Chelation-Tamoxifen Conjugates for Imaging of Estrogen Receptors.
Background: The differential diagnosis of estrogen receptor-positive (ER+) pathway-activated systems by using a labeled antiestrogen helps to select the patients for optimal response to endocrine therapy and to discontinue the treatment when resistance occurs. The authors' purpose was to synthesize chelator-tamoxifen conjugates for imaging ER (+) diseases. Materials and Methods: A hydroxypropyl linker was incorporated between either cyclam or cyclam diacetic acid and tamoxifen analog to produce SC-05-L-1 (Z-1-(1,4,8,11-tetraazacyclotetradecan-1-yl)-3-((5-(4-(2-(diethylamino)ethoxy)phenyl)-4,5-diphenylpent-4-en-1-yl)oxy)propan-2-ol) and SC-05-N-1 (Z-2,2'-(4-(3-((5-(4-(2-(diethylamino)ethoxy)phenyl)-4,5-diphenylpent-4-en-1-yl)oxy)-2-hydroxy-propyl)-1,4,8,11-tetraazacyclotetradecane-1,8-diyl)diacetic acid), respectively. In vitro cell uptake and cell/media ratios of 99mTc-SC-05-L-1 and 99mTc- SC-05-N-1 in ER (+) ovarian cancer cells (TOV-112D and OVCAR3) were performed. To ascertain the specificity of cell uptake, the cell uptake was blocked with estrone. In vivo 99mTc-SC-05-L-1 or 99mTc-SC-05-N-1 single-photon emission computed tomography/computed tomography was conducted in tumor-bearing rodents and compared to 18F-fluoro-2-deoxy-d-glucose (18F-FDG) positron emission tomography/magnetic resonance imaging (a reference technology). Results: The radiochemical purities of 99mTc-SC-05-L-1 and 99mTc-SC-05-N-1 were greater than 99% (n = 10). 99mTc-SC-05-L-1 had higher cell/media ratios than 99mTc-SC-05-N-1 in OVCAR-3 ER (+) cells. The cell uptake of 99mTc-SC-05-L-1 was blocked 80% by estrone indicating an ER-mediated process occurred. 99mTc-SC-05-N-1 was further selected for in vivo imaging studies due to higher maximum tolerated dose and superior water solubility than 99mTc-SC-05-L-1. 99mTc-SC-05-N-1 showed higher tumor uptake and tumor/muscle count density ratios than 18F-FDG in tumor-bearing rodents. Conclusion: 99mTc-SC-05-N-1 showed better differential diagnosis of ovarian tumors than 18F-FDG, indicating great promising in chelator-tamoxifen conjugate for ER pathway-directed systems imaging.


[Replacement of anterior teeth with bridges].
Missing incisors and canines may be replaced with preferably gold-porcelain bridges. To be acceptable in an esthetical sense, the bridge demands, apart from a correct colour and shape, a healthy periodontium, the latter being the subject of this paper. The way in which the outline is prepared, the relationship between depth of the preparation and marginal gingiva and the prevention of periodontal trauma are discussed.


[Renewed interest in neuropsychiatry within child and adolescent psychiatry].
Child and adolescent psychiatry has existed as a subspecialty since the 1920s. In the early days its practitioners regarded observation as their main source of knowledge. In the period after 1970 the anti-psychiatric movement gained momentum, presenting a threat to child and adolescent psychiatrists. Later on, however, it was realised that the influence of the anti-psychiatry movement had been fairly limited and that the most important changes had occurred as a result of the introduction of the empirical method, which in turn has led to renewed interest in neuropsychiatry.


The lipoprotein abnormality in Tangier disease: quantitation of A apoproteins.
In this study we have determined by radioimmunoassay and double immunoelectrophoresis the total quantities and distributions of A apoproteins in three adult patients affected with Tangier disease (hereditary alpha-lipoprotein deficiency). Compared with normal plasma, the total quantities of apoproteins A-I and A-II in Tangier plasma were determined to be less than 1% and 5-7%, respectively. In Tangier patients, approximately 90% of the apoprotein A-I sedimented when ultracentrifugations of plasma were carried out at density 1.21 g/ml KBr. By contrast, more than 95% of the apoprotein A-II floated under those conditions. In normal plasma, approximately 90% of both apoproteins A-I and A-II is found in the 1.063-1.21-g/ml KBr density fraction. These findings suggest that complete dissociation of A apoproteins occurs in Tangier plasma. This dissociation of apoproteins was confirmed by double immunoelectrophoresis with monospecific antisera. Immunochemical and electrophoretic experiments did not provide evidence for a structural abnormality of apoprotein A-I in these patients, The results taken together strongly suggest that normal high-density lipoproteins are absent from Tangier plasma.


COTI-2, A Novel Thiosemicarbazone Derivative, Exhibits Antitumor Activity in HNSCC through p53-dependent and -independent Mechanisms.
TP53 mutations are highly prevalent in head and neck squamous cell carcinoma (HNSCC) and associated with increased resistance to conventional treatment primarily consisting of chemotherapy and radiation. Restoration of wild-type p53 function in TP53-mutant cancer cells represents an attractive therapeutic approach and has been explored in recent years. In this study, the efficacy of a putative p53 reactivator called COTI-2 was evaluated in HNSCC cell lines with different TP53 status.Experimental Design: Clonogenic survival assays and an orthotopic mouse model of oral cancer were used to examine in vitro and in vivo sensitivity of HNSCC cell lines with either wild-type, null, or mutant TP53 to COTI-2 alone, and in combination with cisplatin and/or radiation. Western blotting, cell cycle, live-cell imaging, RNA sequencing, reverse-phase protein array, chromatin immunoprecipitation, and apoptosis analyses were performed to dissect molecular mechanisms. COTI-2 decreased clonogenic survival of HNSCC cells and potentiated response to cisplatin and/or radiation in vitro and in vivo irrespective of TP53 status. Mechanistically, COTI-2 normalized wild-type p53 target gene expression and restored DNA-binding properties to the p53-mutant protein in HNSCC. In addition, COTI-2 induced DNA damage and replication stress responses leading to apoptosis and/or senescence. Furthermore, COTI-2 lead to activation of AMPK and inhibition of the mTOR pathways in vitro in HNSCC cells. COTI-2 inhibits tumor growth in vitro and in vivo in HNSCC likely through p53-dependent and p53-independent mechanisms. Combination of COTI-2 with cisplatin or radiation may be highly relevant in treating patients with HNSCC harboring TP53 mutations.


Characterizing Ebola Transmission Patterns Based on Internet News Reports.
Detailed information on patient exposure, contact patterns, and discharge status is rarely available in real time from traditional surveillance systems in the context of an emerging infectious disease outbreak. Here, we validate the systematic collection of Internet news reports to characterize epidemiological patterns of Ebola virus disease (EVD) infections during the West African 2014-2015 outbreak. Based on 58 news reports, we analyzed 79 EVD clusters (286 cases) ranging in size from 1 to 33 cases between January 2014 and February 2015 in Guinea, Sierra Leone, and Liberia. The majority of reported exposures stemmed from contact with family members (57.3%) followed by hospitals (18.2%) and funerals (12.7%). Our data indicate that funeral exposure was significantly more frequent in Sierra Leone (27.3%) followed by Guinea (18.2%) and Liberia (1.8%; χ(2) test; P < .0001). Funeral exposure was the dominant route of transmission until April 2014 (60%) and was replaced with hospital exposure in June 2014-July 2014 (70%), both of which declined after interventions were put in place. The mean reproduction number of the outbreak was 2.3 (95% confidence interval [CI], 1.8, 2.7). The case fatality rate was estimated at 74.4% (95% CI, 68.3, 79.8). Overall, our findings based on news reports are in close agreement with those derived from traditional epidemiological surveillance data and with those reported for prior outbreaks. Our findings support the use of real-time information from trustworthy news reports to provide timely estimates of key epidemiological parameters that may be hard to ascertain otherwise.


Heat-induced disturbances of intracellular movement and the consistency of the aqueous cytoplasm in HeLa S-3 cells: a laser-Doppler and proton NMR study.
Intracellular particle movements, of both saltatory and streaming types, in HeLa S-3 cells were simultaneously interrupted after 1 h exposure of cells to 43 degrees C, within 10 min at 44 degrees C and within 5 min at 45 degrees C. Intracellular movement inhibited after 15 min at 44 degrees C and 10 min at 45 degrees C was not reversible in cells rescued at 37 degrees C. Brownian motion was not observed in heat-treated cells while they were maintained at elevated temperatures, but became pronounced in blebbing which occurred shortly after they were returned to 37 degrees C. Returning these cells to 45 degrees C intensified the Brownian activity inside blebs, and rapidly induced cell lysis. The same heat-treated cells were simultaneously studied by laser-Doppler microscopy, which confirmed: a) that flow (cytoplasmic streaming) is completely arrested at 44 degrees C within 10 min, b) flow recovered in 10-15 min in cells rescued after 10-15 min at 44 degrees C, c) submicroscopic particles down to the size of water molecules had faster self-diffusion coefficients at 44 degrees C than at 37 degrees C. Proton nmr studies on cells exposed from 4 to 45 degrees C gave corrected relaxation times T1 and T2 which rose with temperature in a predictable manner. Inhibition of cellular movement at elevated temperatures was not specifically attributable to the depletion of intracellular ATP levels.


Prediction of Glucose Tolerance without an Oral Glucose Tolerance Test.
Impaired glucose tolerance (IGT) is diagnosed by a standardized oral glucose tolerance test (OGTT). However, the OGTT is laborious, and when not performed, glucose tolerance cannot be determined from fasting samples retrospectively. We tested if glucose tolerance status is reasonably predictable from a combination of demographic, anthropometric, and laboratory data assessed at one time point in a fasting state. Given a set of 22 variables selected upon clinical feasibility such as sex, age, height, weight, waist circumference, blood pressure, fasting glucose, HbA1c, hemoglobin, mean corpuscular volume, serum potassium, fasting levels of insulin, C-peptide, triglyceride, non-esterified fatty acids (NEFA), proinsulin, prolactin, cholesterol, low-density lipoprotein, HDL, uric acid, liver transaminases, and ferritin, we used supervised machine learning to estimate glucose tolerance status in 2,337 participants of the TUEF study who were recruited before 2012. We tested the performance of 10 different machine learning classifiers on data from 929 participants in the test set who were recruited after 2012. In addition, reproducibility of IGT was analyzed in 78 participants who had 2 repeated OGTTs within 1 year. The most accurate prediction of IGT was reached with the recursive partitioning method (accuracy = 0.78). For all classifiers, mean accuracy was 0.73 ± 0.04. The most important model variable was fasting glucose in all models. Using mean variable importance across all models, fasting glucose was followed by NEFA, triglycerides, HbA1c, and C-peptide. The accuracy of predicting IGT from a previous OGTT was 0.77. Machine learning methods yield moderate accuracy in predicting glucose tolerance from a wide set of clinical and laboratory variables. A substitution of OGTT does not currently seem to be feasible. An important constraint could be the limited reproducibility of glucose tolerance status during a subsequent OGTT.


Compliance with pulmonary medication in general practice.
We wanted to assess compliance with regular pulmonary medication, in 156 patients in a general practice setting. Patients completed a questionnaire on their reported daily intake, the perceived prescription, and their self-assessed perceived compliance with pulmonary medication. Compliance was defined as a reported daily intake > or = 50% of the prescribed amount. Using this definition, 30% of patients were considered to be compliant. Compliant patients had daily symptoms more often, were more often prescribed two or more different medications, and a greater proportion of them had at some time consulted a chest physician. When patients correctly perceived the prescription to refer to medication which had to be taken on a regular basis, they were more likely to be compliant. We conclude that, since less than one third of patients was compliant with medication, more efforts are needed to improve compliance in general practice. Non-compliance with medication may well provide an alternative explanation for the discrepancy between prescribed medication and medical outcome, which has been labelled in the literature as "undertreatment".


Actuated transitory metal--ligand bond as tunable electromechanical switch.
Electrically tunable molecules are highly attractive for the construction of molecular devices, such as switches, transistors, or machines. Here, we present a novel nanomechanical element triggered by an electrical bias as external stimulus. We demonstrate that a transitory chemical bond between a copper atom and coordinating organic molecules adsorbed on a metal surface acts as variable frequency switch, which can be actuated and probed by means of low-temperature scanning tunneling microscopy. Whereas below a threshold bias voltage the bond is permanently either formed or broken the bonding state continuously oscillates at higher voltages. The switching rate of the bistable molecular system can be widely tuned from below 1 Hz up to the kilohertz regime. The quantum yield per tunneling electron to trigger a transition between the two states varies spatially and is related to the local density of states of the bonded and nonbonded configuration.


Prevalence and Characteristics Associated with Chronic Noncancer Pain in Suicide Decedents: A National Study.
The aims were to estimate the prevalence of CNCP in suicide decedents, and compare sociodemographic and clinical characteristics of people who die by suicide (i) with and without a history of CNCP and (ii) among decedents with CNCP who are younger (<65 years) and older (65 + years). We examined all closed cases of intentional deaths in Australia in 2014, utilizing the National Coronial Information System. We identified 2,590 closed cases of intentional deaths in Australia in 2014 in decedents over 18 years of age. CNCP was identified in 14.6% of cases. Decedents with CNCP were more likely to be older, have more mental health and physical health problems, and fewer relationship problems, and were more likely to die by poisoning from drugs, compared with decedents without CNCP. Comparisons of older and younger decedents with CNCP found that compared to younger (<65 years) decedents with CNCP, older decedents (65 + years) were less likely to have mental health problems. This is the first national study to examine the characteristics of suicide deaths with a focus on people with CNCP. Primary care physicians should be aware of the increased risk for suicide in people living with CNCP, and it may be useful for clinicians to screen for CNCP among those presenting with suicidal behaviors.


Heterotopic uterus transplantation in a swine model.
The aim of our study was to examine the feasibility of allogeneic uterine transplantation in a large animal model. We performed heterotopic uterine transplants in genetically defined mini-pigs. Immunosuppression was tacrolimus administered intravenously for the first 12 days posttransplantation followed by oral cyclosporine maintenance immunosuppression. The graft was transplanted heterotopically in the lower abdominal cavity of the recipient. The vaginal vault was exteriorized as a stoma in the lower right abdominal wall. The uterine grafts were followed with endoscopies and biopsies. Ten transplants were performed. Follow-up was until July 2008. At the end of the follow-up period, 5 animals were alive and healthy, 0.5 to 12 months posttransplantation. There were 5 deaths due to pneumonia (n=1), intussusception of the graft (n=1), cardiorespiratory arrest during anesthesia (n=1), and complications of the stoma (n=2). Acute rejections of the graft presented during the 2nd and 3rd month posttransplantation were treated successfully with increase of the maintenance immunosuppression and steroids. Other complications included prolapse and infections of the graft stoma. Pathological changes seen in the endometrial biopsies included acute rejection and acute endometritis. These findings demonstrate that successful uterus transplantation in a large animal model (miniature swine) is feasible using this heterotopic model, and it can be useful for the study of these transplants.


Secondary contacts and genetic admixture shape colonization by an amphiatlantic epibenthic invertebrate.
Research on the genetics of invasive species often focuses on patterns of genetic diversity and population structure within the introduced range. However, a growing body of literature is demonstrating the need to study how native genotypes affect both ecological and evolutionary mechanisms within the introduced range. Here, we used genotyping-by-sequencing to study both native and introduced ranges of the amphiatlantic marine invertebrate Ciona intestinalis. A previous study using microsatellites analysed samples collected along the Swedish west coast and showed the presence of genetically distinct lineages in deep and shallow waters. Using 1,653 single nucleotide polymorphisms (SNPs) from newly collected samples (285 individuals), we first confirmed the presence of this depth-defined genomic divergence along the Swedish coast. We then used approximate Bayesian computation to infer the historical relationship among sites from the North Sea, the English Channel and the northwest Atlantic and found evidence of ancestral divergence between individuals from deep waters off Sweden and individuals from the English Channel. This divergence was followed by a secondary contact that led to a genetic admixture between the ancestral populations (i.e., deep Sweden and English Channel), which originated the genotypes found in shallow Sweden. We then revealed that the colonization of C. intestinalis in the northwest Atlantic was as a result of an admixture between shallow Sweden and the English Channel genotypes across the introduced range. Our results showed the presence of both past and recent genetic admixture events that together may have promoted the successful colonizations of C. intestinalis. Our study suggests that secondary contacts potentially reshape the evolutionary trajectories of invasive species through the promotion of intraspecific hybridization and by altering both colonization patterns and their ecological effects in the introduced range.


A method to find longevity-selected positions in the mammalian proteome.
Evolutionary theory suggests that the force of natural selection decreases with age. To explore the extent to which this prediction directly affects protein structure and function, we used multiple regression to find longevity-selected positions, defined as the columns of a sequence alignment conserved in long-lived but not short-lived mammal species. We analyzed 7,590 orthologous protein families in 33 mammalian species, accounting for body mass, phylogeny, and species-specific mutation rate. Overall, we found that the number of longevity-selected positions in the mammalian proteome is much higher than would be expected by chance. Further, these positions are enriched in domains of several proteins that interact with one another in inflammation and other aging-related processes, as well as in organismal development. We present as an example the kinase domain of anti-müllerian hormone type-2 receptor (AMHR2). AMHR2 inhibits ovarian follicle recruitment and growth, and a homology model of the kinase domain shows that its longevity-selected positions cluster near a SNP associated with delayed human menopause. Distinct from its canonical role in development, this region of AMHR2 may function to regulate the protein's activity in a lifespan-specific manner.


[The design and application of synchronized springy lengthening apparatus for the tibia and tendo calcaneus].
To study the role of the synchronized springy lengthening apparatus for the tibia and calcaneal tendon designed by the author in preventing the clubfoot of secondary to the Ilizarov tibia lengthening. Based on the Ilizarov tibia lengthening apparatus, a special synchronized springy lengthening apparatus for the tibia and calcaneal tendon was designed. The tibial was made of distal and proximal 2 rings respectively and 4 threaded rods, and the calcaneal was made of a half ring, 2 hinges and a threaded rod with spring. The half ring was fixed to the calcaneus by 2 crossed wires. The fracture tibia and fibula, ankle joint, talocalcaneal joint were attached to the apparatus. At the same time of tibia lengthening, the soft tissue was simultaneously stretched, the ankle joint could move, and the leg could bear weight. If the clubfoot angle was larger, the percutaneous fasciotomy of calcaneal tendon was performed; if the angle was less than 20 degrees, the pes deformities were corrected only by the stretch of calcaneal tendon. Seventy-seven patients' tibia were lengthened averagely 4.6 cm, with an average speed of 0.7 mm/d. The healing made tibia lengthened, and the index was 1.35 months/cm. There were not the secondary varus and valgus deformities and clubfoot in all the patients. The clubfoot with 100-400 angle of the 16 patients were corrected after tibia lengthening. The new apparatus coincides with the biomechanical principle and can effectively prevent the secondary deformities of foot such as clubfoot, talipes varus and valgus after tibia lengthening procedure.


Electrophoretic and cytochemical characterization of alpha-naphthyl acetate esterases in acute myeloid leukemia: relationships with membrane receptor and monocyte-specific antigen expression.
Alpha-naphthyl acetate esterases (ANAE) were examined by cytochemical and isoelectric focusing (IEF) techniques in 48 cases of acute myeloid leukemia that were classified by conventional morphological criteria. Four main types of ANAE isoenzyme patterns were found by IEF, and comparisons with the expression of membrane receptors (Fc-IgG and C3b) and monocyte-specific antigens (UCHM1, UCHALF, and E11) suggest relationships between ANAE isoenzyme synthesis and distinct myeloid maturational stages. The results further indicate that the blast cells of acute myelomonocytic leukemia (AMML) may represent an immature variant of monocytic leukemia (AMoL) and that morphological examination alone is inadequate in the assessment of monocytic differentiation in acute myeloid leukemias. Inhibition studies of cytochemical ANAE activity with sodium fluoride (NaF) show that the presence of NaF-sensitive or NaF-resistant ANAE enzymes is often unrelated to the diagnostic category of acute leukemia. The results of this study are examined in relation to current concepts of myeloid differentiation, and the application of these findings to the subclassification of acute myeloid leukemias is discussed.


Asthma outcomes workshop: overview.
Asthma clinical research will highly benefit from standardization of major outcomes in terms of definition and assessment methodology. This will permit useful comparisons across interventional or observational studies and will allow more effective data sharing. National Institutes of Health (NIH) institutes and the Agency for Healthcare Research and Quality convened a workshop involving 7 expert subcommittees to propose which asthma outcomes should be assessed with standardized methodology in future asthma clinical research studies. Each subcommittee utilized comprehensive literature reviews and expert opinion to compile a list of asthma outcomes and classified them as either core (required in future studies), supplemental (to be used according to study aims and standardized), or emerging (requiring validation and standardization). This work was discussed at an NIH-organized workshop in March 2010 and finalized in September 2011. Outcomes for study participant characterization, as well as for prospective clinical trial intervention and observational studies, were proposed for adults and children, and methodologies for outcome collection and reporting were determined. Furthermore, the workshop identified areas in which new outcomes or instruments for their measurement need to be developed and validated. Standardized outcomes for clinical research in asthma have been proposed. Participating NIH institutes and other federal agencies will consider these recommendations in future clinical research initiatives in asthma.


Eye complaints in the office environment: precorneal tear film integrity influenced by eye blinking efficiency.
To achieve a common base for understanding work related eye complaints in the office environment, it is necessary to merge approaches from indoor air science, occupational health, and ophthalmology. Based on database searches, it is concluded that precorneal tear film (PTF) alteration leads to eye complaints that may be caused by: (1) thermal factors (low relative humidity; high room temperature); (2) demanding task content (attention decreases blinking and widens the exposed ocular surface area); and (3) individual characteristics (for example, tear film alterations, blinking anomalies, gland dysfunctions, and use of contact lenses). These factors and conditions are able to progressively increase water evaporation and faster thinning of the PTF, which causes dryness and dry spot formation on the cornea, possibly followed by corneal and conjunctiva epithelial alterations and eye complaints. Another possible cause of eye complaints is certain irritating chemical compounds, in addition to oxidation mixtures that are formed in reactions between ozone and unsaturated organic compounds (alkenes). The effect may be exacerbated by low relative humidity.


What's in a mask? Information masking with forward and backward visual masks.
Three experiments tested how the physical format and information content of forward and backward masks affected the extent of visual pattern masking. This involved using different types of forward and backward masks with target discrimination measured by percentage correct in the first experiment (with a fixed target duration) and by an adaptive threshold procedure in the last two. The rationale behind the manipulation of the content of the masks stemmed from masking theories emphasizing attentional and/or conceptual factors rather than visual ones. Experiment 1 used word masks and showed that masking was reduced (a masking reduction effect) when the forward and backward masks were the same word (although in different case) compared to when the masks were different words. Experiment 2 tested the extent to which a reduction in masking might occur due to the physical similarity between the forward and backward masks by comparing the effect of the same content of the masks in the same versus different case. The result showed a significant reduction in masking for same content masks but no significant effect of case. The last experiment examined whether the reduction in masking effect would be observed with nonword masks--that is, having no high-level representation. No reduction in masking was found from same compared to different nonword masks (Experiment 3). These results support the view that the conscious perception of a rapidly displayed target stimulus is in part determined by high-level perceptual/cognitive factors concerned with masking stimulus grouping and attention.


Efficient bifunctional catalysts for overall water splitting: porous Fe-Mo oxide hybrid nanorods.
Efficient and inexpensive bifunctional catalysts for oxygen evolution reaction (OER) and hydrogen evolution reaction (HER) are essential for water splitting. Herein, we successfully prepare porous Fe-Mo oxide hybrid nanorods through a hydrothermal method followed by annealing at high temperature. They exhibit excellent catalytic activity for OER and HER in alkaline media, and produce a current density of 10 mA cm-2 at overpotentials of 200 and 66 mV. Besides, they work as bifunctional electrode materials for overall water splitting, achieving a current density of 10 mA cm-2 at a voltage of 1.52 V, and maintaining a current density of 60 mA cm-2 for 60 h. The unique morphology with self-supported structure can expose more active sites and facilitate charge transfer, and is not easy to peel off, thus it improves the catalytic activity and stability. This work therefore provides a valuable route for designing and fabricating inexpensive and high-performance catalytic materials for overall water splitting.


Age-Related Changes in Episodic Processing of Scenes: A Functional Activation and Connectivity Study.
The posterior-to-anterior shift in aging (PASA) effect is seen as a compensatory model that enables older adults to meet increased cognitive demands to perform comparably as their young counterparts. However, empirical support for the PASA effect investigating age-related changes in the inferior frontal gyrus (IFG), hippocampus, and parahippocampus has yet to be established. 33 older adults and 48 young adults were administered tasks sensitive to novelty and relational processing of indoor/outdoor scenes in a 3-Tesla MRI scanner. Functional activation and connectivity analyses were applied to examine the age-related changes on the IFG, hippocampus, and parahippocampus among low/high-performing older adults and young adults. Significant parahippocampal activation was generally found in both older (high-performing) and young adults for novelty and relational processing of scenes. Younger adults had significantly greater IFG and parahippocampal activation than older adults, and greater parahippocampal activation compared to low-performing older adults for relational processing-providing partial support for the PASA model. Observations of significant functional connectivity within the medial temporal lobe and greater negative left IFG-right hippocampus/parahippocampus functional connectivity for young compared to low-performing older adults for relational processing also supports the PASA effect partially.


Effects of heat stress and nutrition on lactating Holstein cows: II. Aspects of hepatic growth hormone responsiveness.
Heat stress (HS) is a multibillion-dollar problem for the global dairy industry, and reduced milk yield is the primary contributor to this annual economic loss. Feed intake declines precipitously during HS but accounts for only about 35% of the decreased milk synthesis, indicating that the physiological mechanisms responsible for decreased milk production during HS are only partly understood. Thus, our experimental objectives were to characterize the direct effects of HS on the somatotropic axis, a primary regulator of metabolism and milk yield. We recently reported no differences in mean growth hormone (GH) concentrations, GH pulsatility characteristics, or GH response to growth hormone releasing factor in HS versus pair-fed (PF) thermoneutral controls. Despite similarities in circulating GH characteristics, plasma insulin-like growth factor (IGF)-I concentrations were reduced during heat stress conditions but not in PF animals, suggesting that uncoupling of the hepatic GH-IGF axis may occur during HS. We investigated this possibility by measuring proximal indicators of hepatic GH signaling following a GH bolus. Heat stress but not PF decreased abundance of the GH receptor and GH-dependent signal transducer and activator of transcription (STAT)-5 phosphorylation. Consistent with reduced GH signaling through STAT-5, basal hepatic IGF-I mRNA abundance was lower in HS cows. Thus, the reduced hepatic GH responsiveness (in terms of IGF-I gene expression) observed during HS appears to involve mechanisms at least partially independent of reduced nutrient intake. The physiological significance of reduced hepatic GH receptor abundance during HS is unclear at this time. Aside from reducing IGF-I production, it may reduce other GH-sensitive bioenergetic processes such as gluconeogenesis.


Inhibition of inflammatory and proliferative responses of human keratinocytes exposed to the sesquiterpene lactones dehydrocostuslactone and costunolide.
The imbalance of the intracellular redox state and, in particular, of the glutathione (GSH)/GSH disulfide couple homeostasis, is involved in the pathogenesis of a number of diseases. In many skin diseases, including psoriasis, oxidative stress plays an important role, as demonstrated by the observation that treatments leading to increase of the local levels of oxidant species ameliorate the disease. Recently, dehydrocostuslactone (DCE) and costunolide (CS), two terpenes naturally occurring in many plants, have been found to exert various anti-inflammatory and pro-apoptotic effects on different human cell types. These compounds decrease the level of the intracellular GSH by direct interaction with it, and, therefore, can alter cellular redox state. DCE and CS can trigger S-glutathionylation of various substrates, including the transcription factor STAT3 and JAK1/2 proteins. In the present study, we investigated on the potential role of DCE and CS in regulating inflammatory and proliferative responses of human keratinocytes to cytokines. We demonstrated that DCE and CS decreased intracellular GSH levels in human keratinocytes, as well as inhibited STAT3 and STAT1 phosphorylation and activation triggered by IL-22 or IFN-γ, respectively. Consequently, DCE and CS decreased the IL-22- and IFN-γ-induced expression of inflammatory and regulatory genes in keratinocytes, including CCL2, CXCL10, ICAM-1 and SOCS3. DCE and CS also inhibited proliferation and cell-cycle progression-related gene expression, as well as they promoted cell cycle arrest and apoptosis. In parallel, DCE and CS activated the anti-inflammatory EGFR and ERK1/2 molecules in keratinocytes, and, thus, wound healing in an in vitro injury model. In light of our findings, we can hypothesize that the employment of DCE and CS in psoriasis could efficiently counteract the pro-inflammatory effects of IFN-γ and IL-22 on keratinocytes, revert the apoptosis-resistant phenotype, as well as inhibit hyperproliferation in the psoriatic epidermis.


A Rare Cause of Abdominal Pain in a Patient with Acute Necrotizing Pancreatitis.
Walled-off necrosis (WON) is a potentially lethal late complication of acute pancreatitis (AP) and occurs in less than 10% of AP cases. It can be located in or outside the pancreas. When infected, the mortality rate increases and can reach 100% if the collection is not drained. Its treatment is complex and includes, at the beginning, intravenous antibiotics, which permit sepsis control and a delay in the therapeutic intervention, like drainage. Nowadays, a minimally invasive approach is advised. Depending on the location of the collection, computed tomography (CT)-guided drainage or endoscopic necrosectomy are the primary options, then complemented by surgical necrosectomy if needed. Infected WON of the abdominal wall has been rarely described in the literature and there is no report of any infection with Citrobacter freundii. We present the case of a 61-year-old man with necrotizing AP complicated by WON of the left abdominal wall, infected with Citrobacter freundii that was successfully treated with CT-guided percutaneous drainage and intravenous antibiotics. Infected WON accounts for considerable mortality and its location in the abdominal wall is rare; it can be treated with antibiotics and CT-guided drainage with no need for further intervention.


Liver in systemic disease.
Potential causes of abnormal liver function tests include viral hepatitis, alcohol intake, nonalcoholic fatty liver disease, autoimmune liver diseases, hereditary diseases, hepatobiliary malignancies or infection, gallstones and drug-induced liver injury. Moreover, the liver may be involved in systemic diseases that mainly affect other organs. Therefore, in patients without etiology of liver injury by screening serology and diagnostic imaging, but who have systemic diseases, the abnormal liver function test results might be caused by the systemic disease. In most of these patients, the systemic disease should be treated primarily. However, some patients with systemic disease and severe liver injury or fulminant hepatic failure require intensive treatments of the liver.


Cauliflower mosaic virus P6 Dysfunctions Histone Deacetylase HD2C to Promote Virus Infection.
Histone deacetylases (HDACs) are vital epigenetic modifiers not only in regulating plant development but also in abiotic- and biotic-stress responses. Though to date, the functions of HD2C-an HD2-type HDAC-In plant development and abiotic stress have been intensively explored, its function in biotic stress remains unknown. In this study, we have identified HD2C as an interaction partner of the Cauliflower mosaic virus (CaMV) P6 protein. It functions as a positive regulator in defending against CaMV infection. The hd2c mutants show enhanced susceptibility to CaMV infection. In support, the accumulation of viral DNA, viral transcripts, and the deposition of histone acetylation on the viral minichromosomes are increased in hd2c mutants. P6 interferes with the interaction between HD2C and HDA6, and P6 overexpression lines have similar phenotypes with hd2c mutants. In further investigations, P6 overexpression lines, together with CaMV infection plants, are more sensitive to ABA and NaCl with a concomitant increasing expression of ABA/NaCl-regulated genes. Moreover, the global levels of histone acetylation are increased in P6 overexpression lines and CaMV infection plants. Collectively, our results suggest that P6 dysfunctions histone deacetylase HD2C by physical interaction to promote CaMV infection.


A case of multiple endocrine neoplasia type 1 with primary liver gastrinoma.
Gastrinoma is the most frequent functional pancreaticoduodenal endocrine tumor in patients with multiple endocrine neoplasia type 1 (MEN 1). Primary hepatic gastrinomas in MEN 1 are very rare, with no previous reports published in the literature. We reported the case of a 39 yr old female patient with a history of repeated peptic ulcers and a hypoglycemia episode. Abdominal CT indicated a well-defined liver mass and a pancreatic head mass. Somatostatin-receptor scintigraphy with [(111)In] DTPA octreotide demonstrated a strong uptake of the radiotracer in the left lateral segment at the site of the hepatic mass. After operation, immunohistochemical staining was consistent with pancreatic insulinoma and primary hepatic gastrinoma. As the liver is a common site of metastases from gastrinoma, primary liver gastrinoma has not yet been reported with MEN 1. We diagnosed this patient using immunohistochemical studies and treated this patient by hepatic segmentectomy.


Cord factors from atypical mycobacteria (Mycobacterium alvei, Mycobacterium brumae) stimulate the secretion of some pro-inflammatory cytokines of relevance in tuberculosis.
The ability to induce several cytokines relevant to tuberculosis (TNF-α, IL-1β, IL-6, IL-12p40 and IL-23) by cord factor (trehalose dimycolate) from Mycobacterium alvei CR-21(T) and Mycobacterium brumae CR-270(T) was studied in the cell lines RAW 264.7 and THP-1, and compared to the ability of cord factor from Mycobacterium tuberculosis H37Rv, where this glycolipid appears to be implicated in the pathogenesis of tuberculosis. Details of the fine structure of these molecules were obtained by NMR and MS. The mycoloyl residues were identified as α and (ω-1)-methoxy in M. alvei CR-21(T) and α in M. brumae CR-270(T); in both cases they were di-unsaturated instead of cyclopropanated as found in M. tuberculosis. In RAW 264.7 cells, cord factors from M. alvei CR-21(T), M. brumae CR-270(T) and M. tuberculosis differed in their ability to stimulate IL-6, the higher levels corresponding to the cord factor from M. tuberculosis. In THP-1 cells, a similar overall profile of cytokines was found for M. alvei CR-21(T) and M. brumae CR-270(T), with high proportions of IL-1β and TNF-α, and different from M. tuberculosis, where IL-6 and IL-12p40 prevailed. The data obtained indicate that cord factors from the atypical mycobacteria M. alvei CR-21(T) and M. brumae CR-270(T) stimulated the secretion of several pro-inflammatory cytokines, although there were some differences with those of M. tuberculosis H37Rv. This finding seems to be due to their particular mycoloyl substituents and could be of interest when considering the potential adjuvanticity of these molecules.


Process-Structure-Property Relationships of AISI H13 Tool Steel Processed with Selective Laser Melting.
Due to a good combination of high hardness, wear resistance, toughness, resistance to high operating temperatures, and fairly low material cost, AISI H13 tool steel is commonly used in the manufacture of injection molds. Additive manufacturing (AM) such as selective laser melting (SLM), due to the layer-wise nature of the process, offers substantial geometric design freedom in comparison with conventional subtractive manufacturing methods, thereby enabling a construction of complex near-net shape parts with internal cavities like conformal cooling channels. The quality of SLM-manufactured parts mainly depends on the part geometry, build orientation and scanning strategy, and processing parameters. In this study, samples of H13 tool steel with a size of 10 × 10 × 15 mm3 were SLM-manufactured using a laser power of 100, 200, and 300 W; scanning speed of 200, 400, 600, 800, 1000, and 1200 mm/s; and hatch spacing of 80 and 120 µm. A constant layer thickness of 40 µm, 67° scanning rotation between subsequent layers, and a stripe scanning strategy were maintained during the process. The samples were built considering a preheating of 200 °C. The relative density, surface roughness, crack formation, microstructure, and hardness were evaluated. The relative density is shown to increase with increasing the volumetric energy density up to a value of about 60 J/mm3 and then no significant increase can be pointed out; the maximum relative density of 99.7% was obtained. A preheating of 200 °C generally aids to increase the relative density and eliminate the crack formation. The microstructure of built samples shows fine equiaxed cellular-dendritic structure with martensite and some retained austenite. The microhardness of the as-built samples was found to vary from 650 to 689 HV 0.2, which is comparable to a conventionally produced H13 tool steel.


[Varicella zoster virus and atypical necrotizing retinopathies in HIV and AIDS patients].
Necrotizing retinopathies of suspected viral origin, but which do not meet the criteria for either CMV-retinitis or acute retinal necrosis syndrome, have been grouped together under the term atypical necrotizing retinopathies. Nothing is known about their etiology. Aqueous humor samples were drawn from two HIV-positive and eight patients with AIDS presenting with an atypical necrotizing retinopathy, additionally from six patients with acute retinal necrosis syndrome and 28 patients with active CMV-retinitis at the time of diagnosis as well as from thirty healthy controls at surgery. All samples underwent DNA extraction and amplification for viral DNA of HSV-1, VZV and CMV. VZV-DNA was detected in seven of nine aqueous humor samples derived from patients with atypical necrotizing retinopathies and in four of six samples from patients with acute retinal necrosis syndrome, but not in any one from the 28 patients with CMV retinitis. In the latter group, CMV DNA was detectable in 23 samples, in two of these additionally HSV-1 DNA. No viral DNA was amplified from any of the samples from healthy controls. Varicella zoster virus ist the leading cause of atypical necrotizing retinopathies. This should be considered in the antiviral chemotherapy. Moreover, we were able to establish the diagnosis using DNA amplification for the viruses of the herpes family irrespective of the etiology in 80% of necrotizing retinopathies.


Assessing parental attitudes toward genetic testing for childhood hearing loss: before and after genetic consultation.
We report on the development of a Genetic Attitude Assessment Tool (GAAT) to measure parental attitudes in contemplating genetic testing for childhood hearing loss, and to examine the differences in assessments made before and after genetic counseling. The GAAT tool was administered to a convenient sample of 119 parents of children with bilateral sensorineural hearing loss. The respondents completed the survey either before (n = 77) or after (n = 42) genetic counseling. Exploratory Factor Analysis was applied to identify and quantify the underlying psychosocial structure. Our results showed the validated 54-item GAAT instrument contains six subscales: (1) "test intention," (2) "beliefs in non-genetic causes of hearing loss," (3) "deferral of decision to undergo genetic testing," (4) "appropriate use of genetic testing results," (5) "beliefs in the benefits," and (6) "concerns about stigma." The respondents who answered the survey after genetic counseling had higher "test intention" (P = 0.017) and endorsed to a greater extent "beliefs in the benefits" (P < 0.001). They believed to a lesser extent that childhood hearing loss was due to "non-genetic causes" (P < 0.001) and were less inclined to prefer "decision deferral" (P = 0.031). Respondents who themselves had a hearing loss expressed a significantly weaker belief in "non-genetic causes" of hearing loss (P < 0.0001). In conclusion the validated GAAT instrument is responsive to changes in parental attitudes after genetic counseling. The GAAT may be used to monitor parental attitudes serially, to further understand how parental attitudes change from pre genetic counseling, post genetic counseling, to post test result disclosure.


Does fruit and vegetable consumption impact mental health? Systematic review and meta-analyses of published controlled intervention studies.
Associations between fruit and vegetable (FV) consumption and mental health are suggested, largely from observational studies. This systematic review aimed to identify and summarise all published controlled intervention studies investigating the effects of FV consumption on mental health in adults. Four academic databases (Medline, PsycINFO, PubMed, Web of Science) were searched on 16 September 2022, over all years, for studies that used an intervention design; included FV consumption; included an appropriate non-FV-consumption control; used a validated measure of mental health and were conducted in healthy adults or adults with solely a depressive or anxiety-related condition. Study details were tabulated and combined using meta-analyses. Risk of bias was assessed using the domains of the Cochrane Collaboration. Six studies, enrolling 691 healthy adults and reporting on one or more mental health outcomes, were found. Meta-analyses found small and imprecise effects of FV consumption for: psychological well-being (4 studies, 289 participants) standardised mean difference (SMD) = 0·07 (95 % CI -0·17, 0·30), P = 0·58, I2 = 0 %; depressive symptomology (3 studies, 271 participants) SMD = -0·15 (95 % CI -0·40, 0·10), P = 0·23, I2 = 47 % and anxiety-related symptomology (4 studies, 298 participants) SMD = -0·15 (95 % CI -0·39, 0·08), P = 0·20, I2 = 71 %. Some benefit for psychological well-being was found in change-from-baseline data: SMD = 0·28 (95 % CI 0·05, 0·52), P = 0·02, I2 = 0 %. Risk of bias was high in many studies. Limitations include the consideration only of published studies and stem from the studies found. Given the few, limited studies available and the small size of effects, stronger evidence is needed before recommending FV consumption for mental health.


Association of antenatal depression with adverse consequences for the mother and newborn in rural Ghana: findings from the DON population-based cohort study.
Whilst there is compelling evidence of an almost 2-fold increased risk of still births, and suggestive evidence of increased mortality among offspring of mothers with psychotic disorders, only three studies have addressed the role of antenatal depression (AND) on survival of the baby. We examined these associations in a large cohort of pregnant women in Ghana. A Cohort study nested within 4-weekly surveillance of all women of reproductive age to identify pregnancies and collect data on births and deaths in the Kintampo Health Research Centre study area of Ghana. Women were screened for AND using the Patient Health Questionnaire (PHQ-9) to ascertain DSM-IV major or minor depression. Outcomes were adverse birth outcomes, maternal/infant morbidity, and uptake of key newborn care practices, examined using logistic regression; effect sizes reported as relative risks with 95% confidence intervals. 20679 (89.6%) pregnant women completed the PHQ-9. The prevalence of AND was 9.9% (n = 2032) (95% confidence interval 9.4%-10.2%). AND was associated with: prolonged labour (RR 1.25, 95% CI 1.02-1.53); peripartum complications (RR 1.11, 95% CI 1.07-1.15); postpartum complications (RR 1.27, 96% CI 1.21-1.34); non-vaginal delivery (RR 1.19, 95% CI 1.02-1.40); newborn illness (RR 1.52, 95% CI 1.16-1.99); and bed net use during pregnancy (RR 0.93, 95% CI 0.89-0.98), but not neonatal deaths, still births, low birth weight, immediate breast feeding initiation, or exclusive breastfeeding. AND was marginally associated with preterm births (RR 1.32, 95% CI 0.98-1.76). This paper has contributed important evidence on the role of antenatal depression as a potential contributor to maternal and infant morbidity. Non-pharmacological treatments anchored on primary care delivery structures are recommended as an immediate step. We further recommend that trials are designed to assess if treating antenatal depression in conjunction with improving the quality of obstetric care results in improved maternal and newborn outcomes.


Glutamate transporter mRNA and glutamate-like immunoreactivity in spinal motoneurones.
Glutamate is the major excitatory neurotransmitter in the central nervous system. The release of glutamate is terminated by rapid uptake of glutamate into the presynaptic nerve terminals and into surrounding glial cells. Recently, a neuronal glutamate transporter was cloned from rabbit small intestine, thereby providing the possibility to study the distribution of cells that express glutamate transporter mRNA. Using oligonucleotide probes and in situ hybridization, glutamate transporter mRNA was demonstrated in large cell bodies, presumably motoneurones, in the thoracic spinal cord of the rabbit. Immunohistochemical analysis with rabbit polyclonal antibodies to glutamate showed immunoreactivity in the cytoplasm of large cell bodies in the ventral horn, presumably motoneurones, of the rat spinal cord. Glutamate-LI was in addition demonstrated in the motor end plate in hindlimb muscle of the rat, as visualized by double-labelling with mouse monoclonal antibodies to synaptophysin. Taken together, these data raise the possibility that glutamate has a function at the vertebrate neuromuscular junction.


One experience with 'lower' or 'higher' intensity stressors, respectively enhances or diminishes responsiveness to haloperidol weeks later: implications for understanding drug variability.
This laboratory has previously shown that acute exposure to a variety of brief stressful events can have a very long-lasting influence on subsequent responsiveness to pharmacological and non-pharmacological stressors. In some cases the response to these agents is enhanced, while in others it is diminished: the common denominator being that in each instance the influence of the initial stressor grows stronger with the passage of time. Here, we identify one factor that determines which time-dependent effect is manifest. In 3 separate experiments, male rats were subjected to a single exposure to stressors of either lower or higher intensity and their effects on haloperidol-induced catalepsy and dopamine and dihydroxyphenylacetic acid levels in the nucleus accumbens and medial frontal cortex, measured either 1-2 h or 2 weeks later. The stressors were either environmental (needle jab or 1 h of immobilization), metabolic (200 or 750 mg/kg, i.p. of 2-deoxy-D-glucose), or no effect on haloperidol-induced catalepsy when stressors preceded such behavioral testing by 1-2 h. By contrast, when the interval was 2 weeks, the lower-intensity stressors all increased haloperidol catalepsy, whereas the higher-intensity stressors decreased the same response. In other words, a process that progressed with the passage of time was observed regardless of whether sensitization or diminution of haloperidol's action occurred. In contrast to the uniform bipolar behavioral effects observed, depending on the intensity of the prestressor, the neurochemical findings failed to show any evidence of bipolarity whatever.(ABSTRACT TRUNCATED AT 250 WORDS)


Variability of cerebral blood volume and oxygen extraction: stages of cerebral haemodynamic impairment revisited.
The presence or degree of haemodynamic impairment due to occlusive cerebrovascular disease is often inferred from measurements of cerebral blood flow (CBF), cerebral blood volume (CBV), oxygen extraction fraction (OEF) and the cerebral rate for oxygen metabolism (CMRO2). However, the relationship of these variables, in particular CBV, to regional cerebral haemodynamics is not clearly established in humans with subacute or chronic disease. In the present study, we investigated the relationship of CBV to OEF, CBF and CMRO2, and to subsequent stroke risk in patients with unilateral carotid artery occlusion, in order to define better the associated haemodynamic and metabolic changes. We reviewed data from 81 patients with symptomatic carotid occlusion enrolled in a prospective study of haemodynamic factors and stroke risk. Measurements of CBV, CBF, OEF and CMRO2 were made on entry using PET. Patients were divided into groups by hemispheric ratios and absolute ipsilateral values of OEF and CBV, based on comparison with normal controls. Haemodynamic and metabolic values, risk factors and stroke risk were compared between groups. Based on hemispheric ratios, 45 patients had increased ipsilateral OEF; CBV was increased in 19 of these 45 patients. No differences in CBF, CMRO2 or clinical risk factors were found between these 19 patients and the remaining 26 patients with increased OEF and normal or reduced CBV. Thirteen ipsilateral strokes occurred during follow-up, and 10 of the 13 occurred in the 19 patients with increased OEF and CBV (log rank P < 0.0001). Thirty-two of the 68 patients with complete quantitative PET data had increased OEF by absolute ipsilateral values. CBV was increased in 20 of the 32 patients. No differences in CBF, CMRO2 or clinical risk factors were found between these 20 patients and the remaining 12 patients with increased OEF and normal CBV. Seven of the nine ipsilateral strokes that occurred in the 68 patients occurred in those 20 patients with increased OEF and increased CBV (log rank P = 0.003). The higher risk of ischaemic stroke in patients with increased OEF and CBV suggests that their degree of haemodynamic compromise is more severe than those with increased OEF and normal CBV. In patients with chronic carotid occlusion and increased OEF, increased CBV may indicate pronounced vasodilation due to exhausted autoregulatory vasodilation. The physiological explanation for the measurement of normal CBV in patients with increased OEF is less certain and may reflect preserved autoregulatory capacity.


Effects of ruthenium complexes on experimental tumors: irrelevance of cytotoxicity for metastasis inhibition.
A series of 18 ruthenium(III) complexes, structurally related to the selective antimetastatic drug Na[trans-RuCl4(DMSO)Im], and characterized by the presence of sulfoxide and nitrogen-donor ligands were tested on TLX5 lymphoma and some of them on MCa mammary carcinoma to evaluate the dependence of the degree of cytotoxicity and of antimetastatic activity on the chemical properties. In vitro cytotoxicity is present only at high concentrations (> 10(-4) M), depends upon lipophilicity and is markedly affected by the presence of 5% serum or plasma samples in the culture medium. The comparison of the effects on in vitro cytotoxicity with in vivo antitumor and antimetastatic action points out that these compounds reduce metastasis formation by a mechanism unrelated to a direct tumor cell cytotoxicity. If on one hand Na[trans-RuCl4(TMSO)Iq], the compound that shows the most potent in vitro cytotoxic effects, is the least effective against metastases, on the other Na[trans-RuCl4(DMSO)Im], the compound that better reduces metastasis formation, is rather devoid of cytotoxic effects on tumor cells kept in vitro. In particular, Na[trans-RuCl4(DMSO)Im] seems to distinguish between artificially induced metastases and spontaneous metastases and reduces only the former by a cytotoxic mechanism. Out of all the tested compounds, with the exception of Na[trans-RuCl4(DMSO)Ox], Na[trans-RuCl4(DMSO)Im] is confirmed to be the most selective antimetastatic agent of the group.


Genome-Wide Association Study on Immunoglobulin G Glycosylation Patterns.
Immunoglobulin G (IgG), a glycoprotein secreted by plasma B-cells, plays a major role in the human adaptive immune response and are associated with a wide range of diseases. Glycosylation of the Fc binding region of IgGs, responsible for the antibody's effector function, is essential for prompting a proper immune response. This study focuses on the general genetic impact on IgG glycosylation as well as corresponding subclass specificities. To identify genetic loci involved in IgG glycosylation, we performed a genome-wide association study (GWAS) on liquid chromatography electrospray mass spectrometry (LC-ESI-MS)-measured IgG glycopeptides of 1,823 individuals in the Cooperative Health Research in the Augsburg Region (KORA F4) study cohort. In addition, we performed GWAS on subclass-specific ratios of IgG glycans to gain power in identifying genetic factors underlying single enzymatic steps in the glycosylation pathways. We replicated our findings in 1,836 individuals from the Leiden Longevity Study (LLS). We were able to show subclass-specific genetic influences on single IgG glycan structures. The replicated results indicate that, in addition to genes encoding for glycosyltransferases (i.e., ST6GAL1, B4GALT1, FUT8, and MGAT3), other genetic loci have strong influences on the IgG glycosylation patterns. A novel locus on chromosome 1, harboring RUNX3, which encodes for a transcription factor of the runt domain-containing family, is associated with decreased galactosylation. Interestingly, members of the RUNX family are cross-regulated, and RUNX3 is involved in both IgA class switching and B-cell maturation as well as T-cell differentiation and apoptosis. Besides the involvement of glycosyltransferases in IgG glycosylation, we suggest that, due to the impact of variants within RUNX3, potentially mechanisms involved in B-cell activation and T-cell differentiation during the immune response as well as cell migration and invasion involve IgG glycosylation.


Large-scale gene expression analysis of cholesterol dependence in NS0 cells.
NS0, a nonsecreting mouse myeloma cell, is a major host line used for recombinant antibody production. These cells have a cholesterol-dependent phenotype and rely on an exogenous supply of cholesterol for their survival and growth. To better understand the physiology underlying cholesterol dependence, we compared NS0 cells, cultivated under standard cholesterol-dependent growth conditions (NS0), to cells adapted to cholesterol-independent conditions (NS0 revertant, NS0_r). Large-scale transcriptional analyses were done using the Affymetrix GeneChip array, MG-U74Av2. The transcripts expressed differentially across the two cell lines were identified. Additionally, proteomic tools were employed to analyze cell lysates from these two cell lines. Cellular proteins from both NS0 and NS0_r were subjected to 2D gel electrophoresis. MALDI-TOF mass spectrometry was performed to determine the identity of the differentially expressed spots. We examined the expression level of mouse genes directly involved in cholesterol biosynthesis, lipid metabolism, and central energy metabolism. Most of these genes were downregulated in the revertant cell type, NS0_r, compared to NS0. Overall, a large number of genes are expressed differentially, indicating that the reversal of cholesterol dependency has a profound effect on cell physiology. It is probable that a single gene mutation, activation, or inactivation is responsible for cholesterol auxotrophy. However, the wide-ranging changes in gene expression point to the distinct possibility of a regulatory event affecting the reversibility of auxotrophy, either directly or indirectly.


Randomized clinical trial of open-cell vs closed-cell stents for carotid stenting and effects of stent design on cerebral embolization.
The effect of stent design on cerebral embolization has not been established. The purpose of this trial was to contrast the incidence of subclinical cerebral embolization in high-risk patients undergoing carotid artery stenting (CAS) with open-cell vs closed-cell stents. During an 18-month period, 40 patients were randomized (1:1) to undergo CAS with open-cell (Acculink, n = 20) or closed-cell stents (Xact, n = 20). A single filter device for embolic protection (Accunet filter) was used. Transcranial Doppler (TCD)-detected microembolic signals (MES) during CAS and preprocedural and 24-hour postprocedural diffusion-weighted magnetic resonance imaging (DW-MRI) were used to determine cerebral embolization. Univariate and nonparametric analyses were used to assess associations between stent design and cerebral embolization. CAS was performed in 17 symptomatic patients (43%) and 23 asymptomatic patients (57%) with a similar number of open-cell and closed-cell stents (9/8 and 11/12, respectively). The total and poststenting median ipsilateral MES counts detected by TCD were 264 (interquartile range [IQR], 222-343) and 48 (IQR, 41-66) for open-cell stents and 339 (IQR, 163-408) and 53 (IQR, 23-88) for closed-cell stents, respectively (P > .56). New acute cerebral emboli detected with DW-MRI occurred in 53% and 47% of patients undergoing CAS with open-cell and closed-cell stents, respectively (P = 1.0). The total and ipsilateral median numbers of DW-MRI lesions between groups were not statistically significantly different (ie, 2 [IQR, 0-4] and 1 [IQR, 0-3] for open-cell stents and 1 [IQR, 0-3] and 1 [IQR, 0-2] for closed cell-stents, respectively; P > .4). One asymptomatic patient undergoing CAS with an open-cell stent sustained a minor stroke; the 30-day stroke-death rate in this series was 2.5%. Cerebral embolization, as detected by TCD and DW-MRI, occurs with similar frequency after CAS with open-cell and closed-cell stents. This randomized trial does not support the superiority of any stent design with respect to cerebral embolization.


Prevention of noise-induced hearing loss.
To review the evidence suggesting that occupational hearing conservation programs prevent noise-induced hearing loss; to describe the features, prevalence, and handicap associated with noise-induced hearing loss; and to describe the otolaryngologist's role in prevention of noise-induced hearing loss. Recent statements from the American College of Occupational Medicine, the National Institutes of Health, and the International Organization for Standardization are supplemented by published articles known to the author (no formal literature search was done). Articles that purported to measure the effects of occupational hearing conservation programs on preventing noise-induced hearing loss. Each article was separately critiqued without a priori assessment criteria. Several studies suggest that occupational hearing conservation programs prevent noise-induced hearing loss, but none of these are conclusive. No randomized clinical trial has been reported, of which I am aware, and previously reported data suffer from one or more of the following shortcomings: failure to match treatment and control groups for age, nonoccupational noise exposure, and/or prior hearing loss; failure to control for audiometric learning effects; and inclusion of workers who had already worked long careers without hearing protection (and thus had little risk of additional noise-induced loss). Although noise reduction for individuals obviously can prevent noise-induced hearing loss, to my knowledge, no single study offers convincing evidence of the efficacy of occupational hearing conservation programs, primarily due to methodologic flaws.


[The health system of Bolivia].
This paper describes the Bolivian health system, including its structure and organization, its financing sources, its health expenditure, its physical, material and humans resources, its stewardship activities and the its health research institutions. It also discusses the most recent policy innovations developed in Bolivia: the Maternal and Child Universal Insurance, the Program for the Extension of Coverage to Rural Areas, the Family, Community and Inter-Cultural Health Model and the cash-transfer program Juana Azurduy intended to strengthen maternal and child care.


Identification of the Gbeta5-RGS7 protein complex in the retina.
The G protein beta subunit G beta 5 deviates significantly from the four other members of the G beta family in amino acid sequence, unique expression pattern (only in the CNS), and cytosolic localization. To identify the members of the G beta 5-mediated signaling pathway, we purified the native protein complex containing G beta 5 from the cytosolic fraction of bovine retina. Analysis of the isolated complex revealed that G beta 5 is tightly associated with RGS7, a member of the superfamily of negative regulators of G protein signaling. This finding, for the first time, demonstrates an interaction between a G beta subunit and an RGS protein. G beta 5 was not detected in the outer segments of photoreceptor cells, suggesting that the cytosolic G beta 5-RGS7 complex is not directly involved in phototransduction.


IPSE, a parasite-derived host immunomodulatory protein, is a potential therapeutic for hemorrhagic cystitis.
Chemotherapy-induced hemorrhagic cystitis is characterized by bladder pain and voiding dysfunction caused by hemorrhage and inflammation. Novel therapeutic options to treat hemorrhagic cystitis are needed. We previously reported that systemic administration of the Schistosomiasis hematobium-derived protein H-IPSEH06 (IL-4-inducing principle from Schistosoma mansoni eggs) is superior to three doses of MESNA in alleviating hemorrhagic cystitis (Mbanefo EC, Le L, Pennington LF, Odegaard JI, Jardetzky TS, Alouffi A, Falcone FH, Hsieh MH. FASEB J 32: 4408-4419, 2018). Based on prior reports by others on S. mansoni IPSE (M-IPSE) and additional work by our group, we reasoned that H-IPSE mediates its effects on hemorrhagic cystitis by binding IgE on basophils and inducing IL-4 expression, promoting urothelial proliferation, and translocating to the nucleus to modulate expression of genes implicated in relieving bladder dysfunction. We speculated that local bladder injection of the S. hematobium IPSE ortholog IPSEH03, hereafter called H-IPSEH03, might be more efficacious in preventing hemorrhagic cystitis compared with systemic administration of IPSEH06. We report that H-IPSEH03, like M-IPSE and H-IPSEH06, activates IgE-bearing basophils in a nuclear factor of activated T-cells reporter assay, indicating activation of the cytokine pathway. Furthermore, H-IPSEH03 attenuates ifosfamide-induced increases in bladder wet weight in an IL-4-dependent fashion. H-IPSEH03 relieves hemorrhagic cystitis-associated allodynia and modulates voiding patterns in mice. Finally, H-IPSEH03 drives increased urothelial cell proliferation, suggesting that IPSE induces bladder repair mechanisms. Taken together, H-IPSEH03 may be a potential novel therapeutic to treat hemorrhagic cystitis by basophil activation, attenuation of allodynia, and promotion of urothelial cell proliferation.


Exploring the Value Added of a Guided, Silent Reading Intervention: Effects on Struggling Third-Grade Readers' Achievement.
The authors' purpose was to explore the effects of a supplementary, guided, silent reading intervention with 80 struggling third-grade readers who were retained at grade level as a result of poor performance on the reading portion of a criterion referenced state assessment. The students were distributed in 11 elementary schools in a large, urban school district in the state of Florida. A matched, quasi-experimental design was constructed using propensity scores for this study. Students in the guided, silent reading intervention, Reading Plus, evidenced higher, statistically significant mean scores on the Florida Comprehensive Assessment Test criterion assessment measure of reading at posttest. The effect size, favoring the guided, silent reading intervention group was large, 1 full standard deviation, when comparing the 2 comparison groups' mean posttest scores. As such, the results indicate a large advantage for providing struggling third-grade readers guided silent reading fluency practice in a computer-based practice environment. No significant difference was found between the treatment and control group on the Stanford Achievement Test-10 (SAT-10) posttest scores, although posttest scores for the treatment group trended higher than the control. After conducting a power analysis, it was determined that the sample size (n = 80) was too small to provide sufficient statistical power to detect a difference in third-grade students' SAT-10 scores.


Polarization screening-induced magnetic phase gradients at complex oxide interfaces.
Thin-film oxide heterostructures show great potential for use in spintronic memories, where electronic charge and spin are coupled to transport information. Here we use a La0.7Sr0.3MnO3 (LSMO)/PbZr0.2Ti0.8O3 (PZT) model system to explore how local variations in electronic and magnetic phases mediate this coupling. We present direct, local measurements of valence, ferroelectric polarization and magnetization, from which we map the phases at the LSMO/PZT interface. We combine these experimental results with electronic structure calculations to elucidate the microscopic interactions governing the interfacial response of this system. We observe a magnetic asymmetry at the LSMO/PZT interface that depends on the local PZT polarization and gives rise to gradients in local magnetic moments; this is associated with a metal-insulator transition at the interface, which results in significantly different charge-transfer screening lengths. This study establishes a framework to understand the fundamental asymmetries of magnetoelectric coupling in oxide heterostructures.


Magnetic properties of 1 : 4 complexes of CoCl2 and pyridines carrying carbenes (S(0) = 4/2, 6/2, and 8/2) in diluted frozen solution; influence of carbene multiplicity on heterospin single-molecule magnets.
The microcrystalline sample of a parent complex, [CoCl(2)(py)(4)], showed a single-molecule magnet (SMM) behavior with an effective activation barrier, U(eff)/k(B), of 16 K for reversal of the magnetism in the presence of a dc field of 3 kOe. Pyridine ligands having 2-4 diazo moieties, DYpy; Y = 2, 3l, 3b, and 4, were prepared and confirmed to be quintet, septet, septet, and nonet in the ground state, respectively, after irradiation. The 1 : 4 complexes, CoCl(2)(DYpy)(4); Y = 2, 3l, 3b, and 4 in frozen solutions after irradiation showed the magnetic behaviors of SMMs with total spin multiplicity, S(total) = 17/2, 25/2, 25/2, and 33/2, respectively. Hysteresis loops depending on the temperature were observed and the values of coercive force, H(c), at 1.9 K were 12, 8.4, 11, and 8.1 kOe for CoCl(2)(CYpy)(4); Y = 2, 3l, 3b, and 4, respectively. In dynamic magnetic susceptibility experiments, ac magnetic susceptibility data obeyed the Arrhenius law to give U(eff)/k(B) values of 94, 92, 93, and 87 K for CoCl(2)(CYpy)(4); Y = 2, 3l, 3b, and 4, respectively, while the relaxation times for CoCl(2)(CYpy)(4); Y = 2 and 3l, obtained by dc magnetization decay in the range of 3.5-1.9 K slightly deviated downward from Arrhenius plots on cooling. The dynamic magnetic behaviors for CoCl(2)(CYpy)(4) including [CoCl(2)(py)(4)] and CoCl(2)(C1py)(4) suggested that the generated carbenes interacted with the cobalt ion to increase the relaxation time, τ(q), due to the spin quantum tunneling magnetization, which became larger with increasing S(total) of the complex.


Magnesium Catalyzed Polymerization of End Functionalized Poly(propylene maleate) and Poly(propylene fumarate) for 3D Printing of Bioactive Scaffolds.
The ring-opening copolymerization of maleic anhydride and propylene oxide, using a functionalized primary alcohol initiator and magnesium 2,6-di-tert-butyl phenoxide as a catalyst, was investigated in order to produce high end-group fidelity poly(propylene maleate). Subsequent isomerization of the material into 3D printable poly(propylene fumarate) was utilized to produce thin films and scaffolds possessing groups that can be modified with bioactive groups postpolymerization and postprinting. The surface concentration of these modifiable groups was determined to be 30.0 ± 3.3 pmol·cm-2, and copper-mediated azide-alkyne cycloaddition was used to attach a small molecule dye and cell adhesive GRGDS peptides to the surface as a model system. The films were then studied for cytotoxicity and found to have high cell viability before and after surface modification.


Philosophy's loss, neurology's gain: the endeavor of John Hughlings-Jackson.
The year 2011 marked the centenary of the death of one of the founders of British neurology, John Hughlings-Jackson (1835-1911). By common consent he was a great clinician. But he was more. He endeavored to use clinical observations to throw light on one of the great problems of the modern world, the problem of mind. Hughlings-Jackson's daily contact with mentalities warped by neurological disease caused him to ponder deeply the nature of the mind-brain relationship, nowadays often known simply as the "hard problem." In particular, he saw the danger of conflating mind and brain, a danger that has grown greater with the spectacular growth of neuroscientific knowledge during the last century. Although Hughlings-Jackson's neuroscientific thought is long outdated, his philosophic endeavors remain highly instructive.


Shape controlled assembly of carboxylic acids: formation of a binary monolayer by intercalation into molecular nanotunnels.
Binary self-assembled monolayers (SAMs) combining a Y-shaped aromatic carboxylic acid (1,3,5-benzenetribenzoic acid, H3BTB) and a cage-type alicyclic carboxylic acid (adamantane carboxylic acid, AdCA) were investigated by scanning tunneling microscopy (STM), X-ray photoelectron spectroscopy (XPS), and near edge X-ray absorption fine structure (NEXAFS) spectroscopy. The SAMs, prepared by molecular adsorption from solution on Au substrates modified by underpotential deposition of Ag, exhibit a pronounced dependence of their structure on the assembly protocol. Exposing an H3BTB SAM to AdCA, the highly regular row structure of the native H3BTB layer persists and STM imaging does not show signs of AdCA adsorption. This is in striking contrast to the disordered arrangements of H3BTB and the presence of AdCA employing the inverted adsorption sequence or coadsorption of the two molecules. However, spectroscopic analysis of the H3BTB SAM exposed to AdCA reveals the presence also of the latter, suggesting that the AdCA molecules are hidden in the nanotunnels of the H3BTB monolayer. Direct evidence for the intercalation of AdCA is obtained by STM manipulation experiments which lay bare areas of AdCA molecules upon local removal of H3BTB. Surprisingly, these are densely packed and arranged into a highly ordered monolayer. Formation of such a compact AdCA layer is explained by expulsion of AdCA from the H3BTB nanotunnels of the surrounding intact mixed SAM, driven by release of stress in the nanotunnels built up when AdCA is intercalated.


Management of temporal bone trauma.
The temporal bones are paired structures located on the lateral aspects of the skull and contribute to the skull base. Trauma is usually the result of blunt head injury and can result in damage to the brain and meninges, the middle and internal ear, and the facial nerve. Complications can include intracranial hemorrhage, cerebral contusion, CSF leak and meningitis, hearing loss, vertigo, and facial paralysis. To prevent these complications, diagnosis followed by appropriate medical and surgical management is critical. Diagnosis relies primarily on physical signs and symptoms as well as radiographic imaging. Emergent intervention is required in situations involving herniation of the brain into the middle ear cavity or hemorrhage of the intratemporal carotid artery. Patients with declining facial nerve function are candidates for early surgical intervention. Conductive hearing loss can be corrected surgically as an elective procedure, while sensorineural hearing loss carries a poor prognosis, regardless of management approach. Children generally recover from temporal bone trauma with fewer complications than adults and experience a markedly lower incidence of facial nerve paralysis.


The International Health Regulations (2005), the threat of populism and the COVID-19 pandemic.
The global response to the COVID-19 pandemic has laid bare weaknesses and major challenges in the international approach to managing public health emergencies. Populist sentiment is spreading globally as democratic nations are increasing their support for or electing governments that are perceived to represent "traditional" native interests. Measures need to be taken to proactively address populist sentiment when reviewing the IHR (2005) effectiveness in the COVID-19 pandemic. We discuss how populism can impact the IHR (2005) and conversely how the IHR (2005) may be able to address populist concerns if the global community commits to helping states address public health threats that emerge within their borders.


On the dynamics of chemically stressed populations: the deduction of population consequences from effects on individuals.
A general, simple, and explicit model for the age-dependent growth and reproduction of individuals as a function of food supply is presented. The model assumes a Holling-type functional response coupled with a von Bertalanffy body growth law, a fixed ratio between the energy utilized for reproduction and respiration, and a juvenile stage that ends as soon as the animal attains a sufficient weight. This model is shown to fit the available data on the development of Daphnia magna quite well. The model is used as a basis for studying the effects of chemicals on population growth rate, given the effects on individuals. Effects on individual growth and reproduction are reflected in a concentration-dependent relative reduction of the population growth rate. Effects on feeding rate, digestion, basal metabolism, and survival work out much more dramatically at low natural population growth rates. This already follows from a much simpler model that assumes age-independent reproduction, as exemplified to a good approximation by the rotifer Brachionus rubens. The theoretical results are supplemented with experimental evidence, implying that the stress on a population at a certain concentration of a chemical may indeed be strongly dependent on the feeding state of that population.


Supportive housing and forensic patient outcomes.
In Canada, Review Boards are mandated to evaluate individuals found Not Criminally Responsible on Account of Mental Disorder (NCRMD) on an annual basis and render 1 of 3 dispositions: (a) custody, (b) conditional discharge, or (c) absolute discharge. To promote social reintegration, conditional discharge can be ordered with the condition to live in supportive housing. However, NCRMD accused face great barriers to housing access as a result of the stigma associated with the forensic label. The goal of this study was to evaluate the role of housing in the clinical and criminal trajectories of forensic patients as they reintegrate into the community. Data for this study were extracted from a national study of individuals found NCRMD in Canada (Crocker, Nicholls, Seto, Côté, et al., in press). The present study focuses on a random sample of NCRMD accused in the province of Québec, who were under a conditional discharge disposition during the study period (n = 837). Controlling for sociodemographic, clinical, and criminal variables, survival analysis showed that individuals placed in independent housing following a conditional discharge from the Review Board were 2.5 times more likely to commit a new offense, nearly 3 times more likely to commit an offense against a person, and 1.4 times more likely to be readmitted for psychiatric treatment compared with individuals residing in supportive housing. These results point to the influence housing can have on the trajectories of forensic patients, above and beyond a range of clinical, criminological, and sociodemographic factors.


Meal fatty acids and postprandial vascular reactivity.
With increasing recognition of the pivotal role of vascular dysfunction in the progression of atherosclerosis, the vasculature has emerged as an important target for dietary therapies. Recent studies have indicated that chronic fatty acid manipulation alters vascular reactivity, when measured after an overnight fast. However, individuals spend a large proportion of the day in the postprandial (non-fasted) state. Several studies have shown that high fat meals can impair endothelial function within 3-4 h, a time period often associated with peak postprandial lipaemia. Although the impact of meal fatty acids on the magnitude and duration of the postprandial lipaemic response has been extensively studied, very little is known about their impact on vascular reactivity after a meal.


Longitudinal changes of structural connectivity in traumatic axonal injury.
To identify structural connectivity change occurring during the first 6 months after traumatic brain injury and to evaluate the utility of diffusion tensor tractography for predicting long-term outcome. The participants were 28 patients with mild to severe traumatic axonal injury and 20 age- and sex-matched healthy control subjects. Neuroimaging was obtained 0-9 days postinjury for acute scans and 6-14 months postinjury for chronic scans. Long-term outcome was evaluated on the day of the chronic scan. Twenty-eight fiber regions of 9 major white matter structures were reconstructed, and reliable tractography measurements were determined and used. Although most (23 of 28) patients had severe brain injury, their long-term outcome ranged from good recovery (16 patients) to moderately (5 patients) and severely disabled (7 patients). In concordance with the diverse outcome, the white matter change in patients was heterogeneous, ranging from improved structural connectivity, through no change, to deteriorated connectivity. At the group level, all 9 fiber tracts deteriorated significantly with 7 (corpus callosum, cingulum, angular bundle, cerebral peduncular fibers, uncinate fasciculus, and inferior longitudinal and fronto-occipital fasciculi) showing structural damage acutely and 2 (fornix body and left arcuate fasciculus) chronically. Importantly, the amount of change in tractography measurements correlated with patients' long-term outcome. Acute tractography measurements were able to predict patients' learning and memory performance; chronic measurements also determined performance on processing speed and executive function. Diffusion tensor tractography is a valuable tool for identifying structural connectivity changes occurring between the acute and chronic stages of traumatic brain injury and for predicting patients' long-term outcome.


Neuroradiologic findings in brown snake envenomation: computed tomography demonstration.
A case of fatal brown snake (Pseudonaja textilis) envenomation is presented. The CT examinations show rapid development and progression of atypical bilateral intracerebral haematomas (ICH) which produce a fatal outcome despite correction of the underlying coagulopathy. The striking CT appearance suggests coagulopathy and is predictive of increased mortality.


Investigation of bromide ion effects on disinfection by-products formation and speciation in an Istanbul water supply.
Recent epidemiological studies reported that brominated DBPs may be more carcinogenic than their chlorinated analogs. Thus, this research was designed to investigate the role of bromide ion in the formation and speciation of disinfection by-products (DBPs) during chlorination of Buyukcekmece Lake Water (BLW) in Istanbul. Chlorination of BLW samples was carried out at pH 7.0 with 5 and 12 mg/l chlorine dosages. For each chlorine dosage, six bromide concentrations ranging from 0.05 to 4.0mg/l were added to form a 2 x 6 experimental matrix. In general, increasing bromide concentration gradually shifted trihalomethanes (THMs) and haloacetic acids (HAAs) speciation from chlorinated species to the mixed bromochloro species during chlorination. The halogen substitution ability of HOBr and HOCl during the formation of THMs and HAAs can be estimated through the use of probability theory. It was concluded that, in both halogen substitution for THM and dihalogenated HAA formation, HOBr was found to be 20 times more reactive than HOCl.


Quantitative analysis of organizational culture in occupational health research: a theory-based validation in 30 workplaces of the organizational culture profile instrument.
This study advances a measurement approach for the study of organizational culture in population-based occupational health research, and tests how different organizational culture types are associated with psychological distress, depression, emotional exhaustion, and well-being. Data were collected over a sample of 1,164 employees nested in 30 workplaces. Employees completed the 26-item OCP instrument. Psychological distress was measured with the General Health Questionnaire (12-item); depression with the Beck Depression Inventory (21-item); and emotional exhaustion with five items from the Maslach Burnout Inventory general survey. Exploratory factor analysis evaluated the dimensionality of the OCP scale. Multilevel regression models estimated workplace-level variations, and the contribution of organizational culture factors to mental health and well-being after controlling for gender, age, and living with a partner. Exploratory factor analysis of OCP items revealed four factors explaining about 75% of the variance, and supported the structure of the Competing Values Framework. Factors were labeled Group, Hierarchical, Rational and Developmental. Cronbach's alphas were high (0.82-0.89). Multilevel regression analysis suggested that the four culture types varied significantly between workplaces, and correlated with mental health and well-being outcomes. The Group culture type best distinguished between workplaces and had the strongest associations with the outcomes. This study provides strong support for the use of the OCP scale for measuring organizational culture in population-based occupational health research in a way that is consistent with the Competing Values Framework. The Group organizational culture needs to be considered as a relevant factor in occupational health studies.


An improved assay for bacterial methane mono-oxygenase: some properties of the enzyme from Methylomonas methanica.
Extracts of Methylomonas methanica catalyse the O2-and NAD(P)H-dependent disappearance of bromomethane. The activity is unstable at 2 degrees C but is stable at --70 degrees C for several weeks. Bromomethane mono-oxygenase is particulate and is inhibited by metal-binding reagents, by compounds SKF 525A and Lilly 53325, by some metal ions and by acetylene. Evidence is presented that indicates that bromomethane mono-oxygenase is the enzyme responsible for methane oxidation in vivo.


Incompletely resolved phylogenetic trees inflate estimates of phylogenetic conservatism.
The tendency for more closely related species to share similar traits and ecological strategies can be explained by their longer shared evolutionary histories and represents phylogenetic conservatism. How strongly species traits co-vary with phylogeny can significantly impact how we analyze cross-species data and can influence our interpretation of assembly rules in the rapidly expanding field of community phylogenetics. Phylogenetic conservatism is typically quantified by analyzing the distribution of species values on the phylogenetic tree that connects them. Many phylogenetic approaches, however, assume a completely sampled phylogeny: while we have good estimates of deeper phylogenetic relationships for many species-rich groups, such as birds and flowering plants, we often lack information on more recent interspecific relationships (i.e., within a genus). A common solution has been to represent these relationships as polytomies on trees using taxonomy as a guide. Here we show that such trees can dramatically inflate estimates of phylogenetic conservatism quantified using S. P. Blomberg et al.'s K statistic. Using simulations, we show that even randomly generated traits can appear to be phylogenetically conserved on poorly resolved trees. We provide a simple rarefaction-based solution that can reliably retrieve unbiased estimates of K, and we illustrate our method using data on first flowering times from Thoreau's woods (Concord, Massachusetts, USA).


Inhibition of protein synthesis in Streptococcus faecalis by ochratoxin A.
A non-competitive inhibition of binding of cAMP to bovine protein kinase by ochratoxin A (OTA) is shown. Preliminary evidence of a protein kinase in Streptococcus faecalis is presented. The cAMP stimulation of this kinase is also inhibited by OTA. At the lowest OTA concentrations, RNA and protein synthesis are inhibited in S. faecalis. The inhibition of RNA synthesis is secondary, as in the presence of chloramphenicol no inhibition occurs for 10 min after the addition of OTA. The synthesis but not the induction of beta-P-galactosidase is inhibited by OTA. The polysomes of S. faecalis are stabilized after addition of OTA, showing an inhibition of peptide elongation. The model of action of OTA in bacteria is discussed and it is concluded that inhibition of protein synthesis is the process which might be closest to the primary target of OTA.


The prevalence and risk factors of epiretinal membranes: the Melbourne Collaborative Cohort Study.
To determine the prevalence of epiretinal membranes (ERMs) in Melbourne, Australia and its risk factors in this population. The Melbourne Collaborative Cohort Study is a prospective study investigating the role of diet and life style in the causation of common chronic diseases. Eighty-six percent of participants were of Northern European origin born in Australia or United Kingdom and 14% were migrants from Greece or Italy (Southern European origin). Nonmydriatic digital retinal photography was implemented at Melbourne Collaborative Cohort Study follow-up. The ERMs were recorded as cellophane macular reflex without retinal folds or preretinal macular fibrosis (PMF) with retinal folds. A total of 22,406 participants had retinal photography, 95% (n = 21,241) were eligible for ERM grading. The ERM prevalence were 8.9% (1,882); cellophane macular reflex, 4.9% (1,047); and preretinal macular fibrosis, 3.9% (835). After adjustment for age, sex, level of education, smoking status, level of cholesterol, body mass index, waist-to-hip ratio, waist measurement, blood pressure, diabetes, and stroke, increasing age and Southern European ethnicity was significantly associated with ERMs. Overall, in Southern Europeans, ERMs odd ratio was 1.97 (95% confidence intervals, 1.67-2.31), P < 0.001; preretinal macular fibrosis was 1.82 (95% confidence intervals, 1.43-2.31), P < 0.001; and cellophane macular reflex was 1.93 (1.57-2.38), P < 0.001. In an older Australian population, the prevalence of ERMs was 8.9% and was almost two times higher in participants of Southern European origin than Northern European origin.


Younger and older chronic somatoform pain patients in psycho-diagnostics, physician-patient relationship and treatment outcome.
Patients with chronic pain are found with highly variable clinical presentation and differing physical complaints. They are seen as a heterogenic group. Based on clinical observations, elderly patients seem to differ from younger patients with chronic pain. We examined whether there were systematic differences between young and old pain patients. As part of a routine evaluation of university hospital care, a newly developed psychosomatic treatment model for chronic somatoform pain disorders was examined. The basis for treatment efficacy was a target-oriented, specific somatic and psychological intervention that included a stable physician-patient relationship. Particular attention was paid to differences in treatment outcome with regard to changes in both physical and psychopathological symptom levels. We hypothesised that younger pain patients had higher psychological burden and benefitted more from our treatment than older pain patients. Overall, 179 inpatients (57.5% women) with chronic pain were examined (age between 16 and 79 years). The group as a whole yielded high scores on the somatisation dimension (SCL-90) and showed a considerable amount of psychopathological symptoms, such as depressive mood and anxiety (HADS) and a great emotional instability (FPI-R). Age differences were only found with regards to patients' degree of aggression (SCl-90): younger patients showed higher aggressive tendencies than older ones (p< 0.05). The treatment offered helped patients in both age groups especially with regard to reduction of depressive mood (HADS, p< 0.01) and anxiety levels (HADS, p< 0.01). Regression analysis showed different age groups and gender as significant predictors of anxiety reduction under therapy (R2=.108; model: p< 0.01). Results show that younger chronic pain patients suffer more from a considerable amount of psychological distress than older ones, but our treatment approach was equally effective in both groups. However, age and gender differences, as well as the patient's baseline level of anxiety influenced the outcome. These factors need to be studied in future research.


Recent clinical trials evaluating benefit of drug therapy for modification of HDL cholesterol.
To highlight the recent data evaluating pharmacological manipulation of HDL cholesterol (HDL-C) and examine whether medication-induced changes were associated with improved clinical outcomes and reduced short-term and long-term cardiovascular risks. The review focuses on the studies with niacin and the new cholesteryl ester transfer protein (CETP) inhibitors torcetrapib, dalcetrapib, anacetrapib and evacetrapib. Several large randomized clinical trials have evaluated drug therapy on HDL-C and cardiovascular outcomes. Two studies have evaluated the clinical outcomes following HDL-C raising with niacin. Data from the Heart Protection 2 Treatment of HDL to Reduce the Incidence of Vascular Events and The Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health trials both demonstrated no clinical benefit from use of niacin therapy when added to background statin therapy with regard to short-term and long-term cardiovascular risk reduction. Both studies demonstrated excess side-effects from use of niacin. A number of clinical trials have evaluated HDL-C modification from use of a CETP inhibitor. All of the studies have demonstrated significant increases in HDL-C. To date, the outcome data are not favorable. Use of torcetrapib was associated with excess mortality. Use of dalcetrapib had no effect on short-term and long-term cardiovascular events. Two outcome studies with anacetrapib and evacetrapib are ongoing and will report out in a few years' time. Pharmacological manipulation of HDL-C has not improved the cardiovascular outcomes. Several agents have caused harm or unacceptable side-effects. Further studies are needed before one can recommend the use of additional lipid-modifying therapies beyond statins.


The ras-like protein p25rab3A is partially cytosolic and is expressed only in neural tissue.
An antipeptide antiserum has been developed against a sequence near the C terminus of the small guanine nucleotide-binding protein p25rab3A. This protein is the product of one of a large number of genes that show homology to the ras proto-oncogenes. Immunoblotting with the antiserum specifically detected a 25-kilodalton protein in brain membranes. This protein coeluted from a MonoQ high-resolution ion-exchange column with a 25-kilodalton GTP-binding protein at a salt concentration similar to that known to elute purified p25rab3A. Unlike p21ras, which is exclusively membrane bound, p25rab3A is present in both the cytosol and membrane fractions of rat brain. It was not detected in other tissues, although a band of slightly lower molecular weight was observed with skeletal muscle. Western blot (immunoblot) analysis of five regions of the rat brain indicated that p25rab3A is most abundant in the hypothalamus and hippocampus.