Metabolic re-wiring of isogenic breast epithelial cell lines following epithelial to mesenchymal transition.
Epithelial to mesenchymal transition (EMT) has implications in tumor progression and metastasis. Metabolic alterations have been described in cancer development but studies focused on the metabolic re-wiring that takes place during EMT are still limited. We performed metabolomics profiling of a breast epithelial cell line and its EMT derived mesenchymal phenotype to create genome-scale metabolic models descriptive of both cell lines. Glycolysis and OXPHOS were higher in the epithelial phenotype while amino acid anaplerosis and fatty acid oxidation fueled the mesenchymal phenotype. Through comparative bioinformatics analysis, PPAR-γ1, PPAR- γ2 and AP-1 were found to be the most influential transcription factors associated with metabolic re-wiring. In silico gene essentiality analysis predicts that the LAT1 neutral amino acid transporter is essential for mesenchymal cell survival. Our results define metabolic traits that distinguish an EMT derived mesenchymal cell line from its epithelial progenitor and may have implications in cancer progression and metastasis. Furthermore, the tools presented here can aid in identifying critical metabolic nodes that may serve as therapeutic targets aiming to prevent EMT and inhibit metastatic dissemination.


The short-term outcome of neurotic disorders in the community: the relation of remission to clinical factors and to "neutralizing' life events.
A longitudinal study of neurotic disorder in the community showed that half the cases identified at first interview had remitted one month later. Remission was significantly related to four variables: recency of onset and of peak of the disorders, the occurrence of recent threatening life events and the occurrence of subsequent "neutralizing' life events. A neutralizing event was defined a priori as one which neutralized the impact of an earlier threatening life event or difficulty. One third of all remissions were caused by such an event. Remission of disorder was not significantly related to demographic variables, symptom severity, syndrome type, medical consultation or psychotropic drug prescription. The implications for neurotic disorder in the community are discussed, in particular its relation to life events and the favourable outcome in the absence of treatment.


MRI assessment of surrounding tissues in soft-tissue sarcoma during neoadjuvant chemotherapy can help predicting response and prognosis.
To determine if changes in surrounding tissues of soft-tissue sarcomas (STS) evaluated by MRI during neoadjuvant chemotherapy (NAC) are associated with the histological response and satellite tumorous cells beyond the pseudocapsule on surgical specimen, disease-free survival (DFS) and overall survival (OS). Fifty-seven adult patients with locally advanced high-grade STS of extremities and trunk wall were included in this single-centre retrospective study. All were uniformly treated by 5-6 cycles of anthracycline-based NAC, curative surgery and adjuvant radiotherapy and had available MRI with a gadolinium-chelates administration at baseline and after 2 cycles. Thirty-seven patients also had a pre-operative MRI. Two senior radiologists evaluated MRI growth pattern, oedema, contrast-enhanced oedema, aponeurotic enhancement, and their qualitative changes during NAC. An expert pathologist reviewed all surgical specimens. A good histological response was defined as <10% viable cells. Associations with pathological findings were estimated with Fisher and Chi-square tests and multivariate analysis with binary logistic regression. Survival analyses included log-rank tests. Forty-two patients had poor responses and 25 had satellite tumorous cells on surgical specimen. Changes in surrounding oedema and in contrast-enhanced oedema were associated with responses (p = 0.008 and 0.011, respectively). Diffuse infiltrative growth pattern (IGP) on baseline MRI, changes in margin definition and in contrast-enhanced oedema at early evaluation were associated with satellite tumorous cells (p = 0.039, 0.011 and 0.009, respectively). Diffuse IGP on baseline MRI and stable or increased oedema during treatment were predictors of DFS (p = 0.009 and 0.040, respectively). Surrounding tissues of STS during NAC should be carefully evaluated as they may steer treatment efficacy and patient prognosis.


The presence of apolipoprotein epsilon4 and epsilon2 alleles augments the risk of coronary artery disease in type 2 diabetic patients.
It has been suggested that there is a relationship between apolipoprotein E polymorphism and the severity of coronary artery disease in type II diabetes mellitus (T2DM). The current study specifically aimed to examine whether APOE polymorphism in association with serum lipids-lipoproteins level is a risk factor for developing coronary artery disease (CAD) in diabetic patients living in western of Iran. The APOE genotypes were detected by PCR-RFLP in 152 angiographically documented diabetic CAD patients, 262 non-diabetic (ND) individuals with CAD and 300 unrelated controls (normal coronary artery cases without diabetes) and serum lipid level was measured enzymatically. The APOE-epsilon4 and epsilon2 allele frequencies were significantly higher in the CAD/T2DM and CAD/ND patients than in the control group (p<0.001). Our study demonstrated a significant association between APOE polymorphism and the level of plasma lipids with CAD/T2DM (p=0.001) and CAD/ND (p=0.026) patients. The CAD subjects with T2DM and ND patients carrying APOE-epsilon4 allele had lower plasma HDL-C level (p<0.001), (p=0.008) but had higher plasma LDL-C (p=0.01), total cholesterol (p=0.002), (p=0.03) and TG (p<0.001), (p=0.042) than that of the APOE-epsilon3 carriers, respectively. However, carriers of APOE-epsilon2 had significantly higher levels of plasma TG only. OR of APOE-epsilon4 and epsilon2 alleles in CAD/T2DM and CAD/ND patients were found to be 2.98 (p=0.001),1.86 (p=0.001), 2 (p=0.001), and 1.65 (p=0.001), respectively. The major finding of the present case-control study is that T2DM patients carrying APOE-epsilon2 and epsilon4 alleles have a higher risk of developing CAD than ND patients in the western population of Iran, with APOE-epsilon4 being more closely associated with CAD than the APOE-epsilon2 allele. These results indicated that carriers of APOE-epsilon4 allele have a distinct plasma lipids profile and carrier of this allele with low levels of HDL-C and with high levels of LDL-C may be susceptible to CAD and myocardial infarction specially in diabetic patients. This suggests that a therapeutic modality should be considered for these patients.


The effects of playing wind musical instruments on the occlusal characteristics in a Northern Nigerian Population.
Dentists are often questioned on whether playing a wind musical instrument can adversely affect dental occlusion. This study compared the occlusal characteristics in wind instrument players (WIPs) and non-WIPs. This was a cross-sectional comparative study comprising a group of fifty males aged 18-45 years that had been playing wind instruments for a minimum of 2 years, whereas the control group were non-WIPs in the same environment. All the participants had full complement of dentition. The occlusal characteristics of overjet, overbite, anterior open bite and Little's irregularity were assessed for both groups. Excellent intra-examiner reliability was observed (Cronbach's alpha - 0.997). The Statistical Package for Social Sciences (SPSS Inc., Chicago, IL, USA) version 17 was used for data analysis, and statistical significance level was set at P < 0.05. The number of years of playing wind musical instrument ranged from 2 to 25 years. The mean overjet was 3.46 ± 1.49 mm and 3.18 ± 1.27 mm in the WIP and non-WIP groups, respectively (P > 0.05). The maxillary anterior segment showed statistically significantly higher Little's Irregularity Index score in the WIP group (3.18 ± 3.73 mm) than that in the non-WIP group (1.87 ± 2.21 mm) (P < 0.05). The maxillary Little's Irregularity Index score in trumpet and trombone players (3.55 ± 3.93 mm) was significantly higher than that in saxophone and clarinet players (1.69 ± 2.39 mm). Both the maxillary and mandibular anterior-segment alignments were neither influenced by the number of years nor the frequency of play. Playing wind musical instruments significantly affects the maxillary anterior-segment alignment.


Histopathology of fatal respiratory distress caused by Plasmodium vivax malaria.
An otherwise healthy 20-year-old woman in Goa, India, received antibiotics after a diagnosis of upper respiratory tract infection. One week later, vivax malaria was diagnosed at a health center, but the patient developed respiratory distress and lost consciousness. She arrived at emergency department in shock, breathless, and comatose. She died within minutes. Two independent laboratories later confirmed Plasmodium vivax by microscopy (140,000/microL) and by nested and real-time polymerase chain reaction methods. Post-mortem examination showed congestion of alveolar capillaries by heavy monocytic infiltrates, along with diffuse damage to alveolar membranes consistent with acute respiratory distress syndrome. Parasites seen in lung tissue were roughly proportionate to both peripheral hyperparasitemia and those seen in other organs without lesions. In this patient, vivax malaria caused a rapidly fatal respiratory distress.


Ephaptic coupling of cortical neurons.
The electrochemical processes that underlie neural function manifest themselves in ceaseless spatiotemporal field fluctuations. However, extracellular fields feed back onto the electric potential across the neuronal membrane via ephaptic coupling, independent of synapses. The extent to which such ephaptic coupling alters the functioning of neurons under physiological conditions remains unclear. To address this question, we stimulated and recorded from rat cortical pyramidal neurons in slices with a 12-electrode setup. We found that extracellular fields induced ephaptically mediated changes in the somatic membrane potential that were less than 0.5 mV under subthreshold conditions. Despite their small size, these fields could strongly entrain action potentials, particularly for slow (<8 Hz) fluctuations of the extracellular field. Finally, we simultaneously measured from up to four patched neurons located proximally to each other. Our findings indicate that endogenous brain activity can causally affect neural function through field effects under physiological conditions.


Control of a cell surface major glycoprotein by epidermal growth factor.
When the serum concentration of the culture medium is below 0.7 per-cent, 3T3 mouse cells lose most of their large external transformation sensitive (LETS) protein at the cell surface, Subsequent addition of epidermal growth factor results in the reappearance of massive fibrillar LETS protein networks on the surface of conluent 3T3 cells. Thirteen other hormones tested do not have this effect. It appears that epidermal growth factor can control the expression of LETS protein.


A pilot study to determine the dose and effectiveness of adrenocorticotrophic hormone (H.P. Acthar® Gel) in nephrotic syndrome due to idiopathic membranous nephropathy.
H.P. Acthar(®) Gel is currently the only Food and Drug Administration therapy approved for the treatment of nephrotic syndrome. Active drug ingredients include structurally related melanocortin peptides that bind to cell surface G-protein-coupled receptors known as melanocortin receptors, which are expressed in glomerular podocytes. In animal models of membranous nephropathy, stimulation has been demonstrated to reduce podocyte injury and loss. We hypothesized that H.P. Acthar(®) Gel would improve symptoms of the nephrotic syndrome in patients with idiopathic membranous nephropathy. Twenty patients received a subcutaneous dose of 40 or 80 IU twice weekly. Changes in proteinuria, albumin, cholesterol profile, estimated glomerular filtration rate and serum anti-PLA2R antibodies were assessed at baseline and in response to treatment along with tolerance and safety. Baseline characteristics included mean proteinuria (9.1 ± 3.4 g/day), albumin (2.7 ± 0.8 g/dL), estimated glomerular filtration rate (77 ± 30 mL/min) along with elevated total and low-density lipoprotein (LDL) cholesterol. By 12 months of follow-up, there was a significant improvement in proteinuria in the entire cohort, decreasing to 3.87 ± 4.24 g/day (P < 0.001) with significant improvements in serum albumin, total and LDL cholesterol. A >50% decrease in proteinuria was noted in 65% of the patients with a trend toward better outcomes among patients who received greater cumulative doses. No significant adverse effects were documented. Clearing of serum anti-PLA2R antibodies prior to or in parallel with proteinuria improvement was noted in some, but not all patients. H.P. Acthar(®) Gel is a potential therapy for nephrotic syndrome secondary to idiopathic membranous nephropathy that deserves further study.


Archaeal DNA replication: identifying the pieces to solve a puzzle.
Archaeal organisms are currently recognized as very exciting and useful experimental materials. A major challenge to molecular biologists studying the biology of Archaea is their DNA replication mechanism. Undoubtedly, a full understanding of DNA replication in Archaea requires the identification of all the proteins involved. In each of four completely sequenced genomes, only one DNA polymerase (Pol BI proposed in this review from family B enzyme) was reported. This observation suggested that either a single DNA polymerase performs the task of replicating the genome and repairing the mutations or these genomes contain other DNA polymerases that cannot be identified by amino acid sequence. Recently, a heterodimeric DNA polymerase (Pol II, or Pol D as proposed in this review) was discovered in the hyperthermophilic archaeon, Pyrococcus furiosus. The genes coding for DP1 and DP2, the subunits of this DNA polymerase, are highly conserved in the Euryarchaeota. Euryarchaeotic DP1, the small subunit of Pol II (Pol D), has sequence similarity with the small subunit of eukaryotic DNA polymerase delta. DP2 protein, the large subunit of Pol II (Pol D), seems to be a catalytic subunit. Despite possessing an excellent primer extension ability in vitro, Pol II (Pol D) may yet require accessory proteins to perform all of its functions in euryarchaeotic cells. This review summarizes our present knowledge about archaeal DNA polymerases and their relationship with those accessory proteins, which were predicted from the genome sequences.


The association of punitive parenting practices and adolescent achievement.
This article uses a nationally representative dataset to investigate the extent to which academic-related parenting practices and the home environment during middle childhood (ages 11-13) predict achievement in late adolescence (N = 486; age range: 16-18 years). Results from path analyses indicated that parental endorsement of punitive strategies (e.g., lecture, punish, restrict activities) in response to academic underperformance during middle school predict lower literacy and math achievement 5 years later. In contrast, more cognitively stimulating homes predict higher literacy and math achievement 5 years later. Parenting practices and the home environment indicators, however, did not predict changes in achievement. Socioeconomic and race and ethnicity differences in parenting were also found.


Shear bond strength of orthodontic brackets to porcelain surface using universal adhesive compared to conventional method.
Considering the increase in demand for orthodontic treatment in adults, bracket bond to restored teeth is a clinical challenge. This study sought to compare the shear bond strength (SBS) of orthodontic brackets to feldspathic porcelain using universal adhesive and conventional adhesive with and without silane application. In this in vitro study Fifty-six feldspathic porcelain discs were roughened by bur, and 9.6% hydrofluoric acid was used for surface preparation. Samples were divided into the following four groups (n = 14): Group 1: universal adhesive, Group 2: universal adhesive/silane, Group 3: conventional adhesive, and Group 4: conventional adhesive/silane. Mandibular central incisor brackets were bonded, and SBS was measured by Instron® machine. To assess the mode of failure, adhesive remnant index (ARI) score was determined. The data were analyzed using SPSS software and two-way ANOVA, Bonferroni test, and Kruskal-Wallis test (P < 0.05 considered significant). The highest SBS was noted in the universal adhesive/silane group (12.7 MP) followed by conventional adhesive/silane (11.9 MP), conventional adhesive without silane (7.6 MP), and universal adhesive without silane (4.4 MP). In the absence of silane, the conventional adhesive yielded significantly higher SBS than universal adhesive (P = 0.03). In the presence of silane, the two adhesives showed SBS values significantly higher than the values obtained when silane was not applied, while the two adhesives were not significantly different in terms of SBS in the presence of silane (P = 0.53). Based on ARI score, there were statistically significant differences between Groups 1 and 4 (P = 0.00) and Groups 2 and 4 (P = 0.023). Based on the current results, SBS of bracket to porcelain mainly depends on the use of silane rather than the type of adhesive. Both universal and conventional adhesives yield significantly higher SBS in the presence of silane compared to that in the absence of silane.


Relationship between intraocular pressure and primary open angle glaucoma among white and black Americans. The Baltimore Eye Survey.
A detailed ocular examination, including perimetry, was conducted on 5308 black and white subjects aged 40 years and older in a population-based prevalence survey in east Baltimore, Md. Repeated, detailed examinations were carried out on selected subjects. Roughly half of all subjects with optic nerve damage from primary open angle glaucoma, regardless of race, were unaware that they had the condition. The average intraocular pressure (IOP) among black patients with glaucoma who were receiving treatment was virtually identical to that in those black patients who were not receiving treatment (median IOP, 20 mm Hg); treated eyes of white patients had a lower IOP than those eyes of white patients who were not receiving treatment (mean [+/- SD] IOP, 18.69 +/- 3.23 mm Hg vs 24.15 +/- 5.23 mm Hg; P less than .001). The risk of glaucomatous optic nerve damage increased with the height of the screening IOP, particularly at levels of 22 to 29 and 30 mm Hg and above (relative rate compared with IOP of 15 mm Hg or lower, 12.8 and 40.1 mm Hg, respectively). More than half of all glaucomatous eyes had a screening IOP below 21 mm Hg, whether these eyes were receiving treatment or not. The IOP in glaucomatous eyes tended to rise on follow-up, in contrast with nonglaucomatous eyes in which the IOP was as likely to rise as to fall. Results confirmed that IOP is an important factor in glaucoma, but did not support the traditional distinction between "normal" and "elevated" pressure, nor its corollaries, "low-tension" glaucoma and "high-tension" glaucoma.


Understanding the roles and work of paramedics in primary care: a national cross-sectional survey.
This research aimed to fill a current knowledge gap, namely the current scope of clinical role of paramedics in primary care, in relation to specific constructs such a level of education and clinical experience. The survey was distributed to paramedics in primary care across the UK through the College of Paramedics. A total of 341 surveys were returned (male=215). 90% of responses were from paramedics in England, 1.7% from paramedics in Northern Ireland, 4.6% from paramedics in Scotland and 2.9% from paramedics in Wales. This represents approximately 33% of the primary care paramedic workforce in England and Wales. Estimates for percentages in Northern Ireland and Scotland are unavailable due to the lack of workforce datasets capturing paramedics in primary care. Considerable variation was found in job titles, level of education and provision of clinical supervision of paramedics in primary care. Differing levels of practice were noted, despite guidance documents that attempt to standardise the role. Statistical analysis of quantitative data highlighted that relationships exist between paramedic clinical exposure in primary care, level of education, and ability of independently prescribe medicines and the extent to which clinical presentations are seen and examinations performed. However, free-text responses indicated that challenges in relation to access to further education and clinical supervision to support clinical development resulted in frustration for paramedics who work in this setting. As well as offering an insight into the demographics of the primary care paramedic work force, there is indication of the clinical scope of role undertaken in this setting. Based on our findings, we recommend changes to education and support, governance and legislation to ensure paramedics employed in primary care can work to achieve the full extent of their professional capability.


T-lymphocyte subsets in patients with abnormal body weight: longitudinal studies. in anorexia nervosa and obesity.
In contrast to other types of starvation which are characterized by low CD4+ counts and increased susceptibility to infection, anorexia nervosa is not associated with an increase in infectious complications. To determine why infection risk of anorectics differs from that of other starving populations, we studied T-lymphocytes, including CD4+ and CD8+ phenotypes, in patients with anorexia nervosa, and for comparison, in dieting obese subjects. T-lymphocyte phenotypes were determined by flow cytometric analysis of monoclonal antibody-labeled cells obtained from patients with anorexia nervosa before and after successful therapy and weight gain, and in obese subjects before and after weight loss on a very-low-calorie diet. Weight loss in anorectics and obese dieters was associated with normal CD4+ counts. Unexpectedly, CD8+ counts were low in anorectics, both before and after weight gain, and in obese subjects after (but not before) dieting. Normal CD4+ counts in anorectics and obese dieters, despite marked weight loss, may explain the lack of increased infection risk in these eating-disordered patients, in contrast to other starving populations. The observation that CD8+ counts are low in anorectics with low and restored body weight and in obese patients after dieting has not been previously reported. The persistence of low CD8+ counts in anorectics even after weight gain suggests that some factors other than weight loss per se may be involved, possibly including effects due to stress, comorbid psychiatric conditions, or unidentified aspects of dysregulated pathophysiology secondary to disordered eating.


The effect of calcium ions and peptide ligands on the relative stabilities of the calmodulin dumbbell and compact structures.
A combination of ion mobility and mass spectrometry methods was used to characterize the molecular shape of the protein calmodulin (CaM) and its complexes with calcium and a number of peptide ligands. CaM, a calcium-binding protein composed of 148 amino acid residues, was found by X-ray crystallography to occur both in a globular shape and in the shape of an extended dumbbell. Here, it was found, as solutions of CaM and CaM complexes were sprayed into the solvent-free environment of the mass spectrometer, that major structural features of the molecule and the stoichiometry of the units constituting a complex in solution were preserved in the desolvation process. Two types of CaM structures were observed in our experiments: a compact and an extended form of CaM with measured cross sections in near-perfect agreement with those calculated for the known globular and extended dumbbell X-ray geometries. Calcium-free solutions yielded predominantly an extended CaM conformation. Ca(n)(2+)-CaM complexes were observed in calcium-containing solutions, n = 0-4, with the population of the compact conformation increasing relative to the elongated conformation as n increases. For n = 4, a predominantly compact globular conformation was observed. Solutions containing the peptide CaMKII(290-309), the CaM target domain of the Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) enzyme, yielded predominantly globular Ca(4)(2+)-CaM-CaMKII(290-309) complexes. Similar results were obtained with the 26-residue peptide melittin. For the 14-residue C-terminal melittin fragment, on the other hand, formation of both a 1:1 and a 1:2 CaM-peptide complex was detected. On the basis of the entirety of our results, we conclude that the collapse of extended (dumbbell-like) CaM structures into more compact globular structures occurs upon specific binding of four calcium ions. Furthermore, this calcium-induced structural collapse of CaM appears to be a prerequisite for formation of a particularly stable CaM-peptide complex involving peptides long enough to be engaged in interactions with both lobes of CaM.


Lingual kinematics in dysarthric and nondysarthric speakers with Parkinson's disease.
Articulatory dysfunction is recognised as a major contributor to the speech disturbances seen in Parkinson's disease (PD). The present study aimed to compare lingual kinematics during consonant production within a sentence in eight dysarthric (DPD) and seven nondysarthric (NDPD) speakers with PD with those of eleven nonneurologically impaired normal participants. The tongue tip and tongue back movements of the participants during sentence production were recorded using electromagnetic articulography (EMA). Results showed that both the DPD and NDPD had deviant articulatory movement during consonant production that resulted in longer duration of consonant production. When compared with the NDPD group, the DPD group primarily exhibited increased range of lingual movement and compatible duration of production with an accompanying increase in maximum velocity, maximum acceleration, and maximum deceleration. These findings are contrary to proposed theories that suggest articulatory imprecision in dysarthric speakers with PD is the outcome of reduced range of articulatory movement.


Fertilization-independent Cell-fusion between the Synergid and Central Cell in the Polycomb Mutant.
In flowering plants, fertilization of the central cell gives rise to an embryo-nourishing endosperm. Recently, we reported that the endosperm absorbs the adjacent synergid cell through a cell-fusion, terminating the pollen tube guidance by a rapid inactivation of the synergid cell. Although this synergid-endosperm fusion (SE fusion) initiates soon after fertilization, it was still unknown whether the triggers of SE fusion are stimuli during fertilization or other seed developmental processes. To further dissect out the SE fusion process, we investigated the SE fusion in an Arabidopsis mutant defective for MULTICOPY SUPPRESSOR OF IRA1 (MSI1), a subunit of the polycomb repressive complex 2 (PRC2). The mutant msi1 develops autonomous endosperm without fertilization. Time-lapse imaging revealed a rapid efflux of the synergid contents during the autonomous endosperm development, indicating that the initiation of SE fusion is under the control of some of the events triggered by fertilization of the central cell distinct from the discharge of pollen tube contents and plasma membrane fusion.


Nonunion fracture healing: Evaluation of effectiveness of demineralized bone matrix and mesenchymal stem cells in a novel sheep bone nonunion model.
Nonunion treatment has a high rate of success, although recalcitrant nonunion may determine the need for amputation. Therefore, new treatment options are continuously investigated in order to further reduce the risk of nonunion recurrence. This study aimed to (a) develop a new large animal model for bone atrophic nonunion and (b) compare the efficacy of demineralized bone matrix (DBM) and DBM in combination with mesenchymal stem cells (MSC) in the new nonunion model. The new model consists of a noncritical, full-thickness segmental defect created in the sheep tibia, stabilized by an intramedullary nail, and involves the creation of a locally impaired blood supply achieved through periosteum excision and electrocauterization of the stump ends. Six weeks after defect creation, lack of hard tissue callus and established nonunion was observed in all operated tibiae both by radiographic and clinical evaluation. Nonunion was treated with allogeneic DBM or autologous MSC cultivated on DBM particles (DBM + MSC) for 1 day before implantation. Twelve weeks after treatment, radiographic, microtomographic, histologic, and histomorphometric analysis showed the formation of bone callus in DBM group, whereas the fracture healing appeared at an early stage in DBM + MSC group. Torsional strength and stiffness of the DBM group appeared higher than those of DBM + MSC group, although the differences were not statistically significant. In conclusion, a new sheep bone nonunion model resembling the complexity of the clinical condition was developed. DBM is an effective option for nonunion treatment, whereas MSC do not improve the healing process when cultivated on DBM particles before implantation.


Response to preventive cardiac resynchronization therapy in patients with ischaemic and nonischaemic cardiomyopathy in MADIT-CRT.
There are no data regarding the differential response to cardiac resynchronization therapy with defibrillator (CRT-D) by the aetiology of cardiomyopathy in mildly symptomatic patients. We evaluated the outcome of patients enrolled in MADIT-CRT by ischaemic and non-ischaemic aetiology of cardiomyopathy (ICM and non-ICM, respectively). The clinical response to CRT-D was assessed among ICM (n = 1046) and non-ICM (n = 774) patients enrolled in MADIT-CRT during an average follow-up of 2.4 years, and echocardiographic response was assessed at 1 year. Cardiac resynchronization therapy with defibrillator vs. ICD therapy was associated with respective 34% (P = 0.001) and 44% (P = 0.002) reductions in the risk of heart failure or death among ICM and non-ICM patients (P for interaction = 0.455). In the ICM group, CRT-D was associated with mean (±SD) 29 ± 14% and 18 ± 10% reductions in left ventricular end-systolic volume (LVESV) and left ventricular end-diastolic volume (LVEDV), respectively. In the non-ICM group, CRT-D was associated with significantly greater volume reductions compared with the ICM group [37 ± 16% and 24 ± 12% reductions in LVESV and LVEDV, respectively (P < 0.001 for all)]. Risk subsets in the ICM group that showed a favourable clinical response to CRT-D included patients with QRS ≥150 ms, systolic blood pressure <115 mmHg, and left bundle branch block (LBBB), whereas in the non-ICM group females, patients with diabetes mellitus, and LBBB, displayed a favourable clinical response. Mildly symptomatic ICM and non-ICM patients show significant differences in the echocardiographic response to CRT-D and in the clinical benefit within risk subsets suggesting that risk assessment for CRT-D in this population should be aetiology-specific.


Production of a soluble form of fumarate reductase by multiple gene duplication in Escherichia coli K12.
1. Ampicillin-hyperresistant mutants of Escherichia coli K12 bearing multiple gene duplications in the ampC (beta-lactamase) gene region of the chromosome overproduced at least six proteins with molecular weights 97,000, 80,000, 72,000, 49,000, 33,000 and 26,500 during anaerobic growth. All but two of the proteins (80,000-Mr and 49,000-Mr) were also overproduced during aerobic growth. The distribution of the proteins in soluble and particulate cell fractions was investigated. 2. The 33,000-Mr and 72,000-Mr components were identified as beta-lactamase and the amp-linked frdA gene product, fumarate reductase, respectively. Co-sedimentation of the 26,500-Mr component with the fumarate reductase suggested that the smaller protein could be functionally related to the reductase. The lack of correspondence between the amplified proteins and the products of other amp-linked genes, aspA and mop(groE), indicated that these genes are not included in the repetitive sequence. 3. Fumarate reductase activities were amplified up to 32-fold by the multiple gene duplications. Two forms of fumarate reductase were produced: particulate (membrane-bound) and soluble (cytoplasmic). Production of the soluble form occurred when the binding capacity of the membrane was saturated. Both forms of fumarate reductase were enzymically active but the soluble form was readily inactivated under assay conditions.


Endothelial function, nitric oxide, and cocoa flavanols.
Endothelial dysfunction is the pathophysiologic principle involved in the initiation and progression of arteriosclerosis, thus endothelial function serves as a "barometer" for cardiovascular health that can be used for the evaluation of new therapeutic strategies. This review provides an introduction to the concept of endothelial dysfunction, and it explores the importance of this prognostic marker in the context of clinical, dietary interventions in humans. Moreover, we summarize and evaluate the findings of various clinical trials that demonstrated an improvement of endothelial dysfunction in subjects with cardiovascular risk factors after the acute and chronic consumption of flavanol-rich foods, including cocoa products, red wine, and tea.


Statistical analysis of variation in laboratory growth of carbon nanotube forests and recommendations for improved consistency.
While many promising applications have been demonstrated for vertically aligned carbon nanotube (CNT) forests, lack of consistency in results (e.g., CNT quality, height, and density) continues to hinder knowledge transfer and commercialization. For example, it is well known that CNT growth can be influenced by small concentrations of water vapor, carbon deposits on the reactor wall, and experiment-to-experiment variations in pressure within the reaction chamber. However, even when these parameters are controlled during synthesis, we found that variations in ambient lab conditions can overwhelm attempts to perform parametric optimization studies. We established a standard growth procedure, including the chemical vapor deposition (CVD) recipe, while we varied other variables related to the furnace configuration and experimental procedure. Statistical analysis of 280 samples showed that ambient humidity, barometric pressure, and sample position in the CVD furnace contribute significantly to experiment-to-experiment variation. We investigated how these factors lead to CNT growth variation and recommend practices to improve process repeatability. Initial results using this approach reduced run-to-run variation in CNT forest height and density by more than 50%.


Notification and management of congenital syphilis in the Northern Territory 2009 to 2014.
To determine whether cases of congenital syphilis in the Northern Territory between 2009 and 2014 were correctly notified based on probable or confirmed case criteria stipulated by the Communicable Diseases Network Australia (CDNA). Pregnant women with positive syphilis serology defined as reactive treponemal test and rapid plasma reagin titre ≥1:8 were identified from the Northern Territory Syphilis Register Information System. Risk classification was performed based on local guidelines, and CDNA criteria for probable/confirmed cases of congenital syphilis were applied to determine whether cases were appropriately notified. Thirty-four cases of positive maternal syphilis serology in pregnancy were identified from 31 women; all were Indigenous. Twenty-one cases fulfilled criteria for probable congenital syphilis; 1 case was formally notified to the Centre for Disease Control. Twenty cases (95%) fulfilling CDNA criteria for probable congenital syphilis were not notified over the study period. Application of standard case definitions significantly increases the rate of congenital syphilis cases in the Northern Territory. Improved education regarding CDNA criteria for notification of congenital syphilis is necessary for clinicians and public health staff. Emerging evidence has supported the recent simplification of CDNA criteria for notification of congenital syphilis, effective 1 July 2015.


Arbitrary optical waveform generation using 2D ring resonator arrays.
The direct temporal domain approach can be applied for arbitrary optical waveform generation using 2D ring resonator arrays (RRAs). To demonstrate the approach, we provide numerical examples which show the generation of two very different waveforms from the same input pulse. In particular, we consider a hyperbolic secant input pulse with 8 ps full width half maximum and generate (1) a 50 ps square-like waveform with 5 ps rising and falling times and a 40 ps flat-top as well as (2) a 60 ps triangular waveform with 30 ps rising and falling times, both with a 5x5 RRA. Simulations show that the generated waveforms are well-matched to their targets.


The murine interleukin 2 receptor. IV. Biochemical characterization.
The IL 2 receptor isolated from the IL 2-dependent CTL-L cell line was subjected to biochemical analysis. Pulse-chase and tunicamycin studies, as well as digestion with the endoglycosidases, Endo-F and Endo-H, of 35S-methionine-labeled IL 2 receptors suggested a single protein precursor of 32,000 (p32) daltons. The p32 precursor was rapidly processed by addition of high-mannose-containing core N-linked sugars to intracytoplasmic precursor intermediates of 38,000 (p38) and 40,000 (p40) daltons, which undergo further processing to yield a mature surface receptor with heterogeneous apparent m.w. of 52,000 to 65,000 (p58). Two-dimensional gel studies indicated that p58 exhibited broad charge heterogeneity between pH 4.6 and 6.3. Endo-F digestions of p58 shifted the isoelectric focus point to a more basic 5.5 to 7.4. This considerable charge heterogeneity is consistent with the possibility that other posttranslational modifications to the mouse IL 2 receptor occur besides addition of complex N-linked glycans. Immunoprecipitations of the IL 2 receptor from surface iodinated cells also revealed an additional band at 110,000 (p110) daltons. IEF vs SDS-PAGE two-dimensional gel studies demonstrated that p110 also had an isoelectric focus point identical to p58. Western blot studies with an anti-IL 2 receptor monoclonal antibody (7D4) demonstrated that p38, p40, p58, and p110 each expressed the epitope recognized by this antibody. Thus, it is likely that p110 is not a unique molecule that coprecipitates with the IL 2 receptor. Western blot analysis of mitogen-stimulated T and B lymphocytes also revealed bands similar to p58 and p110, although these bands had an average apparent m.w. 3000 to 6000 less than those seen for CTL-L cells.


Critical assessment of prebiopsy parameters for predicting prostate cancer metastasis and mortality.
Value of characteristics assessed prior to diagnosis predicting aggressive prostate cancer, metastases and mortality in men participating in a screening study were identified. This study included 19950 men, aged 55 to 74 years at first screening, in the European Randomized Study of Screening for Prostate Cancer. Age, Charlson comorbidity, prostate cancer family history, vasectomy status, International Prostate Symptom Score (IPSS) score, digital rectal examination (DRE) status, transrectal ultrasound (TRUS) findings, prostate volume and prostate-specific antigen (PSA) level were assessed. Men were followed for median 11.1 years after first screening visit. Multivariate estimates of the probability of aggressive prostate cancer [stage ≥ T2c, or N1, M1, PSA > 20 ng/mL, or Gleason score ≥ 8], developing distant metastases and dying from prostate cancer stratified for predictors measured before prostate biopsies. Harrell's concordance index (c-index) was used for predictive accuracy. Among 19950 men, 2420 men (12.1%) were diagnosed with prostate cancer, of which 623 men (3.1%) had aggressive prostate cancer, 157 men (0.8%) developed metastases and 104 men (0.5%) died due to a prostate cancer related cause of death. In multivariate analysis, PSA, DRE, TRUS findings and prostate volume had a significant association with detection of aggressive prostate cancer, metastases and prostate cancer mortality. Family history was significantly associated with aggressive prostate cancer. Accuracy for predicting aggressive prostate cancer c-index = 0.90, distant metastases c-index = 0.87, and prostate cancer specific mortality c-index = 0.87. In a large population of men who were screened for prostate cancer, detection of aggressive prostate cancer, metastases and prostate cancer mortality was predicted based on predictors available before biopsy. These results support the value of a multivariate risk assessment and stratification tools.


Altered cerebellar function in mice lacking CaV2.3 Ca2+ channel.
Voltage-dependent Ca(2+) channels play important roles in cerebellar functions including motor coordination and learning. Since abundant expression of Ca(V)2.3 Ca(2+) channel gene in the cerebellum was detected, we searched for possible deficits in the cerebellar functions in the Ca(V)2.3 mutant mice. Behavioral analysis detected in delayed motor learning in rotarod tests in mice heterozygous and homozygous for the Ca(V)2.3 gene disruption (Ca(V)2.3+/- and Ca(V)2.3-/-, respectively). Electrophysiological analysis of mutant mice revealed perplexing results: deficit in long-term depression (LTD) at the parallel fiber Purkinje cell synapse in Ca(V)2.3+/- mice but apparently normal LTD in Ca(V)2.3-/- mice. On the other hand, the number of spikes evoked by current injection in Purkinje cells under the current-clamp mode decreased in Ca(V)2.3 mutant mice in a gene dosage-dependent manner, suggesting that Ca(V)2.3 channel contributed to spike generation in Purkinje cells. Thus, Ca(V)2.3 channel seems to play some roles in cerebellar functions.


"The tools of the trade"--an overview of the pharmacology of the endocannabinoid system.
The endocannabinoid system can be manipulated pharmacologically in a variety of ways, including directly acting agonists and inverse agonists, and indirectly acting compounds which affect the synthesis, cellular accumulation and metabolism of the two main endocannabinoids, anandamide and 2-arachidonoylglycerol. In this overview, the most commonly used compounds are discussed, primarily with respect to their targets of action and to their selectivities vis a vis "off targets". For direct acting compounds such as cannabinoid receptor agonists, it is suggested that the use of several compounds with different chemical structures at relevant doses or concentrations is likely to minimise the risk of misinterpreting an "off target" effect as being an action mediated by cannabinoid receptors. For indirectly acting compounds, the same reasoning applies, and in the case of compounds affecting the accumulation of anandamide, it is important to recognize that the molecular target of these compounds is far from clear. Nonetheless, judicious use of the array of pharmacological tools currently available, and combination of these tools with RNA interference techniques and the use of genetically modified animals, provides a powerful approach with which to characterize the endocannabinoid system in the body.


Identification of insulin-like growth factor-binding protein-3 (IGFBP-3) fragments and IGFBP-5 proteolytic activity in human seminal plasma: a comparison of normal and vasectomized patients.
Previous studies have demonstrated that insulin-like growth factor (IGF) peptides, IGF-binding proteins (IGFBPs), and IGFBP-3 proteolytic activity, are present in human seminal plasma (SP). In this study, we have further characterized the IGFBPs in SP using immunoprecipitation and Western ligand blotting, Western immunoblotting, affinity cross-linking and immunoprecipitation, and RIA of IGFBP-3 using two different assays and have identified additional proteolytic activities for IGFBP-4 and IGFBP-5 in SP. Immunoprecipitation with antibodies to IGFBP-2, IGFBP-3, and IGFBP-4, before and after affinity cross-linking, demonstrated that intact IGFBP-2 and IGFBP-4 are present in SP, but intact IGFBP-3 is absent. Low mol wt fragments of IGFBP-3, which did not bind to IGF-I or IGF-II on Western ligand blot and did not cross-link to IGF-II, were demonstrated on Western immunoblot and were measurable by two different RIAs. Proteolytic activities for IGFBP-4 and IGFBP-5 were demonstrated in SP by incubation with the respective iodinated IGFBPs. On comparing the proteolytic activity for IGFBP-4 by purified prostate-specific antigen (PSA; a known IGFBP-3 protease in SP) or by SP with measured equivalent concentrations of PSA, the dose response and fragment patterns were identical. With IGFBP-5, however, proteolysis by purified PSA was different from that by SP with measured equivalent concentrations of PSA: 1) proteolysis by pure PSA was less efficient than matched concentrations of SP; 2) the pattern of fragments after proteolysis by pure PSA was different from that after proteolysis by matched concentrations of SP; and 3) proteolysis by purified PSA was significantly inhibited by phenylmethylsulfonylfluoride and aprotinin, but proteolysis by SP was not. We conclude that human SP contains intact IGFBP-2 and IGFBP-4, but has only IGFBP-3 fragments with low affinity for IGF peptides; that PSA is able to proteolyze IGFBP-4 and IGFBP-5 (as well as IGFBP-3); and that an additional IGFBP-5 protease is probably present in SP. There was no significant difference in any of these findings in SP from normal volunteers, vasectomized patients, or patients with idiopathic azoospermia. The roles of IGFBPs and IGFBP proteases in the male reproductive system and male infertility remain to be further elucidated.


Cementless total hip replacement in patients with developmental dysplasia of the hip.
This study was conducted to evaluate the clinical and radiographic results of 22 total hip replacements done in 17 consecutive patients for coxarthrosis due to developmental dysplasia or dislocation of the hip. All operations were done using an anterior approach without trochanteric osteotomy. Standard cementless prostheses were used in all cases. There was no custom-designed prosthesis used. The acetabular cup was placed in an anatomic position in the true acetabulum in every case. Bulk autograft was necessary to reconstruct the deficient acetabular roof in only 2 hips. The average follow-up was 63 months (range, 40 months to 95 months). The average Harris Hip Score was improved from a preoperative value of 35 (range, 24 to 46), to 96 (range, 79 to 100) at final follow-up. To date, no revision has been done. Three hips showed radiographic evidence suggestive of aseptic loosening (2 stems and 1 cup), but the clinical results remain satisfactory. There is no incidence of dislocation, sciatic nerve palsy, or infection.


Scalable faceted voids with luminescent enhanced edges in WS2 monolayers.
A scalable approach is needed in the formation of atomically flat edges with specific terminations to enhance local properties for optoelectronic, nanophotonic and energy applications. We demonstrate point defect clustering-driven faceted void formations with luminescent enhanced edges in WS2 monolayers during large-scale CVD growth and controlled annealing. With the aid of aberration-corrected scanning transmission electron microscopy (AC-STEM) high angle annular dark field (HAADF) imaging, we probed atomic terminations of S and W to explain observed luminescence enhancement in alternate edges. Faceted void formation in monolayer WS2 was found to be sensitive to annealing temperature, time, gas environment and precursor supply. Our observations of areal coverage evolution over time revealed competition between monolayer WS2 growth and void formation at 850 °C. While the initial stage was dominated by monolayer growth, defect generation and void growth dominated at later stages and provided an optimum processing window for monolayer WS2 as well as faceted void growth. Growth of faceted voids not only followed the geometry of monolayer facets but also showed similar atomic terminations at the edges and thus enabled local manipulation of photoluminescence enhancement with an order of magnitude increase in intensity. The developed CVD processing enabled multi-fold increase in the luminescent active edge length through the formation of faceted voids within the WS2 monolayer.


Robotic surgery for upper gastrointestinal cancer: Current status and future perspectives.
Robotic surgery with the da Vinci Surgical System has been increasingly applied in a wide range of surgical specialties, especially in urology and gynecology. However, in the field of upper gastrointestinal (GI) tract, the da Vinci Surgical System has yet to be standard as a result of a lack of clear benefits in comparison with conventional minimally invasive surgery. We have been carrying out robotic gastrectomy and esophagectomy for operable patients with resectable upper GI malignancies since 2009, and have demonstrated the potential advantages of the use of the robot in possibly reducing postoperative local complications including pancreatic fistula following gastrectomy and recurrent laryngeal nerve palsy after esophagectomy, even though there have been a couple of problems to be solved including longer duration of operation and higher cost. The present review provides updates on robotic surgery for gastric and esophageal cancer based on our experience and review of the literature.


Modal interaction matrix measurement for liquid-crystal corrector: precision evaluation.
A modal interaction matrix (IM) measurement procedure is introduced for a liquid-crystal (LC) corrector for use in a phase-wrapping technique. Zernike modes are used to reconstruct the aberration wavefront and to drive the LC corrector. Usually the driving area is different from the active area. This difference induces a coupling effect on Zernike modes, which may have an impact on correction precision. In this paper the coupling effect is evaluated due to area difference and decentration, respectively. Then, a simulated turbulence wavefront is used to simulate the reconstruction process to evaluate its influence on reconstruction precision. We present simulation results that show that this method can be used to measure the IM with very high reconstruction precision under proper configuration. In order to maintain precision, the permissible eccentricity distance is also simulated with a result of no more than 5% of the LC corrector diameter.


Synthesis of mesoporous TiO2/SiO2 hybrid films as an efficient photocatalyst by polymeric micelle assembly.
Thermally stable mesoporous TiO2/SiO2 hybrid films with pore size of 50 nm have been synthesized by adopting the polymeric micelle-assembly method. A triblock copolymer, poly(styrene-b-2-vinyl pyridine-b-ethylene oxide), which serves as a template for the mesopores, was utilized to form polymeric micelles. The effective interaction of titanium tetraisopropoxide (TTIP) and tetraethyl orthosilicate (TEOS) with the polymeric micelles enabled us to fabricate stable mesoporous films. By changing the molar ratio of TEOS and TTIP, several mesoporous TiO2/SiO2 hybrid films with different compositions can be synthesized. The presence of amorphous SiO2 phase effectively retards the growth of anatase TiO2 crystal in the pore walls and retains the original mesoporous structure, even at higher temperature (650 °C). These TiO2/SiO2 hybrid films are of very high quality, without any cracks or voids. The addition of SiO2 phase to mesoporous TiO2 films not only adsorbs more organic dyes, but also significantly enhances the photocatalytic activity compared to mesoporous pure TiO2 film without SiO2 phase.


Association of Up-Regulated Plasma Adiponectin With Risk of Incident Depression in a Community-Dwelling Elderly Population.
Despite robust interest in the association between inflammation and depression, anti-inflammatory markers have been scarcely investigated as predictors of the future risk of depression. The aim of this study is to determine whether up-regulation of plasma adiponectin, an anti-inflammatory adipokine, precedes and predicts the development of depression in the elderly. This prospective cohort study was launched in 2005. Among 1,000 participants who were randomly sampled from community-dwelling individuals 65 years or older, 633 euthymic individuals without prior history of depressive disorders were enrolled for a baseline evaluation and follow-up after 5 years. Incident clinically significant depression, including major and minor depressive disorders (by DSM-IV criteria), subsyndromal depression (by operational criteria), and euthymia after antidepressant treatment, was assessed by clinical interviews. Baseline plasma adiponectin values were divided into tertiles (low tertile: ≤ 5.685 μg/mL, middle tertile: 5.686-10.367 μg/mL, high tertile: ≥ 10.368 μg/mL). Among the 261 euthymic individuals who responded to the 5-year follow-up evaluation, 17 developed incident depression (7 from the high tertile, 8 from the middle tertile, and 2 from the low tertile). The risk of incident depression was much higher in the high tertile group than in the low tertile group after adjusting for age, sex, body mass index, burden of chronic medical illnesses, and Mini-Mental State Examination score (odds ratio = 10.64; 95% CI, 1.21-93.84; P = .033). Up-regulation of plasma adiponectin may precede the onset of clinically significant depression in the elderly, and thus plasma adiponectin level is a potential candidate marker for the risk of depression.


Fortunes and misfortunes of political leaders reflected in the eyes of their electors.
Gaze-following is a pivotal social behaviour that, although largely automatic, is permeable to high-order variables like political affiliation. A few years ago we reported that the gaze of Italian right-wing voters was selectively captured by the gaze of their leader Silvio Berlusconi. This effect was particularly evident in voters who saw themselves as similar to Berlusconi. Two years later, we were able to run the present follow-up study because Berlusconi's popularity had drastically dropped due to sex and political scandals, and he resigned from office. In a representative subsample of our original group, we investigated whether perceived similarity and gaze-following reflected Berlusconi's loss in popularity. We were also able to test the same hypothesis in an independent group of right-wing voters when their leader, Renata Polverini, resigned as Governor of 'Regione Lazio' due to political scandals. Our results show that the leaders' fall in popularity paralleled the reduction of their gaze's attracting power, as well as the decrease in similarity perceived by their voters. The less similar right-wing voters felt to their leader, the less they followed his/her gaze. Thus, the present experimental findings suggest that gaze-following can be modulated by complex situational and dispositional factors such as leader's popularity and voter-leader perceived similarity.


Rituximab in cryoglobulinaemic vasculitis, evidence for its effectivity: a case report and review of literature.
Cryoglobulinaemia associated with systemic vasculitis mediated by immune complexes is a rare combination. These immune complexes are composed of immunoglobulins and precipitate when exposed to cold temperature. Cryoglobulinaemic vasculitis, treated or untreated, may lead to substantial morbidity and even mortality. Novel targeted therapies may well provide new therapeutic options following or perhaps even prior to the classical cytotoxic therapies. Systemic B cell depletion with rituximab, a chimeric monoclonal antibody against CD20 antigen, is commonly applied in patients with non-Hodgkin's lymphoma or in refractory rheumatoid factor-positive rheumatoid arthritis. Since B cell clones are the source of cryoglobulins, therapeutic effectiveness of rituximab in cryoglobulinaemic vasculitis may be expected. We describe a 72-year-old woman with mixed cryoglobulinaemia type 2, who has successfully been treated with rituximab infusions after failing on prednisone and azathioprine. We reviewed the literature and found 142 cases of cryoglobulinaemic vasculitis, 138 mixed (type 2 or 3) and four, type 1. Rituximab was applied mostly after failure on other treatments. Significant reduction in levels of rheumatoid factor, cryoglobulins and IgM were reported after rituximab therapy. Of the total 142, cases 119 could be evaluated for the response on rituximab therapy, the other 23 cases only regarding side effects. Of the 119 evaluated patients, 71 (60%) had complete response; 28 (23%), partial response and 20 patients (17%), no response. Data were not blinded or placebo-controlled. Side effects were seen in 27 of the 142 patients. Occurrence of the side effects was associated with high baseline levels of cryoglobulins, with a high dose of rituximab infusion of 1,000 mg and with a high level of complement activation. Death was reported four times and was related with the disease.


How Does Iron Storage Protein Ferritin Interact with Plutonium (and Thorium)?
The impact of the contamination of living organisms by actinide elements has been a constant subject of attention since the 1950s. But to date still little is understood. Ferritin is the major storage and regulation protein of iron in many organisms, it consists of a protein ring and a ferrihydric core at the center. This work sheds light on the interactions of early actinides (Th, Pu) at oxidation state +IV with ferritin and its ability to store those elements at physiological pH compared to Fe. The ferritin-thorium load curve suggests that ThIV saturates the protein (2840 Th atoms per ferritin) in a similar way that Fe does on the protein ring. Complementary spectroscopic techniques (spectrophotometry, infrared spectroscopy, and X-ray absorption spectroscopy) were combined with molecular dynamics to provide a structural model of the interaction of ThIV and PuIV with ferritin. Comparison of spectroscopic data together with MD calculations suggests that ThIV and PuIV are complexed mainly on the protein ring and not on the ferrihydric core. Indeed from XAS data, there is no evidence of Fe neighbors in the Th and Pu environments. On the other hand, carboxylates from amino acids of the protein ring and a possible additional carbonate anion are shaping the cation coordination spheres. This thorough description from a molecular view point of ThIV and PuIV interaction with ferritin, an essential iron storage protein, is a cornerstone in comprehensive nuclear toxicology.


Is the straddle effect in contrast perception limited to second-order spatial vision?
Previous work on the straddle effect in contrast perception (Foley, 2011; Graham & Wolfson, 2007; Wolfson & Graham, 2007, 2009) has used visual patterns and observer tasks of the type known as spatially second-order. After adaptation of about 1 s to a grid of Gabor patches all at one contrast, a second-order test pattern composed of two different test contrasts can be easy or difficult to perceive correctly. When the two test contrasts are both a bit less (or both a bit greater) than the adapt contrast, observers perform very well. However, when the two test contrasts straddle the adapt contrast (i.e., one of the test contrasts is greater than the adapt contrast and the other is less), performance drops dramatically. To explain this drop in performance-the straddle effect-we have suggested a contrast-comparison process. We began to wonder: Are second-order patterns necessary for the straddle effect? Here we show that the answer is "no". We demonstrate the straddle effect using spatially first-order visual patterns and several different observer tasks. We also see the effect of contrast normalization using first-order visual patterns here, analogous to our prior findings with second-order visual patterns. We did find one difference between first- and second-order tasks: Performance in the first-order tasks was slightly lower. This slightly lower performance may be due to slightly greater memory load. For many visual scenes, the important quantity in human contrast processing may not be monotonic with physical contrast but may be something more like the unsigned difference between current contrast and recent average contrast.


A Genetics-First Approach to Dissecting the Heterogeneity of Autism: Phenotypic Comparison of Autism Risk Copy Number Variants.
Certain copy number variants (CNVs) greatly increase the risk of autism. The authors conducted a genetics-first study to investigate whether heterogeneity in the clinical presentation of autism is underpinned by specific genotype-phenotype relationships. This international study included 547 individuals (mean age, 12.3 years [SD=4.2], 54% male) who were ascertained on the basis of having a genetic diagnosis of a rare CNV associated with high risk of autism (82 16p11.2 deletion carriers, 50 16p11.2 duplication carriers, 370 22q11.2 deletion carriers, and 45 22q11.2 duplication carriers), as well as 2,027 individuals (mean age, 9.1 years [SD=4.9], 86% male) with autism of heterogeneous etiology. Assessments included the Autism Diagnostic Interview-Revised and IQ testing. The four genetic variant groups differed in autism symptom severity, autism subdomain profile, and IQ profile. However, substantial variability was observed in phenotypic outcome in individual genetic variant groups (74%-97% of the variance, depending on the trait), whereas variability between groups was low (1%-21%, depending on the trait). CNV carriers who met autism criteria were compared with individuals with heterogeneous autism, and a range of profile differences were identified. When clinical cutoff scores were applied, 54% of individuals with one of the four CNVs who did not meet full autism diagnostic criteria had elevated levels of autistic traits. Many CNV carriers do not meet full diagnostic criteria for autism but nevertheless meet clinical cutoffs for autistic traits. Although profile differences between variants were observed, there is considerable variability in clinical symptoms in the same variant.


The Effect of Real-Time Video-Based Engagement and Feedback during Pedaling on Cadence Control and Exercise Motivation: A Proof-of-Concept Study.
The use of video and music as an intrinsic, dissociative attentional stimulus during exercise is thought to distract from the physical discomfort of exercise, and contribute to improved exercise adherence; however, the effects of video-based feedback and engagement during pedaling on exercise performance and motivation are poorly understood. The aims of the present study were twofold. Firstly, to develop a novel video-based engagement regime for pedaling that links pedaling cadence with the play rate of a video, and secondly, to employ an instrumented pedaling device to assess the influence of the video engagement paradigm on cadence performance and exercise motivation. Eighteen healthy subjects participated in 15-min-duration pedaling sessions while targeting a specific low cadence (60 rotations per minute) and high cadence (100 rotations per minute), including pedaling with the provision of (i) target pedaling cadence information only, (ii) visual feedback on cadence control, including pedaling duration, pedaling cadence, and cadence deviation from target, and (iii) real-time engagement, which involved pedaling at the target speed to maintain the playback rate of a pre-recorded video. Cadence deviation from the target was evaluated, and self-reported exercise motivation examined with a post-exercise survey. Pedaling-cadence deviations significantly reduced with cadence feedback at both low and high cadence (p < 0.05). Participants reported enjoying feedback and video-based engagement during pedaling, with 83% of participants feeling that engagement motivated them to perform pedaling-based exercise. In conclusion, real-time cadence control feedback and video-based engagement during pedaling for healthy individuals may improve performance in targeted pedaling tasks. Through dissociation from the physical cues associated with exercise and fatigue, feedback and engagement may ultimately increase enjoyment and exercise compliance and adherence of pedaling-based exercise. The findings may be useful in prescription and maintenance of targeted pedaling exercises for stroke rehabilitation and exercise therapy.


Global transcriptional response of macrophage-like THP-1 cells to Shiga toxin type 1.
Shiga toxins (Stxs) are bacterial cytotoxins produced by the enteric pathogens Shigella dysenteriae serotype 1 and some serotypes of Escherichia coli that cause bacillary dysentery and hemorrhagic colitis, respectively. To date, approaches to studying the capacity of Stxs to alter gene expression in intoxicated cells have been limited to individual genes. However, it is known that many of the signaling pathways activated by Stxs regulate the expression of multiple genes in mammalian cells. To expand the scope of analysis of gene expression and to better understand the underlying mechanisms for the various effects of Stxs on host cell functions, we carried out comparative microarray analyses to characterize the global transcriptional response of human macrophage-like THP-1 cells to Shiga toxin type 1 (Stx1) and lipopolysaccharides. The data were analyzed by using a rigorous combinatorial approach with three separate statistical algorithms. A total of 36 genes met the criteria of upregulated expression in response to Stx1 treatment, with 14 genes uniquely upregulated by Stx1. Microarray data were validated by real-time reverse transcriptase PCR for genes encoding early growth response 1 (Egr-1) (transcriptional regulator), cyclooxygenase 2 (COX-2; inflammation), and dual specificity phosphatase 1 (DUSP1), DUSP5, and DUSP10 (regulation of mitogen-activated protein kinase signaling). Stx1-mediated signaling through extracellular signal-regulated kinase 1/2 and Egr-1 appears to be involved in the increased expression and production of the proinflammatory mediator tumor necrosis factor alpha. Activation of COX-2 is associated with the increased production of proinflammatory and vasoactive eicosanoids. However, the capacity of Stx1 to increase the expression of genes encoding phosphatases suggests that mechanisms to dampen the macrophage proinflammatory response may be built into host response to the toxins.


Carbon monoxide inhibits sprouting angiogenesis and vascular endothelial growth factor receptor-2 phosphorylation.
Carbon monoxide (CO) is a gaseous autacoid known to positively regulate vascular tone; however, its role in angiogenesis is unknown. The aim of this study was to investigate the effect of CO on angiogenesis and vascular endothelial growth factor (VEGF) receptor-2 phosphorylation. Human umbilical vein endothelial cells (HUVECs) were cultured on growth factor-reduced Matrigel and treated with a CO-releasing molecule (CORM-2) or exposed to CO gas (250 ppm). Here, we report the surprising finding that exposure to CO inhibits vascular endothelial growth factor (VEGF)-induced endothelial cell actin reorganisation, cell proliferation, migration and capillary-like tube formation. Similarly, CO suppressed VEGF-mediated phosphorylation of VEGFR-2 at tyrosine residue 1175 and 1214 and basic fibroblast growth factor- (FGF-2) and VEGF-mediated Akt phosphorylation. Consistent with these data, mice exposed to 250 ppm CO (1h/day for 14 days) exhibited a marked decrease in FGF-2-induced Matrigel plug angiogenesis (p<0.05). These data establish a new biological function for CO in angiogenesis and point to a potential therapeutic use for CO as an anti-angiogenic agent in tumour suppression.


Marginal bone loss in relation to the implant neck surface: an update.
A review is made of the publications on the marginal bone loss of implants with a polished neck, rough neck with microthreading, and rough neck without microthreading. A PubMed search was carried out with the following key words: machined neck implant, polished neck implant, marginal bone loss, covering the period between January 1998 and March 2009. Inclusion was limited to those human clinical studies involving a minimum follow-up of 12 months, and registering the level of bone loss from the time of placement of the implant or prosthetic restoration to the end of follow-up. For most of the authors there were no significant differences in marginal bone loss between polished neck and rough neck implants. On the other hand, implants with a rough neck and microthreading showed significantly less bone loss than those with a polished neck or with a rough neck without microthreading. The survival rate of the implants with a polished neck ranged from 87% to 97.7%, versus 94.5% to 100% for those with a rough neck, and 100% for the rough neck implants with microthreading. No peri-implant disease was registered in the different studies.


Adjustments and complications of mandibular overdentures retained by four implants. A comparison between superstructures with and without cantilever extensions.
The aims of the study were to evaluate the postinsertion care needed by patients treated with four implants to retain mandibular overdentures and to compare two types of superstructures. The study consisted of 54 patients who had been treated with conventional maxillary dentures and mandibular overdentures retained by four implants and a triple-bar superstructure with cantilever extensions (28 patients) or without cantilever extensions (26 patients). Differences between both groups with regard to age, gender, length, and diameter of the implants and preoperative mandibular bone height were tested by means of Student's t and chi-square tests with a probability level of 0.05. No significant differences were found. Both groups were retrospectively compared on adjustments and complications. The follow-up period after insertion of the dentures was 2 years. During the 2-year follow-up, 17 patients of the cantilever-extension group and 20 patients of the group without cantilever extensions needed adjustments, and 17 patients of the cantilever group and 12 patients of the group without cantilever extensions had to be treated because of complications. Significantly more (P < 0.05, chi-square test) superstructure fractures were present in the cantilever group (14 occasions in 7 patients) than in the group without cantilever extensions (1 occasion). All superstructure fractures in the cantilever group involved the cantilever extensions. This study demonstrated a considerable need for postinsertion care, confirming the necessity of routine follow-up services for patients restored with implant-retained overdentures. Furthermore, the results of this study suggest restriction of the use of cantilever extensions.


Seasonal cryptogenic organising pneumonia with biochemical cholestasis: a new clinical entity.
The term cryptogenic organising pneumonia has been used for the combination of dyspnoea, cough, pleuritic pain, widespread shadows on chest radiographs, and histological evidence of intra-alveolar organisation with buds of granulation tissue within the alveoli. We report 12 patients with seasonal recurrence of this disorder for between 3 and 11 years. In all 12 patients, symptoms recurred between late February and early May every year, tending to increase in severity each year, and resolved between June and January. Chest radiography and computed tomography showed bilateral consolidation. Lung biopsy samples showed intra-alveolar buds of granulation tissue. There were many neutrophils within the lumina of medium-sized airways and terminal bronchioles showed evidence of obstruction by granulation tissue. Functionally, the predominant defect was restrictive and only 2 patients (life-long non-smokers) had airflow limitation. All 12 patients had very high activities of liver enzymes, suggesting intrahepatic cholestasis, but no other evidence of liver disease. Cultures of blood, sputum, lung tissue, and bronchoalveolar lavage fluid, viral screening, and complement fixation tests were consistently negative. In all patients all abnormalities responded rapidly to oral steroid therapy. These findings suggest a seasonal syndrome of organising pneumonia and biochemical abnormalities indicative of intrahepatic cholestasis. No aetiological factor has been identified, but the nature and periodicity of the illness point to an inhaled agent present in the environment for a limited period every year.


Overexpression of Pax6 results in microphthalmia, retinal dysplasia and defective retinal ganglion cell axon guidance.
The transcription factor Pax6 is expressed by many cell types in the developing eye. Eyes do not form in homozygous loss-of-function mouse mutants (Pax6Sey/Sey) and are abnormally small in Pax6Sey/+ mutants. Eyes are also abnormally small in PAX77 mice expressing multiple copies of human PAX6 in addition to endogenous Pax6; protein sequences are identical in the two species. The developmental events that lead to microphthalmia in PAX77 mice are not well-characterised, so it is not clear whether over- and under-expression of Pax6/PAX6 cause microphthalmia through similar mechanisms. Here, we examined the consequences of over-expression for the eye and its axonal connections. Eyes form in PAX77+/+ embryos but subsequently degenerate. At E12.5, we found no abnormalities in ocular morphology, retinal cell cycle parameters and the incidence of retinal cell death. From E14.5 on, we observed malformations of the optic disc. From E16.5 into postnatal life there is progressively more severe retinal dysplasia and microphthalmia. Analyses of patterns of gene expression indicated that PAX77+/+ retinae produce a normal range of cell types, including retinal ganglion cells (RGCs). At E14.5 and E16.5, quantitative RT-PCR with probes for a range of molecules associated with retinal development showed only one significant change: a slight reduction in levels of mRNA encoding the secreted morphogen Shh at E16.5. At E16.5, tract-tracing with carbocyanine dyes in PAX77+/+ embryos revealed errors in intraretinal navigation by RGC axons, a decrease in the number of RGC axons reaching the thalamus and an increase in the proportion of ipsilateral projections among those RGC axons that do reach the thalamus. A survey of embryos with different Pax6/PAX6 gene dosage (Pax6Sey/+, Pax6+/+, PAX77+ and PAX77+/+) showed that (1) the total number of RGC axons projected by the retina and (2) the proportions that are sorted into the ipsilateral and contralateral optic tracts at the optic chiasm vary differently with gene dosage. Increasing dosage increases the proportion projecting ipsilaterally regardless of the size of the total projection. Pax6 overexpression does not obviously impair the initial formation of the eye and its major cell-types but prevents normal development of the retina from about E14.5, leading eventually to severe retinal degeneration in postnatal life. This sequence is different to that underlying microphthalmia in Pax6+/- heterozygotes, which is due primarily to defects in the initial stages of lens formation. Before the onset of severe retinal dysplasia, Pax6 overexpression causes defects of retinal axons, preventing their normal growth and navigation through the optic chiasm.


An integrative biological approach to the analysis of tissue culture data: application to the antitumour agent RHPS4.
We describe a mathematical model of cell growth and death and explain how it can be used to integrate data from classic tissue culture experiments on antitumour agents and thus aid the identification of their mechanism of action. Experimental data relating to time- and dose-dependent changes in growth rate, cell cycle distribution, plus apoptotic and senescent fractions, are reinterpreted in terms of modulations to kinetic parameters that describe the rates at which cells transit between phenotypic compartments. The mathematical model is analytical, in the sense that the kinetic parameters are calculated from the experimental data directly, without any fitting process. Since the kinetic parameters are much more directly related to potential molecular targets than are the experimentally measured quantities, this approach can provide a more informative picture of the mechanism of action of the antitumour agent under investigation. We demonstrate the potential value of our model by applying it to data from RHPS4 (3,11-difluoro-6,8,13-trimethyl-8H-quino [4,3,2-kl] acridinium methosulfate). This agent is a DNA-interactive pentacyclic acridine for which at least three potential mechanisms of antitumour activity have been identified. Firstly RHPS4 is a telomerase inhibitor, secondly it is a telomerase-independent destabiliser of telomeres, and thirdly it is a telomere-independent binder to genomic DNA. Each mechanism can induce a separate, but overlapping, pattern of cellular responses, making the interpretation of tissue culture data very complex. Here we study the time- and dose-dependent effects of RHPS4 on the HCT116 cell line, and develop a five-compartment mathematical model to interpret the data. Application of the model to the data suggests that RHPS4 increases the rate at which cells became senescent state but, rather surprisingly, actually inhibits the rate of cell death. As a control, we also apply the model to data describing the time- and dose-dependent effects of doxorubicin since its mechanism of action is better characterised.


In vivo assay for neuroleptic receptor binding in the striatum. Positron tomography in humans.
Using PET, we investigated the potency in six patients of therapeutic doses of neuroleptic drugs for preventing specific binding of trace doses of intravenously administered 76Br-labelled bromospiperone to corpus striatum in vivo. Measured receptor occupancy showed a clear-cut dose-dependent saturation curve with increasing daily oral dose of neuroleptics, indicating the validity and reliability of the method when used as an in vivo radioreceptor assay. Following drug withdrawal in eight patients, recovery to normal or supranormal receptor availability occurred in a matter of days. The results demonstrate an approach that may help resolve controversies about, and design better strategies for, neuroleptic treatment schedules.


Long-read whole genome sequencing reveals HOXD13 alterations in synpolydactyly.
Synpolydactyly 1, also called syndactyly type II (SDTY2), is a genetic limb malformation characterized by polydactyly with syndactyly involving the webbing of the third and fourth fingers, and the fourth and fifth toes. It is caused by heterozygous alterations in HOXD13 with incomplete penetrance and phenotypic variability. In our study, a five-generation family with an SPD phenotype was enrolled in our Rare Disease Genomics Protocol. A comprehensive examination of three generations using Illumina short-read whole-genome sequencing (WGS) did not identify any causative variants. Subsequent WGS using Pacific Biosciences (PacBio) long-read HiFi Circular Consensus Sequencing (CCS) revealed a heterozygous 27-bp duplication in the polyalanine tract of HOXD13. Sanger sequencing of all available family members confirmed that the variant segregates with affected individuals. Reanalysis of an unrelated family with a similar SPD phenotype uncovered a 21-bp (7-alanine) duplication in the same region of HOXD13. Although ExpansionHunter identified these events in most individuals in a retrospective analysis, low sequence coverage due to high GC content in the HOXD13 polyalanine tract makes detection of these events challenging. Our findings highlight the value of long-read WGS in elucidating the molecular etiology of congenital limb malformation disorders.


Leachates of micronized plastic toys provoke embryotoxic effects upon sea urchin Paracentrotus lividus.
Microplastics are defined as plastic fragments <5 mm, and they are found in the ocean where they can impact on the ecosystem. Once released in seawater, microplastics can be internalized by organisms due to their small size, moreover they can also leach out several additives used in plastic manufacturing, such as plasticizers, flame retardants, etc., resulting toxic for biota. The aim of this study was to test the toxicity of micronized PVC products with three different colors, upon Paracentrotus lividus embryos. In particular, we assessed the effects of micronized plastics and microplastic leachates. Results showed a decrease of larval length in plutei exposed to low concentrations of micronized plastics, and a block of larval development in sea urchin embryos exposed to the highest dose. Virgin PVC polymer did not result toxic on P. lividus embryos, while an evident toxic effect due to leached substances in the medium was observed. In particular, the exposure to leachates induced a development arrest immediately after fertilization or morphological alterations in plutei. Finally, PVC products with different colors showed different toxicity, probably due to a different content and/or combination of heavy metals present in coloring agents.


The role of malocclusion in non-obese patients with obstructive sleep apnea syndrome.
The maxillofacial characteristics of patients with obstructive sleep apnea syndrome (OSAS) have previously been analyzed using standard cephalometric analysis. Malocclusion influences the occurrence of sleep apnea, but the pathology of malocclusion in OSAS has not yet been fully investigated. Therefore, we investigated malocclusion in patients with OSAS using cephalometric and dental analysis. Cephalometric and dental analyses were performed to evaluate malocclusion in 97 male patients with OSAS (49.7+/-11.7 years). The number of apnea and hypopnea episodes per hour (apnea-hypopnea index: AHI) was determined by standard polysomnography. The overall prevalence of severe overjet (the horizontal distance between the upper and lower incisors of >or=6 mm) was 43.3%. AHI was significantly correlated with body mass index (BMI) in obese OSAS patients (r=0.385, p=0.010), whereas it was significantly correlated with overjet in non-obese OSAS patients (BMI<25 kg/m2) (r=0.313, p=0.022). Multiple regression analysis revealed that BMI was the significant factor contributing to increased AHI in all patients, and overjet was in non-obese OSAS patients. There were no significant differences between non-obese and obese OSAS patients in the angle of protrusion of the superior alveolar base (SNA) or in the angle of protrusion between the superior and inferior alveolar bases (ANB). The angle of protrusion of the inferior alveolar base (SNB) was significantly smaller in non-obese than in obese OSAS patients. We have shown that overjet was associated with the severity of OSAS in non-obese patients. Our findings suggest that malocclusion may play an important role in the development of sleep apnea/hypopnea.


Intracellular segregation of asialoglycoproteins and their receptor: a prelysosomal event subsequent to dissociation of the ligand-receptor complex.
Rat hepatocytes in monolayer culture rapidly internalized asialoglycoproteins and the receptors to which they are bound. Subsequent to endocytosis, the receptor-ligand complex is dissociated within an acidic endosome (Harford, J., K. Bridges, G. Ashwell, and R. D. Klausner, 1983, J. Biol. Chem. 258:3191-3197; Harford, J., A. W. Wolkoff, G. Ashwell, and R. D. Klausner, 1983, J. Cell Biol. 96:1824-1828). Here we show that addition of the proton ionophore monensin to the cells after dissociation has occurred results in intracellular rebinding of ligand molecules. With increasing time inside the cell, the ability of ligand to reassociate with receptor progressively decreases consistent with a segregation of receptor and ligand. The combination of colchicine and cytochalasin B appears to retard the process of segregation. In contrast, removal of sodium from the medium, while inhibiting degradation of ligand, does not affect the decrease in monensin-mediated rebinding. Nonetheless, both sodium deprivation and treatment with colchicine plus cytochalasin B result in the ligand remaining in a low density, nonlysosomal subcellular fraction. Thus, segregation, like dissociation, appears to occur in a pre-lysosomal endocytic compartment. Perturbation of the endocytic pathway by reduced temperature (18 degrees C) was also explored. Our data are consistent with two temperature-sensitive steps: receptor-ligand dissociation is inhibited and there is an independent temperature-sensitive step involved in delivery of ligand to lysosomes. This second effect was localized as being beyond the point in the pathway sensitive to sodium deprivation.


Characterization of chlorinated solvent contamination in limestone using innovative FLUTe® technologies in combination with other methods in a line of evidence approach.
Characterization of dense non-aqueous phase liquid (DNAPL) source zones in limestone aquifers/bedrock is essential to develop accurate site-specific conceptual models and perform risk assessment. Here innovative field methods were combined to improve determination of source zone architecture, hydrogeology and contaminant distribution. The FACT™ is a new technology and it was applied and tested at a contaminated site with a limestone aquifer, together with a number of existing methods including wire-line coring with core subsampling, FLUTe® transmissivity profiling and multilevel water sampling. Laboratory sorption studies were combined with a model of contaminant uptake on the FACT™ for data interpretation. Limestone aquifers were found particularly difficult to sample with existing methods because of core loss, particularly from soft zones in contact with chert beds. Water FLUTe™ multilevel groundwater sampling (under two flow conditions) and FACT™ sampling and analysis combined with FLUTe® transmissivity profiling and modeling were used to provide a line of evidence for the presence of DNAPL, dissolved and sorbed phase contamination in the limestone fractures and matrix. The combined methods were able to provide detailed vertical profiles of DNAPL and contaminant distributions, water flows and fracture zones in the aquifer and are therefore a powerful tool for site investigation. For the limestone aquifer the results indicate horizontal spreading in the upper crushed zone, vertical migration through fractures in the bryozoan limestone down to about 16-18m depth with some horizontal migrations along horizontal fractures within the limestone. Documentation of the DNAPL source in the limestone aquifer was significantly improved by the use of FACT™ and Water FLUTe™ data.


Development of genetic tools for in vivo virulence analysis of Streptococcus sanguinis.
Completion of the genome sequence of Streptococcus sanguinis SK36 necessitates tools for further characterization of this species. It is often desirable to insert antibiotic resistance markers and other exogenous genes into the chromosome; therefore, we sought to identify a chromosomal site for ectopic expression of foreign genes, and to verify that insertion into this site did not affect important cellular phenotypes. We designed three plasmid constructs for insertion of erm, aad9 or tetM resistance determinants into a genomic region encoding only a small (65 aa) hypothetical protein. To determine whether this insertion affected important cellular properties, SK36 and its erythromycin-resistant derivative, JFP36, were compared for: (i) growth in vitro, (ii) genetic competence, (iii) biofilm formation and (iv) virulence for endocarditis in the rabbit model of infective endocarditis (IE). The spectinomycin-resistant strain, JFP56, and tetracycline-resistant strain, JFP76, were also tested for virulence in vivo. Insertion of erm did not affect growth, competence or biofilm development of JFP36. Recovery of bacteria from heart valves of co-inoculated rabbits was similar to wild-type for JFP36, JFP56 and JFP76, indicating that IE virulence was not significantly affected. The capacity for mutant complementation in vivo was explored in an avirulent ssaB mutant background. Expression of ssaB from its predicted promoter in the target region restored IE virulence. Thus, the chromosomal site utilized is a good candidate for further manipulations of S. sanguinis. In addition, the resistant strains developed may be further applied as controls to facilitate screening for virulence factors in vivo.


Systemic Isotretinoin Treatment and Pregnancy: A Longitudinal Cohort Study from Turkey.
Isotretinoin is known to be the most effective treatment of severe and persistent acne. However, one of the most important adverse effects of this drug is known to be teratogenicity. In this regard, tests are administered before initiating the treatment, to assure that an unknown pregnancy is not present and accordingly, patients are advised to take contraceptive precautions during their systemic isotretinoin treatments. On the contrary, many cases of unwanted pregnancies and relevant abortuses have been reported all over the world. In the Turkish literature, only a few reports have been identified about foetal exposure to isotretinoin. In this respect, a study was carried out on fifty-seven female patients, aiming to fulfil the gap of information mentioned above. Female patients, with ages ranging between 14 and 35 years, were recruited to the study and they were administered isotretinoin treatments (cumulative dose of 120 mg/kg) for an average period of 6 months. The patients were followed up during and after the treatment for a total period of 18 months. As a result, it has been observed that none of the patients got pregnant during the treatment period and relevantly, no abortuses or foetal abnormalities were recorded. Moreover, none of the patients got pregnant 12 months after the termination of the treatment. Additionally, the socio-demographic analysis of the patients indicates that most of the patients were single and 81% of the patients were sexually inactive. Our findings suggest that the low reportage of teratogenicity due to isotretinoin usage in Turkey could be due to several reasons, such as the sociocultural profile of the female patients undertaking the isotretinoin treatment, and strict adherence to contraceptive methods, and/or underreporting of teratogenic incidents due to lack of studies held in cooperation with obstetricians.


Optical detection of rapidly moving objects in space.
We compare the sensitivity of photon-counting and charged-coupled-device (CCD) imagers for rapidly moving objects. Our test case involves the detection of small objects in space, seen against a diffuse zodiacal light background, as observed from a space platform. We contrast photon-counting detectors, with excellent time resolution and negligible readout noise, against CCDs with a significantly larger quantum efficiency. For fast moving objects and small fields of view, the photon-counting detectors are able to detect significantly smaller targets, with the added benefit of providing angle-angle-time metric information in addition to high-time-resolution light curves. For larger fields of view and slower moving objects, the CCDs are more sensitive. These results may motivate the further development of microchannel-plate photon-counting systems and amplified CCDs for detecting and tracking space objects.


Evaluation of trends in the cost of initial cancer treatment.
Despite reports of increases in the cost of cancer treatment, little is known about how costs of cancer treatment have changed over time and what services have contributed to the increases. We used data from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database for 306,709 persons aged 65 and older and diagnosed with breast, lung, colorectal, or prostate cancer between 1991 and 2002 to assess the number of patients assigned to initial cancer care, from 2 months before diagnosis to 12 months after diagnosis, and mean annual Medicare payments for this care according to cancer type and type of treatment. Mutually exclusive treatment categories were cancer-related surgery, chemotherapy, radiation therapy, and other hospitalizations during the period of initial cancer care. Linear regression models were used to assess temporal trends in the percentage of patients receiving treatment and costs for those treated. We extrapolated our results based on the SEER data to the US Medicare population to estimate national Medicare payments by cancer site and treatment category. All statistical tests were two-sided. For patients diagnosed in 2002, Medicare paid an average of $39,891 for initial care for each lung cancer patient, $41 134 for each colorectal cancer patient, and $20,964 for each breast cancer patient, corresponding to inflation-adjusted increases from 1991 of $7139, $5345, and $4189, respectively. During the same interval, the mean Medicare payment for initial care for prostate cancer declined by $196 to $18261 in 2002. Costs for any hospitalization accounted for the largest portion of payments for all cancers. Chemotherapy use increased markedly for all cancers between 1991 and 2002, as did radiation therapy use (except for colorectal cancers). Total 2002 Medicare payments for initial care for these four cancers exceeded $6.7 billion, with colorectal and lung cancers being the most costly overall. The statistically significant increase in costs of initial cancer treatment reflects more patients receiving surgery and adjuvant therapy and rising prices for these treatments. These trends are likely to continue in the near future, although more efficient targeting of costly therapies could mitigate the overall economic impact of this trend.


Phase I trial of taxol given as a 24-hour infusion every 21 days: responses observed in metastatic melanoma.
Taxol, a plant product, has significant activity against certain rodent and human xenograft tumors. It promotes microtubule assembly in vitro, in contrast to vinca alkaloids, which inhibit assembly. In this phase I study, taxol was administered as a 24-hour continuous intravenous (IV) infusion in 65 courses to 26 patients. A premedication regimen of dexamethasone, cimetidine, and diphenhydramine was used to prevent the acute hypersensitivity reactions observed in previous studies of taxol. Only one episode of mild stridor occurred in this study. Peripheral neuropathy was the dose-limiting toxicity and was observed in 40% of patients treated at a dose of 250 mg/m2. Significant neutropenia of brief duration was also common. Pharmacokinetic studies by a high-performance liquid chromatography (HPLC) method demonstrated that drug plasma concentrations increased during the 24-hour infusion and then declined rapidly. Peak plasma concentrations correlated with dose, and less than 5% of taxol was excreted in the urine. Most of the drug was bound to serum components. Partial responses of more than 3 months' duration were observed in four of 12 melanoma patients treated. The recommended phase II dose of taxol on this schedule is 250 mg/m2. Priority should be given to the study of taxol in melanoma.


Breast, colorectal, and prostate cancer risk in the European Prospective Investigation into Cancer and Nutrition-Norfolk in relation to phytoestrogen intake derived from an improved database.
The characterization of phytoestrogen intake and cancer risk has been hindered by the absence of accurate dietary phytoestrogen values. We examined the risk of breast, colorectal, and prostate cancers relative to phytoestrogen intake on the basis of a comprehensive database. Demographic and anthropometric characteristics, a medical history, and 7-d records of diet were collected prospectively from participants (aged 40-79 y) in the European Prospective Investigation into Cancer and Nutrition-Norfolk (EPIC-Norfolk). Five hundred nine food items were analyzed by liquid chromatography-mass spectrometry/mass spectrometry, and (13)C(3)-labeled internal standards were analyzed for isoflavones (genistein, daidzein, glycitein, biochanin A, and formononetin), lignans (secoisolariciresinol and matairesinol), and enterolignans from gut microbial metabolism in animal food sources (equol and enterolactone). From the direct analysis, values for 10,708 foods were calculated. Odds ratios (ORs) for breast (244 cases, 941 controls), colorectal (221 cases, 886 controls), and prostate (204 cases, 812 controls) cancers were calculated relative to phytoestrogen intake. Phytoestrogen intake was not associated with breast cancer among women or colorectal cancer among men. Among women, colorectal cancer risk was inversely associated with enterolactone (OR: 0.33; 95% CI: 0.14, 0.74) and total enterolignans (OR: 0.32; 95% CI: 0.13, 0.79), with a positive trend detected for secoisolariciresinol (OR: 1.60; 95% CI: 0.96, 2.69). A positive trend between enterolignan intake and prostate cancer risk (OR: 1.27; 95% CI: 0.97, 1.66) was attenuated after adjustment for dairy intake (OR: 1.19; 95% CI: 0.77, 1.82). Dietary phytoestrogens may contribute to the risk of colorectal cancer among women and prostate cancer among men.


Cardiovascular genomics.
This article provides an update on cardiovascular genomics using three clinically relevant exemplars, including myocardial infarction (MI) and coronary artery disease (CAD), stroke, and sudden cardiac death (SCD). ORGANIZATIONAL CONSTRUCT: Recent advances in cardiovascular genomic research, testing, and clinical implications are presented. Genomic nurse experts reviewed and summarized recent salient literature to provide updates on three selected cardiovascular genomic conditions. Research is ongoing to discover comprehensive genetic markers contributing to many common forms of cardiovascular disease (CVD), including MI and stroke. However, genomic technologies are increasingly being used clinically, particularly in patients with long QT syndrome (LQTS) or hypertrophic cardiomyopathy (HCM) who are at risk for SCD. Currently, there are no clinically recommended genetic tests for many common forms of CVD even though direct-to-consumer genetic tests are being marketed to healthcare providers and the general public. On the other hand, genetic testing for patients with certain single gene conditions, including channelopathies (e.g., LQTS) and cardiomyopathies (e.g., HCM), is recommended clinically. Nurses play a pivotal role in cardiogenetics and are actively engaged in direct clinical care of patients and families with a wide variety of heritable conditions. It is important for nurses to understand current development of cardiovascular genomics and be prepared to translate the new genomic knowledge into practice.