are significantly associated with the risk of hypertriglyceridemia in individuals with T2DM among the studied population.


Growth and growth hormone secretion in paediatric Cushing's disease.
Although paediatric Cushing's disease is rare, it is associated with severe morbidity in childhood and presents a major diagnostic and therapeutic challenge for the paediatric endocrinologist. Growth failure remains an important feature of paediatric Cushing's disease, both at diagnosis and after successful treatment. However, the development of specific diagnostic tests and important therapeutic advances has contributed significantly to the current management. Transsphenoidal pituitary surgery (TSS) is now accepted as first-line therapy for both adult and paediatric Cushing's disease, offering the best opportunity for cure while preserving normal pituitary function. The cure rate following TSS in our centre is currently 62%; therefore, a significant proportion of children following TSS will remain uncured. Our favoured second-line therapy is pituitary radiotherapy, which is effective, rapid and appears to spare anterior pituitary function, with the exception of GH secretion. Growth failure was a symptom at diagnosis in 74% of patients; mean height SDS -1.81 (-0.28 to -4.17) compared with mean BMI SDS 2.29 (1.72-5.06). Height velocity (HV) was also subnormal; range 0.9-3.8 cm/yr. Chronic hypercortisolaemia suppresses linear growth and a history of symptoms for >2 years was obtained in 72% of our paediatric patients with Cushing's disease. In our series, 9 out of 10 patients did not demonstrate catch-up growth 0.64 years after TSS or pituitary radiotherapy and peak serum GH level to glucagon/ITT stimulation was 0.5-20.9 mU/l. Assessment of GH secretion over a period of 6 to 108 months after cure of paediatric Cushing's disease suggests that impaired GH secretion may persist into adult life. Investigation of possible GHD is performed in our unit in all post-cure patients who do not show optimal catch-up growth. If GH secretion is subnormal, GH replacement is started early and continued until final height, when GH secretion is reassessed. In our series of 10 patients, 9 received GH therapy, combined in 3 with a GnRH analogue to arrest puberty. The results of this treatment were satisfactory with mean height deficit compared with target height improving significantly from mean -1.72 +/- 1.26 SDS at diagnosis to -0.93 +/- 1.13 SDS (p=0.005) at final height or latest assessment, indicating that a favourable final height can be achieved.


Protease-activating receptor-4 induces full platelet spreading on a fibrinogen matrix: involvement of ERK2 and p38 and Ca2+ mobilization.
Although the involvement of protease-activating receptor PAR1 and PAR4 is well established in platelet aggregation, their role in platelet adhesion and spreading has yet to be characterized. We investigated platelet adhesion and spreading on a fibrinogen matrix after PAR1 and PAR4 stimulation in correlation with the activation of two MAPKs, ERK2 and p38. Of the two PAR-activating peptides (PAR-APs), PAR1-AP and PAR4-AP, which both induce adhesion, only PAR4-AP induced full platelet spreading. Although both PAR1-AP and PAR4-AP induced ADP secretion, which is required for platelet spreading, only PAR4-AP induced sustained Ca(2+) mobilization. In these conditions of PAR4 induction, ERK2 and p38 activation were involved in platelet spreading but not in platelet adhesion. p38 phosphorylation was dependent on ADP signaling through P2Y12, its receptor. ERK2 phosphorylation was triggered through integrin alphaIIbbeta3 outside-in signaling and was dependent on the Rho pathway. ERK2 and p38 activation induced phosphorylation of the myosin light chain and actin polymerization, respectively, necessary for cytoskeleton reorganization. These findings provide the first evidence that thrombin requires PAR4 for the full spreading response. ERK2 and p38 and sustained Ca(2+) mobilization, involved in PAR4-induced platelet spreading, contribute to the stabilization of platelet thrombi at sites of high thrombin production.


PHA recovery from biomass.
The recovery of polyhydroxyalkanoates (PHAs) from biomass, that is, from bacterial cells, is one of the major obstacles in the industrial production of these polyesters. Since PHAs are naturally synthesized as intracellular storage compounds for carbon and energy and are for this deposited in the cytoplasm of the bacterial cell, PHAs are more or less tightly linked with the entire biomass, and the polyesters must be released from the cells before their isolation and purification can be conducted. This additional step, that is, the release from the cells, is a major difference from most other biotechnological processes where the product occurs outside of the cells because it is secreted into the medium in a bioreactor or because it is synthesized in vitro in an enzyme reactor in a cell free system. This additional step contributes significantly to the overall costs of production. In this review we provide an overview about the different processes that result in the release of PHA from the cells, and we evaluate these processes with regard to the suitability at large scale in the industry.


Metabolism of estrone sulphate by benign prostatic hyperplasia in vitro.
Homogenates of benign prostatic hyperplastic (BPH) tissue and abdominal muscle were incubated with [3H] estrone sulphate in the presence of NADH and NADPH. The metabolites were extracted with chloroform, isolated by thin layer chromatography (TLC) and identified by addition of 14C-labelled standards followed by sequential chromatography and acetylation. Both tissues transformed the substrate into [3H] estrone and [3H] estradiol-17 beta, but BPH tissue by far exceeded the abdominal muscle in this respect. Estriol and other polar metabolites could not be detected. The specific ability of BPH tissue to convert the major peripheral estrogen estrone sulphate into the terminal biologically active estrogen estradiol-17 beta further indicates an etiological role of estrogens in the development of human BPH.


Colonic exclusion and combined therapy for refractory constipation.
To investigate the therapeutic effectiveness of colonic exclusion and combined therapy for refractory constipation. Thirty-two patients with refractory constipation were randomly divided into treatment group (n = 14) and control group (n = 18). Fourteen patients in treatment group underwent colonic exclusion and end-to-side colorectal anastomosis. Eighteen patients in control group received subtotal colectomy and end-to-end colorectal anastomosis. The therapeutic effects of the operations were assessed by comparing the surgical time, incision length, volume of blood losses, hospital stay, recovery rate and complication incidence. All patients received long-term follow-up. All operations were successful and patients recovered fully after the operations. In comparison of treatment group and control group, the surgical time (h), incision length (cm), volume of blood losses (mL), hospital stay (d) were 87 +/- 16 min vs 194 +/- 23 min (t = 9.85), 10.4 +/- 0.5 cm vs 21.2 +/- 1.8 cm (t = 14.26), 79.5 +/- 31.3 mL vs 286.3 +/- 49.2 mL (t = 17.24), and 11.8 +/- 2.4 d vs 18.6 +/- 2.6 d (t = 6.91), respectively (P < 0.001 for all). The recovery rate and complication incidence were 85.7% vs 88.9% (P = 0.14 > 0.05), 21.4% vs 33.3% (P = 0.73 > 0.05), respectively. Colonic exclusion has better therapeutic efficacy on refractory constipation. It has many advantages such as shorter surgical time, smaller incision, fewer blood losses and shorter hospital stay.


Quantification of U, Th and specific radionuclides in coal from selected coal fired power plants in South Africa.
Most of South Africa's energy is derived from the combustion of coal in pulverized coal-fired power plants (CFPP). However, when compared with the rest of the world, limited information regarding the main radioactive elements (U and Th) and specific radionuclides of interest (K40, Ra226 and Th232) from South African CFPP is available in the public domain. This paper aims to quantify the U, Th and specific radionuclides found in the coal used in selected South African CFPP in comparison to world averages found in literature. The U and Th concentrations were obtained by ICP-MS. The main radionuclides, K40, Ra226 and Th238, were quantified using gamma spectrometry. The U concentration and Th concentrations for the coal used in all the power plants was above the world average of 1.9 mg/kg and 3.2 mg/kg respectively. The coals with the highest Th content originated from the Mpumalanga power plant, while the U content in the Freestate power plant samples was the highest of the three. The concentrations of the K40 were between 88.43±10.75-110.76±8.92 Bq/kg, which are in-line with world averages of 4-785 Bq/kg. Similarly, the Ra226 and Th232 values were between 21.69±2.83-52.63±4.04 Bq/kg and 19.91±1.24-22.97±1.75 Bq/kg respectively, which are also in line with the world averages of 1-206 Bq/kg and 1-170 Bq/kg respectively. Radiological hazard indices such as radium equivalent (Raeq); external hazard index (Hex) and internal hazard index (Hin), that were estimated from these average radionuclide concentrations were less than the prescribed values found in literature. This indicated that no significant health risk was posed by the coal being used from these coal fields.


Understanding nursing practice in stroke units: a Q-methodological study.
Nurses represent the largest professional group working with stroke-survivors, but there is limited evidence regarding nurses' involvement in post-stroke rehabilitation. The purpose of this study was to identify and explore the perspectives of nurses and other multidisciplinary stroke team members on nurses' practice in stroke rehabilitation. Q-methodological study with 63 multidisciplinary stroke unit team members and semi-structured interviews with 27 stroke unit team members. Irrespective of their professional backgrounds, participants shared the view that nurses can make an active contribution to stroke rehabilitation and integrate rehabilitation principles in routine practice. Training in stroke rehabilitation skills was viewed as fundamental to effective stroke care, but nurses do not routinely receive such training. The view that integrating rehabilitation techniques can only occur when nursing staffing levels were high was rejected. There was also little support for the view that nurses are uniquely placed to co-ordinate care, or that nurses have an independent rehabilitation role. The contribution that nurses with stroke rehabilitation skills can make to effective stroke care was understood. However, realising the potential of nurses as full partners in stroke rehabilitation is unlikely to occur without introduction of structured competency-based multidisciplinary training in rehabilitation skills. Implications for Rehabilitation Multidisciplinary rehabilitation in stroke units is a cornerstone of effective stroke care. Views of stroke unit team members on nurses' involvement in rehabilitation have not been reported previously. Nurses can routinely incorporate rehabilitation principles in their care. Specialist competency-based stroke rehabilitation training needs to be provided for nurses as well as for allied health professionals.


Foot drop in patients with extensive 3rd and 4th degree burn, case series study.
Burn injuries can lead to a variety of short- and long-term complications, peripheral neuropathy has been known as the most common neuromuscular complication. 29% of the burn-related peripheral neuropathy has been found in both the upper and lower limbs. Moreover, literature failed to find the causative factors for specific presentations like foot drop in burn patients. This study reports a series of 10 patients who developed foot drop after burn injury and required occupational therapy follow up at King Abdulaziz Medical City in Riyadh. To assess the effect of different risk factors in the outcome of foot drop. 10 case records were reviewed, 70% among the patients were men and 30% were women with a mean age of 39 and a mean BMI of 28. Most of the patients 70% were burned by flame. The mean Total Body Surface Area (TBSA) was 62%. 4 of the cases (40%) were having comorbidities. There was a significant association between death and high TBSA. All cases were managed without surgical intervention, physiotherapy started immediately after the diagnosis of foot drop. Seventy percent of our patients improved while 3 cases have expired. Higher TBSA showed to be significantly associated with death.


Pulsating laminar fully developed channel and pipe flows.
Analytical investigations are carried out on pulsating laminar incompressible fully developed channel and pipe flows. An analytical solution of the velocity profile for arbitrary time-periodic pulsations is derived by approximating the pulsating flow variables by a Fourier series. The explicit interdependence between pulsations of velocity, mass-flow rate, pressure gradient, and wall shear stress are shown by using the proper dimensionless parameters that govern the flow. Utilizing the analytical results, the scaling laws for dimensionless pulsation amplitudes of the velocity, mass-flow rate, pressure gradient, and wall shear stress are analyzed as functions of the dimensionless pulsation frequency. Special attention has been given to the scaling laws describing the flow reversal phenomenon occurring in pulsating flows, such as the condition for flow reversal, the dependency of the reversal duration, and the amplitude. It is shown that two reversal locations away from the wall can occur in pulsating flows in pipes and channels and the reversed amount of mass per period reaches a maximum at a certain dimensionless frequency for a given amplitude of mass-flow rate fluctuations. These analyses are numerically conducted for pipe and channel flows over a large frequency range in a comparative manner.


Disrupted brain network topology in chronic insomnia disorder: A resting-state fMRI study.
This study investigated the topological characteristics of brain functional networks in chronic insomnia disorder (CID) patients. The resting-state functional magnetic resonance imaging and graph theory analysis method were applied to investigate the brain functional connectome patterns among 45 CID patients and 32 healthy controls. The brain functional connectome was constructed by thresholding partial correlation matrices of 90 brain regions from an automated anatomical labeling atlas. The topologic properties of brain functional connectomes at both global and nodal levels were tested. The CID patients had decreased number of module (p = .014) and hierarchy (p = .038), and increased assortativity (p = .035). Furthermore, some brain regions located in the default mode network, dorsal attention network, and sensory-motor network in these patients showed altered nodal centralities. Within these areas, the node betweenness of right central paracentral lobule had positive correlation with the Pittsburgh Sleep Quality Index score (R = 0.319, p = .039). The results imply that functional disruptions of CID patients may be related to disruptions in global and regional topological organization of the brain functional connectome, and provide new and important insights to understand the pathophysiological mechanisms of CID.


Genotoxicity-related chemistry of human metabolites of benzo[ghi]perylene (B[ghi]P) investigated using electro-optical arrays and DNA/microsome biocolloid reactors with LC-MS/MS.
There is limited and sometimes contradictory information about the genotoxicity of the polycyclic aromatic hydrocarbon benzo[ghi]perylene (B[ghi]P). Using recently developed metabolic toxicity screening arrays and a biocolloid reactor-LC-MS/MS approach, both featuring films of DNA and human metabolic enzymes, we demonstrated the relatively low reactivity of metabolically activated B[ghi]P toward DNA. Electro-optical toxicity screening arrays showed that B[ghi]P metabolites damage DNA at a 3-fold lower rate than benzo[a]pyrene (B[a]P), whose metabolites have a strong and well-understood propensity for DNA damage. Metabolic studies using magnetic bead biocolloid reactors coated with microsomal enzymes in 96-well plates showed that cyt P450s 1A1 and 1B1 provide high activity for B[ghi]P and B[a]P conversion. Consistent with published results, the major metabolism of B[ghi]P involved oxidations at 3,4 and 11,12 positions, leading to the formation of B[ghi]P 3,4-oxide and B[ghi]P 3,4,11,12-bisoxide. B[ghi]P 3,4-oxide was synthesized and reacted with deoxyadenosine at N6 and N7 positions and with deoxyguanosine at the N2 position. B[ghi]P 3,4-oxide is hydrolytically unstable and transforms into the 3,4-diol or converts to 3- or 4-hydroxy B[ghi]P. LC-MS/MS of reaction products from the magnetic biocolloid reactor particles coated with DNA and human enzymes revealed for the first time that a major DNA adduct results from the reaction between B[ghi]P 3,4,11,12-bisoxide and deoxyguanosine. Results also demonstrated 5-fold lower formation rates of the major DNA adduct for B[ghi]P metabolites compared to B[a]P. Overall, results from both the electro-optical array and biocolloid reactor-LC-MS/MS consistently suggest a lower human genotoxicity profile of B[ghi]P than B[a]P.


How might qinghaosu (artemisinin) and related compounds kill the intraerythrocytic malaria parasite? A chemist's view.
The antimalarial mechanism of qinghaosu (artemisinin) has been a problem since the late 1970s. During the past decade, several molecular level theories were postulated. However, their further development has been very difficult. By looking into the QHS cleavage process and all possible reaction paths available to the resulting transient radicals, the present commentary reveals those major hidden problems with the existing theories and tries to identify some essential features of the parasiticidal events that may take place within the intraerythrocytic malaria parasite. A seemingly more reasonable theory is also introduced.


Suppression of Arabidopsis AtPUB30 resulted in increased tolerance to salt stress during germination.
The Arabidopsis U-box E3 Ub ligase AtPUB30 participates in the salt stress tolerance as a negative factor in an ABA-independent manner during germination. Based on the in silico expression data, the U-box protein 30 (AtPUB30) from Arabidopsis thaliana was identified as a gene that responds to salt stress. The deduced AtPUB30 protein consists of 448 amino acids with a single U-box motif and five ARM-repeat domains. An in vitro self-ubiquitination assay demonstrated that bacterially expressed AtPUB30 exhibited E3 ubiquitin (Ub) ligase activity and that the U-box domain was essential for the activity. Real-time qRT-PCR and promoter-GUS analyses showed that AtPUB30 was induced by high salinity, but not by drought, cold, or abscisic acid (ABA), in roots but not in shoots. These results suggest that AtPUB30 is an Arabidopsis U-box E3 Ub ligase, the expression of which is selectively enhanced by salt stress in roots. T-DNA-inserted loss-of-function atpub30 mutant plants (atpub30-1 and atpub30-2) were more tolerant to salt stress in the germination stage, as identified by radicle emergence, cotyledon opening, and more vigorous early root growth relative to wild-type plants. Thus, it is likely that AtPUB30 plays a negative role in high salinity tolerance in the germination process. Wild type and mutant plants displayed very similar germination rates when treated with ABA, suggesting that the action of AtPUB30 in the germination stage is ABA independent. The post-germination growth of NaCl-stressed wild type and mutant plants were indistinguishable. Overall, our data suggest that the Arabidopsis U-box E3 Ub ligase AtPUB30 participates in the salt stress tolerance as a negative factor in the germination stage in root tissues.


"Juxtafacet cysts", a misleading name for cystic formations of mobile spine (CYFMOS).
To present 58 cystic space-occupying formations of the spinal canal in 53 cases; these formations are called "juxtafacet cysts". Fifty-Three patients (33 women and 20 men, with an average age of 60.8 years) were evaluated retrospectively by neurosurgery. All of the patients had received simple X-P, computed tomography (CT) and magnetic resonance imaging (MRI) before surgery. The neurological findings were evaluated on admission and in a follow-up review. Surgical intervention was performed on all patients and they underwent gross-total cyst removal. During surgery, the origin of a cyst was well observed. Follow-up data ranged from 6 to 46 months. Patient outcome was graded on a scale of excellent, good, or poor. Histological findings were evaluated. In 53 patients 58 cysts were identified. Four of the patients had multiple cysts. All cysts were associated with mobile spine. Fifty-five cysts were found in the lumbo-sacral region, two cysts were found in the cervico-thoracic region and one cyst in the thoracic region. Forty-two patients presented back pain and 52 patients presented radicular pain. Four patients had a cauda equina syndrome. Sensory disturbance was observed in 24 cases and motor weakness was observed in 21 cases. Claudication was observed in 19 cases. All cases with cervico-thoracic or thoracic cysts presented myelopathy. The duration of these clinical symptoms ranged from 10 days to 10 years. After surgery there was no case of a recurrent cyst during the follow-up period. Thirty-four cases had an excellent outcome, 18 a good outcome, and one a poor outcome. Out of 58 cysts 32 were joint cysts (11 synovial cysts, 21 ganglion cysts). A further 19 were flavum cysts, one was a posterior longitudinal ligament (PLL) cyst and six others were unknown pseudo cysts. In 34 of the cysts we found hemosiderin deposits and in eight amyloid deposits. Present investigation and findings in literature show a clear comparison of these cystic formations and the mobile part of the spine. An anatomical relation to a vertebral joint ("facet") is only found in some of the cases (32 of 58). Further to that, the name "cyst" is not correct either, because most of the cystic formations are presented without a cell lining on their internal wall and therefore they are pseudo-cystic. We think that these cystic formations should be called "cystic formations of mobile spine" (CYFMOS) rather than "juxtafacet cysts". A surgical intervention is the best treatment for these cysts if they cause a compression of nerve roots or/and of the spinal cord.


Refined 1.8 A resolution crystal structure of the porcine epsilon-trypsin.
Porcine epsilon-trypsin is a three-chain inactivated trypsin from the limited autolysis of porcine beta-trypsin. It is cleaved at positions Lys60-Ser61 and Lys145-Ser146. The crystal structure has been determined by using the molecular replacement method, and refined at 1.8 A resolution. The R-value of final model is 0.184. Comparison with the electron density map of porcine beta-trypsin (PTRY) in complex (BBIT), and with that of native bovine beta-trypsin (HTNA), revealed no obvious changes except at the autolysis positions, and no changes at the active center were observed. The autolysis at positions Lys60-Ser61 and Lys145-Ser146 does not affect the conformation of His-57 in the active center and therefore cannot explain for a loss in porcine epsilon-trypsin activity.


Adenylyl cyclase encoded by AC78C participates in sugar perception in Drosophila melanogaster.
In gustatory receptor neurons (GRNs) in Drosophila melanogaster, Gr5a and one of the Gr64s encode sugar receptors with seven transmembrane domains. Previously, we have shown that the responses to various sugars are depressed in DGsalpha mutant flies (Ueno et al., 2006). Because DGsalpha is a homolog of Gs, we hypothesized that the sugar receptors are coupled to adenylyl cyclase (AC) in Drosophila. The aim of this study was to identify the AC that participates in sugar perception. Here, we found that an AC inhibitor, MDL-12330A, depressed the response in GRNs to trehalose as well as sucrose; that an AC gene, AC78C, was expressed in the sugar-sensitive GRNs; that RNAi against AC78C depressed the electrical response in GRNs to sucrose; and that the sugar response in GRNs, as well as sugar intake in a behavioral assay in an AC78C mutant, was depressed at low sugar concentrations. We conclude that AC78C, via cAMP, participates in the sugar-taste signaling pathway at the low concentration range.


Forecasting small-scale dynamics of fluid turbulence using deep neural networks.
Turbulence in fluid flows is characterized by a wide range of interacting scales. Since the scale range increases as some power of the flow Reynolds number, a faithful simulation of the entire scale range is prohibitively expensive at high Reynolds numbers. The most expensive aspect concerns the small-scale motions; thus, major emphasis is placed on understanding and modeling them, taking advantage of their putative universality. In this work, using physics-informed deep learning methods, we present a modeling framework to capture and predict the small-scale dynamics of turbulence, via the velocity gradient tensor. The model is based on obtaining functional closures for the pressure Hessian and viscous Laplacian contributions as functions of velocity gradient tensor. This task is accomplished using deep neural networks that are consistent with physical constraints and explicitly incorporate Reynolds number dependence to account for small-scale intermittency. We then utilize a massive direct numerical simulation database, spanning two orders of magnitude in the large-scale Reynolds number, for training and validation. The model learns from low to moderate Reynolds numbers and successfully predicts velocity gradient statistics at both seen and higher (unseen) Reynolds numbers. The success of our present approach demonstrates the viability of deep learning over traditional modeling approaches in capturing and predicting small-scale features of turbulence.


Align and Pool for EEG Headset Domain Adaptation (ALPHA) to Facilitate Dry Electrode Based SSVEP-BCI.
The steady-state visual evoked potential based brain-computer interface (SSVEP-BCI) implemented in dry electrodes is a promising paradigm for alternative and augmentative communication in real-world applications. To improve its performance and reduce the calibration effort for dry-electrode systems, we utilize cross-device transfer learning by exploiting auxiliary individual wet-electrode electroencephalogram (EEG). We proposed a novel transfer learning framework named ALign and Pool for EEG Headset domain Adaptation (ALPHA), which aligns the spatial pattern and the covariance for domain adaptation. To evaluate its efficacy, 75 subjects performed an experiment of 2 sessions involving a 12-target SSVEP-BCI task. ALPHA significantly outperformed a baseline approach (canonical correlation analysis, CCA) and two competing transfer learning approaches (transfer template CCA, ttCCA and least square transformation, LST) in two transfer directions. When transferring from wet to dry EEG headsets, ALPHA significantly outperformed the fully-calibrated approach of task-related component analysis (TRCA). ALPHA advances the frontier of recalibration-free cross-device transfer learning for SSVEP-BCIs and boosts the performance of dry electrode based systems. ALPHA has methodological and practical implications and pushes the boundary of dry electrode based SSVEP-BCI toward real-world applications.


Reliability and validity of a Swedish version of Kogan's Old People Scale.
Standardized and well-tested instruments are needed in order to study attitudes toward old people. One scale that has been widely used is Kogan's Old People scale. A Swedish version of the scale has been available since 1987. The aim of this study was to test this Swedish version of the scale for reliability and validity, in a sample consisting of students and different health-care professionals. A convenience sample of 319 individuals in western Sweden took part in the study, and data were collected by means of a questionnaire that included the scale. Reliability was assessed as homogeneity and validity as construct validity. All but 4 of the 34 items were found to have significant item-total correlations. The Cronbach's alpha coefficient for the total scale was 0.79. Some evidence of construct validity was found in a three-factor solution, which explained 30% of the variances. Strong evidence of construct validity was shown in the scale's capability to differentiate between individuals who rather preferred to work with old people (p < 0.005) than with young clients. Convergent validity, as a form of construct validity, was also supported for the scale.


Tellurium-Impregnated Porous Cobalt-Doped Carbon Polyhedra as Superior Cathodes for Lithium-Tellurium Batteries.
Lithium-tellurium (Li-Te) batteries are attractive for energy storage owing to their high theoretical volumetric capacity of 2621 mAh cm-3. In this work, highly nanoporous cobalt and nitrogen codoped carbon polyhedra (C-Co-N) derived from a metal-organic framework (MOF) is synthesized and employed as tellurium host for Li-Te batteries. The Te@C-Co-N cathode with a high Te loading of 77.2 wt % exhibits record-breaking electrochemical performances including an ultrahigh initial capacity of 2615.2 mAh cm-3 approaching the theoretical capacity of Te (2621 mAh cm-3), a superior cycling stability with a high capacity retention of 93.6%, a ∼99% Columbic efficiency after 800 cycles as well as rate capacities of 2160, 1327.6, and 894.8 mAh cm-3 at 4, 10, and 20 C, respectively. The redox chemistry of tellurium is revealed by in operando Raman spectroscopic analysis and density functional theory simulations. The results illustrate that the performances are attributed to the highly conductive C-Co-N matrix with an advantageous structure of abundant micropores, which provides highly efficient channels for electron transfer and ionic diffusion as well as sufficient surface area to efficiently host tellurium while mitigating polytelluride dissolution and suppressing volume expansion.


Allpyral: An appraisal.
In Allpyral the alum which has been added to the highly alkaline-pyrididium extract of non-defatted pollen absorbs only 25% of the extracted nitrogenous material, the larger quantity having been discarded with the supernanant. Allpyral contains a relatively small amount of antigenic material compared with conventional aqueous or glycerol preparations. Chemical studies show Allpyral to be a product resulting from an unrealized concept and a faulty method of preparation involving injudicious use of alum.


Analytical characterization of adhering vesicles.
We characterize vesicle adhesion onto homogeneous substrates by means of a perturbative expansion around the infinite adhesion limit, where curvature elasticity effects are absent. At first order in curvature elasticity, we determine analytically various global physical quantities associated with adhering vesicles: height, adhesion radius, etc. Our results are valid for adhesion energies above a certain threshold, that we determine numerically. We discuss the haptotactic force acting on a vesicle in the limit of weak adhesion gradients. We also propose a few methods for measuring adhesion energies and we suggest a possible way of determining the size of suboptical vesicles using controlled adhesion gradients.


Striatal Dopamine Signals and Reward Learning.
We are constantly bombarded by sensory information and constantly making decisions on how to act. In order to optimally adapt behavior, we must judge which sequences of sensory inputs and actions lead to successful outcomes in specific circumstances. Neuronal circuits of the basal ganglia have been strongly implicated in action selection, as well as the learning and execution of goal-directed behaviors, with accumulating evidence supporting the hypothesis that midbrain dopamine neurons might encode a reward signal useful for learning. Here, we review evidence suggesting that midbrain dopaminergic neurons signal reward prediction error, driving synaptic plasticity in the striatum underlying learning. We focus on phasic increases in action potential firing of midbrain dopamine neurons in response to unexpected rewards. These dopamine neurons prominently innervate the dorsal and ventral striatum. In the striatum, the released dopamine binds to dopamine receptors, where it regulates the plasticity of glutamatergic synapses. The increase of striatal dopamine accompanying an unexpected reward activates dopamine type 1 receptors (D1Rs) initiating a signaling cascade that promotes long-term potentiation of recently active glutamatergic input onto striatonigral neurons. Sensorimotor-evoked glutamatergic input, which is active immediately before reward delivery will thus be strengthened onto neurons in the striatum expressing D1Rs. In turn, these neurons cause disinhibition of brainstem motor centers and disinhibition of the motor thalamus, thus promoting motor output to reinforce rewarded stimulus-action outcomes. Although many details of the hypothesis need further investigation, altogether, it seems likely that dopamine signals in the striatum might underlie important aspects of goal-directed reward-based learning.


An effective host material with thermally activated delayed fluorescence formed by confined conjugation for red phosphorescent organic light-emitting diodes.
A thermally activated delayed fluorescence material 2,6-bis(9,9-diphenylacridin-10(9H)-yl)pyrazine was designed and synthesized. The twisted configuration made it possesses very small singlet-triplet splitting. A red electroluminescent device based on this new host material is able to achieve ∼26% external quantum efficiency and relatively flat efficiency roll-off.


CA-50 in patients with pancreatic disease--an evaluation of three different laboratory techniques.
Plasma concentrations of CA-50 antigen in samples from patients suffering from pancreatic cancer, chronic pancreatitis and abdominal pain of unknown origin were analysed by three different techniques, using the same monoclonal antibody, C-50 Mab. These methods include an inhibition assay, an immunoradiometric assay (IRMA), and a dissociation-enhanced lanthanide fluoro-immunoassay (DELFIA). Whereas all three methods had high sensitivities for cancer, they displayed different specificities. With respect to the differential diagnosis between pancreatic cancer and chronic pancreatitis, all three methods are of value, with slightly better discrimination for the inhibition test, and easier performance and better analytic ranges for the IRMA and DELFIA methods.