Sustaining genetic variation in a small population: evidence from the Mauritius kestrel.
We obtained measures of genetic diversity in 10 kestrel species at a suite of 12 microsatellite loci. We estimated the relative effective size (Ne) of the species using a Markov chain Monte Carlo (MCMC) approach, which jointly estimated the locus specific mutation rates as nuisance parameters. There was surprisingly high genetic diversity found in museum specimens of the Mauritius kestrel. Being an endemic species on a small island, it is known to have a long history of small population size. Conversely, kestrels with a continental distribution had Ne estimates that were only one order of magnitude larger and similar to each other, despite having current population sizes that were between one and three orders of magnitude larger than the Mauritius kestrel. We show how many of the theoretical results describing the effective size of a subdivided population can be captured in terms of three rates which describe the branching pattern of the gene genealogy, and that they are useful in estimating the time to migration-drift and mutation-drift equilibrium. We use this approach to argue that population subdivision has helped retain genetic diversity in the Mauritius kestrel, and that the continental species' genetic diversity has yet to reach equilibrium after the range changes following the last ice age. We draw parallels with Hewitt's observation that genetic variation seems to survive species' range compression and is rather vulnerable to range expansion.


[Supervised curricular clinical clerkship: diversifying settings and strengthening teaching-service interaction].
Experience report of the Unochapecó Graduation Nursing Course presenting the implantation trajectory of the supervised curricular practical professional training, striving for the stand out of the contributions referring to the enlargement of the nurse role through the diversification of the practical settings and the possibilities of strengthening of the integration teaching-service. From 2006 on, there was a meaningful enlargement on the insertion of the students with care actions, management and education in the settings of the basic attention system, schools, and community spaces. This made a greater insertion of the students in the social context possible, making feasible its improvement in the abilities required to the professional nurse. On the other hand, it fortified the partnership relations among the graduating institution, professionals, managers and users, enlarging the possibilities of integration education service.


Clinical descriptors for the recognition of central sensitization pain in patients with knee osteoarthritis.
Despite growing awareness of the contribution of central pain mechanisms to knee osteoarthritis pain in a subgroup of patients, routine evaluation of central sensitization is yet to be incorporated into clinical practice. The objective of this perspective is to design a set of clinical descriptors for the recognition of central sensitization in patients with knee osteoarthritis that can be implemented in clinical practice. A narrative review of original research papers was conducted by nine clinicians and researchers from seven different countries to reach agreement on clinically relevant descriptors. It is proposed that identification of a dominance of central sensitization pain is based on descriptors derived from the subjective assessment and the physical examination. In the former, clinicians are recommended to inquire about intensity and duration of pain and its association with structural joint changes, pain distribution, behavior of knee pain, presence of neuropathic-like or centrally mediated symptoms and responsiveness to previous treatment. The latter includes assessment of response to clinical test, mechanical hyperalgesia and allodynia, thermal hyperalgesia, hypoesthesia and reduced vibration sense. This article describes a set of clinically relevant descriptors that might indicate the presence of central sensitization in patients with knee osteoarthritis in clinical practice. Although based on research data, the descriptors proposed in this review require experimental testing in future studies. Implications for Rehabilitation Laboratory evaluation of central sensitization for people with knee osteoarthritis is yet to be incorporated into clinical practice. A set of clinical indicators for the recognition of central sensitization in patients with knee osteoarthritis is proposed. Although based on research data, the clinical indicators proposed require further experimental testing of psychometric properties.


[Increased plasma membrane permeability for Ca2+ in radiation-induced thymocyte apoptosis].
Parameters of the Ca2+ permeability (the 45Ca influx rate in the presence of orthovanadate blocking the Ca(2+)-ATPhase, and the initial rate of the 45Ca uptake) and the DNA fragmentation were determined in rat thymocytes after gamma-irradiation-induced (with a dose of 5 Gy) apoptosis. Within the first 30-90 min after irradiation, the 45Ca influx rate that is characteristic of the membrane passive permeability remained unchanged. The initial rate of the 45Ca uptake that is characteristic of the Ca2+ exchange almost doubled. In 90-180 min, the rate of the 45Ca influx in the irradiated cells increased 1.5 to 2.0 times. An increase in the DNA fragmentation was observed in 90-120 min after irradiation of thymocytes; in 3 h, it developed up to 50%. Thus, modification of the membrane Ca2+ permeability in the irradiated thymocytes precedes a stage of initiation of the DNA degradation. A degree of disturbance of the membrane passive permeability increases as the thymocyte apoptosis progresses. The obtained data suggest that disturbance of the passive Ca2+ permeability and the intracellular Ca2+ homeostasis are responsible for the apoptosis of lethally irradiated thymocytes.


Audible pain squeaks can mediate emotional contagion across pre-exposed rats with a potential effect of auto-conditioning.
Footshock self-experience enhances rodents' reactions to the distress of others. Here, we tested one potential mechanism supporting this phenomenon, namely that animals auto-condition to their own pain squeaks during shock pre-exposure. In Experiment 1, shock pre-exposure increased freezing and 22 kHz distress vocalizations while animals listened to the audible pain-squeaks of others. In Experiment 2 and 3, to test the auto-conditioning theory, we weakened the noxious pre-exposure stimulus not to trigger pain squeaks, and compared pre-exposure protocols in which we paired it with squeak playback against unpaired control conditions. Although all animals later showed fear responses to squeak playbacks, these were weaker than following typical pre-exposure (Experiment 1) and not stronger following paired than unpaired pre-exposure. Experiment 1 thus demonstrates the relevance of audible pain squeaks in the transmission of distress but Experiment 2 and 3 highlight the difficulty to test auto-conditioning: stimuli weak enough to decouple pain experience from hearing self-emitted squeaks are too weak to trigger the experience-dependent increase in fear transmission that we aimed to study. Although our results do not contradict the auto-conditioning hypothesis, they fail to disentangle it from sensitization effects. Future studies could temporarily deafen animals during pre-exposure to further test this hypothesis.


Heeding the message? Determinants of risk behaviours for West Nile virus.
West Nile virus (WNv) emerged in North America in 1999, with the first incursion causing an outbreak of meningoencephalitis in the New York City area which resulted in seven deaths. In the face of WNv, public health professionals recommend various personal protective behaviours (PPBs) that either reduce the risk of mosquito bites (e.g., wearing protective clothing and/or insect repellent when outside at dusk or dawn) or eliminate mosquito breeding sites (e.g., preventing opportunities for standing water to stagnate; cleaning out eavestroughs regularly). This paper evaluates the uptake of the public health message in a WNv hot spot (2002) in order to assess the determinants of the likelihood of undertaking personal protective behaviours to reduce the risk of illness from WNv. A telephone survey was administered to a random sample of adults (n=1650) living in the L6L and L6K Forward Sortation Areas of Oakville, Ontario, Canada. While close to 100% of survey respondents were aware of WNv and approximately 80% recalled receiving information from the public health department regarding the virus, levels of reported personal protective behaviours were relatively low. Through a multivariable modeling process, a range of determinants emerged to explain outcome levels. The message about public education in the face of emerging health threats is clear; that is, that public education is key. But we cannot end the public health presence there--public health researchers must evaluate the uptake of the message.


Characterization of 14-3-3 isoforms expressed in the Echinococcus granulosus pathogenic larval stage.
The 14-3-3 protein family of eukaryotic regulators was studied in Echinococcus granulosus, the causative agent of cystic hydatid disease. These proteins mediate important cellular processes in eukaryotes and are expected to play important roles in parasite biology. Six isoforms of E. granulosus 14-3-3 genes and proteins (Eg14-3-3.1-6) were analyzed, and their phylogenetic relationships were established with bona fide 14-3-3 orthologous proteins from eukaryotic species. Eg14-3-3 isoforms with previous evidence of expression (Eg14-3-3.1-4) in E. granulosus pathogenic larval stage (metacestode) were cloned, and recombinant proteins were used for functional studies. These protein isoforms were detected in different components of E. granulosus metacestode, including interface components with the host. The roles that are played by Eg14-3-3 proteins in parasite biology were inferred from the repertoires of interacting proteins with each isoform, as assessed by gel overlay, cross-linking, and affinity chromatography assays. A total of 95 Eg14-3-3 protein ligands were identified by mass spectrometry. Eg14-3-3 isoforms have shared partners (44 proteins), indicating some overlapping functions; however, they also bind exclusive partners (51 proteins), suggesting Eg14-3-3 functional specialization. These ligand repertoires indicate the involvement of Eg14-3-3 proteins in multiple biochemical pathways in the E. granulosus metacestode and note some degree of isoform specialization.


Angiopoietin-1 and its receptor Tie-2 participate in the regulation of capillary-like tubule formation and survival of endothelial cells.
Angiopoietin-1 (Ang-1) and its receptor Tie-2, a trans-membrane tyrosine kinase uniquely expressed by endothelial cells, are shown by null mutation studies to be essential to developmental angiogenesis. The phenotypic abnormalities in these knockout animals suggest that Tie-2 signaling is necessary for the maintenance and expansion of the primitive capillary network. We present in vitro evidence indicating that the Ang-1/Tie-2 system participates in the regulation of capillary tubule formation and is necessary for the survival of confluent endothelial cells. Although recombinant Ang-1, which induces Tie-2 phosphorylation, has no effect on the proliferation of endothelial cells, treatment of confluent adult bovine aortic endothelial cells (ABAE) cells grown on collagen gels with Ang-1 (100 ng/ml) causes the cells to migrate into the collagen gel and form capillary-like tubules. The tubule-forming effect of Ang-1 is similar to the effect caused by FGF-2. A soluble form of the Tie-2 extracellular domain, in fivefold molar excess, blocks Ang-1-induced tubule formation. Specific elimination of Tie-2 protein expression in cultured ABAE cells as a result of transfection with an antisense oligonucleotide causes cell death in a dose-dependent manner (IC(50) = 50 nM). The antisense treatment has no effect on cells that do not express Tie-2. Cells treated with antisense oligonucleotide show a sixfold increase in the rate of apoptosis as assessed by in situ end labeling of fragmented DNA. These findings are consistent with the view that Ang-1/Tie-2 signaling is essential for both angiogenesis and endothelial cell survival.


Mutans streptococci in saliva and dental caries in children living in a high and a low fluoride area.
The aim of this study was to obtain information about the quantitative distribution of salivary mutans streptococci and the relation to dental caries in children with contrasting levels of natural water fluoride. A total of 698 schoolchildren aged 12 yr were selected from areas with high (1.2 ppm) or low (0.1 ppm) fluoride concentration in the drinking water. They were all examined for the presence and number of mutans streptococci in saliva by a specially prepared plastic strip, the "Strip mutans" method, cultivated in a selective broth. Data on the caries experience were obtained from the dental records and from bite-wing radiographs. Mutans streptococci were identified in 82% of all children with no difference between the two areas. The number of mutans streptococci was however significantly (p less than 0.05) lower among the children from the high fluoride area than those from the low fluoride area. Children with no detectable or low levels (0-10 CFU) of mutans streptococci had less caries experience than children with moderate or high levels (11- greater than 500 CFU) in both areas investigated.


Variation in life-history traits among Daphnia and its relationship to species-level responses to phosphorus limitation.
Currently organisms are experiencing changes in their environment at an unprecedented rate. Therefore, the study of the contributions to and responses in traits linked to fitness is crucial, as they have direct consequences on a population's success in persisting under such a change. Daphnia is used as a model organism as the genus contains keystone primary consumers in aquatic food webs. A life-history table experiment (LHTE) using four species of Daphnia was conducted to compare variation in life-history traits among species across two different environmental conditions (high and low phosphorus availability). Results indicate that the food quality environment had the most impact on life-history traits, while genetic contributions to traits were higher at the species-level than clonal-level. Higher trait variation and species-level responses to P-limitation were more evident in reproductive traits, while growth traits were found to be less affected by food quality and had less variation. Exploring trait variation and potential plasticity in organisms is increasingly important to consider as a potential mechanism for population persistence given the fluctuations in environmental stressors we are currently experiencing.


Sequence of the genome of the temperate, serotype-converting, Pseudomonas aeruginosa bacteriophage D3.
Temperate bacteriophage D3, a member of the virus family Siphoviridae, is responsible for serotype conversion in its host, Pseudomonas aeruginosa. The complete sequence of the double-stranded DNA genome has been determined. The 56,426 bp contains 90 putative open reading frames (ORFs) and four genes specifying tRNAs. The latter are specific for methionine (AUG), glycine (GGA), asparagine (AAC), and threonine (ACA). The tRNAs may function in the translation of certain highly expressed proteins from this relatively AT-rich genome. D3 proteins which exhibited a high degree of sequence similarity to previously characterized phage proteins included the portal, major head, tail, and tail tape measure proteins, endolysin, integrase, helicase, and NinG. The layout of genes was reminiscent of lambdoid phages, with the exception of the placement of the endolysin gene, which parenthetically also lacked a cognate holin. The greatest sequence similarity was found in the morphogenesis genes to coliphages HK022 and HK97. Among the ORFs was discovered the gene encoding the fucosamine O-acetylase, which is in part responsible for the serotype conversion events.


Voicing differences: indigenous and urban radio in Argentina, Chile, and Nigeria.
Indigenous cultures throughout the Americas and the rest of the world have to deal with problems of cultural assimilation, migration, and dissemination of their populations. Some of them, in countries such as Argentina, Chile, and Nigeria, have developed radio programming to maintain home languages; gain access to health, education, and employment information; greet friends and relatives; and re-create traditional culture under circumstances of modern pressures but also to open up opportunities. This article explores the capacity and awareness of these contributions in a multicultural world.


Expression of the catalytic subunit (UL54) and the accessory protein (UL44) of human cytomegalovirus DNA polymerase in a coupled in vitro transcription/translation system.
The catalytic subunit (UL54) and accessory protein (UL44) of human cytomegalovirus (HCMV) DNA polymerase have been cloned and expressed in an in vitro-coupled transcription/translation reticulocyte lysate system. The influence of the 5'-untranslated region (5'-UTR) on the efficiency of expression from the circular plasmids has been investigated. For expression of both UL54 and UL44, a truncated form of the alfalfa mosaic virus (AMV) RNA4 5'-UTR was found to be superior to the full-length AMV 5'-UTR or the original HCMV 5'-UTRs of different lengths. Protein products with Mr approximately 140 and 55 kDa were detected by sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis in the UL54 and UL44 in vitro expression reactions, respectively. The properties of the expressed enzyme were compared with those of native HCMV DNA polymerase purified from HCMV-infected cells. DNA polymerase and 3'-5' exonuclease activities of the expressed UL54/UL44 complex were found to be dependent on salt concentration in the same manner as the activities of the native enzyme. The in vitro-expressed enzyme resembles the purified HCMV DNA polymerase in its affinity for deoxynucleoside triphosphates as well as in its sensitivity to known inhibitors (cidofovir diphosphate, ganciclovir triphosphate, and foscarnet). This straightforward method for protein expression may also be applicable to other enzymes where reproducible generation of fully functional products is desirable.


Spermidine and Ca(2+), but not Na(+), can permeate NMDA receptors consisting of GluN1 and GluN2A or GluN2B in the presence of Mg(2+).
N-Methyl-D-aspartate receptors (NMDA receptors) are known to be permeable to Na(+) and Ca(2+) ions. In this study, we tested whether polyamines (putrescine, spermidine, spermine), organic cations found in cells, can permeate NMDA receptors expressed in Xenopus laevis oocytes and HEK293 cells. It was found that polyamines, especially spermidine, can permeate NMDA channels expressed from GluN1/GluN2A or GluN1/GluN2B activated by glycine and glutamate. Furthermore, spermidine and Ca(2+) influx through NMDA receptors was observed in the presence of Mg(2+), although Na(+) influx was strongly inhibited by Mg(2+). The Km values for spermidine influx through GluN1/GluN2A and GluN1/GluN2B were 2.2 mM and 2.7 mM, respectively in the presence of isotonic extracellular ion solutions. Spermidine uptake by NMDA receptors was dependent on the presence of glycine and glutamate, and inhibited by Ca(2+) and by memantine, an NMDA receptor channel blocker. The Km values for Ca(2+) influx through GluN1/GluN2A and GluN1/GluN2B were 4.6 mM and 3.3 mM, respectively, under the same ionic conditions. The results indicate that spermidine and Ca(2+), but not Na(+), can permeate NMDA receptors in the presence of Mg(2+). Spermidine, if released locally from presynaptic terminals (where its concentration is high in synaptosomes and synaptic vesicles) could permeate NMDA receptors and play a role in synaptic plasticity mediated by NMDA receptors together with Ca(2+).


What is the prognosis for a live birth after unexplained recurrent implantation failure following IVF/ICSI?
What is the cumulative incidence of live birth and mean time to pregnancy (by conception after IVF/ICSI or natural conception) in women experiencing unexplained recurrent implantation failure (RIF) following IVF/ICSI treatment? In 118 women who had experienced RIF, the reported cumulative incidence of live birth during a maximum of 5.5 years follow-up period was 49%, with a calculated median time to pregnancy leading to live birth of 9 months after diagnosis of RIF. Current definitions of RIF include failure to achieve a pregnancy following IVF/ICSI and undergoing three or more fresh embryo transfer procedures of one or two high quality embryos or more than 10 embryos transferred in fresh or frozen cycles. The causes and optimal management of this distressing condition remain uncertain and a range of empirical and often expensive adjuvant therapies is often advocated. Little information is available regarding the long-term prognosis for achieving a pregnancy. Two hundred and twenty-three women under 39 years of age who had experienced RIF without a known cause after IVF/ICSI treatment in two tertiary referral university hospitals between January 2008 and December 2012 were invited to participate in this retrospective cohort follow up study. All eligible women were sent a letter requesting their consent to the anonymous use of their medical file data and were asked to complete a questionnaire enquiring about treatments and pregnancies subsequent to experiencing RIF. Medical files and questionnaires were examined and results were analysed to determine the subsequent cumulative incidence of live birth and time to pregnancy within a maximum 5.5 year follow-up period using Kaplan Meier analysis. Clinical predictors for achieving a live birth were investigated using a Cox hazard model. One hundred and twenty-seven women responded (57%) and data from 118 women (53%) were available for analysis. During the maximum 5.5 year follow up period the overall cumulative incidence of live birth was 49% (95% CI 39-59%). Among women who gave birth, the calculated median time to pregnancy was 9 months after experiencing RIF, where 18% arose from natural conceptions. Since only 57% of the eligible study cohort completed the questionnaire, the risk of response bias limits the applicability of the study findings. This study reports a favorable overall prognosis for achieving live birth in women who have previously experienced RIF, especially in those who continue with further IVF/ICSI treatments. However since 51% did not achieve a live birth during the follow-up period, there is a need to distinguish those most likely to benefit from further treatment. In this study, no clinical factors were found to be predictive of those achieving a subsequent live birth. This study was funded by the University Medical Center Utrecht, in Utrecht and the Academic Medical Centre, in Amsterdam. NSM has received consultancy and speaking fees and research funding from Ferring, MSD, Merck Serono, Abbott, IBSA, Gedion Richter, and Clearblue. During the most recent 5-year period BCJMF has received fees or grant support from the following organizations (in alphabetic order); Actavis/Watson/Uteron, Controversies in Obstetrics & Gynecology (COGI), Dutch Heart Foundation, Dutch Medical Research Counsel (ZonMW), Euroscreen/Ogeda, Ferring, London Womens Clinic (LWC), Merck Serono, Myovant, Netherland Genomic Initiative (NGI), OvaScience, Pantharei Bioscience, PregLem/Gedeon Richter/Finox, Reproductive Biomedicine Online (RBMO), Roche, Teva, World Health Organisation (WHO).None of the authors have disclosures to make in relation to this manuscript.


Cardiac valve calcification: an immutable pathologic finding in chronic kidney disease?
Although less frequent than vascular calcification, cardiac valve calcification (CVC) is a relevant clinical problem affecting about 2%-10% of adults from the general population aged 75 years and older, and is 5- to 10-fold more prevalent in individuals with impaired kidney function. An expanding body of evidence suggests that mineral metabolism abnormalities aside from traditional cardiovascular risk factors are involved in CVC pathogenesis. Nonetheless, very few studies have investigated whether mineral metabolism manipulation impacts CVC. In this issue of the Journal of Nephrology, it is reported that a combination of low-phosphate diet and sevelamer may reduce CVC. Though the observational nature of that study and the lack of a control group significantly limit the generalizability of these results, they fit in with the ongoing debate on the role of chronic kidney disease mineral bone metabolism (CKD-MBD) in the pathogenesis of vascular disease and suggest the importance of mineral metabolism control in patients with CKD.


Clinical performance of porcelain laminate veneers. A retrospective evaluation over a period of 6.5 years.
Three-hundred and seventy-two porcelain laminate veneers were fitted to defective and discoloured teeth in 102 patients. Ninety per cent of the restorations were fitted to unprepared teeth. Restorations were reviewed up to 78 months after cementation. Survival probabilities were calculated using the Kaplan-Meier method. Results showed higher rates of failure and problem development in veneers fitted over existing restorations and in those fitted by inexperienced operators. A considerable number of veneers suffered minor problems that were successfully repaired.


Bidirectional Associations between Obesity and Cognitive Function in Midlife Adults: A Longitudinal Study.
The links between obesity and cognition remain equivocal due to a variety of methodological limitations with current research, such as an overreliance on body mass index (BMI) as a measure of obesity, the use of cross-sectional designs, and inadequate specification over the domains of cognitive function to be examined. To address these issues, we used data from the Cognitive Project of the National Survey of Midlife Development in the United States, a large-scale, longitudinal dataset on non-institutionalized midlife adults (N = 2652), which enabled us to examine the long-term bidirectional relations between obesity and two latent factors of cognition-executive function and episodic memory-while controlling for potential confounds. Results showed that, over a span of nine years, an increase in obesity in Time 1 is associated with a decline in episodic memory in Time 2 (but not executive function), while an increase in executive function in Time 1 (but not episodic memory) is associated with a reduction in obesity in Time 2. These results were elucidated when obesity was indexed with waist-to-hip ratio but not with BMI. Our findings highlight important directions for further research, in particular the use of more valid obesity indices and a greater focus on the bidirectional effects between obesity and cognition.


Coagulase-negative staphylococcal intramammary infections in cows and heifers during the nonlactating and periparturient periods.
Coagulase-negative staphylococci (CNS) are isolated frequently from unbred and primigravid heifers and from lactating and nonlactating dairy cows. The importance of CNS intramammary infections that occur during the nonlactating period has not been adequately delineated. Mammary secretions from udders infected with CNS during early lactation and the nonlactating period have increased somatic cell counts, CNS have been isolated in mammary secretions from cows with clinical mastitis, and a few studies have indicated that CNS infected mammary glands produced significantly less milk during lactation than uninfected mammary glands. In addition, mammary glands of postpubertal heifers infected with CNS were not as well developed as uninfected mammary glands. Consequently, CNS intramammary infections in heifers and cows during the nonlactating period could impair mammary gland growth and development and ultimately influence mammary function during lactation resulting in decreased lactational performance. Some CNS IMI detected in heifers and multiparous cows at calving do not persist into early lactation. Postmilking teat disinfection with an effective germicide and antibiotic therapy during the nonlactating period markedly reduces the prevalence of CNS in dairy herds. Methods of controlling CNS infections in primigravid heifers based on prepartum intramammary antibiotic therapy have been developed, and results have shown that prepartum antibiotic therapy is very effective against CNS and other mastitis pathogens as well. Additional research is required to determine the influence of CNS infections that occur during the nonlactating period on milk yield in the subsequent lactation.


Wear particles and ions from cemented and uncemented titanium-based hip prostheses-a histological and chemical analysis of retrieval material.
Wear debris-induced inflammation is considered to be the main cause for periprosthetic osteolysis in total hip replacements (THR). The objective of this retrieval study was to examine the tissue reactions and exposure to metal ions and wear particles in periprosthetic tissues and blood samples from patients with titanium (Ti)-based hip prostheses that were revised due to wear, osteolysis, and/or aseptic loosening. Semiquantitative, histological tissue evaluations in 30 THR-patients revealed numerous wear debris-loaded macrophages, inflammatory cells, and necrosis in both groups. Particle load was highest in tissues adjacent to loosened cemented Ti stems that contained mainly submicron zirconium (Zr) dioxide particles. Particles containing pure Ti and Ti alloy elements were most abundant in tissues near retrieved uncemented cups. Polyethylene particles were also detected, but accounted only for a small portion of the total particle number. The blood concentrations of Ti and Zr were highly elevated in cases with high abrasive wear and osteolysis. Our findings indicate that wear particles of different chemical composition induced similar inflammatory responses, which suggests that particle size and load might be more important than the wear particle composition in periprosthetic inflammation and osteolysis.


Long-term antiviral efficacy of entecavir and liver histology improvement in Chinese patients with hepatitis B virus-related cirrhosis.
To evaluate the clinical outcomes of 240-wk treatment with entecavir (0.5 mg) in Chinese nucleoside-naive patients with cirrhosis. A total of 204 nucleoside-naive patients with compensated (n = 96) or decompensated (n = 108) hepatitis B virus (HBV)-induced cirrhosis at the Department of Gastroenterology of the China-Japan Union Hospital (Jilin University, Changchun, China) who were treated with entecavir (0.5 mg) for 240 wk were enrolled in this study. Liver biopsy samples obtained from 38 patients prior to treatment (baseline) and at week 240 were evaluated by different independent histopathologists. Efficacy assessments included the proportions of patients who achieved an HBV DNA level < 500 copies/mL, the association of interleukin-28B genetic variation with antivirus therapy, clinical outcomes, and histologic improvement. Changes in liver disease severity were analyzed, and liver histologic evaluation was performed in 38 patients with paired biopsies. Student t tests were used to compare the means of continuous variables between the groups, and the proportions of patients who achieved the endpoints were compared using the χ(2) test. At week 240, 87.5% of the patients with compensated cirrhosis and 92.6% of the patients with decompensated cirrhosis achieved a HBV DNA level < 500 copies/mL. Three patients had genotypic entecavir resistance within the 240-wk period. No significant association was observed between virologic response and interleukin-28 genotype (CT, 88.2% vs CC, 90.6%). The proportion of patients with Child-Pugh class A disease was significantly increased at week 240 (68%) from the baseline (47%; P < 0.01). The proportion of patients with Child-Pugh class B disease was significantly decreased at week 240 (25%) from the baseline (39%; P = 0.02). In the patients with paired liver biopsies, the mean reduction in the Knodell necroinflammatory score from the baseline was 3.58 ± 1.03 points (7.11 ± 1.80 vs 3.53 ± 1.35, P < 0.01). The mean reduction in Ishak fibrosis score from the baseline was 1.26 ± 0.64 points (5.58 ± 0.50 vs 4.32 ± 0.81, P < 0.01). Entecavir is an effective treatment option for patients with HBV-related compensated or decompensated cirrhosis that can result in sustained virologic suppression and histologic improvement.


Glutathione peroxidase 2 and aquaporin 8 as new markers for colonic inflammation in experimental colitis and inflammatory bowel diseases: an important role for H2O2?
Different mouse models of inflammatory bowel diseases (IBD) demonstrate various aspects of the pathophysiology of IBD. We looked for overlapping gene expression profiles in three different mouse models of experimental colitis and analysed whether these overlapping genes are of help to find new genes that could be used as general markers in human IBD. Using Agilent mouse TOX oligonucleotide microarrays, we analysed the gene expression profiles in three widely used models of experimental colitis: 2,4,6-trinitrobenzene sulphonic acid, dextran sodium sulfate and CD4CD45RB transfer and looked for overlapping gene expression in these models. Overlapping genes were analysed using Lightcycler (Roche Diagnostics, Mannheim, Germany) in biopsy materials from human IBD and control tissue. Compared with control mice in dextran sodium sulfate, 2,4,6-trinitrobenzene sulphonic acid and the CD45RB transfer colitis mice five known genes, extracellular proteinase inhibitor (Expi), glutathione peroxidase 2 (Gpx2), mast cell protease 1 (Mcpt1), resistin-like beta (Retnlb) and sulphatase 2 (Sulf2), and two unknown genes were upregulated and the two genes aquaporin 8 (Aqp8) and kallikrein 5 (Klk5) were downregulated in all three models. In human Crohn's disease and ulcerative colitis biopsies, one of the upregulated glutathione peroxidase (Gpx2) and one of the downregulated Aqp8 genes in the mouse models were also differentially expressed in affected colonic tissue of patients with IBD. Experimental mouse models are suitable models for the search of new markers for human IBD. As both Gpx2 and Aqp8 are involved in H2O2 metabolism (Gpx2 as a radical scavenger whereas Aqp8 facilitates its diffusion), upregulation of Gpx2 and downregulation of Aqp8 could be a mechanism to defend against severe oxidative stress and indicate that H2O2 is a universal mediator in the inflammatory process in the colon. This provides a focus on homeostasis of the antioxidant pathway and its importance in IBD.


Assessing patient competence for medical decision making.
Competence frequently becomes an issue when a patient refuses a recommended surgical procedure or medication, refuses a placement option such as a nursing home or threatens to leave the hospital against medical advice. Physicians often struggle to balance the patient's right to self-determination and informed consent with their own mission to provide patients with optimal treatment. At present, few guidelines exist to assist physicians in making competence determinations. Legal precedents and conceptual issues in evaluating competence are reviewed. A protocol for assessing competence is presented.


Revisiting the Role of Leukocytes in Cystic Fibrosis.
Cystic fibrosis in characterized by pulmonary bacterial colonization and hyperinflammation. Lymphocytes, monocytes/macrophages, neutrophils, and dendritic cells of patients with CF express functional CFTR and are directly affected by altered CFTR expression/function, impairing their ability to resolve infections and inflammation. However, the mechanism behind and the contribution of leukocytes in the pathogenesis of CF are still poorly characterized. The recent clinical introduction of specific CFTR modulators added an important tool not only for the clinical management of the disease but also to the investigation of the pathophysiological mechanisms related to CFTR dysfunction and dysregulated immunity. These drugs treat the basic defect in cystic fibrosis (CF) by increasing CFTR function with improvement of lung function and quality of life, and may improve clinical outcomes also by correcting the dysregulated immune function that characterizes CF. Measure of CFTR function, protein expression profiling and several omics methods were used to identify molecular changes in freshly isolated leukocytes of CF patients, highlighting two roles of leukocytes in CF: one more generally related to the mechanism(s) causing immune dysregulation in CF and unresolved inflammation, and another more applicative role, which identifies in myeloid cells, an important tool predictive of the therapeutic response of CF patients. In this review we will summarize available data on CFTR expression and function in leukocyte populations and will discuss potential clinical applications based on available data.


Outcomes following percutaneous upper gastrointestinal decompressive tube placement for malignant bowel obstruction in ovarian cancer.
The objective of this study was to evaluate peri-operative and survival outcomes of ovarian cancer patients undergoing percutaneous upper gastrointestinal decompression for malignant bowel obstruction (MBO). Retrospective chart review was used to identify patients with ovarian, peritoneal, or fallopian tube cancer who underwent palliative decompressive treatment for MBO from 1/2002 to 12/2010. Kaplan-Meier methods were used to estimate the median survival (MS) and multivariate analysis used to determine if any variables were associated with the hazard of death. Fifty-three patients met inclusion criteria. Median length of diagnosis prior to intervention was 21 months. Fifteen (28.3%) patients experienced complications and 9 required revision. Forty-nine (92.5%) experienced relief of symptoms after placement, and 91% tolerated some form of oral intake. Following placement, 19 (36%) patients received additional chemotherapy and 21(41%) patients received total parental nutrition (TPN). Thirty-five patients were discharged home/outpatient facility, 16 to hospice care, and 2 died prior to discharge. MS for all patients was 46 days. Patients who received chemotherapy had a MS of 169 days compared to 33 days (p<0.001). We failed to find an association between survival and TPN or performance status. Malignant bowel obstruction is a common complication of ovarian cancer. Management is palliative; risks and benefits of any therapy must be considered. Percutaneous decompressive therapy provides relief from associated symptoms, and allows patients to be discharged home. Median survival in this group is limited, and decisions regarding aggressive therapy should be individualized.


The validity and reproducibility of cross table radiographs compared with CT scans for the measurement of anteversion of the acetabular component after total hip arthroplasty.
The aim of this study was to assess the reproducibility and validity of cross table radiographs for measuring the anteversion of the acetabular component after total hip arthroplasty (THA) and to compare it with measurements using CT scans. A total of 29 patients who underwent THA between June 2010 and January 2016 were included. There were 17 men and 12 women. Their mean age was 43 years (26 to 65). Seven patients underwent a bilateral procedure. Thus, 36 THAs were included in the study. Lateral radiographs and CT scans were obtained post-operatively and radiographs repeated three weeks later. The anteversion of the acetabular component was measured using the method described by Woo and Morrey and the ischiolateral method described by Pulos et al and these were compared with the results obtained from CT scans. The mean anteversion was 18.35° (3° to 38°) using Woo and Morrey's method, 51.45° (30° to 85°) using the ischiolateral method and 21.22° (2° to 48°) using CT scans. The Pearson correlation coefficient was 0.754 for Woo and Morrey's method and 0.925 for the ischiolateral method. There was a linear correlation between the measurements using the ischiolateral method and those using CT scans. We derived a simple linear equation between the value of the CT scan and that of ischiolateral method to deduce the CT scan value from that of ischiolateral method and vice versa. The anteversion of the acetabular component measured using both plain radiographic methods was consistently valid with good interobserver reproducibility, but the ischiolateral method which is independent of pelvic tilt was more accurate. As CT is costly, associated with a high dose of radiation and not readily available, the ischiolateral method can be used for assessing the anteversion of the acetabular component. Cite this article: Bone Joint J 2017;99-B:1006-11.


The cricothyroid versus Spray-As-You-Go method for topical anesthesia during Endobronchial Ultrasound-guided Transbronchial Needle Aspiration (EBUS-TBNA): The CRISPEN randomized clinical trial.
Guidelines for flexible bronchoscopy in adults recommend both Cricothyroid and Spray-as-you-go method as the acceptable techniques for lignocaine administration. No studies have compared these two methods for topical anesthesia during endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). Co-primary outcomes were the comparison of cough count and operator-rated overall procedure satisfaction on a Visual Analog Scale (VAS) between the groups. The secondary outcomes were cumulative lignocaine dose, time from bronchoscope introduction to crossing the vocal cords, procedure duration, and complications between the groups. Consecutive participants (age >18 years) undergoing EBUS-TBNA were randomized (1:1) to either cricothyroid or spray-as-you-go methods for lignocaine administration. Three hundred and sixty-five participants were randomized (183: Cricothyroid and 182: Spray-as-you-go). Cough count till reaching carina (median [interquartile range]) was significantly lower (cricothyroid, 1 [0-2] vs. spray-as-you-go, 4 [2-6], P < 0.001) and operator rated overall procedure satisfaction, on VAS (mean ± standard deviation) (cricothyroid, 7.96 ± 1.48 vs. spray-as-you-go, 7.29 ± 1.48, P < 0.001) significantly greater in the cricothyroid group. Cumulative lignocaine dose (163.28 ± 31.50 mg vs. 177.0 ± 30.12 mg, P < 0.0001) and time from bronchoscope introduction to crossing the vocal cords (20.80 ± 11.21 s vs. 38.08 ± 15.26 s, P < 0.001) was significantly lower in the cricothyroid group. Procedure duration was similar in both the groups. Minor complications occurred in three patients in cricothyroid and six patients in the spray-as-you-go group (P = 0.31). Cricothyroid lignocaine administration is associated with less cough and superior operator-rated procedure satisfaction during EBUS-TBNA, at a lower cumulative lignocaine dose administered. www.clinicaltrials.gov NCT02981264.


Age of acquisition effects in adult lexical processing reflect loss of plasticity in maturing systems: insights from connectionist networks.
Early learned words are recognized and produced faster than later learned words. The authors showed that such age of acquisition effects are a natural property of connectionist models trained by back-propagation when patterns are introduced at different points into training and learning of early and late patterns is cumulative and interleaved. Analysis of hidden unit activations indicated that the age of acquisition effect reflects a gradual reduction in network plasticity and a consequent failure to differentiate late items as effectively as early ones. Further simulations examined the effects of vocabulary size, learning rate, sparseness of coding, use of a modified learning algorithm, loss of early items, acquisition of very late items, and lesioning the network. The relationship between age of acquisition and word frequency was explored, including analyses of how the relative influence of these factors is modulated by introducing weight decay.


[Quant therapy and the composition of the moister of the eye anterior chamber (an experimental study)].
We examined 12 rabbits, 6 of whom (12 eyes) were exposed to magneto-infrared laser radiation (MILR) and another 6 (12 eyes) were controls. The parameters of pulse and continuous infrared LED radiation were as follows: wavelength--860 nm, pulse capacity--2 W, mean radiation capacity--10 mW, magnetic field strength--up to 17 mTl. A study of the moister of the anterior chamber showed a MILR-induced activated metabolism, i.e. a better acid-base balance (ABB), more intense oxygenation in the ocular tissues and decreased acidosis. Higher concentrations of buffer bases (ABEe and SBEc) cause shifts in ABB towards metabolic alkalosis. A lower concentration of glucose denotes intensified processes related with its utilization. A lack of changes in the quantity of salts in the moister of the anterior chamber rules out the possibility of that the content of glucose would go down due to its dissolution with a big volume of newly produced moister. A lack of an increase in the concentration of whole protein, as observed after MILR, can be regarded as indirect evidence to absence of any adverse effect on the vascular wall.


Top down influence on visuo-tactile interaction modulates neural oscillatory responses.
Multisensory integration involves bottom-up as well as top-down processes. We investigated the influences of top-down control on the neural responses to multisensory stimulation using EEG recording and time-frequency analyses. Participants were stimulated at the index or thumb of the left hand, using tactile vibrators mounted on a foam cube. Simultaneously they received a visual distractor from a light emitting diode adjacent to the active vibrator (spatially congruent trial) or adjacent to the inactive vibrator (spatially incongruent trial). The task was to respond to the elevation of the tactile stimulus (upper or lower), while ignoring the simultaneous visual distractor. To manipulate top-down control on this multisensory stimulation, the proportion of spatially congruent (vs. incongruent) trials was changed across blocks. Our results reveal that the behavioral cost of responding to incongruent than congruent trials (i.e., the crossmodal congruency effect) was modulated by the proportion of congruent trials. Most importantly, the EEG gamma band response and the gamma-theta coupling were also affected by this modulation of top-down control, whereas the late theta band response related to the congruency effect was not. These findings suggest that gamma band response is more than a marker of multisensory binding, being also sensitive to the correspondence between expected and actual multisensory stimulation. By contrast, theta band response was affected by congruency but appears to be largely immune to stimulation expectancy.


Influenza-like illness in residential care homes: a study of the incidence, aetiological agents, natural history and health resource utilisation.
Influenza-like illness (ILI) among elderly people living in residential care homes (RCHEs) is a common cause for hospitalisation. A study was undertaken to examine the incidence, underlying aetiology, natural history and associated healthcare resource utilisation related to ILI in the RCHE population. A prospective study of ILI in four RCHEs in Shatin, Hong Kong was conducted from April 2006 to March 2007. Each RCHE was monitored daily for the occurrence of ILI and followed up until resolution of illness or death. Clinical features were recorded and sputum, nasopharyngeal aspirate, blood and urine specimens were examined for underlying aetiology. 259 episodes of ILI occurred in 194 subjects, with mild peaks in winter and summer, over a sustained level throughout the year. The infectious agent was identified in 61.4% of all episodes, comprising bacterial infection in 53.3% and viral in 46.7%. Multiple infections occurred in 16.2% of subjects. The most frequent organism was Streptococcus pneumoniae, followed by respiratory syncytial virus, Pseudomonas aeruginosa, metapneumovirus and parainfluenza virus types 1 and 3. Clinical features did not vary according to the underlying aetiology, the common presenting features being a decrease in general condition, cognitive and functional deterioration, and withholding of food in addition to fever and respiratory symptoms. Overall, mortality at 1 month/discharge was 9.7%. Infection with methicillin-resistant Staphylococcus aureus, low body mass index and poor function predisposed to mortality. No association was observed between influenza vaccination status and underlying aetiology, clinical features or outcome. The clinical presentation of ILI is non-specific and is mainly due to bacterial and viral infections other than influenza in the RCHE population.


Structurally modified analogues of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) as future antidiabetic agents.
Glucagon-like peptide-1(7-36)amide (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are gastrointestinal insulin-releasing hormones involved in the regulation of postprandial nutrient homeostasis. These two incretin hormones are glucose-dependent stimulators of pancreatic beta-cell function, exhibiting a spectrum of secondary extrapancreatic activities, which favour the efficient control of blood glucose homeostasis. Such actions of GLP-1 and GIP have generated considerable interest in their possible exploitation as novel agents for the treatment of type 2 diabetes. Despite the many attributes of GLP-1 and GIP as possible future antidiabetic agents, their rapid degradation in the circulation by dipeptidyl peptidase IV (DPP IV) to inactive truncated forms GLP-1(9-36)amide and GIP(3-42), severely limits their therapeutic usefulness. This review will consider recent developments in the design and effectiveness of synthetic DPP IV-resistant analogues of GLP-1 and GIP. Consideration will be given to the effects of N-terminal modification and amino acid substitution of GLP-1 and GIP either side of the DPP IV cleavage site on (i) susceptibility to enzymatic degradation, (ii) binding to native hormone receptor, (iii) ability to elevate intracellular cyclic AMP, (iv) potency as insulin secretagogues, and (v) antihyperglycaemic activity in type 2 diabetes. It will be shown that structural modification can produce a varied set of biological activities, ranging from more efficacious analogues to those which antagonise the activity of the native hormone. The antidiabetic properties of the best GLP-1 and GIP analogues indeed promise to provide the basis for novel, effective and long-acting drugs for type 2 diabetes therapy. This approach is currently being pursued actively by the pharmaceutical industry.


Late-stage peptide C-H alkylation for bioorthogonal C-H activation featuring solid phase peptide synthesis.
Methods for the late-stage diversification of structurally complex peptides hold enormous potential for advances in drug discovery, agrochemistry and pharmaceutical industries. While C-H arylations emerged for peptide modifications, they are largely limited to highly reactive, expensive and/or toxic reagents, such as silver(I) salts, in superstoichiometric quantities. In sharp contrast, we herein establish the ruthenium(II)-catalyzed C-H alkylation on structurally complex peptides. The additive-free ruthenium(II)carboxylate C-H activation manifold is characterized by ample substrate scope, racemization-free conditions and the chemo-selective tolerance of otherwise reactive functional groups, such as electrophilic ketone, bromo, ester, amide and nitro substituents. Mechanistic studies by experiment and computation feature an acid-enabled C-H ruthenation, along with a notable protodemetalation step. The transformative peptide C-H activation regime sets the stage for peptide ligation in solution and proves viable in a bioorthogonal fashion for C-H alkylations on user-friendly supports by means of solid phase peptide syntheses.


High parity and fetal morbidity outcomes.
We investigated the association between high parity and fetal morbidity outcomes. We analyzed 22,463,141 singleton deliveries at 20 weeks or more of gestation in the United States from 1989 through 2000. Adjusted odds ratios generated from logistic regression models were used to approximate relative risk for neonatal morbidity in women with 1-4 (moderate parity or type I; referent group), 5-9 (high parity or type II), 10-14 (very high parity or type III) and 15 or more (extremely high parity or type IV) prior live births. Main outcome measures included low and very low birth weight, preterm and very preterm birth, and small and large for gestational age delivery. The overall crude rates for low birth weight, very low birth weight, preterm birth, very preterm birth, and small and large for gestational age were 55, 11, 97, 19, 83, and 129 per 1,000 live births, respectively. The adjusted odds ratios for low birth weight, very low birth weight, preterm, and very preterm delivery increased consistently and in a dose-effect fashion with ascending parity (P for trend < .001). In the case of large for gestational age delivery, the adjusted odds ratio showed an inverted-U pattern, being highest among women in the type III parity cluster. The findings with respect to small for gestational age were inconclusive. High parity is a risk factor for adverse fetal outcomes. However, the impact of heightened parity is more manifest as shortened gestation rather than physical size restriction. These findings could prove beneficial for counseling women of high parity.


Effects of nonselective internal iliac artery angioembolization on pelvic venous flow in the swine model.
Pelvic angioembolization (AE) is a mainstay in the treatment algorithm for pelvic hemorrhage from pelvic fractures. Nonselective AE refers to embolization of the bilateral internal iliac arteries (IIAs) proximally rather than embolization of their tributaries distally. The aim of this study was to quantify the effect of nonselective pelvic AE on pelvic venous flow in a swine model. We hypothesized that internal iliac vein (IIV) flow following IIA AE is reduced by half. Nine Yorkshire swine underwent nonselective right IIA gelfoam AE, followed by left. Pelvic arterial and venous diameter, velocity, and flow were recorded at baseline, after right IIA AE and after left IIA AE. Linear mixed-effect model and signed rank test were used to evaluate significant changes between the three time points. Eight swine (77.8 ± 7.1 kg) underwent successful nonselective IIA AE based on achieving arterial resistive index of 1.0. One case was aborted because of technical difficulties. Compared with baseline, right IIV flow rate dropped by 36% ± 29% (p < 0.05) and 54% ± 29% (p < 0.01) following right and left IIA AE, respectively. Right IIA AE had no initial effect on left IIV flow (0.37% ± 99%, p = 0.95). However, after left IIA AE, left IIV flow reduced by 54% ± 27% (p < 0.01). Internal iliac artery AE had no effect on the external iliac arterial or venous flow rates and no effect on inferior vena cava flow rate. The effect of unilateral and bilateral IIA AE on IIV flow appears to be additive. Despite bilateral IIA AE, pelvic venous flow is diminished but not absent. There is abundant collateral circulation between the external and internal iliac vascular systems. Arterial embolization may reduce venous flow and improve on resuscitation efforts in those with unstable pelvic fractures. Prognostic, level IV.


[The right to health from the point of view of members of a local health council]
Based on a qualitative methodology using interactive techniques (in-depth open interviews), this study discusses both the concept of the right to health and potential ways to claim this right from the point of view of a group of full members of the Local Health Council in the City of São Paulo during the 1993-1996 term. The study also interprets a number of issues related to "health advocacy", a potential locus of support and advice for groups working to improve health conditions for the population.


Type A behavior pattern shortens length of stay in comprehensive rehabilitation units.
[Purpose] The aim of this study was to describe the importance of patient-related factors in rehabilitation. We focused on the type A behavior pattern. If individuals with the type A behavior pattern have better compliance, they would have a shorter length of hospital stay than those with non-type A behavior. We compared the length of stay of patients with the type A behavior pattern with that of patients with a non-type A behavior pattern. [Subjects and Methods] Fifty-seven patients staying in a comprehensive rehabilitation unit participated in this study. Type A behavior pattern, length of stay, and Barthel Index were assessed. We use the Student's t-test to examine the statistical differences in length of stay and Barthel Index at discharge between subjects with type A behavior and those without type A behavior. [Results] Age and Barthel Index at discharge were not significantly different between the two groups. However, length of stay was significantly higher in the non-type A group compared with the type A group. [Conclusion] Patients with the type A behavior pattern had a shorter length of hospital stay than patients with a non-type A behavior pattern. In conclusion, our results suggest that the type A behavior pattern shortens the length of hospital stay. Those data show that we should consider the patient's characteristics in rehabilitation to protect the patient and for financial benefit.


Circadian clock-controlled intestinal expression of the multidrug-resistance gene mdr1a in mice.
P-glycoprotein, the product of the multidrug resistance (mdr) gene, functions as a xenobiotic transporter contributing to the intestinal barrier. Although intestinal expression of the mdr1a gene and its efflux pump function has been shown to exhibit 24-hour variation, the mechanism of the variations remains poorly understood. Here, we demonstrated that the molecular components of the circadian clock act as regulators to control 24-hour variation in the expression of the mdr1a gene. Luciferase reporter assay and gel mobility shift assay were used to study the mechanism of transcriptional regulation of the mdr1a gene by clock gene products. The messenger RNA levels and protein abundances in colon 26 cells and mouse intestine were measured by quantitative real-time polymerase chain reaction and Western blotting, respectively. Hepatic leukemia factor (HLF) and E4 promoter binding protein-4 (E4BP4) regulated transcription of the mdr1a gene by competing with each other for the same DNA binding site. Molecular and biochemical analyses of HLF- and E4BP4-down-regulated colon 26 cells and the intestinal tract of Clock mutant mice suggested that these 2 proteins consisted of a reciprocating mechanism in which HLF activated the transcription of the mdr1a gene, whereas E4BP4 periodically suppressed transcription at the time of day when E4BP4 was abundant. The intestinal expression of the mdr1a gene is influenced by the circadian organization of molecular clockwork. Our present findings provide a link between the circadian timekeeping system and xenobiotic detoxification.


Allostery of actin filaments: molecular dynamics simulations and coarse-grained analysis.
The structural and mechanical properties of monomeric actin (G-actin), the trimer nucleus, and actin filaments (F-actins) are determined as a function of the conformation of the DNase I-binding loop (DB loop) by using all-atom molecular dynamics simulations and coarse-grained (CG) analysis. Recent x-ray structures of ADP-bound G-actin (G-ADP) by Otterbein et al. [Otterbein, L. R., Graceffa, P. & Dominguez, R. (2001) Science 293, 708-711] and ATP-bound G-actin (G-ATP) by Graceffa and Dominguez [Graceffa, P. & Dominguez, R. (2003) J. Biol. Chem. 278, 34172-34180] indicate that the DB loop of actin does not have a well defined secondary structure in the ATP state but folds into an alpha-helix in the ADP state. MD simulations and CG analysis indicate that such a helical DB loop significantly weakens the intermonomer interactions of actin assemblies and thus leads to a wider, shorter, and more disordered filament. The computed persistence lengths of F-actin composed of G-ATP (16 microm) and of G-ADP (8.5 microm) agree well with the experimental values for the two states. Therefore, the loop-to-helix transition of the DB loop may be one of the factors that lead to the changes in structural and mechanical properties of F-actin after ATP hydrolysis. This result may provide a direct connection between the conformational changes of an actin monomer and the structural and mechanical properties of the cytoskeleton. The information provided by MD simulations also helps to understand the possible origin of the special features of actin dynamics.


Quantitative structure-activity relationships of colchicines against P388 leukemia in mice.
A quantitative structure-activity relationship (QSAR) was derived for colchicine and 14 analogues acting against P388 lymphocytic leukemia in mice. Twelve additional compounds were synthesized to reinforce and confirm the correlation. The final correlation indicates that there is a parabolic dependence of antitumor potency on the partition coefficient with log P0=1.17. When an amino nitrogen is present on the B ring, increased potency is favored by acylation of the nitrogen. The most potent compound of the series was the 7-fluoroacetamide analogue. Strong electron-withdrawing groups substituted at the 10 position of the tropolone ring destroy activity. Electron-releasing groups at position 10 improve potency slightly but have a limited effect.


Online monitoring of Escherichia coli and Bacillus thuringiensis spore inactivation after advanced oxidation treatment.
Various studies have shown that advanced oxidation processes (AOPs) such as UV light in combination with hydrogen peroxide is an efficient process for the removal of a large variety of emerging contaminants including microorganisms. The mechanism of destruction in the presence of hydrogen peroxide (H2O2) is the enhanced formation of hydroxyl (·OH) radicals, which have a high oxidation potential. The goal of this study was to utilize in-line advanced oxidation to inactivate microbes, and document the inactivation via an in-line, real-time sensor. Escherichia coli cells and Bacillus thuringiensis spores were exposed to UV/H2O2 treatment in DI water, and the online sensor BioSentry(®) was evaluated for its potential to monitor inactivation in real-time. B. thuringiensis was selected as a non-pathogenic surrogate for B. anthracis, the causative agent of anthrax and a proven biological weapon. UV radiation and UV/H2O2 exposure resulted in a >6 log10 reduction of the viable culturable counts of E. coli vegetative cells, and a 3 log10 reduction of B. thuringiensis spores. Scanning electron microscopy of the treated samples revealed severe damage on the surface of most E. coli cells, yet there was no significant change observed in the morphology of the B. thuringiensis spores. Following AOP exposure, the BioSentry sensor showed an increase in the categories of unknown, rod and spores counts, but overall, did not correspond well with viable count assays. Data from this study show that advanced oxidation processes effectively inactivate E. coli vegetative cells, but not B. thuringiensis spores, which were more resistant to AOP. Further, the BioSentry in-line sensor was not successful in documenting destruction of the microbial cells in real-time.


The spectrum of the non-rapid eye movement sleep electroencephalogram following total sleep deprivation is trait-like.
The sleep electroencephalogram (EEG) spectrum is unique to an individual and stable across multiple baseline recordings. The aim of this study was to examine whether the sleep EEG spectrum exhibits the same stable characteristics after acute total sleep deprivation. Polysomnography (PSG) was recorded in 20 healthy adults across consecutive sleep periods. Three nights of baseline sleep [12 h time in bed (TIB)] following 12 h of wakefulness were interleaved with three nights of recovery sleep (12 h TIB) following 36 h of sustained wakefulness. Spectral analysis of the non-rapid eye movement (NREM) sleep EEG (C3LM derivation) was used to calculate power in 0.25 Hz frequency bins between 0.75 and 16.0 Hz. Intraclass correlation coefficients (ICCs) were calculated to assess stable individual differences for baseline and recovery night spectra separately and combined. ICCs were high across all frequencies for baseline and recovery and for baseline and recovery combined. These results show that the spectrum of the NREM sleep EEG is substantially different among individuals, highly stable within individuals and robust to an experimental challenge (i.e. sleep deprivation) known to have considerable impact on the NREM sleep EEG. These findings indicate that the NREM sleep EEG represents a trait.


HIV infection in the female genital tract: discrete influence of the local mucosal microenvironment.
Women acquire HIV infections predominantly at the genital mucosa through heterosexual transmission. Therefore, the immune milieu at female genital surfaces is a critical determinant of HIV susceptibility. In this review, we recapitulate the evidence suggesting that several distinctive innate immune mechanisms in the female genital tract (FGT) serve to significantly deter or facilitate HIV-1 infection. Epithelial cells lining the FGT play a key role in forming a primary barrier to HIV entry. These cells express Toll-like receptors and other receptors that recognize and respond directly to pathogens, including HIV-1. In addition, innate biological factors produced by epithelial and other cells in the FGT have anti-HIV activity. Female sex hormones, co-infection with other pathogens and components in semen may also exacerbate or down-modulate HIV transmission. A combination of innate and adaptive immune factors and their interactions with the local microenvironment determine the outcome of HIV transmission. Improving our understanding of the female genital microenvironment will be useful in developing treatments that augment and sustain protective immune responses in the genital mucosa, such as microbicides and vaccines, and will provide greater insight into viral pathogenesis in the FGT.


Ethnobotany of Heracleum persicum Desf. ex Fisch., an invasive species in Norway, or how plant names, uses, and other traditions evolve.
Heracleum persicum was introduced to Norway as an ornamental in the 1830's. Towards the end of the 19th century, it started spreading outside gardens, later to become a frequent sight in the major towns and settlements of North Norway - and a veritable pest plant. During the last 100 years or so, a substantial ethnobotanical tradition related to the species has evolved, demonstrating that folk knowledge is not only forgotten and lost, but also charting new terrain. This survey is based on data extracted from all relevant publications, including botanical literature, travel accounts, newspaper notes, etc., as far as they have come to my attention. In addition, information on vernacular names and various uses of the H. persicum in Norway has been extracted from my own, substantial archive of interviews, questionnaires, and correspondence related to the ethnobotany of Norway. Where extant, H. persicum tends to be known to everyone, even by city dwellers who otherwise generally neglect plants. People tend to love or hate it, and in Tromsø, the largest town of northern Norway, the species has become more or less emblematic of the city. Both here and in other areas of northern Norway, it is referred to by a variety of vernacular names, partly borrowed from other species, partly derived from the Latin genus name, and partly coined for this species only. In the latter group, tromsøpalme ('the palm of Tromsø') has proved by far the most popular invention. It was seemingly first used (and coined) by German soldiers during the World War II occupation of Norway, but now largely replaces other vernacular names. The plant is still popular with children, who frequently play in and with it, whereas adults have been more prone to speculate on its origins - and how to get rid of it. Salt is the most popular "herbicide" for this purpose. Over the years, H. persicum has accumulated at least twenty different vernacular names in Norway, and a variety of other traditions. By necessity, all these traditions are less than 180 years old, showing that even modern and urban societies may produce a substantial body of plant lore, which certainly merits ethnobotanical attention.


Excessive weight gain during pregnancy increases carcinogen-induced mammary tumorigenesis in Sprague-Dawley and lean and obese Zucker rats.
Excessive weight gain during pregnancy increases breast cancer risk in women. To determine whether this may be caused by increased pregnancy leptin levels, leptin receptor (Ob-Rb) mutant (fa/fa) and wild-type (FA/FA) female Zucker rats and Sprague-Dawley rats were fed during pregnancy an obesity-inducing high-fat diet (OID) that increased pregnancy weight gain, or a control diet. Because mutant Zucker rats do not readily become pregnant, their pregnancy was mimicked by exposing the rats to subcutaneous silastic capsules containing 150 microg of estradiol and 30 mg of progesterone for 3 wk. Sprague-Dawley rats underwent normal pregnancy. An assessment of hormone levels on gestation d 17 indicated that an exposure to the OID significantly elevated serum leptin concentration but did not affect those of estradiol or insulin-like growth factor 1 (IGF-1). Insulin and adiponectin levels were higher in the obese than lean Zucker rats, but were not related to pregnancy weight gain. Exposure to the OID during pregnancy increased 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumorigenesis in all genetic backgrounds, including leptin receptor mutant Zucker rats. The results also indicated that obese Zucker rats that underwent mimicked pregnancy developed more palpable tumors and hyperplastic alveolar nodules that lean Zucker rats. Further, mammary epithelial cell proliferation assessed using PCNA staining was elevated in obese Zucker rats as was activation of mitogen-activated protein kinase (MAPK); however, neither of these 2 changes occurred in the context of excessive weight gain during pregnancy. It remains to be determined whether an increase in leptin levels was causally associated with an increase in the dams' mammary tumorigenesis, including in obese Zucker rats with dramatically reduced leptin signaling.


Operative techniques in early-stage lung cancer.
Lung cancer is the most common cause of death by malignancy, responsible for more deaths than the next 4 causes combined and predicted to account for nearly 220,000 new cancer diagnoses and 160,000 deaths in 2009. The cornerstone of therapy for early-stage lung cancer is lobectomy and mediastinal lymph node dissection. Although lobectomy is considered the standard procedure, segmentectomy may be appropriate for selected patients. Conventional approaches to resection may be used, including posterolateral and muscle-sparing thoracotomy. However, minimally invasive lobectomy and segmentectomy procedures are now commonly used with superior outcomes.


Cardiac and Respiratory Complications of Necrotizing Autoimmune Myopathy.
To characterize the cardiorespiratory abnormalities in patients with necrotizing autoimmune myopathy (NAM). Cardiopulmonary features of patients with NAM evaluated in our neuromuscular clinic (January 1, 2004, to September 20, 2018) were reviewed retrospectively with respect to autoantibody status and history of cardiac disease. Clinical characteristics and laboratory findings were compared among patient subgroups. We identified 109 patients with NAM: 36 anti-3-hydroxy-3-methylglutaryl coenzyme A reductase autoantibody (anti-HMGCR Ab)-positive, 18 anti-signal recognition particle antibody (anti-SRP Ab)-positive (3 dual anti-HMGCR/anti-SRP Ab-positive), and 58 seronegative. Median age at diagnosis was 60 years (range, 18-86 years). Forty-three patients had dyspnea at presentation and 32 patients had preexisting risk for cardiac disease (10 coronary artery disease and 28 hypertension). The electrocardiogram was abnormal in 55 of 86 patients (33 without cardiac risk factors), including prolonged corrected QT interval (QTc) (n=31), conduction blocks (n=19), and atrial or ventricular ectopic beats (n=10). Echocardiography was abnormal in 34 of 72 patients, including 19 of 45 without preexisting cardiac disease risks. Echocardiographic abnormalities included left ventricular diastolic dysfunction (n=31) and systolic dysfunction (n=8). The left ventricular diastolic dysfunction improved in 4 of 11 patients after treatment. Pulmonary function testing showed changes suggestive of neuromuscular respiratory muscle weakness in 51 of 66 patients and reduced carbon monoxide diffusing capacity in 11 of 35 patients. However, only 6 patients had radiographic evidence of interstitial lung disease (2 anti-HMGCR Ab-positive and 4 seronegative). Overnight oximetry revealed desaturations in 24 of 38 patients. Six patients required mechanical ventilation and 7 required noninvasive ventilatory support. Most patients with NAM exhibited cardiac and respiratory muscle dysfunction. Immunotherapy can improve echocardiographic abnormalities. Interstitial lung disease was rarely identified. Formal evaluation of cardiac and respiratory status should be integral in assessment of patients with NAM.


Comparison of clinical characteristics of patients with heart failure and preserved ejection fraction with atrial fibrillation versus sinus rhythm: Insights from the APOLLON registry.
The aim of this study was to assess the clinical characteristics of patients with heart failure and preserved ejection fraction (HFpEF) and atrial fibrillation (AF) and compare them with those of HFpEF patients without AF. This study was a sub-group analysis of a multicenter, observational, and cross-sectional registry conducted in Turkey (ClinicalTrials.gov identifier: NCT03026114). Patients with HFpEF were divided into 2 groups: HFpEF with AF and HFpEF with sinus rhythm (SR), and the clinical characteristics of the groups were compared. In a total of 819 HFpEF patients (median age: 67 years; 58% women), 313 (38.2%) had AF. Compared to the patients with SR, those with AF were older (70 years vs 66 years; p<0.001) and more symptomatic, with a higher rate of classification as New York Heart Association functional class III-IV, paroxysmal nocturnal dyspnea, orthopnea, palpitations, fatigue, pulmonary crepitations, and peripheral edema. The hospitalization rate for heart failure was higher (28.4% vs 12.6%; p<0.001) in patients with AF, and participants with AF had higher level of N-terminal pro-B-type natriuretic peptide (887 pg/mL vs 394.8 pg/mL; p<0.001) and higher left atrial volume index level. Patients without AF had a higher burden of diabetes mellitus, obstructive sleep apnea, and coronary artery disease. The prescription rate of nondihydropyridine calcium blockers, digoxin, loop diuretics, and anticoagulant drugs was higher in the AF group. The results of this study revealed that in a large Turkish cohort with HFpEF, significant clinical differences were present between those with and without AF and. Further prospective studies are needed to clarify the prognostic implications of AF in this growing heart failure population in our country.


A cost-benefit analysis of alternative device configurations for aviation-checked baggage security screening.
The terrorist attacks of September 11, 2001 have resulted in dramatic changes in aviation security. As of early 2003, an estimated 1,100 explosive detection systems (EDS) and 6,000 explosive trace detection machines (ETD) have been deployed to ensure 100% checked baggage screening at all commercial airports throughout the United States. The prohibitive costs associated with deploying and operating such devices is a serious issue for the Transportation Security Administration. This article evaluates the cost effectiveness of the explosive detection technologies currently deployed to screen checked baggage as well as new technologies that could be used in the future. Both single-device and two-device systems are considered. In particular, the expected annual direct cost of using these devices for 100% checked baggage screening under various scenarios is obtained and the tradeoffs between using single- and two-device strategies are studied. The expected number of successful threats under the different checked baggage screening scenarios with 100% checked baggage screening is also obtained. Lastly, a risk-based screening strategy proposed in the literature is analyzed. The results reported suggest that for the existing security setup, with current device costs and probability parameters, single-device systems are less costly and have fewer expected number of successful threats than two-device systems due to the way the second device affects the alarm or clear decision. The risk-based approach is found to have the potential to significantly improve security. The cost model introduced provides an effective tool for the execution of cost-benefit analyses of alternative device configurations for aviation-checked baggage security screening.


Enhanced prereceptor glucocorticoid metabolism and lipogenesis impair insulin signaling in the liver of fructose-fed rats.
Overconsumption of fructose, as a highly lipogenic sugar, may profoundly affect hepatic metabolism and has been associated with many components of the metabolic syndrome, particularly with insulin resistance and Type 2 diabetes. In this study, we proposed that high fructose diet may enhance lipogenesis and decrease insulin sensitivity in the liver through dysregulation of glucocorticoid signaling. Therefore, we examined the effects of long-term consumption of 10% fructose solution on triglyceridemia, liver histology and intracellular corticosterone level, as well as on 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) and hexose-6-phosphate dehydrogenase (H6PDH) mRNA and protein levels in the rat liver. Glucocorticoid action was assessed by glucocorticoid receptor (GR) expression and intracellular redistribution. We also analyzed the expression of enzymes involved in gluconeogenesis and lipogenesis, phosphoenolpyruvate carboxykinase (PEPCK) and lipin-1. The results have shown that fructose-rich diet led to increase in 11βHSD1 and H6PDH protein levels, while hepatic corticosterone concentration remained unchanged. Concomitantly, GR was increasingly accumulated in the cytoplasm, whereas its nuclear level was unchanged and accompanied by diminished PEPCK mRNA level. Elevation of lipin-1 in the liver microsomes suggested that fructose diet led to an increase in lipogenesis and consequently to hypertriglyceridemia. The observed increase of insulin receptor supstrate-1 phosphorylation on Ser(307) represents a hallmark of impaired insulin signaling in the liver of fructose-fed rat and probably is a consequence of the alterations in 11βHSD1 and lipin-1 levels. Overall, our findings suggest that fructose-rich diet may perturb hepatic prereceptor glucocorticoid metabolism and lipogenesis, resulting in hypertriglyceridemia and attenuated hepatic insulin sensitivity.


Milk Thistle Constituents Inhibit Raloxifene Intestinal Glucuronidation: A Potential Clinically Relevant Natural Product-Drug Interaction.
Women at high risk of developing breast cancer are prescribed selective estrogen response modulators, including raloxifene, as chemoprevention. Patients often seek complementary and alternative treatment modalities, including herbal products, to supplement prescribed medications. Milk thistle preparations, including silibinin and silymarin, are top-selling herbal products that may be consumed by women taking raloxifene, which undergoes extensive first-pass glucuronidation in the intestine. Key constituents in milk thistle, flavonolignans, were previously shown to be potent inhibitors of intestinal UDP-glucuronosyl transferases (UGTs), with IC50s ≤ 10 μM. Taken together, milk thistle preparations may perpetrate unwanted interactions with raloxifene. The objective of this work was to evaluate the inhibitory effects of individual milk thistle constituents on the intestinal glucuronidation of raloxifene using human intestinal microsomes and human embryonic kidney cell lysates overexpressing UGT1A1, UGT1A8, and UGT1A10, isoforms highly expressed in the intestine that are critical to raloxifene clearance. The flavonolignans silybin A and silybin B were potent inhibitors of both raloxifene 4'- and 6-glucuronidation in all enzyme systems. The Kis (human intestinal microsomes, 27-66 µM; UGT1A1, 3.2-8.3 µM; UGT1A8, 19-73 µM; and UGT1A10, 65-120 µM) encompassed reported intestinal tissue concentrations (20-310 µM), prompting prediction of clinical interaction risk using a mechanistic static model. Silibinin and silymarin were predicted to increase raloxifene systemic exposure by 4- to 5-fold, indicating high interaction risk that merits further evaluation. This systematic investigation of the potential interaction between a widely used herbal product and chemopreventive agent underscores the importance of understanding natural product-drug interactions in the context of cancer prevention.


Immunization against social fear learning.
Social fear learning offers an efficient way to transmit information about potential threats; little is known, however, about the learning processes that counteract the social transmission of fear. In three separate experiments, we found that safety information transmitted from another individual (i.e., demonstrator) during preexposure prevented subsequent observational fear learning (Experiments 1-3), and this effect was maintained in a new context involving direct threat confrontation (Experiment 3). This protection from observational fear learning was specific to conditions in which information about both safety and danger was transmitted from the same demonstrator (Experiments 2-3) and was unaffected by increasing the number of the safety demonstrators (Experiment 3). Collectively, these findings demonstrate that observational preexposure can limit social transmission of fear. Future research is needed to better understand the conditions under which such effects generalize across individual demonstrators. (PsycINFO Database Record


Epidemiology and clinical consequences of drug-resistant tuberculosis in a Guatemalan hospital.
To determine the epidemiology and clinical consequences of drug-resistant TB in Guatemala. A prospective study conducted for 12 months. A thoracic referral hospital in western Guatemala. Three hundred and seventy-six patients with confirmed TB. Of 376 confirmed cases, 335 (89%) were culture-positive. Tests of drug sensitivities to four first-line antituberculous drugs were performed in 172 (51%) of the culture-positive cases. Fifty-one patients (30%) were resistant to at least one antimicrobial agent, and 26 (15%) were resistant to at least two drugs. In a multivariate model of clinically available patient characteristics, only cavitary disease (odds ratio=2.1; 95% confidence interval, 1.1-6.6) and a history of taking anti-TB medication for >2 weeks (OR=3.0; 95% CI, 1.5-10.3) were independent predictors of resistance to two or more anti-TB agents. Resistance to two or more anti-TB drugs was the single independent predictor of treatment failure (OR=6.4; 95% CI, 2.3-17.8). Twenty-four of 172 patients (14%) who denied having received prior anti-TB therapy were infected with resistant organisms, suggesting ongoing transmission of drug-resistant strains. Although 84% (69 of 82 cases) of patients with fully susceptible organisms and 89% (17 of 19 cases) with singly resistant organisms were cured, only 45% of patients (10 of 22 cases) infected with organisms resistant to two or more agents were successfully treated. At this sentinel site for complicated TB, a substantial subset of cases who are infected with drug-resistant bacteria cannot be easily identified or treated.


Factors determining recurrence in transient global amnesia.
Aetiology of transient global amnesia (TGA) remains uncertain, though many have been proposed, including ischaemic, migrainous or epileptic pathologies. We attempted to determine risk factors for TGA, as well as prognostic factors that may cause recurrence. We evaluated clinical history, family history and magnetic resonance diffusion-weighted imaging (DWI) studies of 93 prospective patients with TGA. Patients were followed from 2004 to 2016. Fifteen of 93 (16%) patients experienced a recurrence of TGA. Among precipitating events, physical activities inducing Valsalva-like manoeuvres were most common, followed by emotional stress. Eighty-four patients had possible comorbidities or risk factors for TGA, though no single risk factor was ubiquitous. Risk factors associated with recurrence were head injury (isolated vs. recurrent, 16.7% vs. 53.5%, p < 0.01), depression (isolated vs. recurrent, 15.4% vs 46.7%, p = 0.01) and family history of dementia (isolated vs. recurrent, 20.5% vs. 46.7%, p = 0.03). Of 15 patients with confirmed recurrent TGA, two developed dementia and four subjective memory impairment. DWI lesions were observed in 24 patients and were located anywhere within the hippocampus. DWI lesions were not significantly associated with outcomes (recurrence, subjective memory impairment, dementia). We have found that depression, previous head injury and family history of dementia may predict TGA recurrence.


Interaction between statins and clopidogrel: is there anything clinically relevant?
Since their introduction several years ago, the 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase inhibitors-the statins-have been widely used for hyperlipidemia and for the primary/secondary prevention of cardiovascular diseases. They have been shown to be safe as well as efficacious in a number of different clinical trials; however, studies have suggested that they can interact with other co-administered therapies. More recently, the thienopyridines have been successfully integrated with the conventional medical treatment of coronary disease as they showed effectiveness in reducing platelet activity both in stable and unstable settings. They also improve the outcome of patients treated with percutaneous coronary intervention. The potential interaction of statins and thienopyridines is a matter of concern. Despite some preclinical data suggesting an interaction between statins metabolized by the liver cytochrome P3A4-such as atorvastatin, lovastatin and simvastatin-and clopidogrel, there is no compelling clinical evidence to stop their co-administration.


The herpes simplex virus type 1 tegument protein VP22 is encoded by gene UL49.
VP22 is a major tegument protein of herpes simplex virus type 1 and is highly phosphorylated in the infected cell. Indirect evidence exists to suggest that it is encoded by gene UL49, present in the BamHI F fragment of the genome. Using the polymerase chain reaction we have cloned the UL49 open reading frame into a mammalian expression vector under the control of the human cytomegalovirus immediate early gene promoter. After transfection into COS-7 cells expression of the gene product was detected by means of Western blotting and immunofluorescence. The results clearly indicate that the protein encoded by UL49 is VP22, and that in transfected cells it appears to have characteristics similar to those of the protein synthesized in infected cells.


Emotion Regulation, Subjective Well-Being, and Perceived Stress in Daily Life of Geriatric Nurses.
This daily diary study examined the within-person coupling between four emotion regulation strategies and both subjective well-being and perceived stress in daily life of geriatric nurses. Participants (N = 89) described how they regulated their emotions in terms of cognitive reappraisal and suppression. They also indicated their subjective well-being and level of perceived stress each day over 3 weeks. At the within-person level, cognitive reappraisal intended to increase positive emotions was positively associated with higher subjective well-being and negatively associated with perceived stress. Suppression of the expression of positive emotions was negatively associated with subjective well-being and positively associated with perceived stress. However, cognitive reappraisal intended to down-regulate negative emotions and suppression as a strategy to inhibit the expression of negative emotions were not associated with daily well-being or perceived stress. Off-days were rated as days with higher subjective well-being and lower perceived stress in contrast to working days. At the between-person level, individuals who reported more daily negative affect reported increased suppression of positive emotions, corroborating the within-person findings. Moreover, findings indicated that nurses with more years of experience in the job reported higher subjective well-being and less perceived stress. These results provide insights into important daily emotional processes of geriatric nurses, both at workdays and in their leisure time.


The long-term effects of pregnancy and bromocriptine treatment on prolactinomas--the value of radiologic studies.
To evaluate the long-term effects of pregnancy and bromocriptine treatment on prolactin-secreting pituitary tumors in women undergoing infertility treatment for prolactinomas. The records of 17 patients with prolactinomas were reviewed. Data regarding age, prepregnancy baseline and postpartum serum prolactin levels, and radiologic studies including CT or MRI were assessed. 16 patients were treated with bromocriptine before achieving pregnancy. Bromocriptine therapy was resumed after delivery for the duration of 1 to 14 years. 45% of pregnancies did not affect the size of prolactinomas, 27% of pregnancies showed a decrease in size of prolactinomas or radiologic evidence of resolution of the tumor and 27% of pregnancies demonstrated radiologic increase in the size of prolactinomas. It is safe for patients with prolactinomas to achieve pregnancy following bromocriptine treatment. Pregnancy may lead to a slight decrease in the size of prolactinomas, increase in size, no change, and in some cases, complete resolution. There were no visual field changes during the pregnancies. Pregnancy and long-term bromocriptine treatment may be helpful in reduction of the size of the tumor.


A Question-Centric Model for Visual Question Answering in Medical Imaging.
Deep learning methods have proven extremely effective at performing a variety of medical image analysis tasks. With their potential use in clinical routine, their lack of transparency has however been one of their few weak points, raising concerns regarding their behavior and failure modes. While most research to infer model behavior has focused on indirect strategies that estimate prediction uncertainties and visualize model support in the input image space, the ability to explicitly query a prediction model regarding its image content offers a more direct way to determine the behavior of trained models. To this end, we present a novel Visual Question Answering approach that allows an image to be queried by means of a written question. Experiments on a variety of medical and natural image datasets show that by fusing image and question features in a novel way, the proposed approach achieves an equal or higher accuracy compared to current methods.


Variation of urinary follicle-stimulating hormone level after menopause : From the results of Japan Nurses' Health Study.
The change in follicle-stimulating hormone (FSH) during the menopausal transition and associations of FSH with various diseases have been assessed by using blood samples. We examined cross-sectionally the variation of FSH levels, associations of estrone and estradiol with FSH, and associations of BMI with these hormones by using urinary samples from peri- and postmenopausal women in Japan. Of 4472 participants in the Urinary Isoflavone Concentration Survey of the Japan Nurses' Health Study, we analyzed urinary levels of estrone, estradiol and FSH in 547 women aged from 45 to 54 years. Urinary FSH levels varied widely in postmenopausal women and the pattern of change in urinary FSH levels seems to be similar to that in blood FSH levels in previous studies. There were no significant differences in age, body mass index (BMI), estradiol, estrone and estradiol/estrone ratio among three groups according to the tertile of FSH. In postmenopausal women, there were significant associations of BMI with levels of estrone and estradiol, but there was no significant association of BMI with FSH. Studies using urinary samples will allow us to establish a study project as a large-scale population-based study to determine associations between FSH and various diseases after menopause. J. Med. Invest. 66 : 297-302, August, 2019.


Abnormal white matter structure in hoarding disorder.
Although preliminary neuroimaging research suggests that patients with hoarding disorder (HD) show widespread abnormal task-related activity in the brain, there has been no research on alterations in the white matter tracts in these patients. The aim of this study was to investigate the characteristics of the major white matter tracts in patients with HD. Tract-based spatial statistics were used to search for white matter tract abnormalities throughout the brain in 25 patients with HD and 36 healthy controls. Post hoc analysis of regions of interest was performed to detect correlations with clinical features. Compared with the controls, patients with HD showed decreased fractional anisotropy and increased radial diffusivity in anatomically widespread white matter tracts. Post hoc analysis of regions of interest revealed a significant negative correlation between the severity of hoarding symptoms and fractional anisotropy in the left anterior limb of the internal capsule and a positive correlation between the severity of these symptoms and radial diffusivity in the right anterior thalamic radiation. Patients with HD showed a broad range of alterations in the frontal white matter tracts, including the frontothalamic circuit, frontoparietal network, and frontolimbic pathway. The findings of this study indicate associations between frontal white matter abnormalities related to the severity of hoarding symptoms in HD and the cortical regions involved in cognitive dysfunction. The insights provided would be useful for understanding the neurobiological basis of HD.


Targeting the NLRP3 Inflammasome in Glaucoma.
Glaucoma is a group of optic neuropathies characterised by the degeneration of retinal ganglion cells, resulting in damage to the optic nerve head (ONH) and loss of vision in one or both eyes. Increased intraocular pressure (IOP) is one of the major aetiological risk factors in glaucoma, and is currently the only modifiable risk factor. However, 30-40% of glaucoma patients do not present with elevated IOP and still proceed to lose vision. The pathophysiology of glaucoma is therefore not completely understood, and there is a need for the development of IOP-independent neuroprotective therapies to preserve vision. Neuroinflammation has been shown to play a key role in glaucoma and, specifically, the NLRP3 inflammasome, a key driver of inflammation, has recently been implicated. The NLRP3 inflammasome is expressed in the eye and its activation is reported in pre-clinical studies of glaucoma. Activation of the NLRP3 inflammasome results in IL-1β processing. This pro inflammatory cytokine is elevated in the blood of glaucoma patients and is believed to drive neurotoxic inflammation, resulting in axon degeneration and the death of retinal ganglion cells (RGCs). This review discusses glaucoma as an inflammatory disease and evaluates targeting the NLRP3 inflammasome as a therapeutic strategy. A hypothetical mechanism for the action of the NLRP3 inflammasome in glaucoma is presented.