Are antimicrobial peripherally inserted central catheters associated with reduction in central line-associated bloodstream infection? A systematic review and meta-analysis.
Antimicrobial peripherally inserted central catheters (PICCs) may reduce the risk of central line-associated bloodstream infection (CLABSI). However, data regarding efficacy are limited. We aimed to evaluate whether antimicrobial PICCs are associated with CLABSI reduction. MEDLINE, EMBASE, CINHAL, and Web of Science were searched from inception to July 2016; conference proceedings were searched to identify additional studies. Study selection and data extraction were performed independently by 2 authors. Of 597 citations identified, 8 studies involving 12,879 patients met eligibility criteria. Studies included adult and pediatric patients from intensive care, long-term care, and general ward settings. The incidence of CLABSI in patients with antimicrobial PICCs was 0.2% (95% confidence interval [CI], 0.0%-0.5%), and the incidence among nonantimicrobial catheters was 5.3% (95% CI, 2.6%-8.8%). Compared with noncoated PICCs, antimicrobial PICCs were associated with a significant reduction in CLABSI (relative risk [RR], 0.29; 95% CI, 0.10-0.78). Statistical heterogeneity (I2, 71.6%; T2 = 1.07) was resolved by publication type, with peer-reviewed articles showing greater reduction in CLABSI (RR, 0.21; 95% CI, 0.06-0.74). Twenty-six patients (95% CI, 21-75) need to be treated with antimicrobial PICCs to prevent 1 CLABSI. Studies of adults at greater baseline risk of CLABSI experienced greater reduction in CLABSI (RR, 0.20; P = .003). Available evidence suggests that antimicrobial PICCs may reduce CLABSI, especially in high-risk subgroups. Randomized trials are needed to assess efficacy across patient populations.


Claudin 11 deficiency in mice results in loss of the Sertoli cell epithelial phenotype in the testis.
Tissue integrity relies on barriers formed between epithelial cells. In the testis, the barrier is formed at the initiation of puberty by a tight junction complex between adjacent Sertoli cells, thereby defining an adluminal compartment where meiosis and spermiogenesis occur. Claudin 11 is an obligatory protein for tight junction formation and barrier integrity in the testis. It is expressed by Sertoli cells, and spermatogenesis does not proceed beyond meiosis in its absence, resulting in male sterility. Sertoli cell maturation--arrest of proliferation and expression of proteins to support germ cell development--parallels tight junction assembly; however, the pathophysiology underlying the loss of tight junctions in the mature testis remains largely undefined. Here, using immunohistochemistry and microarrays we demonstrate that adult Cldn11(-/-) mouse Sertoli cells can proliferate while maintaining expression of mature markers. Sertoli cells detach from the basement membrane, acquire a fibroblast cell shape, are eliminated through the lumen together with apoptotic germ cells, and are found in epididymis. These changes are associated with tight junction regulation as well as actin-related and cell cycle gene expression. Thus, Cldn11(-/-) Sertoli cells exhibit a unique phenotype whereby loss of tight junction integrity results in loss of the epithelial phenotype.


Population Structures of 'Candidatus Liberibacter asiaticus' in Southern China.
Huanglongbing (HLB) is a highly detrimental citrus disease associated with 'Candidatus Liberibacter asiaticus', a nonculturable alpha-proteobacterium. Characterization of the bacterial populations is important for development of disease management strategies. In this study, the 'Ca. L. asiaticus' populations in eight provinces in southern China where HLB is endemic were analyzed based on tandem repeat number (TRN) variations in a previously characterized genomic locus CLIBASIA_01645. Of the 224 HLB samples collected, 175 (78.3%) samples yielded single polymerase chain reaction (PCR) amplicons (the single amplicon group, SAG) and 49 (21.7%) samples produced multiple PCR amplicons (the multiple amplicon group, MAG). Variations in SAG are summarized by Nei's diversity index (H) and ratio of TRN ≤ 10/TRN > 10 genotypes (R10). Variations in the MAG are described by the percentage of occurrence (PMAG). At an orchard-level comparison, the 'Ca. L. asiaticus' population from a Guangdong orchard (n = 24) showed H = 0.50, R10 = 23, and PMAG = 0, significantly different from that of the non-Guangdong orchards in Yunnan (n = 23), H = 0.83, R10 = 2.3, and PMAG = 11.5, and in Hainan (n = 35), H = 0.88, R10 = 1.5, and PMAG = 16.7. In a region-level consideration, the Guangdong 'Ca. L. asiaticus' population (n = 78) was H = 0.77, R10 = 25, and PMAG = 1.3, whereas the non-Guangdong population (n = 84) was H = 0.91, R10 = 1.6, and PMAG = 26.9. Overall, significant differences were observed between the 'Ca. L. asiaticus' population from Guangdong Province and those from the other provinces. A strong aggregation of TRN = 6, 7, and 8 genotypes is characteristic to the 'Ca. L. asiaticus' population in Guangdong. Referenced to genome annotation, we propose that rearrangement of tandem repeats at locus CLIBASIA_01645 could be associated with bacterial environmental adaptation.


L-plastin Ser5 phosphorylation in breast cancer cells and in vitro is mediated by RSK downstream of the ERK/MAPK pathway.
Deregulated cell migration and invasion are hallmarks of metastatic cancer cells. Phosphorylation on residue Ser5 of the actin-bundling protein L-plastin activates L-plastin and has been reported to be crucial for invasion and metastasis. Here, we investigate signal transduction leading to L-plastin Ser5 phosphorylation using 4 human breast cancer cell lines. Whole-genome microarray analysis comparing cell lines with different invasive capacities and corresponding variations in L-plastin Ser5 phosphorylation level revealed that genes of the ERK/MAPK pathway are differentially expressed. It is noteworthy that in vitro kinase assays showed that ERK/MAPK pathway downstream ribosomal protein S6 kinases α-1 (RSK1) and α-3 (RSK2) are able to directly phosphorylate L-plastin on Ser5. Small interfering RNA- or short hairpin RNA-mediated knockdown and activation/inhibition studies followed by immunoblot analysis and computational modeling confirmed that ribosomal S6 kinase (RSK) is an essential activator of L-plastin. Migration and invasion assays showed that RSK knockdown led to a decrease of up to 30% of migration and invasion of MDA-MB-435S cells. Although the presence of L-plastin was not necessary for migration/invasion of these cells, immunofluorescence assays illustrated RSK-dependent recruitment of Ser5-phosphorylated L-plastin to migratory structures. Altogether, we provide evidence that the ERK/MAPK pathway is involved in L-plastin Ser5 phosphorylation in breast cancer cells with RSK1 and RSK2 kinases able to directly phosphorylate L-plastin residue Ser5.


Collection and characterization of semen from green iguanas (Iguana iguana).
To determine an efficient method for the collection of semen samples by means of electroejaculation, characterize spermatozoa quality and quantity, and determine the effect of refrigerated storage on motility of spermatozoa obtained from green iguanas (Iguana iguana). 18 adult green iguanas. Green iguanas were anesthetized, and semen samples were obtained by means of electroejaculation. Up to 3 series of electrostimulations were performed; the procedure was stopped after a semen sample was obtained. Various semen sample variables were evaluated. Semen samples were obtained from 16 iguanas; most (n = 10) iguanas produced a semen sample after the second series of electrostimulations. Median semen sample volume was 0.05 mL. Mean spermatozoa concentration was 2 69.0 × 10(6) spermatozoa/mL. Median percentage of motile spermatozoa was 78%. The only morphological abnormality of spermatozoa was bent tails (mean percentage in a semen sample, 5.7%). Spermatozoa motility decreased significantly during refrigeration (4°C); median percentage motility after 24, 48, and 72 hours of refrigeration was 60%, 33%, and 0%, respectively. Results of this study suggested electroejaculation can be performed to collect semen samples from green iguanas, characteristics of iguana semen samples are similar to those for semen samples obtained from other reptiles, and motility of iguana spermatozoa decreases during refrigeration within 48 to 72 hours.


Thiazolidinedione exposure increases the expression of uncoupling protein 1 in cultured human preadipocytes.
Thiazolidinediones (TZDs) are a novel class of insulin-sensitizing agents used in the treatment of NIDDM and are potent agonists for the nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARgamma). The thiazolidinedione BRL 49653 has been shown to promote the differentiation of the HIB-1B brown preadipocyte cell line and to increase rat interscapular brown adipose tissue (BAT) mass. Given the importance of brown fat in the control of energy metabolism in rodents, this may represent an important therapeutic effect of this class of compound. To date, however, no studies examining the effects of TZDs on human brown fat have been reported. In the present study, we have measured uncoupling protein 1 (UCP-1) mRNA, a specific marker for BAT, in isolated adipocytes and subcultured preadipocytes prepared from different adult human adipose tissue depots. Consistent with previous studies of adult human whole adipose tissue, UCP-1 mRNA was detectable in isolated human adipocytes prepared from all depots studied with a rank order of perirenal, omental, and subcutaneous. BRL 49653 treatment of subcultured human pre-adipocytes prepared from all depots resulted in increased levels of UCP-1 mRNA, compared with those of the vehicle-treated cells. When exposed to BRL 49653 for 5 days, preadipocytes from the human perirenal depot accumulated lipid, and a proportion of cells showed clear mitochondrial staining for UCP-1 protein by confocal microscopy. Thus, cells of the brown fat lineage were detectable in all human adipose depots studied, and cultured human pre-adipocytes, particularly from the perirenal depot, showed a marked increase in UCP-1 expression in response to thiazolidinediones. Given the role of brown adipocytes in the enhancement of energy expenditure, promotion of brown fat adipogenesis by thiazolidinediones could contribute to the beneficial effects of these drugs on insulin resistance in humans.


Cancer in the offspring of radiation workers: an investigation of employment timing and a reanalysis using updated dose information.
An earlier case-control study found no evidence of paternal preconceptional irradiation (PPI) as a cause of childhood leukaemia and non-Hodgkin's lymphoma (LNHL). Although fathers of children with LNHL were more likely to have been radiation workers, the risk was most marked in those with doses below the level of detection. The timing of paternal employment as a radiation worker has now been examined. The previously reported elevated risk of LNHL in the children of male radiation workers was limited to those whose fathers were still radiation workers at conception or whose employment also continued until diagnosis. Children whose fathers stopped radiation work prior to their conception were found to have no excess risk of LNHL. It was not possible to distinguish between the risks associated with paternal radiation work at conception and at the time of diagnosis. A reanalysis of the original study hypothesis incorporating updated dosimetric information gave similar results to those obtained previously. In particular, the risks of LNHL did not show an association with radiation doses received by the father before conception. It seems likely that the increased risk of LNHL among the children of male radiation workers is associated with an increased exposure to some infective agent consequent on high levels of population mixing.


A Hospital Level Analysis of 30-Day Readmission Performance for Heart Failure Patients and Long-Term Survival: Findings from Get With The Guidelines-Heart Failure.
Medicare utilizes 30-day risk-standardized readmission rates (RSRR) as a measure of hospital quality and applies penalties based on this measure. The objective of this study was to identify the relationship between hospital performance on 30-day RSRR in heart failure (HF) patients and long-term patient survival. Data were collected from Get With The Guidelines (GWTG)-HF and linked with Medicare data. Based on hospital performance for 30-day RSRR, hospitals were grouped into performance quartiles: top 25% (N=11,181), 25-50% (N=10,367), 50-75% (N=8729), and bottom 25% (N=7180). The primary outcome was mortality at 3 years applying Cox proportional hazards regression adjusted for patient and hospital characteristics. The overall 30-day readmission rate was 19.8% and the 3-year mortality rates were 61.8%, 61.0%, 62.6%, and 59.9% for top 25%, 25-50%, 50-75%, and bottom 25% hospitals for 30-day RSRR performance, respectively. Compared to bottom 25% performing hospitals, adjusted hazard ratios (HR) for 3-year mortality were HR 0.96 (95% confidence interval [CI] 0.90-1.01), HR 0.89 (95% CI 0.84-0.94), HR 1.01 (95% CI 0.95-1.06) for the top 25%, 25-50% and 50-75% hospitals respectively. Median survival time was highest for the bottom 25% hospitals on the 30-day RSRR metric. Hospital performance on 30-day readmissions in HF has no or little association with risk adjusted 3-year mortality or median survival. There is a compelling need to utilize more meaningful and patient-centered outcome measures for reporting and incentivizing quality care for HF.


Native and modified LDL activate extracellular signal-regulated kinases in mesangial cells.
Glycation and/or oxidation of LDL may promote diabetic nephropathy. The mitogen-activated protein kinase (MAPK) cascade, which includes extracellular signal-regulated protein kinases (ERKs), modulates cell function. Therefore, we examined the effects of LDL on ERK phosphorylation in cultured rat mesangial cells. In cells exposed to 100 microg/ml native LDL or LDL modified by glycation, and/or mild or marked (copper-mediated) oxidation, ERK activation peaked at 5 min. Five minutes of exposure to 10-100 microg/ml native or modified LDL produced a concentration-dependent (up to sevenfold) increase in ERK activity. Also, 10 microg/ml native LDL and mildly modified LDL (glycated and/or mildly oxidized) produced significantly greater ERK activation than that induced by copper-oxidized LDL +/- glycation (P < 0.05). Pretreatment of cells with Src kinase and MAPK kinase inhibitors blocked ERK activation by 50-80% (P < 0.05). Native and mildly modified LDL, which are recognized by the native LDL receptor, induced a transient spike of intracellular calcium. Copper-oxidized (+/- glycation) LDL, recognized by the scavenger receptor, induced a sustained rise in intracellular calcium. The intracellular calcium chelator (EGTA/AM) further increased ERK activation by native and mildly modified LDL (P < 0.05). These findings demonstrate that native and modified LDL activate ERKs 1 and 2, an early mitogenic signal, in mesangial cells and provide evidence for a potential link between modified LDL and the development of glomerular injury in diabetes.


Concordant divergence of mitogenomes and a mitonuclear gene cluster in bird lineages inhabiting different climates.
Metabolic processes in eukaryotic cells depend on interactions between mitochondrial and nuclear gene products (mitonuclear interactions). These interactions could have a direct role in population divergence. Here, we study mitonuclear co-evolution in a widespread bird that experienced population divergence followed by bidirectional mitochondrial introgression into different nuclear backgrounds. Using >60,000 single nucleotide polymorphisms, we quantify patterns of nuclear genetic differentiation between populations that occupy areas with different climates and harbour deeply divergent mitochondrial lineages despite ongoing nuclear gene flow. We find that strong genetic differentiation and sequence divergence in a region of ~15.4 megabases on chromosome 1A mirror the geographic pattern of mitochondrial DNA divergence. This result is seen in two different transects representing populations with different nuclear backgrounds. The chromosome 1A region is enriched for genes performing mitochondrial functions (N-mt genes). Molecular signatures of selective sweeps in this region alongside those in the mitochondrial genome suggest a history of adaptive mitonuclear co-introgression. Moreover, evidence for large linkage disequilibrium blocks in this genomic region suggests that low recombination could facilitate functional interactions between co-evolved nuclear alleles. Our results are consistent with mitonuclear co-evolution as an important mechanism for population divergence and local adaptation.


Resilience Training: A Pilot Study of a Mindfulness-Based Program with Depressed Healthcare Professionals.
Mindfulness-based programs have been primarily used to target anxiety or the prevention of relapse in recurrent depression; however, limited research has been conducted on the use of mindfulness programs for relief of current depressive symptoms. To investigate the potential effect of resilience training (RT) on symptom relief for current or recurrent depression, and other psychological/behavioral outcomes. Wait-list comparison pilot study. Penny George Institute for Health and Healing, Allina Health, Minneapolis, MN. A total of 40 actively working healthcare professionals age 18-65 years. RT is an eight-week mindfulness-based program that synergizes elements of mindfulness meditation with nutrition and exercise. The first 20 consecutive individuals meeting all eligibility criteria were assigned to the RT group. The next 20 consecutive eligible individuals were placed into the wait-list control group and had an eight-week waiting period before starting the RT program. Psychological/behavioral outcomes were measured before and after completion of the RT program and two months after completion. Wait-list participants also had measures taken just before starting on the wait-list. The RT group exhibited a 63-70% (P ≤ .01) reduction in depression, a 48% (P ≤ .01) reduction in stress, a 23% (P ≤ .01) reduction in trait anxiety, and a 52% (P ≤ .01) reduction in presenteeism (a per-employee savings of $1846 over the eight-week program). All outcomes were statistically significantly different from the wait-list group. Most improvements persisted up to two months after completion of the RT program. Further replication with a larger sample size, and enhanced control group is warranted.


Hemocompatibility evaluation of poly(diol citrate) in vitro for vascular tissue engineering.
One of the ongoing challenges in tissue engineering is the synthesis of a hemocompatible vascular graft. Specifically, the material used in the construct should have antithrombogenic properties and support the growth of vascular cells. Our laboratory has designed a novel biodegradable, elastomeric copolymer, poly(1,8-octanediol citrate) (POC), with mechanical and degradation properties suitable for vascular tissue engineering. The hemocompatibility of POC in vitro and its ability to support the attachment and differentiation of human aortic endothelial cell (HAEC) was assessed. The thrombogenicity and inflammatory potential of POC were assessed relative to poly(l-lactide-co-glycolide) and expanded poly(tetrafluoroethylene), as they have been used in FDA-approved devices for blood contact. Specifically, platelet aggregation and activation, protein adsorption, plasma clotting, and hemolysis were investigated. To assess the inflammatory potential of POC, the release of IL-1beta and TNF-alpha from THP-1 cells was measured. The cell compatibility of POC was assessed by confirming HAEC differentiation and attachment under flow conditions. POC exhibited decreased platelet adhesion and clotting relative to control materials. Hemolysis was negligible and protein adsorption was comparable to reference materials. IL-1beta and TNF-alpha release from THP-1 cells was comparable among all materials tested, suggesting minimal inflammatory potential. POC supported HAEC differentiation and attachment without any premodification of the surface. The results described herein are encouraging and suggest that POC is hemocompatible and an adequate candidate biomaterial for in vivo vascular tissue engineering.


An archaeal orthologue of the universal protein Kae1 is an iron metalloprotein which exhibits atypical DNA-binding properties and apurinic-endonuclease activity in vitro.
The Kae1 (Kinase-associated endopeptidase 1) protein is a member of the recently identified transcription complex EKC and telomeres maintenance complex KEOPS in yeast. Kae1 homologues are encoded by all sequenced genomes in the three domains of life. Although annotated as putative endopeptidases, the actual functions of these universal proteins are unknown. Here we show that the purified Kae1 protein (Pa-Kae1) from Pyrococcus abyssi is an iron-protein with a novel type of ATP-binding site. Surprisingly, this protein did not exhibit endopeptidase activity in vitro but binds cooperatively to single and double-stranded DNA and induces unusual DNA conformational change. Furthermore, Pa-Kae1 exhibits a class I apurinic (AP)-endonuclease activity (AP-lyase). Both DNA binding and AP-endonuclease activity are inhibited by ATP. Kae1 is thus a novel and atypical universal DNA interacting protein whose importance could rival those of RecA (RadA/Rad51) in the maintenance of genome integrity in all living cells.


Silent cerebral infarct definitions and full-scale IQ loss in children with sickle cell anemia.
To evaluate whether application of the adult definition of silent cerebral infarct (SCI) (T2-weighted hyperintensity ≥5 mm with corresponding T1-weighted hypointensity on MRI) is associated with full-scale IQ (FSIQ) loss in children with sickle cell anemia (SCA), and if so, whether this loss is greater than that of the reference pediatric definition of SCI (T2-weighted hyperintensity ≥3 mm in children on MRI; change in FSIQ -5.2 points; p = 0.017; 95% confidence interval [CI] -9.48 to -0.93). Among children with SCA screened for SCI in the Silent Cerebral Infarct Transfusion trial, ages 5-14 years, a total of 150 participants (107 with SCIs and 43 without SCIs) were administered the Wechsler Abbreviated Scale of Intelligence. A multivariable linear regression was used to model FSIQ in this population, with varying definitions of SCI independently substituted for the SCI covariate. The adult definition of SCI applied to 27% of the pediatric participants with SCIs and was not associated with a statistically significant change in FSIQ (unstandardized coefficient -3.9 points; p = 0.114; 95% CI -8.75 to 0.95), with predicted mean FSIQ of 92.1 and 96.0, respectively, for those with and without the adult definition of SCI. The adult definition of SCI may be too restrictive and was not associated with significant FSIQ decline in children with SCA. Based on these findings, we find no utility in applying the adult definition of SCI to children with SCA and recommend maintaining the current pediatric definition of SCI in this population.


In situ spacecraft observations of a structured electron diffusion region during magnetopause reconnection.
The electron diffusion region (EDR) is the region where magnetic reconnection is initiated and electrons are energized. Because of experimental difficulties, the structure of the EDR is still poorly understood. A key question is whether the EDR has a homogeneous or patchy structure. Here we report Magnetospheric Multiscale (MMS) spacecraft observations providing evidence of inhomogeneous current densities and energy conversion over a few electron inertial lengths within an EDR at the terrestrial magnetopause, suggesting that the EDR can be rather structured. These inhomogenenities are revealed through multipoint measurements because the spacecraft separation is comparable to a few electron inertial lengths, allowing the entire MMS tetrahedron to be within the EDR most of the time. These observations are consistent with recent high-resolution and low-noise kinetic simulations.


SU-E-I-99: An Ultra-High Resolution Small Field-Of-View Solid State X-Ray Imaging Detector Based on an Electron Multiplying CCD.
To demonstrate the ultra-high resolution capability of a small field-of-view (FOV) solid state x-ray imaging detector based on an EMCCD sensor. A micro-solid state x-ray image intensifier (micro-SSXII) was developed to serve as an ultra-high resolution region-of-interest (ROI) imaging detector. It is based on an 8 micron, 1004 by 1002 pixel electron multiplying CCD (EMCCD) optically coupled to a 100 micron thick CsI(Tl) phosphor through a fiber optic window resulting in a FOV of 8 mm. The modulation transfer function (MTF) of the micro-SSXII was measured by the slanted edge method. A cast of a rat kidney (made by mixing resin and iodine for contrast) and a mammography line pair test object were imaged at 50 kVp to demonstrate the detector's ultra-high resolution capability visually. The MTF was determined and was 5% at 20 cycles/mm. This is consistent with the clear visualization of the maximum 20 lp/mm group in the image of the mammography test object. Also, iodine bubbles with diameters as small as 25 microns, which are formed by the non-uniform mixing of the iodine in the resin cast, can be clearly identified in the rat kidney vessels. The ultra-high resolution capability (>20 lp/mm) but small FOV (8 mm) of the micro-SSXII in combination with a low-energy x-ray source may have application for investigations of vascular specimen details and other fine structures where optical or other surface imagers would be unsuited for evaluating features below the surface. Contact radiography with this imager combined with a large higher-load focal spot x-ray tube may be a promising substitute for magnification radiography which is limited by the use of specialized low output microfocus x-ray tubes and geometric un-sharpness for large magnifications. Supported in part by: NIH Grants R01-EB008425, R01-EB002873 and an equipment grant from Toshiba Medical Systems Corp.


Episode-of-Care Characteristics and Costs for Hip and Knee Replacement Surgery in Hospitals Belonging to the High Value Healthcare Collaborative Compared With Similar Hospitals in the Same Health Care Markets.
To inform consumers and restrain health care cost growth, efforts to promote transparency and to reimburse for care episodes are accelerating in the United States. To compare characteristics and costs of 30-day episode of care for hip and knee replacement occurring in High Value Healthcare Collaborative (HVHC)-member hospitals to those occurring in like non-HVHC-member hospitals in the same 15 health care markets before interventions by HVHC members to improve health care value for those interventions. This is a retrospective analysis of fee-for-service Medicare data from 2012 and 2013. For hip arthroplasty, 4030 HVHC-member and 7572 non-HVHC-member, and for knee arthroplasty, 6542 HVHC-member and 13,900 non-HVHC-member fee-for-service Medicare patients aged 65 and older. Volumes, patient demographics, hospital stay characteristics, and acute and postacute care standardized costs for a 30-day episode of care. HVHC-member hospitals differed from similar non-HVHC-member hospitals in the same health care markets when considering volumes of surgeries, patient demographics, Charlson scores, and patient distance to care during the index admission. There was little variation in acute care costs of hip or knee replacement surgery across health care markets; however, there was substantial variation in postacute care costs across those same markets. We saw less variation in postacute care costs within markets than across markets. Regression analyses showed that HVHC-member status was not associated with shorter lengths of stay, different complication rates, or lower total or postacute care costs for hip or knee replacement. Health care regions appear to be a more important predictor of episode costs of care than HVHC status.


High expression in involuting reproductive tissues of uterocalin/24p3, a lipocalin and acute phase protein.
During reproduction the mass and number of cells in the uterus and the mammary gland increase rapidly and then diminish more rapidly after their reproductive functions are completed. The diminishment of tissue mass, known as involution, involves an ordered series of events that includes apoptosis of resident cells, neutrophil invasion, the release of degradative enzymes and phagocytosis of cellular debris. Local signals are believed to regulate the progression of involution in each tissue. Here we show that the mammary gland and uterus express high levels of uterocalin, a protein that specifically induces apoptosis in neutrophils and other leucocytes. In the mammary gland, uterocalin expression is induced by weaning. In both tissues, uterocalin is expressed at extremely high levels such that it constitutes an average of 0.2-0.5% of the total extractable protein at its peak. Epithelial cells in the uterus and mammary gland produce uterocalin. In each case, the protein is secreted into the tissue lumen, with mammary-derived uterocalin being found in the milk. The period of highest uterocalin expression in vivo is consistent with the hypothesis that one of its physiological roles is to induce apoptosis of infiltrating neutrophils and thereby delay the entry of neutrophils into the tissue. It is proposed that the role of uterocalin during involution is to provide a window of time during which resident cells are protected from the degradative enzymes, free radicals and other secreted products of activated phagocytes to allow these cells to prepare to survive the processes of involution.


Measuring the hydrogen/deuterium exchange of proteins at high spatial resolution by mass spectrometry: overcoming gas-phase hydrogen/deuterium scrambling.
Proteins are dynamic molecules that exhibit conformational flexibility to function properly. Well-known examples of this are allosteric regulation of protein activity and ligand-induced conformational changes in protein receptors. Detailed knowledge of the conformational properties of proteins is therefore pertinent to both basic and applied research, including drug development, since the majority of drugs target protein receptors and a growing number of drugs introduced to the market are therapeutic peptides or proteins. X-ray crystallography provides a static picture at atomic resolution of the lowest-energy structure of the native ensemble. There is a growing need for sensitive analytical tools to explore all of the significant molecular structures in the conformational landscape of proteins. Hydrogen/deuterium exchange monitored by mass spectrometry (HDX-MS) has recently emerged as a powerful method for characterizing protein conformational dynamics. The basis of this method is the fact that backbone amides in stable hydrogen-bonded structures (e.g., α-helices and β-sheets) are protected against exchange with the aqueous solvent. All protein structures are dynamic, however, and eventually all of the protecting hydrogen bonds will transiently break as the protein--according to thermodynamic principles--cycles through partially unfolded states that correspond to excited free energy levels. As a result, all of the backbone amides will eventually become temporarily solvent-exposed and exchange-competent over time. Consequently, a folded protein in D2O will gradually incorporate deuterium into its backbone amides, and the kinetics of the process can be readily monitored by mass spectrometry. The deuterium uptake kinetics for the intact protein (global exchange kinetics) represents the sum of the exchange kinetics for the individual backbone amides. Local exchange kinetics is typically achieved by using pepsin digestion under quench conditions (i.e., under cold acidic conditions where the amide hydrogen exchange rate is slowed by many orders of magnitude). The ability to localize the individual deuterated residues (the spatial resolution) is determined by the size (typically ∼7-15 residues) and the number of peptic peptides. These peptides provide a relatively coarse-grained picture of the protein dynamics. A fundamental understanding of the relationship between protein function/dysfunction and conformational dynamics requires in many cases higher resolution and ultimately single-residue resolution. In this Account, we summarize our efforts to achieve single-residue deuterium levels in proteins by electron-based or laser-induced gas-phase fragmentation methods. A crucial analytical requirement for this approach is that the pattern of deuterium labeling from solution is retained in the gas-phase fragment ions. It is therefore essential to control and minimize any occurrence of gas-phase randomization of the solution deuterium label (H/D scrambling) during the MS experiment. For this purpose, we have developed model peptide probes to accurately measure the onset and extent of H/D scrambling. Our analytical procedures to control the occurrence of H/D scrambling are detailed along with the physical parameters that induce it during MS analysis. In light of the growing use of gas-phase dissociation experiments to measure the HDX of proteins in order to obtain a detailed characterization and understanding of the dynamic conformations and interactions of proteins at the molecular level, we discuss the perspectives and challenges of future high-resolution HDX-MS methodology.


Aspergillus pituitary abscess.
Pituitary abscess is rare and most of the cases are of bacterial origin. True fungal pituitary abscess is extremely rare only five cases have been reported. In this report, we present a case of aspergillus pituitary abscess. Mortality rate in intracranial aspergillosis is close to 100% especially in immunsuppressed patients when undiagnosed and untreated. In focal CNS aspergillosis total cure can be achieved in approximately 30% of the cases by surgical drainage and intensive antifungal therapy. Although this is the first reported case with magnetic resonance imaging examination the definitive diagnosis was established only by histopathological examination. A 42 year-old man was referred to our hospital with the diagnosis of sellar suprasellar mass accompanied by frontal headache and decreased visual acuity. His medical history was insignificant. Physical examination was normal and the patient was afebrile. The neurological examination revealed bilateral papilledema and bitemporal hemianopsia but no stiff neck and motor or sensory deficit. In the light of MRI examination, the preoperative diagnosis was pituitary abscess secondary to paranasal sinus infection or hemorrhagic pituitary adenoma. The patient was successfully treated by transsphenoidal surgery. Histopathological examination of sphenoid sinus mucosa revealed normal mucosal appearance with inflammation and histopathological examination of the intrasellar mass resulted in the diagnosis of aspergillosis. All cultures obtained from sphenoid sinus were reported as having no growth. However in the second week after the operation fungal culture of the intrasellar mass grew aspergillus. After 8 weeks of amphothericine-B treatment, the patient was discharged. At the last follow up examination two years after the operation, the patient was symptom free with normal pituitary function. Aspergillus pituitary abscess should be considered in the differential diagnosis of a pituitary mass. The correct diagnosis of pituitary aspergillosis can only be achieved by histopathological examination because clinical and radiological findings including MRI are not specific and culture results are obtained later. Immediately after the diagnosis, intensive antifungal therapy should be started for a successful treatment.


Functional analysis of the fibrinogen-related scabrous gene from Drosophila melanogaster identifies potential effector and stimulatory protein domains.
The scabrous (sca) gene encodes a secreted dimeric glycoprotein with putative coiled-coil domains N-terminally and a C-terminal region related to the blood clot protein fibrinogen. Homozygous sca mutants have extra bristle organs and rough eyes. We describe a GAL4-based expression system for testing rescue of the sca mutant phenotype by altered SCA proteins and for misexpression. We find that deletion of the fibrinogen-related domain (FReD) greatly decreases SCA function, confirming the importance of this conserved region. SCA function could not be restored by FReDs from human fibrinogen chain genes. However, proteins lacking any FReD still showed some function in both rescue and misexpression experiments, suggesting that putative effector-binding regions lie outside this domain. Consistent with this, proteins expressing only the FReD had no rescuing activity but were recessive negative; i.e., they enhanced the phenotype of sca mutations but had no phenotype in the presence of a wild-type sca allele. This suggests that the FReD contributes to SCA function by binding to other components of the bristle determination pathway, increasing the activity of the linked N-terminal region.


Fungal diagnostics.
Early diagnosis of fungal infection is critical to effective treatment. There are many impediments to diagnosis such as a diminishing number of clinical mycologists, cost, time to result, and requirements for sensitivity and specificity. In addition, fungal diagnostics must meet the contrasting needs presented by the increasing diversity of fungi found in association with the use of immunosuppressive agents in countries with high levels of medical care and the need for diagnostics in resource-limited countries where large numbers of opportunistic infections occur in patients with AIDS. Traditional approaches to diagnosis include direct microscopic examination of clinical samples, histopathology, culture, and serology. Emerging technologies include molecular diagnostics and antigen detection in clinical samples. Innovative new technologies that use molecular and immunoassay platforms have the potential to meet the needs of both resource-rich and resource-limited clinical environments.


Psychosocial factors in the neurobiology of schizophrenia: a selective review.
Various forms of social adversity have been implicated in the development and emergence of psychosis. However, how and when these events exert their influences are not clear. In this paper, we attempt to examine these putative psychosocial factors and place them in a temporal context and propose a neurobiological mechanism linking these factors. Medline databases were searched between 1966 and 2007 followed by the cross-checking of references using the following keywords: psychosocial, stress, stressors, life events, psychological, combined with psychosis and schizophrenia. While some findings are conflicting, there are a number of positive studies which suggest that factors like prenatal stress, urban birth and childhood trauma accentuate the vulnerability for schizophrenia and other psychoses while other factors like life events, migration particularly being a minority group, and high expressed emotions, which occur later in the vulnerable individual may move the individual towards the tipping point for psychosis. Overall, there is evidence to implicate psychosocial factors in the pathophysiology of schizophrenia. These factors may act via a common pathway, which involves stress-induced dysregulation of the HPA axis and the dopaminergic systems. To establish the causal relationship of the various factors would require prospective studies that are adequately powered.


A combination of esomeprazole and aspirin reduces tissue concentrations of prostaglandin E(2) in patients with Barrett's esophagus.
BACKGROUND& AIMS: Proton pump inhibitors and nonsteroidal anti-inflammatory drugs might prevent esophageal adenocarcinoma in patients with Barrett's esophagus (BE), but there are limited data from clinical trials to support this concept. We conducted a randomized, double-blind, placebo-controlled, phase 2 trial to assess the effects of the combination of aspirin (3 different doses) and esomeprazole on tissue concentrations of prostaglandin (PG) E(2) in patients with BE with no dysplasia or low-grade dysplasia. Participants were recruited through the multicenter Cancer Prevention Network and randomly assigned to groups that were given 40 mg esomeprazole twice daily in combination with an aspirin placebo once daily (arm A; n = 30), with 81 mg aspirin once daily (arm B; n = 47), or with 325 mg aspirin once daily (arm C; n = 45) for 28 days. We collected esophageal biopsy specimens before and after the intervention period to determine the absolute change in mean concentration of PGE(2) (the primary end point). Based on data from 114 patients, baseline characteristics were similar among groups. The absolute mean tissue concentration of PGE(2) was reduced by 67.6 ± 229.68 pg/mL in arm A, 123.9 ± 284.0 pg/mL in arm B (P = .10 vs arm A), and 174.9 ± 263.62 pg/mL in arm C (P = .02 vs arm A). In combination with esomeprazole, short-term administration of higher doses of aspirin, but not lower doses or no aspirin, significantly reduced tissue concentrations of PGE(2) in patients with BE with either no dysplasia or low-grade dysplasia. These data support further evaluation of higher doses of aspirin and esomeprazole to prevent esophageal adenocarcinoma in these patients. Clinical trial registration number NCT00474903.


Autologous reconstruction following nipple sparing mastectomy: a comprehensive review of the current literature.
As surgical methods continue to evolve and patients become more educated consumers of their medical care, both oncologic breast surgeons and reconstructive plastic surgeons should understand the current options for surgical management of breast cancer. This review evaluates the current autologous breast reconstruction options following nipple sparing mastectomy (NSM). A comprehensive review of the current literature discussing autologous reconstruction after NSM was performed. Fat grafting alone has been used to reconstruct small to medium sized-breasts over multiple injection sessions. Goldilocks mastectomy-like reconstructions can be used for larger, more ptotic breasts. Pedicled latissimus dorsi (LD) flaps can be used, but usually need to be modified to ensure sufficient breast volume. While the lower abdominal tissue remains the most common donor site in free tissue transfer, other donor sites can be used if there is insufficient volume or inadequate perforators. Periareolar incisions are associated with the highest rates of overall complications and nipple areola complex necrosis. It has not been determined whether implant-based or autologous reconstructions have lower complication rates. Both prior radiation and large, ptotic breasts present unique challenges during reconstruction. Overall, there is a high rate of patient satisfaction with breast reconstruction following NSM. Autologous breast reconstruction after NSM is a safe method of breast cancer surgical management with aesthetically excellent results. Multiple techniques have been described along the reconstructive ladder. Special consideration should be given to choices of incision, previously irradiated breasts, and large, ptotic breasts.


Modulation of insulin receptor, insulin receptor substrate-1, and phosphatidylinositol 3-kinase in liver and muscle of dexamethasone-treated rats.
Insulin rapidly stimulates tyrosine kinase activity of its receptor resulting in phosphorylation of its cytosolic substrate, insulin receptor substrate-1 (IRS-1), which in turn associates with phosphatidylinositol 3-kinase (PI 3-kinase), thus activating the enzyme. Glucocorticoid treatment is known to produce insulin resistance, but the exact molecular mechanism is unknown. In the present study we have examined the levels and phosphorylation state of the insulin receptor and IRS-1, as well as the association/activation between IRS-1 and PI 3-kinase in the liver and muscle of rats treated with dexamethasone. After dexamethasone treatment (1 mg/kg per d for 5 d), there was no change in insulin receptor concentration in liver of rats as determined by immunoblotting with antibody to the COOH-terminus of the receptor. However, insulin stimulation of receptor autophosphorylation determined by immunoblotting with antiphosphotyrosine antibody was reduced by 46.7 +/- 9.1%. IRS-1 and PI 3-kinase protein levels increased in liver of dexamethasone-treated animals by 73 and 25%, respectively (P < 0.05). By contrast, IRS-1 phosphorylation was decreased by 31.3 +/- 10.9% (P < 0.05), and insulin stimulated PI 3-kinase activity in anti-IRS-1 immunoprecipitates was decreased by 79.5 +/- 11.2% (P < 0.02). In muscle, the changes were less dramatic, and often in opposite direction of those observed in liver. Thus, there was no significant change in insulin receptor level or phosphorylation after dexamethasone treatment. IRS-1 and PI 3-kinase levels were decreased to 38.6 and 65.6%, respectively (P < 0.01 and P < 0.05). IRS-1 phosphorylation showed no significant change in muscle, but insulin-stimulated IRS-1 associated PI 3-kinase was decreased by 41%. Thus, dexamethasone has differential effects on the proteins involved in the early steps in insulin action in liver and muscle. In both tissues, dexamethasone treatment results in a reduction in insulin-stimulated IRS-1-associated P I3-kinase, which may play a role in the pathogenesis of insulin resistance at the cellular level in these animals.


Enhanced food anticipatory activity associated with enhanced activation of extrahypothalamic neural pathways in serotonin2C receptor null mutant mice.
The ability to entrain circadian rhythms to food availability is important for survival. Food-entrained circadian rhythms are characterized by increased locomotor activity in anticipation of food availability (food anticipatory activity). However, the molecular components and neural circuitry underlying the regulation of food anticipatory activity remain unclear. Here we show that serotonin(2C) receptor (5-HT2CR) null mutant mice subjected to a daytime restricted feeding schedule exhibit enhanced food anticipatory activity compared to wild-type littermates, without phenotypic differences in the impact of restricted feeding on food consumption, body weight loss, or blood glucose levels. Moreover, we show that the enhanced food anticipatory activity in 5-HT2CR null mutant mice develops independent of external light cues and persists during two days of total food deprivation, indicating that food anticipatory activity in 5-HT2CR null mutant mice reflects the locomotor output of a food-entrainable oscillator. Whereas restricted feeding induces c-fos expression to a similar extent in hypothalamic nuclei of wild-type and null mutant animals, it produces enhanced expression in the nucleus accumbens and other extrahypothalamic regions of null mutant mice relative to wild-type subjects. These data suggest that 5-HT2CRs gate food anticipatory activity through mechanisms involving extrahypothalamic neural pathways.


Mud-bath treatment in spondylitis associated with inflammatory bowel disease--a pilot randomised clinical trial.
The objective of this study was to evaluate the effects and the tolerability of mud packs and thermal baths in a group of patients affected with this disease. Twenty-four patients with spondylitis and Crohn's disease or ulcerative colitis, treated with 5-ASA or sulfasalazine, were randomised and assessed by an investigator independent from the spa staff: 12 were submitted to a cycle of mud-bath treatment (12 mud packs and 12 thermal baths over a period of two weeks) and 12 were enrolled as controls. Patients were evaluated by BASDAI, BASFI, BAS-G and VAS for back pain before, at the end of a cycle of mud-bath treatment, and after 12 and 24 weeks. C reactive protein serum levels detected by high sensitivity nephelometric method and gut symptoms evaluated by CDAI or Powell-Tuck index were assessed at the same time periods. A significant reduction of clinical evaluation indices of spondylitis was observed at the end of the cycle of mud-bath treatment. BASDAI50 improvement remained significant until the end of the follow-up (24 weeks). C reactive protein serum levels didn't show significant changes. No patient referred any gut symptom exacerbation. No significant changes in clinical evaluation indices, in IBD activity indices and in CRP serum levels were observed in the control group. Mud-bath treatment in patients with spondylitis associated with inflammatory bowel disease is well tolerated and may improve spinal symptoms and function for several months.


The relation of reported alcohol ingestion to plasma levels of estrogens and androgens in premenopausal women (Maryland, United States).
We undertook a cross-sectional study in 107 premenopausal women in Maryland (United States) of alcohol intake and hormonal status in order to evaluate whether plasma hormone levels might mediate the reported positive relation between alcohol ingestion and breast cancer risk. Alcohol ingestion was estimated using a drinking pattern questionnaire, a food frequency questionnaire, and seven-day food records. Fasting blood specimens were collected on days 5-7, 12-15, and 21-23 of each participant's menstrual cycle and pooled to create follicular, midcycle, and luteal phase samples, respectively, for analysis. Estrone, estrone sulfate, estradiol, androstenedione, and dehydroepiandrosterone sulfate (DHEAS) in plasma were measured by radioimmunoassay, and sex-hormone binding globulin (SHBG) was measured by an immunoradiometric assay. After adjusting for age, weight, and total energy intake, alcohol ingestion was not associated with plasma estrogens in the follicular, midcycle, or luteal phases of the menstrual cycle, nor with the level of SHBG or DHEAS in plasma averaged from the three phases of the cycle. Alcohol, however, was significantly positively associated with the average level of plasma androstenedione. Based on these cross-sectional findings among premenopausal women, the increased risk of breast cancer related to alcohol ingestion does not appear to be mediated by elevated plasma estrogen levels. Androstenedione, however, may mediate the alcohol/breast cancer-association.


Role of connexin37 and connexin40 in vascular development.
Mice lacking both connexin37 (Cx37) and connexin40 (Cx40), gap junction proteins expressed in vascular endothelium, die perinatally with pronounced vascular abnormalities. Early vasculogenesis proceeds normally, but by E18.5 Cx37(-/-)Cx40(-/-) animals display vessel dilatation and congestion as well as localized hemorrhages in skin, testis, intestines, and lungs. Abnormal vascular channels are present in the testis, often forming cavernous hemangioma-like defects. Unusually large, distended vessels are also present in the submucosa and lamina propria of the intestine. Ablation of Cx40 has a greater effect on endothelial dye-transfer than ablation of Cx37, and the effect of Cx40 ablation is age-dependent. Only in embryonic aortas lacking both Cx37 and Cx40 is there a complete loss of endothelial coupling. Surprisingly, elimination of Cx40 results in a large drop in aortic endothelial Cx37 on western blots, and deletion of Cx37 also reduces endothelial Cx40 levels. In contrast, in the medial layer, both Cx37 and Cx43 increase when Cx40 is ablated. These studies indicate that Cx37 and Cx40 are collectively critical for endothelial communication and provide evidence of an important role for gap junctions in vascular development. In addition, Cx37 and Cx40 appear to be mutually dependent on each other for normal expression in vascular endothelium.


A survey of training and practice patterns of massage therapists in two US states.
Despite the growing popularity of therapeutic massage in the US, little is known about the training or practice characteristics of massage therapists. The objective of this study was to describe these characteristics. As part of a study of random samples of complementary and alternative medicine (CAM) practitioners, we interviewed 226 massage therapists licensed in Connecticut and Washington state by telephone in 1998 and 1999 (85% of those contacted) and then asked a sample of them to record information on 20 consecutive visits to their practices (total of 2005 consecutive visits). Most massage therapists were women (85%), white (95%), and had completed some continuing education training (79% in Connecticut and 52% in Washington). They treated a limited number of conditions, most commonly musculoskeletal (59% and 63%) (especially back, neck, and shoulder problems), wellness care (20% and 19%), and psychological complaints (9% and 6%) (especially anxiety and depression). Practitioners commonly used one or more assessment techniques (67% and 74%) and gave a massage emphasizing Swedish (81% and 77%), deep tissue (63% and 65%), and trigger/pressure point techniques (52% and 46%). Self-care recommendations, including increasing water intake, body awareness, and specific forms of movement, were made as part of more than 80% of visits. Although most patients self-referred to massage, more than one-quarter were receiving concomitant care for the same problem from a physician. Massage therapists rarely communicated with these physicians. This study provides new information about licensed massage therapists that should be useful to physicians and other healthcare providers interested in learning about massage therapy in order to advise their patients about this popular CAM therapy.


A survey of scale insects (Sternorryncha: Coccoidea) occurring on table grapes in South Africa.
Increasing international trade and tourism have led to an increase in the introduction of exotic pests that pose a considerable economic threat to the agro-ecosystems of importing countries. Scale insects (Sternorryncha: Coccoidea) may be contaminants of export consignments from the South African deciduous fruit industry to the European Union, Israel, United Kingdom and the United States, for example. Infestations of immature scale insects found on South African fruit destined for export have resulted in increasing rates of rejection of such consignments. To identify the risk posed by scale insect species listed as phytosanitary pests on table grapes to the abovementioned importing countries, a field survey was undertaken in 2004-2005 in vineyards throughout all grape-producing regions in South Africa. Coccoidea species found during the current field survey were Planococcus ficus (Signoret), Pseudococcus longispinus (Targioni Tozzetti), Coccus hesperidum L. and Nipaecoccus viridis (Newstead). With the exception of Pl. ficus, which has only been collected from Vitis vinifera (Vitaceae) and Ficus carica (Moraceae) in South Africa, these species are polyphagous and have a wide host range. None of the scale insect species found to occur in vineyards in South Africa pose a phytosanitary risk to countries where fruit are exported except for Ferrisia malvastra (McDaniel) and N. viridis that have not been recorded in the USA. All scale insects previously found in vineyards in South Africa are listed and their phytosanitary status discussed. The results of the survey show that the risk of exporting scale insect pests of phytosanitary importance on table grapes from South Africa is limited.


Were vertebrates octoploid?
It has long been suggested that gene and genome duplication play important roles in the evolution of organismal complexity. For example, work by Ohno proposed that two rounds of whole genome doubling (tetraploidy) occurred during the evolution of vertebrates: the extra genes permitting an increase in physiological and anatomical complexity. Several modifications of this 'two tetraploidies' hypothesis have been proposed, taking into account accumulating data, and there is wide acceptance of the basic scheme. In the past few years, however, several authors have raised doubts, citing lack of direct support or even evidence to the contrary. Here, we review the evidence for and against the occurrence of tetraploidies in early vertebrate evolution, and present a new compilation of molecular phylogenetic data for amphioxus. We argue that evidence in favour of tetraploidy, based primarily on genome and gene family analyses, is strong. Furthermore, we show that two observations used as evidence against genome duplication are in fact compatible with the hypothesis: but only if the genome doubling occurred by two closely spaced sequential rounds of autotetraploidy. We propose that early vertebrates passed through an autoautooctoploid phase in the evolution of their genomes.


Invasive pneumococcal disease in England and Wales: vaccination implications.
Knowledge of the epidemiology of invasive pneumococcal disease (IPD) will aid in planning the use of pneumococcal vaccines. A United Kingdom (UK)-based surveillance in England and Wales (1995-1997) of 11,528 individuals with IPD and a local enhanced surveillance in the Oxford (UK) area (1995-1999) have been analyzed. IPD has a high attack rate in children, with 37.1-48.1 cases per 100,000 infants <1 year old per year, and in older persons, with 21.2-36.2 cases per 100,000 persons >65 years old per year, for England, Wales, and Oxford. The 7-valent conjugate vaccine includes serotypes causing < or =79% of IPD in children <5 years old, but only 66% in adults >65 years old. The data also indicate that IPD varies by serotype, age, and country, emphasizing that the epidemiology of IPD is heterogeneous and requires continued surveillance.


Optical reflectivity of a disordered monolayer of highly scattering particles: coherent scattering model versus experiment.
Recently a multiple-scattering model for the reflectivity of a disordered monolayer of scattering particles on a flat surface was put forth [J. Opt. Soc. Am.29, 1161 (2012)]. The approximate theoretical model provides relatively simple formulas for the reflectivity, but it was developed for a monodisperse monolayer. Here we extend the model to the case of a polydisperse monolayer and derive the appropriate formulas to calculate the optical transmissivity of the monolayer supported by a flat interface. A second objective of this paper is to test the approximate theoretical model against experimental data with highly scattering particles. We prepared monolayers of three different surface coverage fractions of polydisperse alumina and titanium dioxide particles deposited randomly on a glass slide. We measured their optical reflectivity and transmissivity versus the angle of incidence using a laser with a wavelength of 670 nm. Using the nominal values for the particles' most probable radius and refractive index, we fitted the theoretical model to the experimental curves and found that it reproduces very well the experimental curves. Interestingly, a dip in the reflectivity curves at large angles of incidence is present for the alumina monolayers but not in the titanium dioxide monolayers. The dip corresponds to a maximum in the scattering efficiency by the alumina monolayers. The theoretical model reproduces very well this behavior.


Radar Image of Asteroid 1989 PB.
Radar observations of the near-Earth asteroid 1989 PB, made shortly after its optical discovery, yield a sequence of delay-Doppler images that reveal it to consist of two distinct lobes that appear to be in contact. It seems likely that the two lobes once were separate and that they collided to produce the current "contact-binary" configuration.


Reflective properties of iridophores and fluorescent 'eyespots' in the loliginid squid Alloteuthis subulata and Loligo vulgaris.
Observations were made of the reflective properties of the iridophore stripes of the squid Alloteuthis subulata and Loligo vulgaris, and the likely functions of these stripes are considered in terms of concealment and signalling. In both species, the mantle muscle is almost transparent. Stripes of iridophores run along the length of each side of the mantle, some of which, when viewed at normal incidence in white light, reflect red, others green or blue. When viewed obliquely, the wavebands best reflected move towards the blue/ultraviolet end of the spectrum and their reflections are almost 100% polarised. These are properties of quarter-wavelength stacks of chitin and cytoplasm, predicted in theoretical analyses made by Sir A. F. Huxley and Professor M. F. Land. The reflecting surfaces of the individual iridophores are almost flat and, in a given stripe, these surfaces are within a few degrees of being parallel. Both species of squid have conspicuous, brightly coloured reflectors above their eyes. These 'eyespots' have iridescent layers similar to those found on the mantle but are overlaid by a green fluorescent layer that does not change colour or become polarised as it is viewed more obliquely. In the sea, all reflections from the iridophore stripes will be largely confined to the blue-green parts of the spectrum and all reflections in other wavebands, such as those in the red and near ultraviolet, will be weak. The functions of the iridophores reflecting red at normal incidence must be sought in their reflections of blue-green at oblique angles of incidence. These squid rely for their camouflage mainly on their transparency, and the ventral iridophores and the red, green and blue reflective stripes must be used mainly for signalling. The reflectivities of some of these stripes are relatively low, allowing a large fraction of the incident light to be transmitted into the mantle cavity. Despite their low reflectivities, the stripes are very conspicuous when viewed from some limited directions because they reflect light from directions for which the radiances are much higher than those of the backgrounds against which they are viewed. The reflective patterns seen, for example, by neighbouring squid when schooling depend on the orientation of the squid in the external light field and the position of the squid relative to these neighbours.


The context-tree kernel for strings.
We propose a new kernel for strings which borrows ideas and techniques from information theory and data compression. This kernel can be used in combination with any kernel method, in particular Support Vector Machines for string classification, with notable applications in proteomics. By using a Bayesian averaging framework with conjugate priors on a class of Markovian models known as probabilistic suffix trees or context-trees, we compute the value of this kernel in linear time and space while only using the information contained in the spectrum of the considered strings. This is ensured through an adaptation of a compression method known as the context-tree weighting algorithm. Encouraging classification results are reported on a standard protein homology detection experiment, showing that the context-tree kernel performs well with respect to other state-of-the-art methods while using no biological prior knowledge.


Cycloheximide induces a subset of low temperature-inducible genes in maize.
To investigate further the signal transduction pathway that mediates the cold-stress response in maize, we isolated a low temperature-inducible cDNA clone (ZmCDPK1) that encodes a calcium-dependent protein kinase. Time-course experiments revealed that the low-temperature induction of ZmCDPK1 precedes that of mlip15, another cold-inducible gene that codes for a DNA-binding protein of the basic region/leucine zipper (bZIP) type, indicating that ZmCDPK1 might be located upstream of mlip15 in the cold-stress signal transduction pathway. We observed that the steady-state mRNA level of mlip15 drastically increased after cycloheximide treatment. In addition to mlip15, cycloheximide elevates the transcript levels of two other low temperature-induced genes, ZmCDPK1, and Adh1, which encodes alcohol dehydrogenase 1. In contrast, the chalcone synthase gene was only inducible by low temperature. The accumulation of the mlip15 transcript at low temperatures and in response to cycloheximide was significantly reduced by pretreatment with a calcium chelator, suggesting that calcium is involved in both cases of mlip15 induction. The signal transduction pathways triggered by low temperature and cycloheximide are discussed in relation to these observations.


Reliability and clinical utility of the chronic pain classification in the 11th Revision of the International Classification of Diseases from a global perspective: results from India, Cuba, and New Zealand.
Chronic pain affects 1 in 5 persons and contributes substantially to the global burden of disease. The 11th Revision of the International Classification of Diseases (ICD-11) includes a comprehensive classification of chronic pain. The aim of this ecological implementation field study was to evaluate the classification's interrater reliability and clinical utility in countries with different income levels. The study was conducted in 4 pain clinics in Cuba, India, and New Zealand. Twenty-one clinicians used the ICD-11 to diagnose and code n = 353 patients with chronic pain. Of these, 111 were assessed by 2 clinicians, and Fleiss' kappa was calculated to establish interrater reliability for any diagnosis assigned to ≥15 patients. The clinicians rated the clinical utility of all diagnoses. The interrater reliability could be calculated for 11 diagnoses. It was substantial for 10 diagnoses and moderate for 1 (kappa: 0.596-0.783). The mean clinical utility of the ICD-11 chronic pain diagnoses was rated as 8.45 ± 1.69/10. Clinical utility was rated higher for ICD-11 than for the commonly used classification systems (P < 0.001, η2 = 0.25) and differed between all centers (P < 0.001, η2 = 0.60). The utility of the ICD-11 diagnoses was rated higher than the commonly used diagnoses in Dunedin and Havana, and no difference was found in Kolkata and Hyderabad. The study showed the high interrater reliability of the new chronic pain diagnoses. The perceived clinical utility of the diagnoses indicates their superiority or equality compared with the classification systems currently used in pain clinics. These results suggest the global applicability of the classification in specialized pain treatment settings.


The concordance of directly and indirectly measured built environment attributes and physical activity adoption.
Physical activity (PA) adoption is essential for obesity prevention and control, yet ethnic minority women report lower levels of PA and are at higher risk for obesity and its comorbidities compared to Caucasians. Epidemiological studies and ecologic models of health behavior suggest that built environmental factors are associated with health behaviors like PA, but few studies have examined the association between built environment attribute concordance and PA, and no known studies have examined attribute concordance and PA adoption. The purpose of this study was to associate the degree of concordance between directly and indirectly measured built environment attributes with changes in PA over time among African American and Hispanic Latina women participating in a PA intervention. Women (N = 410) completed measures of PA at Time 1 (T1) and Time 2 (T2); environmental data collected at T1 were used to compute concordance between directly and indirectly measured built environment attributes. The association between changes in PA and the degree of concordance between each directly and indirectly measured environmental attribute was assessed using repeated measures analyses. There were no significant associations between built environment attribute concordance values and change in self-reported or objectively measured PA. Self-reported PA significantly increased over time (F(1,184) = 7.82, p = .006), but this increase did not vary by ethnicity or any built environment attribute concordance variable. Built environment attribute concordance may not be associated with PA changes over time among minority women. In an effort to promote PA, investigators should clarify specific built environment attributes that are important for PA adoption and whether accurate perceptions of these attributes are necessary, particularly among the vulnerable population of minority women.


Role of dietary fats in modulating cardiometabolic risk during moderate weight gain: a randomized double-blind overfeeding trial (LIPOGAIN study).
Whether the type of dietary fat could alter cardiometabolic responses to a hypercaloric diet is unknown. In addition, subclinical cardiometabolic consequences of moderate weight gain require further study. In a 7-week, double-blind, parallel-group, randomized controlled trial, 39 healthy, lean individuals (mean age of 27±4) consumed muffins (51% of energy [%E] from fat and 44%E refined carbohydrates) providing 750 kcal/day added to their habitual diets. All muffins had identical contents, except for type of fat; sunflower oil rich in polyunsaturated fatty acids (PUFA diet) or palm oil rich in saturated fatty acids (SFA diet). Despite comparable weight gain in the 2 groups, total: high-density lipoprotein (HDL) cholesterol, low-density lipoprotein:HDL cholesterol, and apolipoprotein B:AI ratios decreased during the PUFA versus the SFA diet (-0.37±0.59 versus +0.07±0.29, -0.31±0.49 versus +0.05±0.28, and -0.07±0.11 versus +0.01±0.07, P=0.003, P=0.007, and P=0.01 for between-group differences), whereas no significant differences were observed for other cardiometabolic risk markers. In the whole group (ie, independently of fat type), body weight increased (+2.2%, P<0.001) together with increased plasma proinsulin (+21%, P=0.007), insulin (+17%, P=0.003), proprotein convertase subtilisin/kexin type 9, (+9%, P=0.008) fibroblast growth factor-21 (+31%, P=0.04), endothelial markers vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and E-selectin (+9, +5, and +10%, respectively, P<0.01 for all), whereas nonesterified fatty acids decreased (-28%, P=0.001). Excess energy from PUFA versus SFA reduces atherogenic lipoproteins. Modest weight gain in young individuals induces hyperproinsulinemia and increases biomarkers of endothelial dysfunction, effects that may be partly outweighed by the lipid-lowering effects of PUFA. http://ClinicalTrials.gov. Unique identifier: NCT01427140.


Multicentered epidemiological study of factors associated with total bacterial count in the saliva of older people requiring nursing care.
To clarify whether the number of present teeth, independent of other well-known factors, was associated with the total bacterial count in the saliva of older people requiring care at nursing homes in a multicentered epidemiological survey. The participants were 618 older people (mean age 86.8 ± 6.9 years; 122 men, 496 women) residing in 14 nursing homes across Japan. The dependent variable was the participant's salivary bacterial count, and the independent variables were basic demographic data, oral conditions and activity of daily living (measured by Barthel Index). Statistical analysis was first carried out by Student's t-test, Pearson's correlation coefficient analysis and Spearman's rank correlation coefficient analysis. Independent variables found to have a significant relationship to their salivary bacterial count by the univariate analyses were further examined by stepwise multivariate analysis. The independent variables shown by univariate analysis to have a significant positive relationship with higher salivary bacterial count were presence of food residue (P = 0.001), absence of mouth dryness (P = 0.001), need of oral care assistance (P = 0.001), inability to keep the mouth opened (P = 0.009), inability to gargle (P = 0.002), denture use (P = 0.004), higher number of present teeth (P = 0.006) and lower Barthel Index (P = 0.001). Subsequent multivariate analysis identified presence of food residue (P = 0.031), higher number of present teeth (P = 0.043) and lower Barthel Index (P = 0.001) as independent associated factors for higher salivary bacterial count. The present study found that presence of food residue, higher number of present teeth and decreased activity of daily living were significantly related to higher bacterial count in the saliva of older people requiring care. Geriatr Gerontol Int 2017; 17: 219-225.


Use of novel cationic bile salts in cholesterol crystallization and solubilization in vitro.
Unnatural bile salts have been synthesized with a cationic group at the side chain of natural bile acids. These cationic bile salts aggregate in water and aqueous salt solutions in a manner similar to their natural counterparts. The critical micellar concentrations of the cationic bile salts were measured using a fluorescence method. Cationic bile salts aggregated at a concentration lower than natural deoxycholic acid. Since dihydroxy bile salt micelles are well known for cholesterol dissolution/removal, the dissolution in the cationic micelles has been evaluated. The cationic analogs dissolve approximately 70 mg/dL of cholesterol, which is comparable to taurochenodeoxycholate micelle under identical bile salt concentrations. Cholesterol dissolution in cationic bile salt micelle enhanced upon adding various amounts of PC. Cholesterol crystallization was studied in model bile at various cationic bile salt concentrations. The addition of 5, 15 and 30 mM of the cationic bile salts attenuated the crystallization process, without influencing the crystal observation time or decreasing the final amount of crystals formed. All these effects were comparable to those observed with cholic acid. These findings suggest that cationic bile salts have physico-chemical properties analogous to those of natural anionic bile salts, and thus may have therapeutic potential.


Prospective evaluation and characteristics of patients with suspected primary hyperaldosteronism.
Primary hyperaldosteronism (PH), resulting in hypokalaemic hypertension, may be due to an aldosterone-producing adenoma (APA) or bilateral zona glomerulosa hyperplasia. Six patients with suspected PH were identified at the University Hospital of the West Indies and standardized screening was carried out. Plasma renin activity (PRA) and serum aldosterone concentrations (SAC) were measured, followed by confirmatory intravenous saline suppression test. The patients were all women, of median age 48 years (interquartile range, IQR: 41-51.7 years). They tended to be overweight with suboptimal blood pressure control. Median serum potassium was 3.1 mmol/L (IQR 2.7 - 3.3 mmol/l) and kaliuresis was elevated or inappropriately normal. All individuals had suppressed PRA (< 0.6 ng/ml/hr) and elevated SAC (> 30 ng/dl), with SAC/PRA ratios > 50. Five patients had confirmed PH (ie post-saline SAC > 10 ng/dl); PH could not be definitely excluded in the sixth patient (ie post-saline SAC 5 - 10 ng/dl). Imaging studies revealed normal adrenal glands in one patient, unilateral adrenal enlargement in three patients, and unilateral adrenal masses in two patients. Only one of these latter two patients was shown to have an adrenal adenoma on histological examination. In this series, there appears to be fewer cases of the APA subtype of PH than expected. It remains to be seen whether the distribution of PH subtypes in Jamaica is actually different from elsewhere. This, and the cost-effectiveness of different approaches to screening, identification and management of patients suspected of having PH in Jamaica are areas for further study.


The impact of early twentieth century illegitimacy across three generations. Longevity and intergenerational health correlates.
This study contributes to the understanding of how social mortality patterns are reproduced across generations by documenting associations of women's marital status at childbirth in the beginning of last century with selected health indicators across three subsequent generations of their offspring, and by highlighting a special set of plausible mechanisms linked to this particular event in history. We use the Multigenerational Uppsala Birth Cohort Study (UBCoS) database consisting of 12,168 individuals born at Uppsala University Hospital in 1915-1929 (UG1), their children (UG2) and grandchildren (UG3). Results showed that men and women born outside wedlock (BOW) in early twentieth century Sweden were at an increased risk of adult mortality compared to those who were born in wedlock (BIW), and the men were also significantly less likely to reach their 80th birthday. The question of childhood social disadvantage and its long-term consequences for health is then taken one step further by examining their offspring in two subsequent generations in terms of four specific anthropometric and psychological outcomes at the time of military conscription, all known to predict disease and mortality later in life. Results showed that sons of men BOW as well as sons and grandsons of women BOW had significantly lower psychological functioning and cognitive ability. Regarding body mass index and height, however, significant associations were found only among descendants of men BOW. The anthropometric and psychological disadvantages found among descendents of individuals BOW were partly mediated by their social class background. The four outcomes observed early in the lives of UG2s and UG3s do in fact constitute early health determinants, each potentially influencing longevity and mortality risk in these generations. We conclude that the social disadvantage imposed on those BOW in early twentieth century Sweden appears to be reproduced as a health disadvantage in their children and grandchildren, with likely consequences for mortality among these.


Disability Benefit Generosity and Labor Force Withdrawal.
A key component for estimating the optimal size and structure of disability insurance (DI) programs is the elasticity of DI claiming with respect to benefit generosity. Yet, in many countries, including the United States, all workers face identical benefit schedules, which are a function of one's labor market history, making it difficult to separate the effect of the benefit level from the effect of unobserved preferences for work on individuals' claiming decisions. To circumvent this problem, we exploit exogenous variation in DI benefits in Austria arising from several reforms to its DI and old age pension system in the 1990s and 2000s. We use comprehensive administrative social security records data on the universe of Austrian workers to compute benefit levels under six different regimes, allowing us to identify and precisely estimate the elasticity of DI claiming with respect to benefit generosity. We find that, over this time period, a one percent increase in potential DI benefits was associated with a 1.2 percent increase in DI claiming.


The effect of somatosensory input on motor imagery depends upon motor imagery capability.
We investigated that the relationship between motor imagery ability and the effect of tactile input associated with holding a tennis racket on motor imagery of the forehand and backhand swings. The effect was assessed by the time utilized for motor imagery (mental chronometry). Seventeen tennis players imagined forehand and backhand swings with a forehand grip, a backhand grip or while holding nothing. In all cases, imaging the swings took longer than the time taken for a real swing. For imagery of the backhand swing, holding a racket with a backhand grip decreased the imaging time (p < 0.05) as compared to the trials with a forehand grip or while holding nothing. On the other hand, holding the racket with a backhand grip tended to increase the time required for forehand swing imagery. These results suggest that a congruent grip improves, and an incongruent grip deteriorates, motor imagery of the backhand swing. For players who took a longer time in the condition where they held nothing (i.e., poor imaging ability), the effect of a congruent backhand grip was greater (r = 0.67, p < 0.01). However, a congruent forehand grip did not improve motor imagery of the forehand swing. Since 15 of the participants in the present study favored the forehand swing compared to the backhand swing, the participants would have been more familiar with the forehand swing. Thus it would have been easy to vividly imagine the (familiar) forehand swing even when they were not holding a racket. We speculate that tactile input associated with holding a tool improves a vividness of motor imagery of a less familiar movement, especially for those who have poor imaging ability. In the future, it will be important to clarify whether the effect of tactile input associated with holding a tool is dependent upon movement familiarity/performance level.


Dietary patterns and adenocarcinoma of the esophagus and distal stomach.
Dietary pattern analysis is a unique approach to studying relations between diet and disease. Our objective was to describe the dietary patterns of an eastern Nebraska population and investigate the associations between those dietary patterns and risks of adenocarcinoma of the esophagus and distal stomach. We recruited 124 subjects with esophageal adenocarcinoma, 124 subjects with distal stomach adenocarcinoma, and 449 control subjects in a population-based, case-control study. Six dietary patterns were identified with the use of cluster analysis. The first dietary pattern represented healthy food choices and had higher energy contributions from fruit and vegetables and grain products and lower energy contributions from red meats, processed meats, and gravy than did the other dietary patterns. In contrast, a second dietary pattern was high in meats and low in fruit and cereals. The other 4 dietary patterns were each characterized by a concentrated energy source: salty snacks, desserts, milk, and white bread, respectively. The test of overall difference in cancer risk across dietary patterns was significant for distal stomach adenocarcinoma (P = 0.04) but not for esophageal adenocarcinoma. Risk of esophageal adenocarcinoma was inversely associated with intakes of dairy products, fish, all vegetables, citrus fruit and juices, and dark bread and was positively associated with gravy intake. Risk of distal stomach adenocarcinoma was positively associated with red meat intake. Our study suggests that a diet high in fruit and vegetables may decrease the risk of esophageal adenocarcinoma and that a diet high in meats may increase the risk of distal stomach adenocarcinoma.


ATP hydrolyzing salivary enzymes of caterpillars suppress plant defenses.
The oral secretions of herbivores are important recognition cues that can be used by plants to mediate induced defenses. In this study, a degradation of adenosine-5'-triphosphate (ATP) in tomato leaves was detected after treatment with Helicoverpa zea saliva. Correspondingly, a high level of ATPase activity in saliva was detected and three ATP hydrolyzing enzymes: apyrase, ATP synthase and ATPase 13A1 were identified in salivary glands. To determine the functions of these proteins in mediating defenses, they were cloned from H. zea and expressed in Escherichia coli. By applying the purified expressed apyrase, ATP synthase or ATPase 13A1 to wounded tomato leaves, it was determined that these ATP hydrolyzing enzymes suppressed the defensive genes regulated by the jasmonic acid and ethylene pathways in tomato plant. Suppression of glandular trichome production was also observed after treatment. Blood-feeding arthropods employ 5'-nucleotidase family of apyrases to circumvent host responses and the H. zea apyrase, is also a member of this family. The comparatively high degree of sequence similarity of the H. zea salivary apyrase with mosquito apyrases suggests a broader evolutionary role for salivary apyrases than previously envisioned.


Electrically induced mechanomyograms reflect inspiratory muscle strength in young or elderly subjects.
Respiratory muscle strength has been used as a tool for evaluating respiratory rehabilitation in chronic obstructive pulmonary disease. However, mouth pressure measurement evaluated by maximum expiratory mouth pressure (PEmax) or inspiratory mouth pressure (PImax) offers an indirect method for measuring respiratory muscle strength. We demonstrated the evaluation of diaphragm contractility using a mechanomyogram (MMG), which is the mechanical signal generated by the motion of the diaphragm induced by the electric stimulation of the phrenic nerve. Study participants were 21 young and 20 elderly subjects with no symptoms of respiratory disease. The elderly subjects were divided into non-smoker or smoker groups. The smoker group was defined as subjects having a Brinkman Index of greater than 300. We measured basic spirometric parameters, mouth pressure (PEmax, PImax), and diaphragmatic MMG. Diaphragmatic MMG showed more clear contrast between young subjects and elderly non-smoker or smoker subjects than the conventional method for respiratory muscle contraction (PEmax, PImax). In addition, the diaphragmatic MMG strongly correlated with inspiratory muscle strength. Diaphragmatic MMG may reflect diaphragmatic contractility more directly and sensitively than the conventional method.


Multistatic adaptive microwave imaging for early breast cancer detection.
We propose a new multistatic adaptive microwave imaging (MAMI) method for early breast cancer detection. MAMI is a two-stage robust Capon beamforming (RCB) based image formation algorithm. MAMI exhibits higher resolution, lower sidelobes, and better noise and interference rejection capabilities than the existing approaches. The effectiveness of using MAMI for breast cancer detection is demonstrated via a simulated 3-D breast model and several numerical examples.


Coeliac disease in China, a field waiting for exploration.
no systematic studies on the prevalence of coeliac disease (CD) have been reported from China. In western populations CD is more common in patients with insulin dependent diabetes mellitus (IDDM) and in diarrhoea-predominant irritable bowel syndrome (D-IBS). We have screened patients with these conditions presenting to the outpatient department of a large hospital of "Traditional Chinese Medicine" (TCM) in Nanjing, Jiangsu province, P.R. China. we tested sera of 78 unrelated Han Chinese patients (5 IDDM and 73 D-IBS), using ELISA serological tests for IgG anti-gliadin antibodies (IgG-AGA) and IgA anti-tissue transglutaminase antibodies (IgA-tTG). six out of 78 patients (7.7%) were positive for IgG-AGA (two men and four women) and two (2.6%) were positive for IgA-tTGs. One of the latter patients was negative for IgG-AGA. Besides, one patient had a dubious IgA-tTG antibody and a positive IgG-AGA. None of the six patients agreed to undergo duodenal biopsy. Two out of these six patients followed a gluten-free diet for one year. In one patient the diarrhoea ceased and his body weight increased. Another stopped losing weight. this study previously published as a letter in GUT (Wu J, Xia B, von Blomberg BME, Zhao C, Yang XW, Crusius JBA, Peña AS. Coeliac disease: emerging in China? Gut 2010; 59(3): 418-9) demonstrated that CD may exist in the Jiangsu province of P.R. China. The present article draws attention to the difficulties of following a standard protocol in China such as established in western countries and highlights important factors less well known in the west in relation to the development of CD in China. Wheat production became significant in China between 1600 and 1300 B.C. After the Han dynasty (500-200 B.C.), wheat was one of the main cereals in China. One the major wheat fields in China is located in the Jiangsu province where the research for this article was performed. A review of Chinese literature shows that the predominant HLA-DQ CD risk alleles and haplotypes are present in the Jiangsu province. Genetic background, food consumption, and the results of our study suggest that CD should actively be investigated in P.R. China.


Plantlets from somatic callus tissue of the East Indian Rosewood (Dalbergia latifolia Roxb.).
Callus-mediated shoot bud formation was demonstrated in Dalbergia latifolia Roxb. (East Indian Rosewood). Cultures were raised from shoot explants of six year-old plants on Murashige and Skoog (MS) medium supplemented with naphthaleneacetic acid (NAA) and benzyladenine (BA). A sequential treatment of callus with increasing BA levels and decreasing NAA ensured shoot bud induction. Rooting of shoots was achieved by a three-step culture procedure involving 1) White's(W) liquid medium containing indoleacetic acid (IAA), naphthaleneacetic acid and indolebutyric acid (IBA), 2) half-strength MS agar-solidified medium with charcoal (0.25%) and 3) half-strength MS liquid medium.


Bilberry extract, its major polyphenolic compounds, and the soy isoflavone genistein antagonize the cytostatic drug erlotinib in human epithelial cells.
Erlotinib (Tarceva®) is a chemotherapeutic drug approved for the treatment of pancreatic cancer and non-small cell lung cancer. Its primary mode of action is the inhibition of the epidermal growth factor receptor (EGFR), a receptor tyrosine kinase (RTK). Recently, RTK-inhibiting polyphenols have been reported to interact synergistically with erlotinib. Furthermore some anthocyanidins and anthocyanin-rich berry extracts have been reported to inhibit tyrosine kinases, including the EGFR, which raises the question of potential interactions with erlotinib. Polyphenol-rich preparations such as berry- or soy-based products are commercially available as food supplements. In the present study we tested a bilberry extract, its major anthocyanin and potential intestinal degradation products, as well as genistein, with respect to possible interactions with erlotinib. Cell growth inhibition was assessed using the sulforhodamine B assay, while interactions with EGFR phosphorylation were analyzed by SDS-PAGE/western blotting with subsequent immunodetection. Genistein, bilberry extract, delphinidin-3-O-glucoside and delphinidin were found to antagonize erlotinib whereas phloroglucinol aldehyde was found to enhance cytostatic effects of the drug on human epithelial A431 cells. Genistein also antagonized the EGFR inhibitory effects of erlotinib, whereas bilberry anthocyanins showed no significant interactions in this regard. Our data indicate that different polyphenols are potentially able to impair the cytostatic effect of erlotinib in vitro. Genistein interacts via the modulation of erlotinib-mediated EGFR inhibition whereas bilberry anthocyanins modulated the growth-inhibitory effect of erlotinib without affecting EGFR phosphorylation, thus indicating a different mechanism of interference.


Treatment of an unusual complication of transfemoral TAVI with a new technique: successful occlusion of ventricular septal defect by opening the closure device in the ascending aorta.
Ventricular septal defect (VSD) is a rare complication of transcatheter aortic valve implantation (TAVI) via the transfemoral approach. Aetiological factors leading to VSD have been reported as post-balloon dilatation, oversized prosthesis implantation, and severe calcification of the aorta. However, we present a case of VSD occurring after TAVI with an Edwards Sapien XT prosthesis without any distinct aetiological factors. We used a new technique for closure of the significant VSD; opening the left ventricular disc of the closure device in the ascending aorta and successfully implanting the device without any damage to the bioprosthetic valve.


Plant hybrid zones as centers of biodiversity: the herbivore community of two endemic Tasmanian eucalypts.
We found the hybrid zone between Eucalyptus amygdalina and Eucalyptus risdonii to be a center of insect and fungal species richness and abundance. Of 40 taxa examined, 73% were significantly more abundant in the hybrid zone than in pure zones, 25% showed on significant differences, and 2% were most abundant on a pure host species. The average hybrid tree supported 53% more insect and fungal species, and relative abundances were, on average, 4 times greater on hybrids than on either eucalypt species growing in pure stands. Hybrids may act as refugia for rare species: 5 of 40 species were largely restricted to the hybrid zone. Also, 50% of the species coexisted only in the hybrid zone, making for mique species assemblages. Although hybrids support more species and greater abundances, all hybrids are not equal: 68% of the 40 taxa examined were significantly more abundant on one hybrid phenotype than another. While herbivore concentrations on F1 type intermediates were rare, concentrations were common on phenotypes resembling backcrosses either to E. amygdalina or E. risdonii. For specialist herbivores, the hybrid phenotype most heavily utilized appears to be determined by its phenotypic affinity to its host species. Generalists exhibit an overall greater abundance on hybrids, but are less likely to utilize one hybrid phenotype over another. Mechanistic explanations for these distributions are numerous and probably species specific, but are likely to include: increased genetic susceptibility of hybrids due to hybrid breakdown; increased stress in the hybrid zone resulting in greater plant susceptibility; and a greater diversity of resources in the hybrid zone which could support more species. Seed capsule production by hybrids and their parental species is negatively correlated with herbivory. However, it is difficult to determine whether herbivores cause this pattern as hybrids may have inherently lower sexual reproduction. Laws enacted to protect rare and endangered species do not include hybrids. We argue that a re-examination of our current "hybrid policy" is warranted. Plant hybrid zones are centers of plant evolution and speciation, sources of economically important plants and potential biocontrol agents, and, as our study suggests, also provide essential habitats for phytophagous communities.


Panmixia supports divergence with gene flow in Darwin's small ground finch, Geospiza fuliginosa, on Santa Cruz, Galápagos Islands.
The divergence-with-gene-flow model of speciation has a strong theoretical basis with a growing number of plausible examples in nature, but remains hotly debated. Darwin's finches of the Galápagos Archipelago have played an important role in our understanding of speciation processes. Recent studies suggest that this group may also provide insights into speciation via divergence with gene flow. On the island of Santa Cruz, recent studies found evidence for adaptive divergence in Darwin's small ground finch, Geospiza fuliginosa, between ecologically contrasting arid and humid zones. Despite the short geographical distance between these zones, strong disruptive selection during low rainfall periods is expected to generate and maintain adaptive divergence. Conversely, during high rainfall periods, when disruptive selection is predicted to be weakened, population divergence in adaptive traits is expected to break down. Because periods of low and high rainfall irregularly alternate, the geographical pattern of adaptive divergence can be assumed to break down and, importantly, regenerate in situ. Here, we use microsatellite allele frequency data to assess the genetic population structure of G. fuliginosa on Santa Cruz. We sample 21 sites and four ecological zones across the island. We reject hypotheses of population substructure linked to ecological and geographical differences among sites in favour of a single panmictic population. Panmixia implies high levels of gene flow within Santa Cruz, which favours selection over genetic drift as a valid process generating phenotypic divergence in G. fuliginosa on Santa Cruz. We discuss how our findings may support classic adaptation, phenotypic plasticity, matching habitat choice or any combination of these three processes.


A unified synthesis of topologically diverse Aspidosperma alkaloids through divergent iminium-trapping.
Aspidospermidine, vincadifformine, 1,2-dehydroaspidospermidine, goniomitine, and quebrachamine, five Aspidosperma alkaloids distributed within three structurally diverse topologies, were synthesized from a single molecular scaffold, namely indole-valerolactam 6. This common intermediate can be divergently manipulated, through the incorporation of conformational and electronic constraints that influence the chemo-selectivity of the iminium ion derived therefrom, between three different reaction paths: N(1) vs. C(3) cyclization (indole numbering) vs. over-reduction. Moreover, a catalytic carbene insertion for direct C(3)-H indole functionalization is reported for the first time in an approach to goniomitine (4), and a following tandem ester reduction/iminium generation/cyclization secured its tetracyclic system. The development of a highly diastereoselective one-pot hemi-reduction/cyclization/deprotection process to obtain a cis-pyridocarbazole directly allowed the synthesis of pentacyclic Aspidosperma alkaloids 1, 2, and 3.


What became of Arthur Conan Doyle's father? The last years of Charles Altamont Doyle.
This paper examines the fate of Arthur Conan Doyle's father, Charles Altamont Doyle, a Victorian illustrator, who spent his last years as an asylum inmate. Based on new archival research, it looks at the reasons for his institutionalisation and what befell him during his stay. It will consider Doyle's claim that he was wrongfully confined and also the suggestion that his family were responsible for having him committed. Finally, the paper will examine the nature of Doyle's condition and the creative work he produced whilst an asylum inmate.