Structure and functions of the placenta in common minke (Balaenoptera acutorostrata), Bryde's (B. brydei) and sei (B. borealis) whales.
The structure and functions of placentas were examined in 3 species of rorqual whales, common minke (Balaenoptera acutorostrata), Bryde's (B. brydei) and sei (B. borealis) whales, with the aim of confirming the structural characteristics of the chorion, including the presence of the areolar part, and clarifying steroidogenic activities and fetomaternal interactions in the placentas of these whales. Placentas were collected from the second phase of the Japanese Whale Research Program under Special Permit in the North Pacific (JARPN II). Histological and ultrastructural examinations revealed that these whale placentas were epitheliochorial placentas with the interdigitation of chorionic villi lined by monolayer uninucleate cells (trophoblast cells) and endometrial crypts as well as folded placentation by fold-like chorionic villi. Moreover, well-developed pouch-like areolae were observed in the placentas, and active absorption was suggested in the chorionic epithelial cells of the areolar part (areolar trophoblast cells). Berlin blue staining showed the presence of ferric ions (Fe(3+)) in the uterine glandular epithelial cells and within the stroma of chorionic villi in the areolar part. An immunohistochemical examination revealed tartrate-resistant acid phosphatase (TRAP; known as uteroferrin in uteri) in the cytoplasm of glandular cells and areolar trophoblast cells. This result suggested that, in cetaceans, uteroferrin is used to supply iron to the fetus. Furthermore, immunoreactivity for P450scc and P450arom was detected in trophoblast cells, but not in areolar trophoblast cells, suggesting that trophoblast cells synthesize estrogen in whale placentas. Therefore, we herein immunohistochemically revealed the localization of aromatase and uteroferrin in cetacean placentas during pregnancy for the first time.


Gene Expression analysis associated with salt stress in a reciprocally crossed rice population.
The rice landrace Horkuch, endemic to the southern saline coast of Bangladesh, is known to have salt tolerance traits and can therefore contribute to a high yielding recipient for breeding purposes. In this study, we reciprocally crossed Horkuch with high yielding but salt sensitive IR29 to detect the complement of genes that were responsible for conferring salt tolerance versus sensitivity at the seedling developmental stage. We looked at tolerant and sensitive F3 families from individual F2 segregating plants and analyzed them for differential gene expressions using RNAseq. In general, we observed higher numbers of genes differentially expressed in leaves compared to root tissues. This included both upregulation and downregulation of gene expression across our experimental factors. Gene expression decreased in sensitive leaf after stress exposure where tolerant plants showed the opposite trend. In root, tolerant plants expression decreased at higher time points of stress exposure. We also observed a strong maternal cytoplasmic effect on gene expression and this was most evident in roots where there was upregulation in functional enrichments related to phosphorylation, electron carriers, transporter and cation transmembrane activities. Stress groups (tolerant and sensitive) response in F3 families were distinctive in both cytoplasmic backgrounds and involved uniquely upregulated genes in tolerant progenies including membrane sensor proteins, enzymes involved with signaling pathways, such as those producing trehalose and G-protein coupled receptor proteins, photosynthesis-related enzymes and golgi body recycling as well as prolamin precursor proteins involved in refolding of proteins. On the other hand, sensitivity was found to be associated with differential upregulation of only a few redox proteins and higher number of apoptosis related genes compared to the tolerant response. Overall, our highly replicated experimental design was powerful and allowed the detection of relatively subtle differential expression. Our future goal is to correlate these expression differences with QTLs in this population, which would help identify the relative importance of specific genetic loci and provide a direct avenue for combining higher levels of salt tolerance with better agronomic traits in rice.


Heart failure registries - Future directions.
Heart failure (HF) is a growing, global public health issue. Despite advances in HF care, many challenges remain and HF outcomes are poor. Some of the major reasons for this are the lack of understanding and treatment for certain HF sub-types as well as the lack of implementation of treatment in areas where effective treatment exists. HF registries provide the opportunity to transform clinical research and patient care. Recently the registry-based randomized clinical trial has emerged as a pragmatic and inexpensive alternative to the gold standard in clinical trial design, the randomized controlled trial. Registries may also provide platforms for strategy trials, implementation trials, and screening. Using examples from the Swedish Heart Failure Registry and others, the present review provides insights into how registry-based research can address many of the unmet needs in HF.


Chloroquine mediated modulation of Anopheles gambiae gene expression.
Plasmodium development in the mosquito is crucial for malaria transmission and depends on the parasite's interaction with a variety of cell types and specific mosquito factors that have both positive and negative effects on infection. Whereas the defensive response of the mosquito contributes to a decrease in parasite numbers during these stages, some components of the blood meal are known to favor infection, potentiating the risk of increased transmission. The presence of the antimalarial drug chloroquine in the mosquito's blood meal has been associated with an increase in Plasmodium infectivity for the mosquito, which is possibly caused by chloroquine interfering with the capacity of the mosquito to defend against the infection. In this study, we report a detailed survey of the Anopheles gambiae genes that are differentially regulated by the presence of chloroquine in the blood meal, using an A. gambiae cDNA microarray. The effect of chloroquine on transcript abundance was evaluated separately for non-infected and Plasmodium berghei-infected mosquitoes. Chloroquine was found to affect the abundance of transcripts that encode proteins involved in a variety of processes, including immunity, apoptosis, cytoskeleton and the response to oxidative stress. This pattern of differential gene expression may explain the weakened mosquito defense response which accounts for the increased infectivity observed in chloroquine-treated mosquitoes. The results of the present study suggest that chloroquine can interfere with several putative mosquito mechanisms of defense against Plasmodium at the level of gene expression and highlight the need for a better understanding of the impacts of antimalarial agents on parasite transmission.


Herb-drug interaction between the extract of Hibiscus sabdariffa L. and hydrochlorothiazide in experimental animals.
Decoctions of Hibiscus sabdariffa L. (Family Malvaceae) are very popular for the preparation of homemade refreshing drinks and are also used medicinally for a variety of ailments. Particularly remarkable are the various scientific reports supporting diuretic and antihypertensive potentials. It is therefore not unusual for patients who are on orthodox antihypertensive medications to use medicinal H. sabdariffa drinks concomitantly without regard to the possibility of herb-drug interactions. This possibility necessitated this study in which the pharmacokinetic and pharmacodynamic interactions of H. sabdariffa extract (HSE) and hydrochlorothiazide (HCT), a commonly prescribed diuretic drug, were examined. The effects of concomitant administration of HSE on urine volume, urine pH, and urinary concentrations of sodium, bicarbonate, and chloride ions, as well as on the pharmacokinetic parameters of HCT, were determined in experimental rats and rabbits. Co-administration of HSE with HCT caused a significant increase in the volume of urine excreted and resulted in a decrease in the pH of urine and the concentrations of sodium, bicarbonate, and chloride ions. Co-administration of HSE (20-40 mg/kg) with HCT (10 mg/kg) increased and prolonged the plasma concentration, the mean area under the concentration-time curve, and the volume of distribution of HCT achieved over the 24-hour sampling period. The plasma clearance and the elimination rate constant of HCT decreased with increasing dose of HSE co-administered with the HCT. The results of this study reveal a possible herb-drug interaction involving HCT and HSE, used as an ingredient in medicinal or refreshing drinks in many countries.


Interactive effects of subanesthetic ketamine and subhypnotic lorazepam in humans.
Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist with psychotogenic and dissociative effects in healthy humans. These cognitive and perceptual effects in humans are reportedly reduced by benzodiazepine premedication. This study assessed the interactive effects of a ketamine (i.v. bolus of 0.26 mg/kg followed by an infusion of 0.65 mg/kg per hour) and lorazepam 2 mg., PO, in humans. Twenty-three healthy subjects completed 4 test days involving the oral administration of lorazepam or matched placebo 2 h prior to the i.v. infusion of ketamine or placebo. Ketamine: 1) produced behaviors similar to the positive and negative symptoms of schizophrenia as assessed by the Brief Psychiatric Rating Scale (BPRS); 2) evoked perceptual alterations as measured by the Clinician-Administered Dissociative States Scale (CADSS); 3) impaired performance on the Wisconsin Card Sorting Test (WCST) and other tests sensitive to frontal cortical impairment; and 4) had amnestic effects. Lorazepam produced attention impairments, concrete proverb interpretations, and recall impairments. Lorazepam reduced ketamine-associated emotional distress and there was a non-significant trend for it to decrease perceptual alterations produced by ketamine. However, it failed to reduce many cognitive and behavioral effects of ketamine, including psychosis. Further, lorazepam exacerbated the sedative, attention-impairing, and amnestic effects of ketamine. There was no evidence of pharmacokinetic interaction between these medications. These data suggest that subhypnotic lorazepam and ketamine show a spectrum of interactive effects, ranging from antagonism to potentiation.


Dietary therapies for functional bowel symptoms: Recent advances, challenges, and future directions.
Functional gastrointestinal symptoms in irritable bowel syndrome (IBS) and quiescent inflammatory bowel disease (IBD) cause significant morbidity and a reduction in quality of life. Multiple dietary therapies are now available to treat these symptoms, but supporting evidence for many is limited. In addition to a further need for studies demonstrating efficacy and mechanism of action of dietary therapies, the risk of nutritional inadequacy, alterations to the microbiome and changes in quality of life are key concerns requiring elucidation. Identifying predictors of response to dietary therapy is an important goal as management could be tailored to the individual to target specific dietary components, and thereby reduce the level of dietary restriction necessary. This review discusses the available dietary therapies to treat symptoms in patients with IBS and patients with quiescent IBD suffering from IBS symptoms, with the aim to understand where current dietary evidence lies and how to move forward in dietary research in this field.


Cloning, characterization and functional analysis of two type 1 diacylglycerol acyltransferases (DGAT1s) from Tetraena mongolica.
Two cDNAs encoding putative type 1 acyl-CoA: diacylglycerol acyltransferases (DGAT1, EC 188.8.131.52), were cloned from Tetraena mongolica, an extreme xerophyte with high oil content in the stems. The 1 488-bp and 1 485-bp of the open reading frame (ORF) of the two cDNAs, designated as TmDGAT1a and TmDGAT1b, were both predicted to encode proteins of 495 and 494 amino acids, respectively. Southern blot analysis revealed that TmDGAT1a and TmDGAT1b both had low copy numbers in the T. mongolica genome. In addition to ubiquitous expression with different intensity in different tissues, including stems, leaves and roots, TmDGAT1a and TmDGAT1b, were found to be strongly induced by high salinity, drought and osmotic stress, resulting in a remarkable increase of triacylglycerol (TAG) accumulation in T. mongolica plantlets. TmDGAT1a and TmDGAT1b activities were confirmed in the yeast H1246 quadruple mutant (DGA1, LRO1, ARE1, ARE2) by restoring DGAT activity of the mutant host to produce TAG. Overexpression of TmDGAT1a and TmDGAT1b in soybean hairy roots as well as in T. mongolica calli both resulted in an increase in oil content (ranging from 37% to 108%), accompanied by altered fatty acid profiles.


Grazed wet meadows are sink habitats for the southern dunlin (Calidris alpina schinzii) due to nest trampling by cattle.
The effect of habitat management is commonly evaluated by measuring population growth, which does not distinguish changes in reproductive success from changes in survival or the effects of immigration or emigration. Management has rarely been evaluated considering complete life cycle of the target organisms, including also possible negative impacts from management. We evaluated the effectiveness of cattle grazing in the restoration of coastal meadows as a breeding habitat for small and medium-sized ground-nesting birds by examining the size and demography of a southern dunlin (Calidris alpina schinzii) breeding population. Using a stochastic renesting model that includes within-season variation in breeding parameters, we evaluated the effect of grazing time and stocking rates on reproduction. The census data indicated that the population was stable when nest trampling was prevented, but detailed demographic models showed that the population on managed meadows was a sink that persisted by attracting immigrants. Even small reductions in reproductive success caused by trampling were detrimental to long-term viability. We suggest that the best management strategy is to postpone grazing to after the 19th of June, which is about three weeks later than what is optimal from the farmer's point of view. The differing results from the two evaluation approaches warn against planning and evaluating management only based on census population size and highlight the need to consider target-specific life history characteristics and demography. Even though grazing management is crucial for creating and maintaining suitable habitats, we found that it was insufficient in maintaining a viable population without additional measures that increase nest success. In the presently studied case and in populations with similar breeding cycles, impacts from nest trampling can be avoided by starting grazing when about 70% of the breeding season has past.


Soluble PD-L1 in NSCLC Patients Treated with Checkpoint Inhibitors and Its Correlation with Metabolic Parameters.
We investigated the role of soluble PD-L1 (sPD-L1) in non-small cell lung carcinoma (NSCLC) patients treated with immune checkpoint inhibitors (ICI) and analyzed its association with clinical outcomes and metabolic parameters by 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT). Between July 2017 and May 2019, we enrolled 20 candidate patients of ICI therapy who had serum frozen samples and 18F-FDG PET/CT available, both at baseline and at the first response evaluation. This analysis is embedded into a larger prospective study (NCT03563482). Twelve out of 20 patients received nivolumab, one patient received combination of nivolumab and ipilimumab, whereas the others received pembrolizumab. Median sPD-L1 level at baseline was 27.22 pg/mL. We found a significant association between patients with elevated sPD-L1, above the median value, and high metabolic tumor burden, expressed by metabolic tumor volume (MTV, 115.3 vs. 35.5, p = 0.034) and total lesion glycolysis (TLG, 687 vs. 210.1, p = 0.049). At the first restaging after 7-8 weeks, median sPD-L1 levels significantly increased as compared to baseline median value (43.9 pg/mL, p = 0.017). No significant differences in response rates were detected, according to both morphological and metabolic response criteria. Likewise, no difference in survival outcomes were observed between low sPD-L1 and high sPD-L1 patients. The increase of sPD-L1 concentrations during ICI treatment may reflect the expansion of tumor volume and the tumor lysis. Moreover, it is supposed that sPD-L1 has its own biological action, either by reducing membrane PD-1 sites available for nivolumab or by inducing lymphocytes exhaustion after binding their membrane PD-1. Further, larger studies are needed to confirm our preliminary results on the role of sPD-L1 during ICI therapy.


Surgical procedures for papillary thyroid carcinoma located in the thyroid isthmus: an intention-to-treat analysis.
We sought to evaluate and compare the outcomes of different surgical protocols for papillary thyroid cancer (PTC) located in the isthmus in a retrospective intention-to-treat analysis. The data of 3,068 patients who received thyroidectomy due to thyroid cancer in our center were reviewed. Of these, 103 patients had a dominant carcinoma located in the isthmus. Various baseline and tumor characteristics and surgical outcomes were evaluated and compared with respect to the different surgical protocols (85 cases with total thyroidectomy and 18 cases with less-than-total thyroidectomy). Univariate and multivariate analyses were performed to identify resected patients who developed recurrence with isthmic PTC. The postoperative complication rates were comparable between the two groups (17.6% versus 11.1%, P=0.500). Although the total thyroidectomy group showed a much higher rate (P=0.004) and number (P<0.001) of parathyroidectomies, long-term follow-up indicated that parathyroid autotransplantation did not significantly damage the function of the parathyroid (P>0.05). Tumor recurrence was observed in five patients, including two patients in the total thyroidectomy group and three patients in the less-than-total thyroidectomy group; the tumor recurrence rate in the total thyroidectomy group was significantly lower than that in the less-than-total thyroidectomy group (P=0.040). Univariate and multivariate analyses indicated less-than-total thyroidectomy as a risk factor for tumor recurrence in PTC cases with tumors located at the isthmus (hazard ratio: 1.870, 95% confidence interval: 1.320-2.218, P<0.001). Our findings indicate that total thyroidectomy is an appropriate initial surgical protocol for isthmic PTC due to the lower recurrence rate, comparable postoperative complication rate, and parathyroid function recovery.


[Alkaline phosphatase isoenzymes in serum and bronchoalveolar lavage from patients with bronchopulmonary disease].
In this study, we are looking at the principal isoenzymes of alkaline phosphatase (ALP), as injury markers of cellular membranes from bronchial epithelium, in 80 patients diagnosed with bronchopulmonary pathology from different ethology, using serum samples and bronchoalveolar lavage fluid (BAL). Patients were grouped according to age as following: 26 preterm neonates suffering respiratory distress syndrome requiring mechanical ventilation; 32 children ranging from 2 to 12 years old, and 22 adults (30-65 years old) examined by bronchoscopy for the purpose of diagnosis. Results obtained from all pathological groups were compared with a control group showing similar characteristics. Isoenzymes were separated by electrophoresis on agarose gel and were quantified by desitometry. Total protein was measured in BAL; ALP activity was expressed in UI/mg x 10-3 of protein. We found that macromolecular ALP fraction was significantly increased in the serum of neonates with distress (p < 0.01), in the patients 2-12 years and adults affected by pulmonary pathology (p < 0.001). The electrophoresis of ALP isoenzymes showed a unique isoenzymatic band corresponding with its macromolecular fraction in the BAL fluid. We conclude that increased macromolecular fraction of alkaline phosphatase found in the serum of patients diagnosed with respiratory problems could have its origin in damaged pulmonary tissue.


The protagonist's first perspective influences the encoding of spatial information in narratives.
Three experiments examined the first-perspective alignment effect that is observed when retrieving spatial information from memory about described environments. Participants read narratives that described the viewpoint of a protagonist in fictitious environments and then pointed to the memorized locations of described objects from imagined perspectives. Results from Experiments 1 and 2 showed that performance was best when participants responded from the protagonist's first perspective even though object locations were described from a different perspective. In Experiment 3, in which participants were physically oriented with the perspective used to describe object locations, performance from that description perspective was better than that from the protagonist's first perspective, which was, in turn, better than performance from other perspectives. These findings suggest that when reading narratives, people default to using a reference frame that is aligned with their own facing direction, although physical movement may facilitate retrieval from other perspectives.


Functionality of Embryo Sacs in Pear Cultivars 'Ingeborg' and 'Celina' as Related to Fruit Set under Nordic Climate.
Since the European pear (Pyrus communis L.) is a self-incompatible fruit species, synchrony and compatibility between female parts of the mother plant and male gametes from the pollen donor must be fulfilled. Besides pollination and fertilization, normal embryo and zygote development is one of the prerequisites for the satisfactory yields in pears. The main goal of this experiment was to investigate the functionality of embryo sacs and the embryo's early stages of growth in relation to the fruit set of diploid ('Celina') and the triploid ('Ingeborg') pear cultivars under specific Norwegian climatic conditions. For this purpose, flowers were collected at the beginning of flowering, and on the third, sixth, ninth, and twelfth days after the beginning of this phenophase for two consecutive years. Ovaries were dehydrated, embedded in paraffin wax, sectioned, stained, and observed under the light microscope. In the analyzed cultivars, results showed different tendencies in embryo sac development and degradation processes, in both experimental years, which is probably due to the genetic background of the examined cultivars. Also, fertilization success and fruit set were higher in the second year of study due to the higher average temperature during the flowering period. Diploid cultivar 'Celina' showed much better adaptation to high temperatures in relation to triploid cultivar 'Ingeborg'.


Lymphocyte subsets in normal airway mucosa of the human nose.
The distribution and number of lymphocytes, monocytes/macrophages, and cells expressing HLA-DR antigen were studied in frozen biopsy sections of nasal mucosa from 40 healthy adults, using monoclonal antibody avidin-biotin immunoperoxidase techniques. The lymphocyte to monocyte/macrophage ratio was estimated to be 10:1; the T cell to B cell ratio was 3:1; and the T helper/inducer cell to T suppressor/cytotoxic cell ratio averaged 2.5:1. Regional differences were observed with a relatively increased number of T suppressor/cytotoxic cells around submucosal glands, and a relatively large number of B cells in lymphocyte aggregates in the lamina propria. The HLA-DR antigen was expressed in epithelial cells, suggesting involvement of surface epithelium of human airway in local immune responses.


Skeletal and cardiac myopathy in HIV-1 transgenic rats.
The mechanism by which human immunodeficiency virus (HIV)-1 infection in humans leads to the erosion of lean body mass is poorly defined. Therefore, the purpose of the present study was to determine whether transgenic (Tg) rats that constitutively overexpress HIV-1 viral proteins exhibit muscle wasting and to elucidate putative mechanisms. Over 7 mo, Tg rats gained less body weight than pair-fed controls exclusively as a result of a proportional reduction in lean, not fat, mass. Fast- and slow-twitch muscle atrophy in Tg rats did not result from a reduction in the in vivo-determined rate of protein synthesis. In contrast, urinary excretion of 3-methylhistidine, as well as the content of atrogin-1 and the 14-kDa actin fragment, was elevated in gastrocnemius of Tg rats, suggesting increased muscle proteolysis. Similarly, Tg rats had reduced cardiac mass, which was independent of a change in protein synthesis. This decreased cardiac mass was associated with a reduction in stroke volume, but cardiac output was maintained by a compensatory increase in heart rate. The HIV-induced muscle atrophy was associated with increased whole body energy expenditure, which was not due to an elevated body temperature or secondary bacterial infection. Furthermore, the atrophic response could not be attributed to the development of insulin resistance, decreased levels of circulating amino acids, or increased tissue cytokines. However, skeletal muscle and, to a lesser extent, circulating insulin-like growth factor I was reduced in Tg rats. Although hepatic injury was implicated by increased plasma levels of aspartate and alanine aminotransferases, hepatic protein synthesis was not different between control and Tg rats. Hence, HIV-1 Tg rats develop atrophy of cardiac and skeletal muscle, the latter of which results primarily from an increased protein degradation and may be related to the marked reduction in muscle insulin-like growth factor I.


Hemoadsorption of high-mobility-group box 1 using a porous polymethylmethacrylate fiber in a swine acute liver failure model.
High-mobility-group box chromosomal protein 1 has been identified as an important mediator of various kinds of acute and chronic inflammation. In this study, we aimed to develop a column that effectively adsorbs high-mobility-group box chromosomal protein 1 by altering the pore size of the fiber. First, we produced three types of porous polymethylmethacrylate fiber by altering the concentration of polymethylmethacrylate dissolved in dimethylsulfoxide. We then selected a fiber based on the results of an in vitro incubation test of high-mobility-group box chromosomal protein 1 adsorption. Using the selected fiber, we constructed a new column and tested its high-mobility-group box chromosomal protein 1 adsorption capacity during 4-h extracorporeal hemoperfusion in a swine acute liver failure model. Electron microscope observation showed that the three types of fibers had different pore sizes on the surface and in cross section, which were dependent on the concentration of polymethylmethacrylate. In the in vitro incubation test, fiber with moderate-sized pores demonstrated the highest adsorption capacity. In the in vivo hemoperfusion study, the ratio of the high-mobility-group box chromosomal protein 1 concentration at the outlet versus the inlet of the column was significantly lower with the new column than with the control column during 4-h extracorporeal hemoperfusion. The normalized plasma level of high-mobility-group box chromosomal protein 1 at 12 h after the completion of hemoperfusion was significantly lower with the new column than with the control column. The newly developed polymethylmethacrylate column adsorbs high-mobility-group box chromosomal protein 1 during hemoperfusion in swine ALF model.


The Facets of Diversity: The EFMC Perspective.
Diversity in science refers to cultivating talent, while promoting full inclusion across the community. In medicinal chemistry and chemical biology, it enhances creativity and encourages contributions from multiple perspectives, leading to better decision making and broader scientific impact. The European Federation for Medicinal chemistry and Chemical biology (EFMC) embraces and promotes diversity, to ensure representation of all talents, and enable equality of opportunity through fairness and transparency. EFMC has historically paid continuous attention to diversity in terms of culture, geography and equilibrium between academia and industry, with over the last few years a focus on increasing gender balance, aiming at a fair representation of the scientific community and equal opportunities independently of gender. EFMC promotes cultural diversity as it reinforces openness and mutual respect. All scientific organizations of a scope compatible with its remit are welcome within EFMC, where their members benefit from a welcoming, psychologically safe, and stimulating environment. Herein, we describe the state of diversity within the EFMC, how the situation has evolved over the years and where diversity should be further encouraged.


Nonpharmacological interventions aimed at modifying health and behavioural outcomes for adults with asthma: a critical review.
Evidence suggests that living with asthma is linked with psychological and behavioural factors including self-management and treatment adherence, and therefore, there is a reasonable hypothesis that nonpharmacological treatments may improve health outcomes in people living with this condition. A systematic review of randomized controlled trials (RCTs) of nonpharmacological interventions for adults with asthma was designed. Databases searched included The Cochrane Airways Group Register of trials, CENTRAL and Psychinfo. The literature search was conducted until May 2014. Twenty-three studies met the inclusion criteria and were organized into four groups: relaxation-based therapies (n = 9); mindfulness (n = 1), biofeedback techniques (n = 3); cognitive behavioural therapies (CBT) (n = 5); and multicomponent interventions (n = 5). A variety of outcome measures were used, even when trials belonged to the same grouping, which limited the ability to conduct meaningful meta-analyses. Deficiencies in the current evidence base, notably trial heterogeneity, means that application to clinical practice is limited and clear guidelines regarding the use of nonpharmacological therapies in asthma is limited. Relaxation and CBT, however, appear to have a consistent positive effect on asthma-related quality of life and some psychological outcomes, and lung function (relaxation only). Future trials should be informed by previous work to harmonize the interventions under study and outcome measures used to determine their effectiveness; only then will meaningful meta-analyses inform clinical practice.


[EEG correlates for efficiency of the nonverbal creative performance (drawing)].
This work was aimed at a search for EEG corellates of efficiency of nonverbal creative performance. Standardized Torrens technique which makes it possible to quantitatively assess creativity was used. The EEG records were performed before and during test performance, EEG parameters were compared to Torrens scores on three scales: flexibility, originality and efficiency. Absolute values of spatial synchronization, coherence and spectral power both in the baseline and during the performance were calculated. Changes in these parameters were traced during the transition from the state of quiet wakefulness to creative performance. The narrow-band analysis of coherence and spectral power allowed the number and orientation of processes associated with creativity scales to be assessed. The absence of substantial EEG changes during the test performance is indicative of the steady, nondynamical functional state of the brain.


Ginsenoside Rg3 inhibits colorectal tumor growth through the down-regulation of Wnt/ß-catenin signaling.
Colorectal cancer (CRC) is one of the most common and deadly malignancies in the world. Most CRCs are initiated by aberrant activation of the Wnt/ß-catenin signaling pathway. Despite the advances in its early diagnosis, optimized surgical approaches, and chemotherapies, the clinical management of advanced CRC requires effective adjuvant agents. Ginsenoside Rg3 is a single compound isolated from American ginseng (Panax quinquefolius L., Araliaceae) and Asian ginseng (Panax ginseng C. A. Meyer). We investigated the anticancer activity of Rg3 on colon cancer cells and its potential molecular mechanism behind Rg3's anticancer activity. We found that Rg3 inhibits cell proliferation and viability of cancer cells in vitro. This inhibitory effect of Rg3 is, at least in part, mediated by blocking nuclear translocation of the ß-catenin protein and hence inhibiting ß-catenin/Tcf transcriptional activity. Allelic deletion of the oncogenic ß-catenin in HCT116 cells renders the cells more sensitive to Rg3-induced growth inhibition. Using the xenograft tumor model of human colon cancer, we have demonstrated that Rg3 effectively inhibits the growth of tumors derived from the human colon cancer cell line HCT116. Histologic examination revealed that Rg3 inhibits cancer cell proliferation, decreases PNCA expression and diminishes nuclear staining intensity of ß-catenin. Taken together, our results strongly suggest that the anticancer activity of Rg3 may be in part caused by blocking the nuclear translocation of ß-catenin in colon cancer cells. This line of investigation may lead to the development of novel therapies in which Rg3 can be used as an effective adjuvant agent for the clinical management of colorectal cancers.


A historical account of Hoogsteen base-pairs in duplex DNA.
In 1957, a unique pattern of hydrogen bonding between N3 and O4 on uracil and N7 and N6 on adenine was proposed to explain how poly(rU) strands can associate with poly(rA)-poly(rU) duplexes to form triplexes. Two years later, Karst Hoogsteen visualized such a noncanonical A-T base-pair through X-ray analysis of co-crystals containing 9-methyladenine and 1-methylthymine. Subsequent X-ray analyses of guanine and cytosine derivatives yielded the expected Watson-Crick base-pairing, but those of adenine and thymine (or uridine) did not yield Watson-Crick base-pairs, instead favoring "Hoogsteen" base-pairing. More than two decades ensued without experimental "proof" for A-T Watson-Crick base-pairs, while Hoogsteen base-pairs continued to surface in AT-rich sequences, closing base-pairs of apical loops, in structures of DNA bound to antibiotics and proteins, damaged and chemically modified DNA, and in polymerases that replicate DNA via Hoogsteen pairing. Recently, NMR studies have shown that base-pairs in duplex DNA exist as a dynamic equilibrium between Watson-Crick and Hoogsteen forms. There is now little doubt that Hoogsteen base-pairs exist in significant abundance in genomic DNA, where they can expand the structural and functional versatility of duplex DNA beyond that which can be achieved based only on Watson-Crick base-pairing. Here, we provide a historical account of the discovery and characterization of Hoogsteen base-pairs, hoping that this will inform future studies exploring the occurrence and functional importance of these alternative base-pairs.


Altered methylation in gene-specific and GC-rich regions of DNA is progressive and nonrandom during promotion of skin tumorigenesis.
Altered DNA methylation, an epigenetic mechanism, likely contributes to tumorigenesis, with an inverse relationship existing between methylation in a promoter region and transcription. Using the SENCAR two-stage mouse skin tumorigenesis model, altered methylation was characterized in precancerous tissue and in tumor tissue. Mouse skin was initiated with 7,12-dimethylbenz[a]anthracene and promoted three times a week with 3, 9, 18, or 27 mg cigarette smoke condensate (CSC) for 4, 8, or 29 weeks; tumors were collected at 29 weeks. In addition, reversibility of changes in methylation was assessed following cessation of the promoting stimulus. DNA was isolated, and GC-rich methylation was assessed quantitatively via methylation-sensitive restriction digestion, arbitrarily primed PCR, and electrophoretic separation of PCR products. Analysis focused on regions of altered methylation (RAMs), which persisted from 4 to 8 weeks and from 8 weeks to tumor tissue. Persistent RAMs (i.e., seen in precancerous tissue and carried forward to tumors) are likely to play a key role in tumorigenesis. Twenty-two CpG sites in the upstream region of the Ha-ras promoter were unmethylated in control skin, 27 mg CSC, and tumor tissue. At two CpG sites closer to the transcriptional start site the incidence of hypomethylation increased with the dose of CSC. Hypomethylation was detected in all tumor samples. Expression of Ha-ras increased with 18 and 27 mg CSC promotion and more so in tumor tissue. These data support our hypothesis that tumor promotion involves instability of the epigenome, providing an environment where changes in the methylation status of specific regions of the genome accumulate progressively and contribute to the clonal expansion of initiated cells that leads to tumor formation.


Pasteurella haemolytica leukotoxin: chemiluminescent responses of peripheral blood leukocytes from several different mammalian species to leukotoxin- and opsonin-treated living and killed Pasteurella haemolytica and Staphylococcus aureus.
A luminol-dependent chemiluminescence (LDCL) assay was used to assess the response of polymorphonuclear leukocyte (PMN) preparations from 4 species of ruminants (ie, cattle, sheep, goats, and antelopes) and 6 species of nonruminants (ie, swine, dogs, cats, rabbits, horses, and persons) to both opsonized and nonopsonized preparations of living and heat-killed Pasteurella haemolytica and Staphylococcus aureus and to opsonized and nonopsonized heat-killed strains of each bacterium in the presence of sterile culture supernatant (leukotoxin) from P haemolytica. The LDCL responses of PMN preparations from each of the species studied were greater for living than for heat-killed S aureus. The most efficient LDCL emission was observed with reaction mixtures containing opsonized living S aureus. Regardless whether they contained killed or living bacteria, the opsonized S aureus preparations elicited LDCL emissions more efficiently than did the corresponding nonopsonized preparations. Living P haemolytica cells and their sterile culture supernatant inhibited the LDCL emissions of phagocytically stimulated PMN preparations from ruminants, but not those from nonruminants. The LDCL response of ruminant PMN to nonopsonized living P haemolytica was characterized by the development of a peak response at 10 minutes of incubation followed by a precipitous decrease and a subsequent complete cessation of chemiluminescence. The peak LDCL response was higher for opsonized living P haemolytica than for nonopsonized living bacteria, and the increased response lasted longer. However, opsonization of living P haemolytica with the serum samples tested only temporarily spared the ruminant PMN preparations from the detrimental effects of leukotoxin.(ABSTRACT TRUNCATED AT 250 WORDS)


Sliding-banyan network performance analysis.
The sliding-banyan (SB) network employs an interleaved multistage shuffle-exchange topology, implemented with a three-dimensional free-space interconnection architecture that connects a multichip backplane to itself. Surface-normal emitters and detectors, which compose the stages' input-output, are spatially multiplexed within the same chip location, along with electronic control and switching resources. A simple deflection self-routing scheme minimizes internal contention, providing efficient use of switching and interconnection resources. The blocking performance of the SB is quantified through simulations based on realistic nonuniform traffic patterns. Results show that the SB architecture requires significantly fewer resources than other self-routing banyan-based networks. The multistage-switching and interconnection-resource requirements are close to the theoretical minimum for nonblocking networks, and the SB's distributed self-routing control resources grow only approximately linearly with the number of nodes, providing good scalability.


Plasmodium berghei subunit vaccine: repeat synthetic peptide of circumsporozoite protein comprising T- and B-cell epitopes fails to confer immunity.
In the murine malaria model induced by Plasmodium berghei, we studied the immunogenicity of the repeat region of the circumsporozoite (CS) protein, which is the main target of the antibody response in infected animals. We immunized several strains with a synthetic peptide--Y(DPPPPNPN)3--corresponding to one of the two P. berghei repeat sequences in complete Freund's adjuvant. Only C57BL/6 immune sera reacted with the synthetic peptide in ELISA and with the native CS protein on P. berghei sporozoites, as detected by immunofluorescence. From lymph node cells of immunized C57BL/6 we isolated two repeat-specific T-cell lines which proliferated in the presence of the synthetic peptide or the recombinant CS protein. We analysed the protective role of this repeat-specific response by injecting infectious sporozoites into mice immunized with irradiated sporozoites or with the repeat peptide. The percentage of mice developing parasitaemia was 80-90% in the peptide-immunized group and only 10-20% in the group immunized with irradiated sporozoites. Anti-repeat antibody titres were comparable in the two groups. On the basis of these results, we can conclude that the T- and B-cell response to the CS repeat obtained with this synthetic peptide immunization is not sufficient for a protective immunity.


Twice as High Diet-Induced Thermogenesis After Breakfast vs Dinner On High-Calorie as Well as Low-Calorie Meals.
The question of whether there is daytime time variation in diet-induced thermogenesis (DIT) has not been clearly answered. Moreover, it is unclear whether a potential diurnal variation in DIT is preserved during hypocaloric nutrition. We hypothesized that DIT varies depending on the time of day and explored whether this physiological regulation is preserved after low-calorie compared with high-calorie intake. Under blinded conditions, 16 normal-weight men twice underwent a 3-day in-laboratory, randomized, crossover study. Volunteers consumed a predetermined low-calorie breakfast (11% of individual daily kilocalorie requirement) and high-calorie dinner (69%) in one condition and vice versa in the other. DIT was measured by indirect calorimetry, parameters of glucose metabolism were determined, and hunger and appetite for sweets were rated on a scale. Identical calorie consumption led to a 2.5-times higher DIT increase in the morning than in the evening after high-calorie and low-calorie meals (P < .001). The food-induced increase of blood glucose and insulin concentrations was diminished after breakfast compared with dinner (P < .001). Low-calorie breakfast increased feelings of hunger (P < .001), specifically appetite for sweets (P = .007), in the course of the day. DIT is clearly higher in the morning than in the evening, irrespective of the consumed calorie amount; that is, this physiological rhythmicity is preserved during hypocaloric nutrition. Extensive breakfasting should therefore be preferred over large dinner meals to prevent obesity and high blood glucose peaks even under conditions of a hypocaloric diet.


Zingiber officinale var. rubrum: Red Ginger's Medicinal Uses.
Zingiber officinale var. rubrum (red ginger) is widely used in traditional medicine in Asia. Unlike other gingers, it is not used as a spice in cuisines. To date, a total of 169 chemical constituents have been reported from red ginger. The constituents include vanilloids, monoterpenes, sesquiterpenes, diterpenes, flavonoids, amino acids, etc. Red ginger has many therapeutic roles in various diseases, including inflammatory diseases, vomiting, rubella, atherosclerosis, tuberculosis, growth disorders, and cancer. Scientific evidence suggests that red ginger exhibits immunomodulatory, antihypertensive, antihyperlipidemic, antihyperuricemic, antimicrobial, and cytotoxic activities. These biological activities are the underlying causes of red ginger's therapeutic benefits. In addition, there have been few reports on adverse side effects of red ginger. This review aims to provide insights in terms the bioactive constituents and their biosynthesis, biological activities, molecular mechanisms, pharmacokinetics, and qualitative and quantitative analysis of red ginger.


Neurofibromin, the Neurofibromatosis Type 1 Ras-GAP, Is Required for Appropriate P0 Expression and Myelination.
The neurofibromatosis type 1 (NF1) gene product, neurofibromin, regulates activation of the Ras intracellular signaling pathway in Schwann cells. Schwann cells purified from mouse embryos with null mutations in the Nf1 gene increase expression of the major myelin glycoprotein P0. v-Ras expression in cultured Schwann cells partially mimics loss of Nf1, suggesting a role for Ras in upregulation of P0 expression in Nf1-deficient cells. We tested whether loss of Nf1 alters the ability of Schwann cells to form myelin. No significant changes in myelin formation resulted when Nf1-deficient or v-Ras-expressing Schwann cells were cultured with normal neurons. Yet, in organotypic cultures of neurons, Schwann cells, and fibroblasts without neurofibromin, myelination was dramatically reduced. We suggest that Nf1-dependent signaling cascades in neurons and/or fibroblasts, as well as Schwann cells, are required for normal myelination.


Multivalent feedback regulation of HMG CoA reductase, a control mechanism coordinating isoprenoid synthesis and cell growth.
The availability of compactin (ML-236B), a potent competitive inhibitor of 3-hydroxy-3-methylglutaryl Coenzyme A reductase, has permitted the demonstration of a hitherto unsuspected aspect of mevalonate metabolism and isoprenoid synthesis in cultured mammalian cells. 3-Hydroxy-3-methylglutaryl Coenzyme A reductase, the enzyme that synthesizes mevalonate, appears to be regulated through a multivalent feedback mechanism. Full suppression of the reductase requires the presence of at least two regulators: 1) cholesterol, which is normally derived exogenously from plasma low density lipoprotein (LDL), and 2) a nonsterol product, which is normally synthesized endogenously from mevalonate. Evidence indicates that both of these regulators of the reductase may be essential for the growth of mammalian cells in culture. The multivalent feedback regulation of 3-hydroxy-3-methylglutaryl Coenzyme A reductase, together with secondary regulatory changes in other enzymes of the sterol synthetic pathway, coordinates the branched pathway of mevalonate metabolism so as to assure a constant supply of cholesterol and nonsterol products. These new findings have important implications for the understanding of isoprenoid metabolism and its relation to cell growth.


In situ powder X-ray diffraction study of magnetic CoFe2O4 nanocrystallite synthesis.
The evolution of size and size distribution during hydrothermal synthesis of nanocrystalline CoFe2O4 has been studied by in situ synchrotron powder X-ray diffraction (PXRD). Varying synthesis temperature or [OH(-)] concentration in the precursor proves to have no significant effect on the final volume-weighted nanocrystallite sizes (∼12 nm) of CoFe2O4. However, analysis by whole powder pattern modeling of the [OH(-)] concentration series reveals a substantial difference in the number-weighted size distributions when varying the amount of base used. Furthermore, changing the metal ion concentration prior to NaOH addition in the precursor preparation gives a handle to control the nanoparticle sizes (∼5-15 nm). All in situ experiments show almost instantaneous formation of the CoFe2O4 nanocrystallites, without significant growth or broadening of the size distribution after 60 s. Magnetic hysteresis curve measurements illustrate, how this facilitates the tailoring of materials with specific magnetic properties, as larger particles (∼15 nm) exhibit hard magnetic properties while the smaller particles (∼6-7 nm) are superparamagnetic.


Usefulness of the severity classification for predicting drug-free remission in Japanese patients with adult-onset Still's disease.
To investigate the usefulness of severity classification for predicting outcomes in patients with adult-onset Still's disease (AOSD). This was a multi-centre retrospective cohort study. AOSD patients were classified into mild, moderate, and severe groups based on severity classification (Japanese Ministry of Health, Labour and Welfare) during the initial treatment, and clinical features were compared among these groups. The primary endpoints were the AOSD-related mortality and drug-free remission rate. For comparison, the same analysis was performed in parallel for patient groups stratified by the modified Pouchot systemic score. According to severity classification, 49 (35%), 37 (26%), and 56 patients (39%) were classified into mild, moderate, and severe groups, respectively. Patients in the severe group showed higher frequency of severe complications and the use of biological agents. Although AOSD-related survival was not significantly different (p = .0776), four of the five fatal cases were classified into the severe group. The severe group showed a reduced rate of drug-free remission (p = .0125). Patient groups classified by systemic score did not correlate with survival or drug-free remission. Severity classification is useful for predicting outcomes in patients with AOSD.


Arthroscopic suprascapular nerve decompression: transarticular and subacromial approach.
Entrapment of the suprascapular nerve (SSN) is an increasingly recognized entity that can occur due to traction or compression-related etiology. Traction injuries of the SSN are unlikely to respond to surgical management and frequently improve with rest and avoidance of overhead activity. Compression injuries, on the other hand, frequently require surgical decompression for pain relief. SSN entrapment caused by compression at the suprascapular notch by the transverse scapular ligament gives rise to pain and atrophy of both the supraspinatus and infraspinatus muscles. However, compression at the spinoglenoid notch is more insidious because pain fibers may not be involved, causing isolated external rotation weakness. We present our preferred surgical technique for safe decompression of the SSN at the suprascapular and spinoglenoid notch using a subacromial and intra-articular approach, respectively. The key to ensuring efficient and uncomplicated decompression of the SSN relies on an intimate knowledge of the neurovascular anatomy and related landmarks.


Regulation of ecto-apyrase CD39 (ENTPD1) expression by phosphodiesterase III (PDE3).
The ectoenzyme CD39 suppresses thrombosis and inflammation by suppressing ATP and ADP to AMP. However, mechanisms of CD39 transcriptional and post-translational regulation are not well known. Here we show that CD39 levels are modulated by inhibition of phosphodiesterase 3 (PDE3). RAW macrophages and human umbilical vein endothelial cells (HUVECs) were treated with the PDE3 inhibitors cilostazol and milrinone, then analyzed using qRT-PCR, immunoprecipitation/Western blot, immunofluorescent staining, radio-thin-layer chromatography, a malachite green assay, and ELISA. HUVECs expressed elevated CD39 protein (2-fold [P<0.05] for cilostazol and 2.5-fold [P<0.01] for milrinone), while macrophage CD39 mRNA and protein were both elevated after PDE3 inhibition. HUVEC ATPase activity increased by 25% with cilostazol and milrinone treatment (P<0.05 and P<0.01, respectively), as did ADPase activity (47% and 61%, P<0.001). There was also a dose-dependent elevation of soluble CD39 after treatment with 8-Br-cAMP, with maximal elevation of 60% more CD39 present compared to controls (1 mM, P<0.001). Protein harvested after 8-Br-cAMP treatment showed that ubiquitination of CD39 was decreased by 43% compared to controls. A DMSO or PBS vehicle control was included for each experiment based on solubility of cilostazol, milrinone, and 8-Br-cAMP. These results indicate that PDE3 inhibition regulates endothelial CD39 at a post-translational level.


The surgical treatment of parosteal osteosarcoma in long bones.
The cases of twenty-five patients with Stage-I parosteal osteosarcoma were analyzed to ascertain the incidence of recurrence after forty-two various surgical procedures that produced an intracapsular, marginal, wide, or radical excisional margin. Ten intracapsular resections were followed by local recurrence in each patient. This procedure usually was done to shell-out a presumably benign lesion. Marginal excision was successful in nine of seventeen patients. When a marginal excision was knowingly done to preserve a major neurovascular bundle, the risk of recurrence was less (three of eleven) than when it was done to shell-out a presumptively benign lesion (five of six). The fourteen procedures that achieved wide margins obtained local control--that is, there was no recurrence--in each patient. There was one radical procedure without recurrence.


Analysis of human meiotic recombination events with a parent-sibling tracing approach.
Meiotic recombination ensures that each child inherits distinct genetic materials from each parent, but the distribution of crossovers along meiotic chromosomes remains difficult to identify. In this study, we developed a parent-sibling tracing (PST) approach from previously reported methods to identify meiotic crossover sites of GEO GSE6754 data set. This approach requires only the single nucleotide polymorphism (SNP) data of the pedigrees of both parents and at least two of children. Compared to other SNP-based algorithms (identity by descent or pediSNP), fewer uninformative SNPs were derived with the use of PST. Analysis of a GEO GSE6754 data set containing 2,145 maternal and paternal meiotic events revealed that the pattern and distribution of paternal and maternal recombination sites vary along the chromosomes. Lower crossover rates near the centromeres were more prominent in males than in females. Based on analysis of repetitive sequences, we also showed that recombination hotspots are positively correlated with SINE/MIR repetitive elements and negatively correlated with LINE/L1 elements. The number of meiotic recombination events was positively correlated with the number of shorter tandem repeat sequences. The advantages of the PST approach include the ability to use only two-generation pedigrees with two siblings and the ability to perform gender-specific analyses of repetitive elements and tandem repeat sequences while including fewer uninformative SNP regions in the results.


School-based health centers as patient-centered medical homes.
School-based health centers (SBHCs) have been suggested as possible patient-centered medical homes. Our objectives were to determine, in a low-income, urban population, adolescents' reasons for visiting SBHCs and the value parents place on SBHC services, and adolescents' and parents' assessment of how well SBHCs fulfill criteria for a medical home as defined by the American Academy of Pediatrics. A cross-sectional, mailed survey of a random sample of 495 adolescent SBHC users and 497 parents of SBHC users from 10 SBHCs in Denver, CO from May to October 2012. Eligible adolescents were registered in an SBHC with ≥ 1 visit during the 2011 to 2012 school year. Response rates were 40% (198/495) among adolescents and 36% (181/497) among parents. The top 3 reasons for visits were for illness (78%), vaccines (69%), and sexual health education (63%). Factors reported as very important by >75% of parents in the decision to enroll their adolescent in an SBHC included clinic offering sick or injury visits, sports physicals, and vaccinations. More than 70% of adolescents gave favorable responses (always or usually, excellent or good) to questions about American Academy of Pediatrics medical home criteria (accessibility, continuity, comprehensiveness, family-centeredness, coordination, and compassion). Most parents (83%) reported that they could always or usually trust the SBHC provider to take good care of their child; 82% were satisfied with provider-to-provider communication. In a low-income urban population, SBHCs met criteria of a medical home from adolescents' and parents' perspectives. Policymakers and communities should recognize that SBHCs play an important role in the medical community, especially for underserved adolescents.


Molecular Distribution, 13C-Isotope, and Enantiomeric Compositions of Carbonaceous Chondrite Monocarboxylic Acids.
The water-soluble organic compounds in carbonaceous chondrite meteorites constitute a record of the synthetic reactions occurring at the birth of the solar system and those taking place during parent body alteration and may have been important for the later origins and development of life on Earth. In this present work, we have developed a novel methodology for the simultaneous analysis of the molecular distribution, compound-specific δ13C and enantiomeric compositions of aliphatic monocarboxylic acids (MCA) extracted from the hot-water extracts of sixteen carbonaceous chondrites from CM, CR, CO, CV and CK groups. We observed high concentrations of meteoritic MCAs, with total carbon weight percentages which in some cases approached those of carbonates and insoluble organic matter. Moreover, we found that the concentration of MCAs in CR chondrites is higher than in the other meteorite groups, with acetic acid exhibiting the highest concentration in all samples. The abundance of MCAs decreased with increasing molecular weight and with increasing aqueous and/or thermal alteration experienced by the meteorite sample. The δ13C isotopic values of MCAs ranged from -52 to +27‰, and aside from an inverse relationship between δ13C value and carbon straight-chain length for C3-C6 MCAs in Murchison, the 13C-isotopic values did not correlate with the number of carbon atoms per molecule. We also observed racemic compositions of 2-methylbutanoic acid in CM and CR chondrites. We used this novel analytical protocol and collective data to shed new light on the prebiotic origins of chondritic MCAs.


Barriers to comorbidity service delivery: the complexities of dual diagnosis and the need to agree on terminology and conceptual frameworks.
This paper draws from a literature review commissioned as part of a larger project evaluating comorbidity treatment service models, which was funded by the Australian Government Department of Health and Ageing as part of the National Comorbidity Initiative. The co-occurrence of mental health and substance use disorders (comorbidity) is a common and complex problem. This paper outlines conceptual and practical complexities and barriers associated with comorbidity treatment service delivery, particularly around the variable nature of comorbidity, and the impacts of the separation of the mental health (MH) and alcohol and other drug (AOD) sectors with their differing institutional cultures, aetiological concepts, philosophical underpinnings, educational requirements, administrative arrangements, and screening and treatment approaches. Issues pertaining to the lack of consistent definitions and conceptual frameworks for comorbidity are discussed, particularly in relation to the reported lack of communication, collaboration, and linkages between the sectors. It is suggested that the adoption of consistent terminology and conceptual frameworks may provide a valuable step towards consistency in service provision and research and could lead to improved capacity to address the many issues relating to comorbidity service provision and treatment efficacy.


Predicting Alzheimer disease with β-amyloid imaging: results from the Australian imaging, biomarkers, and lifestyle study of ageing.
Biomarkers for Alzheimer disease (AD) can detect the disease pathology in asymptomatic subjects and individuals with mild cognitive impairment (MCI), but their cognitive prognosis remains uncertain. We aimed to determine the prognostic value of β-amyloid imaging, alone and in combination with memory performance, hippocampal atrophy, and apolipoprotein E ε4 status in nondemented, older individuals. A total of 183 healthy individuals (age = 72.0 ± 7.26 years) and 87 participants with MCI (age = 73.7 ± 8.27) in the Australian Imaging, Biomarkers, and Lifestyle study of ageing were studied. Clinical reclassification was performed after 3 years, blind to biomarker findings. β-Amyloid imaging was considered positive if the (11) C-Pittsburgh compound B cortical to reference ratio was ≥1.5. Thirteen percent of healthy persons progressed (15 to MCI, 8 to dementia), and 59% of the MCI cohort progressed to probable AD. Multivariate analysis showed β-amyloid imaging as the single variable most strongly associated with progression. Of combinations, subtle memory impairment (Z score = -0.5 to -1.5) with a positive amyloid scan was most strongly associated with progression in healthy individuals (odds ratio [OR] = 16, 95% confidence interval [CI] = 3.7-68; positive predictive value [PPV] = 50%, 95% CI = 19-81; negative predictive value [NPV] = 94%, 95% CI = 88-98). Almost all amnestic MCI subjects (Z score ≤ -1.5) with a positive amyloid scan developed AD (OR = ∞; PPV = 86%, 95% CI = 72-95; NPV = 100%, 95% CI = 80-100). Hippocampal atrophy and ε4 status did not add further predictive value. Subtle memory impairment with a positive β-amyloid scan identifies healthy individuals at high risk for MCI or AD. Clearly amnestic patients with a positive amyloid scan have prodromal AD and a poor prognosis for dementia within 3 years.


Phase 1 study of oral azacitidine (CC-486) plus R-CHOP in previously untreated intermediate- to high-risk DLBCL.
Resistance to standard immunochemotherapy remains an unmet challenge in diffuse large B-cell lymphoma (DLBCL), and aberrant DNA methylation may contribute to chemoresistance. Promising early-phase results were reported with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) plus subcutaneous azacitidine, a hypomethylating agent. In this phase 1 study, we evaluated CC-486 (oral azacitidine) plus 6 cycles of R-CHOP in patients with previously untreated intermediate- to high-risk DLBCL or grade 3B/transformed follicular lymphoma. CC-486 doses of 100, 150, 200, or 300 mg given 7 days before cycle 1 and on days 8-21 of cycles 1-5 were evaluated; additional patients were enrolled in the expansion phase to examine preliminary efficacy. The primary objectives were to determine the safety and the maximum tolerated dose (MTD) of CC-486 in combination with R-CHOP. The most common grade 3/4 toxicities were hematologic, including neutropenia (62.7%) and febrile neutropenia (25.4%); grade 3/4 nonhematologic toxicities were uncommon (<7%). The MTD was not established; 2 patients had dose-limiting toxicities (1 with grade 4 febrile neutropenia; 1 with grade 4 prolonged neutropenia). The recommended phase 2 dose was established as 300 mg. The overall response rate was 94.9%, with 52 patients (88.1%) achieving complete responses. With a median follow-up of 28.9 months, estimated 1- and 2-year progression-free survival rates were 84.1% and 78.6%, respectively. Overall, epigenetic priming with CC-486 before R-CHOP can be delivered with acceptable safety to patients with previously untreated intermediate- to high-risk DLBCL or grade 3B/transformed follicular lymphoma. ClinicalTrials.gov: NCT02343536.


When to trust the data: further investigations of system error in a scientific reasoning task.
When evaluating experimental evidence, how do people deal with the possibility that some of the feedback is erroneous? The potential for error means that evidence evaluation must include decisions about when to "trust the data." In this paper we present two studies that focus on subjects' responses to erroneous feedback in a hypothesis testing situation-a variant of Wason's (1960) 2-4-6 rule discovery task in which some feedback was subject to system error: "hits" were reported as "misses" and vice versa. Our results show that, in contrast to previous research, people are equally adept at identifying false negatives and false positives; further, successful subjects were less likely to use a positive test strategy (Klayman & Ha, 1987) than were unsuccessful subjects. Finally, although others have found that generating possible hypotheses prior to experimentation increases success and task efficiency, such a manipulation did little to mitigate the effects of system error.


Project house water: a novel interdisciplinary framework to assess the environmental and socioeconomic consequences of flood-related impacts.
Protecting our water resources in terms of quality and quantity is considered one of the big challenges of the twenty-first century, which requires global and multidisciplinary solutions. A specific threat to water resources, in particular, is the increased occurrence and frequency of flood events due to climate change which has significant environmental and socioeconomic impacts. In addition to climate change, flooding (or subsequent erosion and run-off) may be exacerbated by, or result from, land use activities, obstruction of waterways, or urbanization of floodplains, as well as mining and other anthropogenic activities that alter natural flow regimes. Climate change and other anthropogenic induced flood events threaten the quantity of water as well as the quality of ecosystems and associated aquatic life. The quality of water can be significantly reduced through the unintentional distribution of pollutants, damage of infrastructure, and distribution of sediments and suspended materials during flood events. To understand and predict how flood events and associated distribution of pollutants may impact ecosystem and human health, as well as infrastructure, large-scale interdisciplinary collaborative efforts are required, which involve ecotoxicologists, hydrologists, chemists, geoscientists, water engineers, and socioeconomists. The research network "project house water" consists of a number of experts from a wide range of disciplines and was established to improve our current understanding of flood events and associated societal and environmental impacts. The concept of project house and similar seed fund and boost fund projects was established by the RWTH Aachen University within the framework of the German excellence initiative with support of the German research foundation (DFG) to promote and fund interdisciplinary research projects and provide a platform for scientists to collaborate on innovative, challenging research. Project house water consists of six proof-of-concept studies in very diverse and interdisciplinary areas of research (ecotoxicology, water, and chemical process engineering, geography, sociology, economy). The goal is to promote and foster high-quality research in the areas of water research and flood-risk assessments that combine and build off-laboratory experiments with modeling, monitoring, and surveys, as well as the use of applied methods and techniques across a variety of disciplines.


[Smoking and coronary arteriosclerosis in ischemic heart disease (clinical coronary x-ray studies)].
A relationship was studied between the intensity of smoking and changes revealed in the coronary arteries by coronarography in 498 patients with ischemic heart disease. Marked atherosclerosis was found in 94% of "regular" smokers and in 69% of the persons who did not smoke or smoked only a little. A particularly clear connection between the intensity of smoking and affection of the coronary arteries was registered in patients with ischemic heart disease under the age of 40. All of them had grades III and IV stenosis of the coronary arteries. The results discussed confirm that smoking is a serious "risk factor" of the development of ischemic heart disease, especially in young individuals.


Metal-containing polymers via electropolymerization.
Electropolymerization represents a suitable and well-established approach for the assembly of polymer structures, in particular with regard to the formation of thin, insoluble films. Utilization of monomers that are functionalized with metal complex units allows the combination of structural and functional benefits of polymers and metal moieties. Since a broad range of both electropolymerizable monomers and metal complexes are available, various structures and, thus, applications are possible. Recent developments in the field of synthesis and potential applications of metal-functionalized polymers obtained via electropolymerization are presented, highlighting the significant advances in this field of research.


QTL analysis of Na+ and K+ concentrations in roots and shoots under different levels of NaCl stress in rice (Oryza sativa L.).
The key to plant survival under NaCl salt stress is maintaining a low Na(+) level or Na(+)/K(+) ratio in the cells. A population of recombinant inbred lines (RILs, F(2:9)) derived from a cross between the salt-tolerant japonica rice variety Jiucaiqing and the salt-sensitive indica variety IR26, was used to determine Na(+) and K(+) concentrations in the roots and shoots under three different NaCl stress conditions (0, 100 and 120 mM NaCl). A total of nine additive QTLs were identified by QTL Cartographer program using single-environment phenotypic values, whereas eight additive QTLs were identified by QTL IciMapping program. Among these additive QTLs, five were identified by both programs. Epistatic QTLs and QTL-by-environment interactions were detected by QTLNetwork program in the joint analyses of multi-environment phenotypic values, and one additive QTL and nine epistatic QTLs were identified. There were three epistatic QTLs identified for Na(+) in roots (RNC), three additive QTLs and two epistatic QTLs identified for Na(+) in shoots (SNC), four additive QTLs identified for K(+) in roots (RKC), four additive QTLs and three epistatic QTLs identified for K(+) in shoots (SKC) and one additive QTL and one epistatic QTL for salt tolerance rating (STR). The phenotypic variation explained by each additive, epistatic QTL and QTL×environment interaction ranged from 8.5 to 18.9%, 0.5 to 5.3% and 0.7 to 7.5%, respectively. By comparing the chromosomal positions of these additive QTLs with those previously identified, five additive QTLs, qSNC9, qSKC1, qSKC9, qRKC4 and qSTR7, might represent novel salt tolerance loci. The identification of salt tolerance in selected RILs showed that a major QTL qSNC11 played a significant role in rice salt tolerance, and could be used to improve salt tolerance of commercial rice varieties with marker-assisted selection (MAS) approach.


BMP2-induced inflammation can be suppressed by the osteoinductive growth factor NELL-1.
Bone-morphogenetic protein 2 (BMP2) is currently the only Food and Drug Administration-approved osteoinductive growth factor used in clinical settings for bone regeneration and repair. However, the use of BMP2 is encumbered by numerous clinical complications, including postoperative inflammation and life-threatening cervical swelling. Thus, methods to prevent BMP2-induced inflammation would have far-reaching clinical implications toward improving current BMP2-based methods for bone regeneration. For the first time, we investigate the potential role of the growth factor Nel-like molecule-1 (NELL-1) in inhibiting BMP2-induced inflammation. Adult rats underwent a femoral bone onlay procedure, treated with either BMP2 protein (4 mg/mL), NELL-1 protein (4 mg/mL), or both proteins combined. Animals were evaluated at 3, 7, and 14 days postoperatively by histology, histomorphometry, immunohistochemistry, and real-time PCR for markers of inflammation (TNFα, IL6). The relative levels of TNFα and IL6 in serum were also detected by ELISA. The mechanism for NELL-1's anti-inflammatory effect was further assessed through examining inflammatory markers and generation of reactive oxygen species (ROS) in the mouse embryonic fibroblast NIH3T3 cells. BMP2 significantly induced local inflammation, including an early and pronounced polymorphonuclear cell infiltration accompanied by increased expression of TNFα and IL6. Treatment with NELL-1 alone elicited no significant inflammatory response. However, NELL-1 significantly attenuated BMP2-induced inflammation by all markers and at all timepoints. These local findings were also confirmed using systemic serum inflammatory biomarkers (TNFα, IL6). In each case, NELL-1 fully reversed BMP2-induced systemic inflammation. Lastly, our findings were recapitulated in vitro, where NELL-1 suppressed BMP2 induced expression of inflammatory markers, as well as NF-κB transcriptional activity and generation of ROS. BMP2-induced inflammation is a serious public health concern with potentially life-threatening complications. In the present study, we observed that the growth factor, NELL-1, significantly attenuates or completely reverses BMP2-induced inflammation. The mechanisms of NELL-1's anti-inflammatory effect are only partially elucidated, and may include reduction of NF-κB transcriptional activity or ROS generation.


A nuclear magnetic resonance study of secondary and tertiary structure in yeast tRNAPhe.
We present experimental evidence which confirms recently proposed ring current prediction methods for assigning hydrogen-bond proton nuclear magnetic resonance (NMR) spectra from tRNA (Robillard, G. T., Tarr, C. E., Vosman, F., & Berendsen, H. J. C. (1976) Nature (London) 262, 363-369; Robillard, G. T., Tarr, C. E., Vosman, F., & Sussman, J. L. (1977) Biophys. Chem. 6, 291-298). The evidence is a series of temperature-dependent studies on yeast tRNAPhe monitoring both the high- and low-field NMR spectral regions, which are correlated with independent optical and temperature-jump (temp-jump) studies performed under identical ionic strength conditions. Using assignments derived from the new prediction methods, the melting patterns of the hydrogen-bonded resonances agree with those expected on the basis of optical, temp-jump, and NMR studies on the high-field spectral region. The implication of these results is that previous assignment procedures are at least partially incorrect and, therefore, studies based on those procedures must be reexamined.


Sleep and fatigue in newly graduated nurses-Experiences and strategies for handling shiftwork.
To explore newly graduated nurses' strategies for, and experiences of, sleep problems and fatigue when starting shiftwork. A more comprehensive insight into nurses' strategies, sleep problems, fatigue experiences and contributing factors is needed to understand what support should be provided. For graduate nurses, the first years of practice are often stressful, with many reporting high levels of burnout symptoms. Usually, starting working as a nurse also means an introduction to shiftwork, which is related to sleep problems. Sleep problems may impair stress management and, at the same time, stress may cause sleep problems. Previously, sleep problems and fatigue have been associated with burnout, poor health and increased accident risk. Semi-structured interviews were conducted with nurses (N = 11) from four different Swedish hospitals, and qualitative inductive content analysis was used. The study was approved by the Regional Ethical Review Board in Stockholm. The COREQ checklist was followed. Many nurses lacked effective strategies for managing sleep and fatigue in relation to shiftwork. Various strategies were used, of which some might interfere with factors regulating and promoting sleep such as the homeostatic drive. Sleep problems were common during quick returns, often due to difficulties unwinding before sleep, and high workloads exacerbated the problems. The described consequences of fatigue in a clinical work context indicated impaired executive and nonexecutive cognitive function. The findings indicate that supporting strategies and behaviours for sleep and fatigue in an intervention for newly graduated nurses starting shiftwork may be of importance to improve well-being among nurses and increase patient safety. This study highlights the importance of addressing sleep and fatigue issues in nursing education and work introduction programmes to increase patient safety and improve well-being among nurses.


Of Mice, Dogs, Pigs, and Men: Choosing the Appropriate Model for Immuno-Oncology Research.
The immune system plays dual roles in response to cancer. The host immune system protects against tumor formation via immunosurveillance; however, recognition of the tumor by immune cells also induces sculpting mechanisms leading to a Darwinian selection of tumor cell variants with reduced immunogenicity. Cancer immunoediting is the concept used to describe the complex interplay between tumor cells and the immune system. This concept, commonly referred to as the three E's, is encompassed by 3 distinct phases of elimination, equilibrium, and escape. Despite impressive results in the clinic, cancer immunotherapy still has room for improvement as many patients remain unresponsive to therapy. Moreover, many of the preclinical results obtained in the widely used mouse models of cancer are lost in translation to human patients. To improve the success rate of immuno-oncology research and preclinical testing of immune-based anticancer therapies, using alternative animal models more closely related to humans is a promising approach. Here, we describe 2 of the major alternative model systems: canine (spontaneous) and porcine (experimental) cancer models. Although dogs display a high rate of spontaneous tumor formation, an increased number of genetically modified porcine models exist. We suggest that the optimal immuno-oncology model may depend on the stage of cancer immunoediting in question. In particular, the spontaneous canine tumor models provide a unique platform for evaluating therapies aimed at the escape phase of cancer, while genetically engineered swine allow for elucidation of tumor-immune cell interactions especially during the phases of elimination and equilibrium.


Functional architecture of dopamine neurons driving fear extinction learning.
The ability to extinguish fear responses to stimuli that no longer predict danger is critical for adaptive behavior and increases the likelihood of survival. During fear extinction, dopamine (DA) neurons signal the absence of the expected aversive outcome, and this extinction prediction error (EPE) signal is crucial for initiating and driving extinction learning. However, the neural circuits underlying the EPE signal have remained elusive. Here, we investigate the input-output circuitry of EPE-encoding DA neurons in male mice. By employing projection-specific fiber photometry and optogenetics, we demonstrate that these neurons project to a restricted subregion of the nucleus accumbens. Comprehensive anatomical analyses, as well as projection-specific chemogenetic manipulations combined with recordings of DA biosensors, further uncover the dorsal raphe as one key input structure critical for generating the EPE signal. Together, our results reveal for the first time the functional architecture of EPE-encoding DA neurons crucial for driving fear extinction learning.


Observations on some aetiological factors in Burkitt's lymphoma.
A prospective study of the socio-economic status and physical growth of seventy-six children aged 3-10 years, with Burkitt's lymphoma (BL), has revealed that most of the patients were from the lowest socio-economic classes. Majority of the fathers were farmers, labourers or petty traders. The BL children were, as a group, significantly lighter in weight and shorter than controls. It is postulated that although the weights were probably adversely affected by the illness itself, the shorter heights which were most likely present before the onset of the illness, indicated chronic undernutrition. This, together with a low level of immunization would predispose the children to frequent infections, including malaria. Frequent infections would thus condition the reticuloendothelial system to be more susceptible to the lymphoproliferative properties of the EB virus, resulting in malignant changes such as Burkitt's lymphoma.


Synthesis and structure determination of the adducts formed by electrochemical oxidation of 1,2,3,4-Tetrahydro-7,12-dimethylbenz[a]anthracene in the presence of deoxyribonucleosides or adenine.
Study of DNA adducts formed with aromatic hydrocarbons is part of the strategy to elucidate the mechanisms of tumor initiation by these compounds. 1,2,3,4-Tetrahydro-7,12-dimethylbenz[a]anthracene (THDMBA) is of special interest because it allows discrimination between the pathways of bioactivation by one-electron oxidation and monooxygenation. To study and identify adducts formed biologically, synthetic adducts are needed as reference standards. THDMBA was electrochemically oxidized in the presence of deoxyadenosine (dA), adenine (Ade), deoxyguanosine (dG), or deoxycytidine (dC). In the presence of dA, four adducts were isolated: 7-methyl-1,2,3,4-tetrahydrobenz[a]anthracene-12-CH2-N7Ade (7-MTHBA-12-CH2-N7Ade, 3.6%), 12-MTHBA-7-CH2-N7Ade (4.2%), 7-MTHBA-12-CH2-N6dA (5.8%), and 12-exo-methylene-7-MTHBA-7-N6dA (22.8%); a dehydrogenated product, 7,12-di-exo-methylene-THBA (44.2%), was also obtained. In the presence of Ade, nine adducts were synthesized: 7-MTHBA-12-CH2-N7Ade (1.1%), 12-MTHBA-7-CH2-N7Ade (2.4%), 7-MTHBA-12-CH2-N1Ade (10.2%), 12-MTHBA-7-CH2-N1Ade (13.2%), 7-MTHBA-12CH2-N3Ade (1.7%), 12-MTHBA-7-CH2-N3Ade (1.7%), 7-exo-methylene-12-MTHBA-12-N3Ade (11.2%), 12-exo-methylene-7-MTHBA-7-N3Ade (27.9%), and 12-exo-methylene-7-MTHBA-7-N6Ade (12.1%), as well as the dehydrogenated product 7,12-di-exo-methylene-THBA (16.7%). In the presence of dG, three adducts were produced: 7-MTHBA-12-CH2-N7Gua (24.2%), 12-MTHBA-7-CH2-N7Gua (12.2%), and 7-MTHBA-12-CH2-N2dG (3.7%), as well as the dehydrogenated product 7,12-di-exo-methylene-THBA (38.9%). Anodic oxidation in the presence of dC yielded a large amount of 7,12-di-exo-methylene-THBA (80.4%), but no adducts. The structure of the adducts was elucidated by using UV, NMR, and MS. The N-7 positions in dG, dA, and Ade, the 2-NH2 in dG, and the N-1 position in Ade form exclusively methyl-linked adducts. In contrast, the 6-NH2 group of dA and Ade and the N-3 of Ade prefer to attack the meso-anthracenic positions rather than the methyl groups. The order of reactivity of dG and dA in the formation of methyl-linked THDMBA adducts agrees well with that previously found for 7,12-dimethylbenz[a]anthracene [RamaKrishna et al. (1992) J. Am. Chem. Soc. 114, 1863-1874.


Acid alpha-naphthyl acetate esterase activity in nucleated red cells of human fetal liver.
Acid alpha-naphthyl acetate esterase (ANAE) activity was investigated in nucleated red cells obtained from nine human fetal livers at 9-24 weeks of gestation. A strong ANAE activity was demonstrated in fetal liver erythroblasts with a staining pattern of a perinuclear ring. Occasionally some polychromatophilic normoblasts expressed a focal ANAE activity usually observed in human T-lymphocytes. Some 50-70% of erythroblasts in human fetal livers showed a ring-like staining pattern. A slight decrease of ANAE positivity was observed in cells of fetal livers after 17 weeks of gestation.


Progress in research on gold nanoparticles in cancer management.
The rapid advancement of nanotechnology in recent years has fuelled burgeoning interest in the field of nanoparticle research, particularly its application in cancer management. At present, there seems to be heightened interest in the application of gold nanoparticles (AuNPs) to the management of cancer, encompassing diagnosis, monitoring, and treatment. AuNPs could be used as drug delivery agents that target cancer cells or in gene therapy. These efforts are undertaken in the hope of revolutionizing current methods and strategies for cancer treatment. This review will focus on the current applications of AuNPs in cancer management. OBJECTIVES, DATA SOURCES, STUDY APPRAISAL AND SYNTHESIS METHODS, RESULTS:: objectives, data sources, study eligibility criteria, participants, and interventions, study appraisal and synthesis methods, results are not required, as the study will be a literature review. Just introduction, ethics and dissemination, and conclusion are applicable. Ethical approval and informed consent are not required, as the study is a literature review and does not involve direct contact with patients or alterations to patient care. AuNPs have many properties that are of great value for the diagnosis and treatment of tumors. AuNPs are small in size and can penetrate widely and deposit on the tumor site, bind to many proteins and drugs, target delivery drugs, and have good biocompatibility. The application of AuNPs in the diagnosis and treatment of tumors is very considerable. In the near future, AuNPs will certainly play an important role in the treatment of tumors.


[Changes in hemodynamics during regional anesthesia and medicinal sedation in children traumatology].
Thirty-nine patients, aged 8 to 15, who were operated for damaged bones in the upper lower limbs were examined. The parameters of central hemodynamics, heart rate and arterial pressure were studied (monitor HP "Viridia m3", USA). Strike volume was determined automatically (rheography monitor NCCOM-3"Boomed Co.", USA). Cardiac output, body area, stroke index and the peripheral vascular resistance were calculated by the routine formulae. Group 1 comprised 20 children who were operated on with the halothane-oxide-oxygen narcosis. Group 2 comprised 19 patients who received regional anesthesia combined with drug sedation (midazolam). A 1% lydokain solution with adrenalin was used as a local anesthetic. The block of the brachial plexus with auxiliary approach and the "3 in 1" block were in use. The changes of hemodynamics detected in the children of group 1 revealed an insufficient analgetic and antistress efficiency of halothane. The data obtained for group 2 are indicative of insignificant hemodynamic changes observed at all examination stages and related with the impact exerted by drugs, used for sedation and regional anesthesia, on the vascular tonus of the original undetected hypovolemia. A lack of complications, a fast awakening and recovery of an adequate consciousness after combined regional anesthesia as well as comfort and a lack of need in extra analgetics that are normally used in the immediate postoperative period make it possible to refer to the discussed anesthesia variation as to the preferential one in cases of surgeries for damaged bones in children.


Tepidimonas ignava gen. nov., sp. nov., a new chemolithoheterotrophic and slightly thermophilic member of the beta-Proteobacteria.
A bacterial isolate with an optimum growth temperature of about 55 degrees C was recovered on a medium composed of one part Kligler's iron agar and four parts of Thermus Agar from the host spring at São Pedro do Sul in central Portugal. Phylogenetic analyses using the 16S rRNA gene sequence of strain SPS-1037T indicated that the new organism represented a new genus and species of beta-Proteobacteria. The major fatty acids of strain SPS-1037T are C16:0 and C17:0. Ubiquinone 8 is the major respiratory quinone, and the major polar lipids are phosphatidylethanolamine and phosphatidylglycerol. The new isolate is aerobic and chemolithoheterotrophic. Thiosulfate and tetrathionate were oxidized to sulfate. The growth yield of the organism was improved by the addition of thiosulfate to media containing organic carbon sources, but the organism did not grow autotrophically under the conditions examined. Heterotrophic growth of strain SPS-1037T occurs on amino acids and organic acids, but this organism does not assimilate carbohydrates. On the basis of the phylogenetic analyses, and physiological and biochemical characteristics, it is proposed that strain SPS-1037T represents a new genus and a new species for which the name Tepidimonas ignava is proposed.


Ethical and Professionalism Implications of Physician Employment and Health Care Business Practices: A Policy Paper From the American College of Physicians.
The environment in which physicians practice and patients receive care continues to change. Increasing employment of physicians, changing practice models, new regulatory requirements, and market dynamics all affect medical practice; some changes may also place greater emphasis on the business of medicine. Fundamental ethical principles and professional values about the patient-physician relationship, the primacy of patient welfare over self-interest, and the role of medicine as a moral community and learned profession need to be applied to the changing environment, and physicians must consider the effect the practice environment has on their ethical and professional responsibilities. Recognizing that all health care delivery arrangements come with advantages, disadvantages, and salient questions for ethics and professionalism, this American College of Physicians policy paper examines the ethical implications of issues that are particularly relevant today, including incentives in the shift to value-based care, physician contract clauses that affect care, private equity ownership, clinical priority setting, and physician leadership. Physicians should take the lead in helping to ensure that relationships and practices are structured to explicitly recognize and support the commitments of the physician and the profession of medicine to patients and patient care.


Print to detect: a rapid and ultrasensitive phage-based dipstick assay for foodborne pathogens.
Foodborne pathogens are a burden to the economy and a constant threat to public health. The ability to rapidly detect the presence of foodborne pathogens is a vital component of any strategy towards establishing a safe and secure food supply chain. Bacteriophages (phages) are viruses capable of infecting and replicating within bacteria in a strain-specific manner. The ubiquitous and selective nature of phages makes them ideal for the detection and biocontrol of bacteria. Therefore, the objective of this research was to develop and test a phage-based paper dipstick biosensor for the detection of various foodborne pathogens in food matrices. The first step was to identify the best method for immobilizing phages on paper such that their biological activity (infectivity) was preserved. It was found that piezoelectric inkjet printing resulted in lower loss of phage infectivity when compared with other printing methods (namely gravure and blade coating) and that ColorLok paper was ideally suited to create functional sensors. The phage-based bioactive papers developed with use of piezoelectric inkjet printing actively lysed their target bacteria and retained this antibacterial activity for up to 1 week when stored at room temperature and 80% relative humidity. These bioactive paper strips in combination with quantitative real-time PCR were used for quantitative determination of target bacteria in broth and food matrices. A phage dipstick was used to capture and infect Escherichia coli O157:H7, E. coli O45:H2, and Salmonella Newport in spinach, ground beef and chicken homogenates, respectively, and quantitative real-time PCR was used to detect the progeny phages. A detection limit of 10-50 colony-forming units per millilitre was demonstrated with a total assay time of 8 h, which was the duration of a typical work shift in an industrial setting. This detection method is rapid and cost-effective, and may potentially be applied to a broad range of bacterial foodborne pathogens. Graphical abstract .


Chronic kidney disease prevalence estimates among racial/ethnic groups: the Multi-Ethnic Study of Atherosclerosis.
Muscle mass is not a major determinant of serum cystatin C levels, and its use to estimate GFR may lead to more congruent estimates of chronic kidney disease (CKD) across gender and racial/ethnic groups. The Multi-Ethnic Study of Atherosclerosis is a population-based study of 6814 men and women who are aged 45 to 85 yr and do not have clinical cardiovascular disease. Estimated CKD prevalence, defined as an estimated GFR <60 ml/min per 1.73 m(2) body surface area, was compared using three different GFR prediction equations: The abbreviated Modification of Diet in Renal Disease (MDRD) equation and two equations based on serum cystatin C. Among women, CKD prevalence estimates across the four racial/ethnic groups using the MDRD- or the cystatin C-based GFR equations, which include gender and race coefficients, varied by approximately two-fold (P < 0.0001) but were more congruent with use of a serum cystatin C-based equation without the use of coefficients (P = 0.3). CKD prevalence estimates did not differ significantly across racial/ethnic groups among men with the MDRD (P = 0.07) or cystatin C formula without coefficients (P = 0.05) but did differ significantly with the cystatin C formula, which incorporates gender and race coefficients (P = 0.006). CKD prevalence estimates vary across racial/ethnic groups, and the degree of variability depends on the method used to estimate GFR, especially among women. Further research is needed to determine the accuracy and precision of GFR prediction equations in racially diverse populations.


Heterogeneity of cognitive profiles in aging: successful aging, normal aging, and individuals at risk for cognitive decline.
Neuropsychological clinical decision-making is complicated by the fact that variability in test performance increases with advancing age. This research explores the presence of homogeneous subgroups in 120 neurologically healthy individuals, from 55 to 85 years of age. Subjects at risk for dementing diseases were diagnosed as Aging-Associated Cognitive Decline (AACD) and Mild Cognitive Impairment (MCI). Cluster analysis was applied on 11 neuropsychological variables assessing logical memory immediate recall and retention percentage, visual memory immediate recall and retention, conceptual thinking, naming, verbal fluency, constructional functions, motor speed, flexibility and finger tapping. Five clusters were extracted, one representing cognitively successfully aged, and two consisting of individuals with normal or average level of performance. One cluster was characterized by older subjects with difficulties in visual memory, visuoconstructional functions, and speed and attention, most of the younger subjects in the same cluster had a diagnosis of AACD or MCI. The fifth cluster represented individuals at risk for dementing diseases; most of them were diagnosed having AACD and more than half had a diagnosis of MCI. Age, activity and intellectual levels, and to a lesser degree education, were significantly related to the cluster solution. The present findings caution against treating samples of elderly individuals as homogeneous.


Mutagenesis breeding for increased 3-deoxyanthocyanidin accumulation in leaves of Sorghum bicolor (L.) Moench: a source of natural food pigment.
Natural food colorants with functional properties are of increasing interest. Prior papers indicate the chemical suitability of sorghum leaf 3-deoxyanthocyanidins as natural food colorants. Via mutagenesis-assisted breeding, a sorghum variety that greatly overaccumulates 3-deoxyanthocyanidins of leaf tissue, named REDforGREEN (RG), has been isolated and characterized. Interestingly, RG not only caused increased 3-deoxyanthocyanidins but also caused increased tannins, chlorogenic acid, and total phenolics in the leaf tissue. Chemical composition of pigments was established through high-performance liquid chromatography (HPLC) that identified luteolinidin (LUT) and apigeninidin (APG) as the main 3-deoxyanthocianidin species. Specifically, 3-deoxyanthocianidin levels were 1768 μg g⁻¹ LUT and 421 μg g⁻¹ APG in RG leaves compared with trace amounts in wild type, representing 1000-fold greater levels in the mutant leaves. Thus, RG represents a useful sorghum mutagenesis variant to develop as a functionalized food colorant.


A cytotoxic T-lymphocyte clone derived from mice with progressively growing tumors.
Tumor-specific T-cell clones were derived from spleen cells of mice bearing a syngeneic PHS-5 tumor (a P815 mastocytoma mutant). Cells were expanded in vitro and characterized and assayed for activity against the relevant tumor in vivo. Clone cells were CD4-, CD8+ T lymphocytes, as determined by fluorescence activated cell sorting analysis and were specifically cytotoxic against P815 tumor cells in vitro, as shown in chromium 51 release assays. These cells require both antigen and interleukin 2 to proliferate; neither alone is sufficient, even with the addition of interleukin 1. In an experimental P815 liver metastasis model, the adoptive transfer of GD11 or GD11.17 clone cells and injection of recombinant interleukin 2 (7500 U intraperitoneally) 3 days after infusion of tumor cells reduced the number of tumor nodules, while the adoptive transfer of lymphokine-activated killer cells was ineffective.


Can narrow-band imaging be used to determine the surgical margin of superficial hypopharyngeal cancer?
Narrow-band imaging (NBI) is a novel optical technique that uses narrow bandwidth filters in a video endoscope system to improve the diagnostic capability of endoscopes in characterizing tissues. It is well known that early identification of neoplasia in the gastrointestinal tract using this technique might make it possible to reduce the suffering of patients caused by loss of function or severe complications after radical surgery. Several reports have introduced this system as a preoperative examination to evaluate the lateral spread of the neoplastic lesions in the oropharynx or hypopharynx. We experienced a case with hypopharyngeal cancer in which we were able to avoid underestimating cancer lesions following insufficient resection using the NBI system. A 62-year-old female underwent partial hypopharyngectomy with the margin estimated by an NBI view coupled with reconstruction of the hypopharynx while preserving the larynx. The resected specimen was cut into serial sections for a detailed pathology examination. The surgical margin seemed to be wide enough and it could be assumed that if possible we should observe these cancers with conventional electroendoscopy and NBI before treatment.