[Gastrointestinal human myiasis caused by Eristalis tenax].
The myiasis observed in Bariloche are characterized and the probable conditions under which the infestations took place established. The larvae obtained from faeces of 2 patients were identified as Eristalis tenax (Diptera: Syrphidae) according to Hartley (1961) and Organización Panamericana de la Salud keys (1962). These 2 cases of human gastrointestinal myiasis were the first to be registered in Bariloche (Patagonia, Argentina) and their characteristics were similar to those described for this species in other parts of the world. The lack of specific control measures in the domestic water supply system was the most probable cause of the infestation. This event extends the distribution of E. tenax and human gastrointestinal myiasis in South America to 41 degrees 03' S.


Comparison of a once daily with a twice daily subcutaneous low molecular weight heparin regimen in the treatment of deep vein thrombosis. FRAXODI group.
Clinical trials have been performed to compare with standard heparin a once or a twice daily regimen of low-molecular-weight heparin but no direct comparison has been done between these two low-molecular-weight heparin regimens in terms of efficacy and safety with a long-term clinical evaluation. Patients with proximal deep vein thrombosis, confirmed by venography were randomly assigned to either nadroparin (10,250 AXa IU/ml) twice daily or nadroparin (20,500 AXa IU/ml) once daily for at least 5 days. Regimens were adjusted to bodyweight. Oral anticoagulants were started on day 1 or 2 and continued for 3 months. Patients were followed up for 3 months. The composite outcome of venous thromboembolism and death possibly related to pulmonary embolism was the primary measure of efficacy. Major bleeding was the principal measure of safety. The study was designed to show equivalence between the two regimens. Recurrent thromboembolic events or death possibly related to pulmonary embolism were reported in 13 patients in the once daily group (4.1%) and in 24 patients of the twice daily group (7.2%): (absolute difference 3.1% in favor of the once daily regimen; 95% confidence interval -6.6%, +0.5%). Major bleeding episodes during nadroparin treatment occurred in 4 (1.3%) and 4 patients (1.2%) in the once and twice daily groups, respectively. A nadroparin regimen of one injection per day is at least as effective and safe as the same total daily dose divided over two injections for the treatment of acute deep vein thrombosis.


Cloning, sequencing, and nucleolar targeting of the basal-body-binding nucleolar protein BN46/51.
BN46/51 is an acidic protein found in the granular component of the nucleolus of the amebo-flagellate Naegleria gruberi. When Naegleria amebae differentiate into swimming flagellates, BN46/51 is found associated with the basal body complex at the base of the flagella. In order to determine the factors responsible for targeting BN46/51 to a specific subnucleolar region, cDNAs coding for both subunits were isolated and sequenced. Two clones, JG4.1 and JG12.1 representing the 46 kDa and 51 kDa subunits, respectively, were investigated in detail. JG12.1 encoded a polypeptide of 263 amino acids with a predicted size of 30.1 kDa that co-migrated with the 51 kDa subunit of BN46/51 when expressed in yeast. JG4.1 encoded a polypeptide of 249 amino acids with a predicted size of 28.8 kDa that co-migrated with the 46 kDa subunit of BN46/51. JG4.1 was identical to JG12.1 except for the addition of an aspartic acid between positions 94 and 95 of the JG12.1 sequence and the absence of 45 amino acids beginning at position 113. The predicted amino acid sequences were not closely related to any previously reported. However, the sequences did have 26-31% identity to a group of FKPBs (FK506 binding proteins) but lacked the peptidyl-prolyl cis-trans isomerase domain of the FKBPs. Both subunits contained two KKE and three KKX repeats found in other nucleolar proteins and in some microtubule binding proteins. Using 'Far Western' blots of nucleolar proteins, BN46/51 bound to polypeptides of 44 kDa and 74 kDa. The 44 kDa component was identified as the Naegleria homologue of fibrillarin. BN46/51 bound specifically to the nucleoli of fixed mammalian cells, cells which lack a BN46/51 related polypeptide. When the JG4.1 and JG12.1 cDNAs were expressed in yeast, each subunit was independently targeted to the yeast nucleolus. We conclude that BN46/51 represents a unique nucleolar protein that can form specific complexes with fibrillarin and other nucleolar proteins. We suggest that the association of BN46/51 with the MTOC of basal bodies may reflect its role in connecting the nucleolus with the MTOC activity for the mitotic spindle. This would provide a mechanism for nucleolar segregation during the closed mitosis of Naegleria amebae.


Tirant Stealthily Invaded Natural Drosophila melanogaster Populations during the Last Century.
It was long thought that solely three different transposable elements (TEs)-the I-element, the P-element, and hobo-invaded natural Drosophila melanogaster populations within the last century. By sequencing the "living fossils" of Drosophila research, that is, D. melanogaster strains sampled from natural populations at different time points, we show that a fourth TE, Tirant, invaded D. melanogaster populations during the past century. Tirant likely spread in D. melanogaster populations around 1938, followed by the I-element, hobo, and, lastly, the P-element. In addition to the recent insertions of the canonical Tirant, D. melanogaster strains harbor degraded Tirant sequences in the heterochromatin which are likely due to an ancient invasion, likely predating the split of D. melanogaster and D. simulans. These degraded insertions produce distinct piRNAs that were unable to prevent the novel Tirant invasion. In contrast to the I-element, P-element, and hobo, we did not find that Tirant induces any hybrid dysgenesis symptoms. This absence of apparent phenotypic effects may explain the late discovery of the Tirant invasion. Recent Tirant insertions were found in all investigated natural populations. Populations from Tasmania carry distinct Tirant sequences, likely due to a founder effect. By investigating the TE composition of natural populations and strains sampled at different time points, insertion site polymorphisms, piRNAs, and phenotypic effects, we provide a comprehensive study of a natural TE invasion.


Linking in vitro and in vivo survival of clinical Leishmania donovani strains.
Leishmania donovani is an intracellular protozoan parasite that causes a lethal systemic disease, visceral leishmaniasis (VL), and is transmitted between mammalian hosts by phlebotomine sandflies. Leishmania expertly survives in these 'hostile' environments with a unique redox system protecting against oxidative damage, and host manipulation skills suppressing oxidative outbursts of the mammalian host. Treating patients imposes an additional stress on the parasite and sodium stibogluconate (SSG) was used for over 70 years in the Indian subcontinent. We evaluated whether the survival capacity of clinical L. donovani isolates varies significantly at different stages of their life cycle by comparing proliferation, oxidative stress tolerance and infection capacity of 3 Nepalese L. donovani strains in several in vitro and in vivo models. In general, the two strains that were resistant to SSG, a stress encountered in patients, attained stationary phase at a higher parasite density, contained a higher amount of metacyclic parasites and had a greater capacity to cause in vivo infection in mice compared to the SSG-sensitive strain. The 2 SSG-resistant strains had superior survival skills as promastigotes and as amastigotes compared to the SSG-sensitive strain. These results could indicate that Leishmania parasites adapting successfully to antimonial drug pressure acquire an overall increased fitness, which stands in contrast to what is found for other organisms, where drug resistance is usually linked to a fitness cost. Further validation experiments are under way to verify this hypothesis.


Er3+ Photoluminescence in Er2@C82 and Er2C2@C82 Metallofullerenes Elucidated by Density Functional Theory.
Metallofullerenes with two erbium atoms encapsulated in IPR C82 cage isomers Cs-6 (I), C2v-9 (II), and C3v-8 (III) were investigated using density functional theory. The calculations suggest that erbium atoms assume a trivalent state with Er (4f11) valence electronic configuration in Er2@C82 and Er2C2@C82, where two electrons (6s2) per Er atom are transferred to the cage carrying four negative charges (C824-), while the third electron is promoted from the 4f to the 5d shell, becoming involved in covalent bonding to near atoms. Experimentally, Er3+-like emission from 4I13/2 to 4I15/2 was observed, and our calculations indicate that the Er-Er covalent metal bond in Er2@C82, and the Er-C/C2 covalent bonds in Er2C2@C82, can account for the observed photoluminescence despite the cage with C824-. Such existence is the reason that the C2 unit was found to be neutral on the basis of MEM-Rietveld X-ray measurements, although formally it should be described as C22-. Our prediction for isomer photoluminescence intensity agrees with the experimentally determined order (III > I > II), where the most pronounced activity of isomer III in Er2C2@C82 stems from its higher charge of formal Er3+ and its largest HOMO-LUMO gap.


Alpha 1-antitrypsin allo- and phenotypes in gastric and duodenal ulcer.
Serum alpha 1-antitrypsin (A1AT) allo- and phenotypes (including M1, M2 and M3 alleles) were studied in 99 patients with gastric ulcer (GU) and 56 patients with duodenal ulcer (DU) using agarose isoelectric focusing. The results were compared with the A1AT data of a random population sample of similar genetic background (1422 persons). An increase in M2 allotype and M1M2 phenotype as well as a decrease in Z allotype of A1AT was seen in GU in comparison to DU and the random population. There were no particular clinical features which would distinguish patients with M2 allotype from the remainder of the GU group. However, a trend toward elevated serum pepsinogen I and II levels in patients with M2 allotype was seen. When the pepsinogen levels were compared in the GU patient groups with and without M2 allotype, matched between themselves by the state of the gastric mucosa, a statistically significant difference was revealed between pepsinogen II levels in these two groups. No associations were found between DU and any of the A1AT phenotypes.


Signaling from cytokine receptors that affect TH1 responses
Receptors of the various cytokines although structurally diverse, can yet be grouped into four major families of receptor proteins. Most cytokines that function in the immune system bind to either the Class I or Class II receptor families. Two other important receptor families are the immunoglobulin superfamily receptor and the TNF receptor family. Members of these receptor families also have critical roles in the immune system. A common feature of all these receptor families is that they do not exhibit any intrinsic tyrosine kinase activity. Receptor signaling is initiated through recruitment of kinases and through recruitment of cytosolic proteins to the receptor. In this review we will examine receptor signaling pathways initiated from five receptors that are all involved in either initiating T helper-1 (Th1) responses, or in downregulating Th1 responses. The following receptors: Interleukin (IL)-12, Interferon (IFN), IL-4, IL-10, and Tumor necrosis factor (TNF)-alpha will be examined. Signaling initiated from IL-12, IFN-gamma and TNF-alpha are important for inducing Th1 responses, and on the other hand signaling from IL-4 and IL-10 receptors inhibit Th1 responses. We will also discuss human immunodeficiencies resulting from mutations in the genes that encode the Type I cytokine receptors.


Hydrogen peroxide-inducible proteins in Salmonella typhimurium overlap with heat shock and other stress proteins.
Hydrogen peroxide treatment induces the synthesis of 30 proteins in Salmonella typhimurium. Five of these proteins are also induced by heat shock, including the highly conserved DnaK protein. The induction of one of these five proteins by heat shock is dependent on oxyR, a positive regulator of hydrogen peroxide-inducible genes, while the induction of the other four by heat shock is oxyR independent. Five of the 30 hydrogen peroxide-inducible proteins have been identified, and their structural genes have been mapped. Other stresses such as nalidixic acid, ethanol, or cumene hydroperoxide treatment also induce subsets of the 30 hydrogen peroxide-inducible proteins as well as additional proteins. Hydrogen peroxide-inducible proteins are shown to be largely different from those proteins induced by aerobiosis. In addition, the expression of the katG (catalase) gene is shown to be regulated by oxyR at the level of mRNA.


Impact of HDL genetic risk scores on coronary artery calcified plaque and mortality in individuals with type 2 diabetes from the Diabetes Heart Study.
Patients with type 2 diabetes (T2D) are at elevated risk for cardiovascular disease (CVD) events and mortality. Recent studies have assessed the impact of genetic variants affecting high-density lipoprotein cholesterol (HDL) concentrations on CVD risk in the general population. This study examined the utility of HDL-associated single nucleotide polymorphisms (SNPs) for CVD risk prediction in European Americans with T2D enrolled in the Diabetes Heart Study (DHS). Genetic risk scores (GRS) of HDL-associated SNPs were constructed and evaluated for potential associations with mortality and with coronary artery calcified atherosclerotic plaque (CAC), a measure of subclinical CVD strongly associated with CVD events and mortality. Two sets of SNPs were used to construct GRS; while all SNPs were selected primarily for their impacts on HDL, one set of SNPs had pleiotropic effects on other lipid parameters, while the other set lacked effects on low-density lipoprotein cholesterol (LDL) or triglyceride concentrations. The GRS were specifically associated with HDL concentrations (4.90 × 10(-7) < p < 0.02) in models adjusted for age, sex, and body mass index (BMI), but were not associated with LDL or triglycerides. Cox proportional hazards regression analysis suggested the HDL-associated GRS had no impact on risk of CVD-mortality (0.48 < p < 0.99) in models adjusted for other known CVD risk factors. However, associations between several of the GRS and CAC were observed (3.85 × 10(-4) < p < 0.03) in models adjusted for other known CVD risk factors. The GRS analyzed in this study provide a tool for assessment of HDL-associated SNPs and their impact on CVD risk in T2D. The observed associations between several of the GRS and CAC suggest a potential role for HDL-associated SNPs on subclinical CVD risk in patients with T2D.


Biochemical and genetic characterization of nirB mutants of Escherichia coli K 12 pleiotropically defective in nitrite and sulphite reduction.
Mutants of Escherichia coli K12 defective in the nirB gene lack NADH-dependent nitrite reductase activity and reduce nitrite slowly during anaerobic growth. With one exception these mutants require cysteine for growth. Cytochrome C552 synthesis and the assimilation of ammonia are unaffected by the nirB mutation. The defective gene is located between the crp and aroB genes at minute 73 on the E. coli chromosome. Mapping and reversion studies indicate the nirB is identical to the previously described cysG gene. It is suggested that the product of the cysG+ (nirB+)¿gene is an enzyme required for the synthesis of sirohaem, a prosthetic group of enzymes which catalyse the six-electron reduction of nitrite to ammonia and sulphite to sulphide.


Fabrication of a honeycomb-like bimetallic SERS substrate for the detection of triphenyltin chloride.
Triphenyltin chloride (TPhT) is an organotin compound that causes intensive toxicological risk to the environment and humans. A detection method with high sensitivity and stability is therefore desired to better detect TPhT. In this study, a novel SERS substrate was prepared by sputtering an ultra-thin Au layer on a honeycomb-like silver nanoarray fabricated via the nanosphere lithography method. The ultra-thin Au layer was formed by sputtering the intermittent Au nanoparticles on the silver nanoarray, resulting in bimetallic coupling with dramatically increased hotspots and extremely high SERS enhancement with an analytical enhancement factor (AEF) of 6.08 × 109 using Rhodamine 6G (R6G) as the probe molecule. Based on density functional theory (DFT) simulations, the Raman characteristic peaks of TPhT at 999 cm-1 and 655 cm-1 were selected for TPhT detection. The AEF of the SERS substrate HC5-AgAu was calculated to be 3.38 × 106 with the detection concentration of TPhT down to 10-10 M. The as-prepared honeycomb-like silver-gold bimetallic SERS substrate demonstrated great stability and sensitivity for TPhT detection, which might also be applied in monitoring many other environmental pollutants.


Investigation of possible vaccine-induced epizootics of infectious bovine rhinotracheitis, using restriction endonuclease analysis of viral DNA.
Viral DNA was extracted from each of 14 modified-live (ML) bovine herpesvirus 1 vaccines, representing all of the ML infectious bovine rhinotracheitis virus (IBRV) vaccines licensed by the US Department of Agriculture for use in cattle. Restriction endonucleases Pst I and Bgl II were used to establish restriction enzyme patterns for the vaccinal viruses. Viral DNA from isolates obtained from 6 field samples of IBRV (1 from Colorado, 1 from West Virginia, 3 from Wisconsin, 1 from South Dakota) were digested with restriction endonucleases, and patterns were compared to evaluate the role of vaccinal virus in these field epizootics of infectious bovine rhinotracheitis. Animals from which field samples were obtained had been vaccinated with ML IBRV vaccine before the epizootic of infectious bovine rhinotracheitis occurred in the herds. In 2 of the 6 field samples, DNA restriction endonuclease analyses patterns from the isolates were indistinguishable from the pattern for the vaccinal viruses used. In the remaining 4 field samples, DNA restriction endonuclease analyses patterns of the IBRV from isolates were different from those of the vaccinal viruses.


Effects of chard (Beta vulgaris L. var. Cicla) extract on pancreatic B cells in streptozotocin-diabetic rats: a morphological and biochemical study.
Chard (Beta vulgaris L. var. cicla) is used as a hypoglycemic agent by diabetic patients in Turkey. The present study was carried out in order to detect whether this plant, used in folk remedies for decreasing blood glucose levels, affects pancreatic B cells and blood glucose. In the diabetic group, a decrease in the number of B cells of Langerhans islets and in the secretory materials, a swollen granular endoplasmic reticulum cisternae and widened intercellular areas in some of B cells were observed. But, in a diabetic group given chard extract, an increase in the number of B cells of Langerhans islets and in the secretory granules were noted, together with many hypertrophic Golgi apparatus and granules of low densities. The extract while having no effect on blood glucose and body weight in the normal group, reduced the blood glucose value in streptozotocin-induced hyperglycemic animals. But, in a diabetic group given chard, the body weight significantly increased in comparison to the diabetic group; maximum reduction in blood glucose levels was observed on the 42nd day. According to the morphological and biochemical results obtained, it is concluded that the extract of this plant when administered by gavage may reduce blood glucose levels by regeneration of the B cells.


Comparing Treatment Response Between Older and Younger Patients with Chronic Hepatitis C Virus Infection on Direct-acting Antiviral Agents.
To compare sustained virologic response 12 weeks post-treatment completion (SVR12) and patient characteristics for older versus younger patients with chronic hepatitis C virus infection (HCV) receiving direct-acting antiviral (DAA) agent therapy. This retrospective cohort study included patients with chronic HCV who received DAA therapy, between 2015 and 2018, in the largest health system in Rhode Island (N=154). Patient characteristics, comorbid diagnoses, and SVR12 status were compared between older (aged ≥60 years) and younger (<60 years) adults using chi-squared tests. Overall, 94.1% (95% CI: 90.4-97.8) achieved SVR12; response rates were 91.8% (95% CI: 84.9-98.6) for older adults and 95.6% (95% CI: 91.5-99.8) for younger adults (p=0.51). Our findings refute the historical notion that older adults were a "difficult-to-treat" subpopulation for whom clinicians should expect less treatment success. This is no longer the case with DAA therapy.


The effect of siblings on early development: a potential contributor to personality differences in mammals.
Although most mammals grow up in the company of same or different age sibs (or half sibs), surprisingly little attention has been given to how relations among them might influence the development of individual differences in morphology, physiology, and behavior. Here we review evidence from our work on domestic and wild European rabbits, and more recently on laboratory rats, mice, and domestic cats, supporting the proposition that in mammals early sibling relations contribute to the development of individual differences in these three domains and thereby to long-term behavioral differences of the kind we might consider part of an animal's behavioral style or personality. First we report a consistent and marked negative relation between litter size and individuals' body mass at birth and weaning, as well as marked within-litter differences in prenatal body mass and placental efficiency. We then report individual differences in preweaning behaviors associated with these morphological variables such as position occupied in the litter huddle and development of motor ability, as well as physiological differences in thermoregulation, immune parameters, and endocrine indicators of stress. Finally, we report first evidence from wild rabbits that early relations among littermates may have long-term consequences for individual differences in behavioral style. We conclude that in mammals, individual differences in early growth, physiology and behavior potentially important for the development of animal personality, are shaped to an appreciable extent by early sibling relations and that this little-researched field deserves closer attention.


In vivo insulin secretion and action in hyperglycemic rat.
This work was designed to study the effects of insulin secretion and action in vivo of moderate hyperglycemia induced by glucose infusion during 4 days in unrestrained rats. The maintenance of a glycemia around 170 mg/dl throughout the infusion time necessitated a gradual increase of glucose infusion rate from 11.5 to 19 g/day. Throughout the infusion period, plasma insulin-to-glucose ratio remained much higher in hyperglycemic rats (HG) than in controls. Glucose tolerance and insulin secretion tests were performed 2 h after the end of the infusion, when glycemia and insulinemia were back to basal values. Incremental plasma glucose values were significantly lower in HG than in control rats without significant changes in incremental plasma insulin concentrations, suggesting an increased insulin efficiency. At the same insulin level, glucose utilization was higher in HG than in control rats during euglycemic-hyperinsulinemic clamps. These data show that short-term hyperglycemia and hyperinsulinemia do not induce a defect in insulin secretion in vivo and do increase tissue sensitivity to insulin.


IL-17 controls central nervous system autoimmunity through the intestinal microbiome.
Interleukin-17A- (IL-17A) and IL-17F-producing CD4+ T helper cells (TH17 cells) are implicated in the development of chronic inflammatory diseases, such as multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). TH17 cells also orchestrate leukocyte invasion of the central nervous system (CNS) and subsequent tissue damage. However, the role of IL-17A and IL-17F as effector cytokines is still confused with the encephalitogenic function of the cells that produce these cytokines, namely, TH17 cells, fueling a long-standing debate in the neuroimmunology field. Here, we demonstrated that mice deficient for IL-17A/F lose their susceptibility to EAE, which correlated with an altered composition of their gut microbiota. However, loss of IL-17A/F in TH cells did not diminish their encephalitogenic capacity. Reconstitution of a wild-type-like intestinal microbiota or reintroduction of IL-17A specifically into the gut epithelium of IL-17A/F-deficient mice reestablished their susceptibility to EAE. Thus, our data demonstrated that IL-17A and IL-17F are not encephalitogenic mediators but rather modulators of intestinal homeostasis that indirectly alter CNS-directed autoimmunity.


Low Frequency of Intratumor Heterogeneity in Bladder Cancer Tissue Microarrays.
Intratumoral heterogeneity (ITH) is associated with clinical challenges such as possible differences in response to treatment and difficulties in classifying the tumor. Previously, ITH has been described in bladder cancer using detailed genetic analyses. However, in this disease, it is not known to what extent ITH actually occurs, or if it involves molecular subtyping, when assessment is achieved by immunohistochemistry (IHC) on the protein level using tissue microarrays (TMAs), the method most widely applied when analyzing large sample numbers. We aimed to investigate ITH by IHC in bladder cancer TMAs. Staining for eleven immunohistochemical markers (CK5, Cyclin D1, E-Cadherin, EGFR, FGFR, GATA3, HER2, p16, p63, P-Cadherin and RB1) was performed, and differences in staining patterns were assessed both within 1981 individual tissue-cores and by comparing two cores from the same tumor in 948 cases according to our pre-specified criteria. Presence of ITH was associated with clinicopathological data such as stage, grade, molecular subtype and survival. Intracore ITH in one or several markers was associated with grade 3, stage T1 and the genomically unstable molecular subtype. ITH in three or more markers was found in 5% between cores (intercore heterogeneity) and in 2% within cores (intracore heterogeneity). No association with survival was found for any of the ITH groups. We observed ITH in a small proportion of the tumors, suggesting that ITH has only a limited impact on TMA bladder cancer studies.


Economic and educational factors played roles in the development of regional vision impairment in Shandong province, China.
We analyze regional factors and spatial distribution of children's vision impairment in Shandong province, to explore the spatial changes brought by time and their influencing factors, so as to provide scientific basis for prevention of childhood vision impairment. This study covers five complete cross-sectional surveys from 2013 to 2017, involving about 29.24 million students. Spatial autocorrelation and hotspot analysis methods were used to analyze spatial features. The associated factors were analyzed by multinomial logistic regression. The vision impairment prevalence showed a trend of decreasing first and then increasing from 2013 to 2017, with slight changes. In terms of regional spatial differences, Weihai and Yantai have the highest VI rates in all years, and there was a large-scale spatial aggregation phenomenon. The southern low-value clusters, however, showed a trend of weakening from year to year. Further exploration revealed that economic factors and number of full-time teachers were verified as risk factors for regional vision impairment levels. The slight rebound of the prevalence of vision impairment and the high rate in the eastern and northern regions of Shandong province need more attention. It is suggested that relevant departments should focus on the influence of regional economic and educational factors when formulating relevant strategies.


The Western Australian family connections genealogical project: detection of familial occurrences of single gene and chromosomal disorders.
To investigate using a Western Australian (WA) genealogical database for the identification of single gene and chromosome disorders among families. Hospital admissions for single gene and chromosome disorders recorded during 2000-2006 were identified from the WA Hospital Morbidity Data System. The proportion of these conditions occurring in family groups was then identified using genealogical links created through the WA Family Connections Genealogical Project. There were 216 family clusters among 11,303 people who were recorded as having a genetic or chromosomal disorder on their hospital admission record. The most common single gene conditions found to occur in multiple family members included blood clotting disorders such as Factor VIII deficiency and Von Willebrand's disease, followed by cystic fibrosis, myotonic dystrophies, neurofibromatosis, tuberous sclerosis, and osteogenesis imperfecta. Single gene disorders most commonly occurring in multiple family members have been identified using the WA Family Connections Genealogical Project. These disorders reflect the most common single gene disorders requiring hospital admission, but which are not fatal before reproductive age and do not result in a loss of fertility. They are also restricted to disorders with earlier onset, as the WA Family Connections Genealogical Project currently covers 2-3 of the most recent generations. This study demonstrates the utility of record linkage genealogies to identify kindred with genetic disorders, offering a rich resource of information for focused genetic epidemiological research.


Carbohydrate availability affects growth and metabolism in peach fruit.
Along with sucrose, sorbitol represents the main photosynthetic product and form of translocated carbon in peach. This study aimed at determining whether peach fruit carbohydrate metabolism is affected by changes in source-sink balance, and specifically whether sorbitol or sucrose availability regulates fruit enzyme activities and growth. In various trials, different levels of assimilate availability to growing fruits were induced in vivo by varying crop load of entire trees, leaf : fruit ratio (L:F) of fruiting shoots, or by interrupting the phloem stream (girdling) to individual fruits. In vitro, fruit tissue was incubated in presence/absence of sorbitol and sucrose. Relative growth rate (RGR), enzyme activities and carbohydrates were measured at different fruit growth stages of various peach cultivars in different years. At stage III, high crop load induced higher acid invertase (AI, EC 188.8.131.52) activities and hexose : sucrose ratios. Both sorbitol and sucrose contents were proportional to L:F, while sorbitol dehydrogenase (SDH, EC 184.108.40.206) activity was the only enzyme activity directly related to L:F in both fruit growth stages. Girdling reduced fruit RGR and all major carbohydrates after 4 days and SDH activity already after 48 h, but it did not affect sucrose synthase (SS, EC 126.96.36.199), AI and neutral invertase (NI, EC 126.96.36.199). Fruit incubation in sorbitol for 24 h induced higher SDH activities than in buffer alone. In general, assimilate availability affected both sorbitol and sucrose metabolism in peach fruit, and sorbitol may function as a signal for modulating SDH activity. Under highly competitive conditions, AI activity may be enhanced by assimilate depletion, providing a mechanism to increase fruit sink strength by increasing hexose concentrations.


Antimicrobial efficacy of clindamycin and triple antibiotic paste as root canal medicaments on tubular infection: An in vitro study.
This study compared the antibacterial effect of 2% clindamycin and 2% and 100% concentration of triple antibiotic paste (TAP) on an Enterococcus faecalis biofilm. Dentinal tubules of 100 root specimens were infected and randomly assigned to five groups. A total of 1000 mg mL-1 of TAP, 20 mg mL-1 of TAP and clindamycin, calcium hydroxide or methylcellulose (control) were placed in the root canal for 1 week. After treatment, dentine shavings were collected from 200 and 400 μm dentine depth and the number of colony-forming units (CFU) per mg was determined. Reduction in viable bacteria in first three groups was significantly better than calcium hydroxide and control groups. However, the antimicrobial effectiveness among these three groups was not significantly different from each other. There was no significant difference between data at 200 and 400 μm in all groups except the Ca(OH)2 group. The antibiofilm effect of clindamycin was comparable with TAP, so it may be used instead of TAP.


Attributes of nuclear imaging centers impacting physician referrals for single-photon emission computed tomography myocardial perfusion imaging tests.
To evaluate nuclear imaging center attributes that cardiologists and primary care physicians (PCPs) consider when referring patients for single-photon emission computed tomography myocardial perfusion imaging (SPECT-MPI) tests, and how these attributes impact physician referral decisions in the United States. A targeted literature review and seven one-to-one interviews with physicians and imaging center directors were conducted to identify attributes that could impact physicians' referral decisions. The impact of the identified attributes was assessed via an online discrete choice survey among eligible PCPs and cardiologists randomly selected from a nationally representative panel, and quantified with an odds ratio (OR) scale estimated with a multivariable logistic regression. Nine two-level attributes were identified: ease of the referral process, waiting time for tests, insurance preauthorization assistance, time to receive results, conclusive test reports, patient satisfaction, a protocol for rapid conversion from an exercise to a pharmacological stress test, patient communication, and assistance with parking/wheelchair access. A total of 410 physicians, including 208 (50.7%) cardiologists and 202 (49.3%) PCPs completed the survey. Among all physicians, a protocol that allows for a rapid conversion from an exercise to a pharmacological stress test (OR = 2.9) and preauthorization assistance (OR = 2.6) were the most impactful attributes. Additionally, cardiologists preferred imaging centers that provide an easy referral process (OR = 2.7), while PCPs favored centers offering a conclusive test report (OR = 2.4). Some center features that might impact physician referral decision were not evaluated in this study, if they were not easily changeable from an imaging center's perspective. The availability of a protocol for rapid conversion from an exercise to a pharmacological stress test and preauthorization assistance had the most significant impact on physician referral decisions for SPECT-MPI. Additionally, cardiologists preferred centers providing an easy referral process, while PCPs favored those offering a concluding statement and actionable steps in test reports.


Nutrient intake from multivitamin/mineral supplements is similar among users from five ethnic groups: the Multiethnic Cohort Study.
A multivitamin/mineral supplement is the most widely used type of dietary supplement among American adults. Therefore, accurate assessment of intake from this supplement is crucial when studying diet and chronic diseases. From 1999 to 2001, the Multiethnic Cohort Study collected detailed information on multivitamin/mineral use among five ethnic groups: African Americans, Native Hawaiians, Japanese Americans, Latinos, and whites. Daily nutrient intakes from multivitamin/minerals were calculated using the nutrient composition specified on the product label. For reported supplements with insufficient detail to match to a specific product, default nutrient profiles were assigned. Multivitamin/mineral use was reported by 50% of the participants (38% for Native Hawaiians to 57% for whites). Default profiles were assigned for 38% of users. The median daily nutrient intakes from multivitamin/minerals among users (n=75,865) were well above the Recommended Daily Allowance or Adequate Intake for vitamins A, B-6, B-12, and E, thiamin, riboflavin, niacin, pantothenic acid, folate, and zinc. Although nutrient intakes from multivitamin/minerals varied widely among individuals, there was no substantial difference in the median intake across ethnic groups. To accurately estimate nutrient intakes from multivitamin/minerals, detailed information on the product consumed should be collected. When detailed information is not available, the same default nutrient profiles can be used when estimating intakes for these five ethnic groups.


[Edematous form of neurocysticercosis: report of 4 cases].
Four cases of the oedematous form of neurocysticercosis are reported. This form is relatively rare and characterized by symptoms of intracranial hypertension and severe bilateral papilledema. Focal convulsive disorders are common. CSF studies show positive reaction for cysticercosis and ventriculography, the presence of small, narrowed lateral ventricles. Treatment based on ACTH and dexamethasone revelead good evolution as far as intracranial hypertension is concerned, not requiring surgical decompression as used before.


Complementary and alternative medicine use by osteoporotic patients in Australia (CAMEO-A): a prospective study.
Complementary and alternative medicine (CAM) therapies have become increasingly popular and are used regularly by patients with osteoporosis in Australasia and worldwide. This study was done to determine the prevalence and patterns of use of CAM in an Australian osteoporosis clinic. This was a prospective, cross-sectional questionnaire-based study of 202 patients attending an academic osteoporosis clinic in Sydney, Australia. Subject had a mean age of 68.5 +/- 10.9 years, 79.7% were female, and 55.9% were born overseas. CAM use was reported by 104 patients (51.5%) using the standard and 62 patients (30.7%) using the stringent definition of CAM. The most frequent CAM were multivitamins (24.0%), acupuncture (19.2%), t'ai chi (14.4%), and yoga (12.5%). Seventy-three percent (73%) did not consult a physician before starting CAM and 23.1% stated that their treating specialists were unaware of CAM use. The most common reasons for using CAM were having a holistic approach (53.0%) and inadequate pain control (29.0%). CAM users were associated with Asian country of birth (23.1% versus 12.2%, p = 0.03), more frequent clinic visits over a 12-month period (1.8 versus 1.5 times, p = 0.03), and a trend for a worse lumbar spine T-score (-2.35 versus -2.20 SD, p = 0.05) and higher rates of university education (26.0% versus 14.3%, p = 0.05). It is estimated that $696 million is spent annually on CAM by patients with osteoporosis. Patients attending osteoporosis clinics frequently use CAM. Physicians may need to routinely inquire about a history of CAM use to ensure better screening for possible adverse clinical interactions.


Intraspecific competition between co-infecting parasite strains enhances host survival in African trypanosomes.
It is becoming increasingly clear that under natural conditions parasitic infections commonly consist of co-infections with multiple conspecific strains. Multiple-strain infections lead to intraspecific interactions and may have important ecological and evolutionary effects on both hosts and parasites. However, experimental evidence on intraspecific competition or facilitation in infections has been scarce because of the technical challenges of distinguishing and tracking individual co-infecting strains. To overcome this limitation, we engineered transgenic strains of the protozoan parasite Trypanosoma brucei, the causal agent of human African sleeping sickness. Different strains were transfected with fluorescence genes of different colors to make them visually distinguishable in order to investigate the effects of multiple-strain infections on parasite population dynamics and host fitness. We infected mice either with each strain alone or with mixes of two strains. Our results show a strong mutual competitive suppression of co-infecting T. brucei strains very early in infection. This mutual suppression changes within-host parasite dynamics and alleviates the effects of infection on the host. The strength of suppression depends on the density of the co-infecting strain, and differences in life-history traits between the strains determine the consequences of strain-strain competition for the host. Unexpectedly, co-infection with a less virulent strain significantly enhances host survival (+15%). Analysis of the strain dynamics reveals that this is due to the suppression of the density of the more virulent strain (-33%), whose degree of impact ultimately determines the physical condition of the host. The competitive suppression is likely caused by allelopathic interference or by apparent competition mediated by strain-specific immune responses. These findings highlight the importance of intraspecific variation for parasite-parasite and parasite-host interactions. To fully understand parasite and disease dynamics, the genetic diversity of infections must be taken into account. Through changes in parasite dynamics, intraspecific variation may further affect transmission dynamics and select for increased virulence of each strain. The precise mechanisms underlying mutual suppression are not yet understood but may be exploitable to fight this devastating parasite. Our results are therefore not only of basic ecological interest investigating an important form of intraspecific competition, but may also have applied relevance for public health.


Creating nurturing environments: a science-based framework for promoting child health and development within high-poverty neighborhoods.
Living in poverty and living in areas of concentrated poverty pose multiple risks for child development and for overall health and wellbeing. Poverty is a major risk factor for several mental, emotional, and behavioral disorders, as well as for other developmental challenges and physical health problems. In this paper, the Promise Neighborhoods Research Consortium describes a science-based framework for the promotion of child health and development within distressed high-poverty neighborhoods. We lay out a model of child and adolescent developmental outcomes and integrate knowledge of potent and malleable influences to define a comprehensive intervention framework to bring about a significant increase in the proportion of young people in high-poverty neighborhoods who will develop successfully. Based on a synthesis of research from diverse fields, we designed the Creating Nurturing Environments framework to guide community-wide efforts to improve child outcomes and reduce health and educational inequalities.


A self-retaining retractor for improved exposure of the infrarenal abdominal aorta.
A simple method of achieving better exposure of the infrarenal abdominal aorta during aortoiliac surgery is reported. Once the aorta is exposed, the peritoneum, retroperitoneal fat and the inferior vena cava are spread by an orthostatic retractor, of a Weilaner type, modified by the author, to meet this particular requirement.


Critically-ill COVID-19 patient.
Coronavirus disease 2019 (COVID-19) stands out as the major pandemic that we have experienced in the last century. As it affects every social structure, it brought the importance of intensive care support once again to the agenda of healthcare system after causing severe acute respiratory syndrome. The precautions to be taken against this virus, where our knowledge is extremely small, intensive care units take an indispensable place in pandemic planning. In this review, we aimed to emphasize the crucial points regarding intensive care management of COVID-19 patients, which we have written not only for intensivists but also for all healthcare professionals.


Reproductive timing and reliance on hoarded capital resources by lactating red squirrels.
Successful reproduction in a seasonal environment can be accomplished with resources that are stored before use ("capital resources") or resources that are used immediately ("income resources"). Research examining capital versus income resource usage during reproduction has primarily focused on assigning species to positions along a capital-income gradient. Here, we examine the causes and reproductive consequences of among and within-year variation in hoarded capital versus income resource usage by female North American red squirrels (Tamiasciurus hudsonicus) during mid-lactation in a highly seasonal environment. Among years, the proportion of feeding events that were on capital resources (PROPCAP) averaged 39 % during the yearly median mid-lactation periods, but ranged widely between 2 and 100 %. In years with earlier parturition dates, females primarily used hoarded capital resources during mid-lactation, whereas in years with later parturition dates, females primarily used income resources during mid-lactation. Within years, PROPCAP during mid-lactation tended to be greater in early-breeding females than in late-breeding females. Rates of water flux in females during mid-lactation provided further evidence that late-breeding females used more water-rich income resources. The proportion of litters that were partially or completely lost, and the litter mass that lactating females supported, was not influenced by the large among-year differences in hoarded capital resource usage. Red squirrels appear to delay reproduction following years with low cone production to time peak reproductive demands to be late enough to be supported by income resources that only become available later in the season. In conclusion, our results offer a rare example of the capacity of a food-hoarding mammal to support reproduction exploiting a wide range of capital and income resources.


[Revertants of recA-strains of Escherichia coli K-12].
The paper presents the results of a study of revertants of strains AB2463 recA13, AB2465 rec15, No 41 rec16. It is shown that revertants are characterized as intermediate strains between recA and rec+ (on the level of recB, recC strains) on their recombination proficiency in crosses with Hfr, sensitivity to UV and gamma-rays and in F-heterogenote formed cultures on their capacity of the formation of recombinants between episome and chromosome and the capacity to chromosome mobilization. In the same time revertants do not differ from rec+ in the frequency of spontaneous and UV-induction of prophage constitution of recombinants formed in crosses, and in the synthesis of beta-galactosidase in postconjugation period. It is found that the mutations studied are mapped apparently in recA gene.


Buckling-Based Non-Linear Mechanical Sensor.
Mechanical sensors provide core keys for high-end research in quantitative understanding of fundamental phenomena and practical applications such as the force or pressure sensor, accelerometer and gyroscope. In particular, in situ sensitive and reliable detection is essential for measurements of the mechanical vibration and displacement forces in inertial sensors or seismometers. However, enhancing sensitivity, reducing response time and equipping sensors with a measurement capability of bidirectional mechanical perturbations remains challenging. Here, we demonstrate the buckling cantilever-based non-linear dynamic mechanical sensor which addresses intrinsic limitations associated with high sensitivity, reliability and durability. The cantilever is attached on to a high-Q tuning fork and initially buckled by being pressed against a solid surface while a flexural stress is applied. Then, buckling instability occurs near the bifurcation region due to lateral movement, which allows high-sensitive detection of the lateral and perpendicular surface acoustic waves with bandwidth-limited temporal response of less than 1 ms.


Physical anthropology and the description of the 'savage' in the Brazilian Anthropological Exhibition of 1882.
This paper discusses attempts to popularize scientific knowledge about anthropology through exhibitions of natives in the United States and Brazil from the nineteenth century to the beginnings of the twentieth century. In the First Brazilian Anthropological Exposition (Rio de Janeiro, 1882), a group of Botocudos was characterized in a manner that can be related to the reification of the myth of the savage, an important part of the European culture that played a significant role in the construction of anthropological knowledge in the nineteenth century. From the analyses of such exhibitions, we derive implications for science popularization and education, concerning the ideological undertones of scientific knowledge.


The temporal Doppler effect: when the future feels closer than the past.
People routinely remember events that have passed and imagine those that are yet to come. The past and the future are sometimes psychologically close ("just around the corner") and other times psychologically distant ("ages away"). Four studies demonstrate a systematic asymmetry whereby future events are psychologically closer than past events of equivalent objective distance. When considering specific times (e.g., 1 year) or events (e.g., Valentine's Day), people consistently reported that the future was closer than the past. We suggest that this asymmetry arises because the subjective experience of movement through time (whereby future events approach and past events recede) is analogous to the physical experience of movement through space. Consistent with this hypothesis, experimentally reversing the metaphorical arrow of time (by having participants move backward through virtual space) completely eliminated the past-future asymmetry. We discuss how reducing psychological distance to the future may function to prepare people for upcoming action.


Efficacy of a typical clean-in-place protocol against in vitro membrane biofilms.
This study evaluates the effectiveness of a typical clean-in-place (CIP) protocol against in vitro biofilms on whey reverse osmosis (RO) membranes developed under static condition. Bacterial isolates obtained from RO membrane biofilms were used to develop single and multispecies biofilms under laboratory conditions. A typical commercial CIP protocol was tested against the 24-h-old biofilms, and included 6 sequential treatment steps based on alkali, surfactant, acid, enzyme, a second surfactant, and a sanitizer treatment step. Experiments were conducted in 4 replicates and the data were statistically analyzed. The results revealed a variation in the resistance of mixed-species biofilms against the individual steps in the sequential CIP protocol. The overall 6 steps protocol, although resulted in a greater reduction, also resulted in the detection of survivors even after the final sanitizer step, reflect the ineffectiveness of the CIP protocol for complete removal of biofilms. Posttreatment counts of 0.71 log after the sequential CIP of mixed-species biofilm revealed the resistance of biofilm constitutive microbiota. Mixed-species biofilms, constituting different genera including Bacillus, Staphylococcus, and Streptococcus, were observed to be more resistant than most of the single-species biofilms. However, among the single-species biofilms, significantly different resistance pattern was observed for Bacillus isolates compared with the other bacterial isolates. All 5 isolates of Bacillus were found resistant with survivor counts of more than 1.0 log against the sequential CIP protocol tested. Thus, it can be concluded that the tested CIP protocol had a limited effectiveness to clean membrane biofilms formed on the whey RO membranes.


Design, Synthesis, and Structure-Activity Relationship of New Pyrimidinamine Derivatives Containing an Aryloxy Pyridine Moiety.
The pyrimidinamine diflumetorim is an ideal template for the discovery of agrochemical lead compounds due to its unique mode of action, novel chemical structure, and lack of reported resistance. To develop a new pyrimidinamine fungicide effective against cucumber downy mildew (CDM), a series of new pyrimidinamine derivatives containing an aryloxy pyridine moiety were designed and synthesized by employing the recently reported intermediate derivatization method (IDM). The structures of all compounds were identified by 1H NMR, elemental analyses, HRMS, and X-ray diffraction. Bioassays demonstrated that some of the title compounds exhibited excellent fungicidal activities against CDM. Compound 9 gave the best activity (EC50 = 0.19 mg/L), which is significantly better than the commercial fungicides diflumetorim, flumorph, and cyazofamid. The relationship between structure and fungicidal activity of the synthesized pyrimidinamines was explored. The study showed that compound 9 is a promising fungicide candidate for further development.


Viral hepatocarcinogenesis: from infection to cancer.
Hepatocellular carcinoma (HCC) is a worldwide health issue that has started receiving attention but is still poorly understood. However, the hepatitis B virus (HBV) and the hepatitis C virus (HCV) are known to be two major causative agents of HCC. They differ in their modes of infection, their treatment options, their genomes and their carcinogenic abilities. However, both share a link with HCC through alterations of the host genome. In order to continue in our search for the mechanisms behind viral hepatocarcinogenesis, the individual entities (HBV, HCV, HCC and host), their natural history, treatment options and genomic properties must be further understood. Additionally, an understanding of the genomics, the link between the entities, is crucial for the success of the ongoing search for therapeutic options for HCC. Similar to most types of cancer, hepatocarcinogenesis is a multistep process involving different genetic alterations that ultimately lead to malignant transformation of the hepatocyte. As technology advances and research continues, the genetic changes and influences among these entities will prove essential to improved diagnostic and therapeutic options. It remains a challenge to provide a clear picture of the connection between virus and cancer. We review (i) the epidemiological link between HBV/HCV infection to HCC; (ii) prevention and control of chronic hepatitis B or C in reducing HCC risk; and (iii) genetic characters of viruses and hosts and the mechanisms associated with HCC susceptibilities, with the intention of providing a direction for future research and treatment.


Reflexive reaction to feelings predicts failed smoking cessation better than does lack of general self-control.
Many treatment-seeking smokers have difficulty quitting and maintaining abstinence. Trait impulsivity versus self-control is relevant to this problem. However, impulsivity is a multifaceted construct, and different measures emphasize different parts of it. This study compared 2 self-report measures of self-control versus impulsiveness as predictors of smoking cessation. One measure taps a very specific tendency to respond impulsively when experiencing emotions. The other taps overall self-control without reference to emotional states. Adult smokers (N = 116) recruited from the community participated in a group-based smoking cessation intervention. The sample was racially/ethnically diverse, mostly male, middle aged, single, low income, and moderately nicotine dependent. Self-reports on scales titled Reflexive reaction to feelings and Self-control were completed at entry. Seven-day point prevalence abstinence (ppa) was assessed at end-of-therapy (EOT) and at 3- and 6-month follow-ups. A generalized estimating equation (GEE) tested overall relationships of the self-report scales with 7-day ppa across the assessments. Bivariate analyses revealed inverse associations between Reflexive reaction to feelings and 7-day ppa; a positive association emerged between Self-control and 7-day ppa only at EOT. A GEE found that elevated scores on Reflexive reaction to feelings predicted failure in smoking cessation across the study period (adjusted odds ratio [AOR] = 0.69 [0.49-0.96], p = .03) and that Self-control scores did not do so significantly (AOR = 1.26 [0.80-1.99], p = .32). Results add to a literature suggesting the importance of emotion-related impulsivity to behavioral problems by showing its relevance to smoking cessation in treatment-seekers. (PsycINFO Database Record


Geometric and electronic structures of multiple-decker one-end open sandwich clusters: Eu(n)(C8H8)n- (n = 1-4).
We have measured the photoelectron spectra of the multiple-decker 1:1 sandwich clusters of Eu(n)(COT)n- (n = 1-4; COT = 1,3,5,7-cyclooctatetraene), synthesized in the gas phase, and studied theoretically the bonding scheme, charge distribution, valence orbital energies, and photodetachment energies. We calculated the ground electronic state X- and the first excited electronic state A-, both of which have strong ionic bonding and a characteristic charge distribution. Moreover, we found that the valence orbital energies of Eu (6s) and COT (L delta) depend strongly on cluster size and their positions in the clusters. With the calculated vertical detachment energies for these valence orbitals, we assigned the peaks in the experimental photoelectron spectra and analyzed the origin of their interesting behavior by employing simple point charge models. From these analyses, it became clear that the characteristic behavior of the spectra is due to the strong ionic bonding and the charge distribution. In addition, using the point charge models, we estimated the vertical detachment energies of the one-dimensional polymer [Eu(COT)]infinity-.


Characterization of the maintenance functions of IncFIV plasmid R124.
The genetic arrangement of the regions involved in R124 replication and incompatibility have been located and their homology to the IncFI basic replicons has been assessed. We show that R124 has homology with all three basic replicons, RepFIA, RepFIB, and RepFIC, and that these regions, FIVA, RepFIVB, and RepFIVC, are widely separated on the R124 genome. Cloning of autonomously replicating fragments has shown that RepFIVB and RepFIVC are functional in R124 and express incompatibility. The FIVA region was unable to form a functional replicon and when cloned into pUC8 lacked incompatibility activity. A fourth region of R124 was identified, which although not essential for replication stabilized mini-R124 plasmid replication and exhibited incompatibility with R124. This region, designated IncIV, showed no homology to RepFIA, RepFIB, or RepFIC. Incompatibility expression of IncIV required only the EcoRI fragment E13 but the strength of the reaction was modified in the presence of other fragments. The replication and incompatibility properties of an R124 deletion derivative indicated that R124 can switch its replication to either RepFIVB or RepFIVC when in the presence of an incompatible plasmid. The ambiguous incompatibility reactions reported for R124 is a result of the expression of the two functional replicons, RepFIVB and RepFIVC, and that expressed by IncIV.


An alternative approach for the induction of premature chromosome condensation in human peripheral blood lymphocytes using mitotic Akodon cells.
Purpose: The premature chromosome condensation (PCC) technique is used to study exposure to external radiation through the determination of chromosome fragments observed in interphase cells. The presence of large telomeric signals in CHO cells interferes with the detection of PCC fragments and the identification of dicentric chromosomes. We present an improved method for the fusion of G0-lymphocytes with mitotic Akodon cells (few chromosomes and weakly-staining telomeric sequences) to induce PCC in combination with rapid quantification of dicentric chromosomes and centric rings as an alternative to the classical CHO cell fusion technique.Materials and methods: Whole blood from three healthy volunteers was γ-irradiated with 0, 2, or 4 Gy. Following a 24 h incubation post-exposure at 37 °C, chromosome spreads of isolated lymphocytes were prepared by standard PCC procedures using mitotic Akodon cells.Results: The percentage of scorable fusions, measured by telomere/centromere (T/C) staining, for Akodon-induced PCC was higher than that for CHO-induced PCC, irrespective of radiation exposure. Importantly, both techniques gave the same result for biodosimetry evaluation.Conclusion: The mitotic Akodon cell-induced PCC fusion assay, in combination with the scoring of dicentric chromosomes and rings by T/C staining of G0-lymphocytes is a suitable alternative for fast and reliable dose estimation after accidental radiation exposure.


Eradication of Aujeszky's disease virus from a Swedish pig herd using gI-/TK-vaccine.
An attenuated glycoprotein I-negative (gI-)/thymidine kinase-negative (TK-) constructed vaccine was used to eradicate Aujeszky's disease virus from a large farrow-to-finish herd in Sweden. The herd had had problems every year for seven years and two attempts to eradicate the virus without vaccination had failed. At the start of the vaccination programme 86 per cent of the 396 breeding animals were seropositive to the virus. In spite of evidence of virus circulation in the fattening units, no fatteners were vaccinated. The breeding stock was vaccinated every four months and monitored serologically. Seropositive sows and boars were culled at an economic rate. During the programme, four breeding animals seroconverted to gI. Another seven animals which seroconverted to gI were suspected to have been infected shortly before the first test and vaccination. When all the seropositive breeding animals had been culled, the fattening units were sampled and no seropositive animals were found. The herd was declared gI-negative 39 months after the start of the programme. Monitoring of the herd for another four years, until all the vaccinated animals had been culled, showed that the herd remained free from Aujeszky's disease virus.


Modelling West Nile Virus and Usutu Virus Pathogenicity in Human Neural Stem Cells.
West Nile virus (WNV) and Usutu virus (USUV) are genetically related neurotropic mosquito-borne flaviviruses, which frequently co-circulate in nature. Despite USUV seeming to be less pathogenic for humans than WNV, the clinical manifestations induced by these two viruses often overlap and may evolve to produce severe neurological complications. The aim of this study was to investigate the effects of WNV and USUV infection on human induced pluripotent stem cell-derived neural stem cells (hNSCs), as a model of the neural progenitor cells in the developing fetal brain and in adult brain. Zika virus (ZIKV), a flavivirus with known tropism for NSCs, was used as the positive control. Infection of hNSCs and viral production, effects on cell viability, apoptosis, and innate antiviral responses were compared among viruses. WNV displayed the highest replication efficiency and cytopathic effects in hNSCs, followed by USUV and then ZIKV. In these cells, both WNV and USUV induced the overexpression of innate antiviral response genes at significantly higher levels than ZIKV. Expression of interferon type I, interleukin-1β and caspase-3 was significantly more elevated in WNV- than USUV-infected hNSCs, in agreement with the higher neuropathogenicity of WNV and the ability to inhibit the interferon response pathway.


SETBP1 overexpression acts in the place of class-defining mutations to drive FLT3-ITD-mutant AML.
Advances in cancer genomics have revealed genomic classes of acute myeloid leukemia (AML) characterized by class-defining mutations, such as chimeric fusion genes or in genes such as NPM1, MLL, and CEBPA. These class-defining mutations frequently synergize with internal tandem duplications in FLT3 (FLT3-ITDs) to drive leukemogenesis. However, ∼20% of FLT3-ITD-positive AMLs bare no class-defining mutations, and mechanisms of leukemic transformation in these cases are unknown. To identify pathways that drive FLT3-ITD mutant AML in the absence of class-defining mutations, we performed an insertional mutagenesis (IM) screening in Flt3-ITD mice, using Sleeping Beauty transposons. All mice developed acute leukemia (predominantly AML) after a median of 73 days. Analysis of transposon insertions in 38 samples from Flt3-ITD/IM leukemic mice identified recurrent integrations at 22 loci, including Setbp1 (20/38), Ets1 (11/38), Ash1l (8/38), Notch1 (8/38), Erg (7/38), and Runx1 (5/38). Insertions at Setbp1 led exclusively to AML and activated a transcriptional program similar, but not identical, to those of NPM1-mutant and MLL-rearranged AMLs. Guide RNA targeting of Setbp1 was highly detrimental to Flt3ITD/+/Setbp1IM+, but not to Flt3ITD/+/Npm1cA/+, AMLs. Also, analysis of RNA-sequencing data from hundreds of human AMLs revealed that SETBP1 expression is significantly higher in FLT3-ITD AMLs lacking class-defining mutations. These findings propose that SETBP1 overexpression collaborates with FLT3-ITD to drive a subtype of human AML. To identify genetic vulnerabilities of these AMLs, we performed genome-wide CRISPR-Cas9 screening in Flt3ITD/+/Setbp1IM+ AMLs and identified potential therapeutic targets, including Kdm1a, Brd3, Ezh2, and Hmgcr. Our study gives new insights into epigenetic pathways that can drive AMLs lacking class-defining mutations and proposes therapeutic approaches against such cases.


Aminoglutethimide as treatment of postmenopausal women with advanced breast carcinoma.
Hormone-dependent breast carcinomas respond to deprivation of biologically active estrogens with objectively quantifiable tumor regression. Aminoglutethimide, a known inhibitor of steroid synthesis, is also a potent blocker of the aromatase enzyme and, thus, of estrogen production. We developed an effective regimen to inhibit estrogen production in postmenopausal women using aminoglutethimide and replacement glucocorticoid. One hundred forty-seven women initially received aminoglutethimide and replacement glucocorticoid as treatment of metastatic breast carcinoma. One hundred twenty-nine women are currently evaluable for assessment of clinical and hormonal responses. Thirty-seven percent of unselected women and 49% of estrogen receptor-positive patients experienced objective tumor regression. Responses occurred predominantly in soft tissue (47%) and bone (35%) and lasted 30 +/- 9.1 months for complete and 14 +/- 1.5 months for partial regressions. Plasma and urinary estrogen levels fell equally in responder versus nonresponder groups whereas androgen levels declined less in patients with progressive disease.


Comparison of interphase FISH and metaphase cytogenetics to study myelodysplastic syndrome: an Eastern Cooperative Oncology Group (ECOG) study.
Cytogenetic analysis can be important in determining the prognosis and diagnosis of a number of hematological disorders, including myelodysplastic syndromes (MDS). Here, we compared metaphase chromosomal analyses on bone marrow aspirates from MDS patients with interphase fluorescence in situ hybridization (FISH) using probes specific for chromosomes nos. 5, 7, 8, 11, 13 and 20. Forty-three patients enrolled in ECOG protocol E1996 for low risk MDS and five patients enrolled in ECOG protocol E3996 for high risk MDS were studied by both metaphase chromosomal analysis and interphase FISH. Excluding those with a clonal loss of the Y chromosome, an abnormal clone was detected by cytogenetic analysis in 18 of 48 samples (37.5%). In comparison, our FISH panel detected an abnormal clone in 17 of 48 samples (35.4%). Twenty-nine of 30 samples with apparently normal karyotypes, including those with a missing Y chromosome, were also normal by our FISH panel. One patient had an occult deletion of chromosome 11 that was detected by FISH. These results indicate that around 60% of patients with MDS do not have abnormalities that are detectable by either chromosomal or FISH studies. In addition, it appears that interphase FISH studies are nearly as sensitive as cytogenetic analyses and can be a useful tool in studying bone marrow aspirates where cytogenetic analysis is not possible.


A higher-order tensor vessel tractography for segmentation of vascular structures.
A new vascular structure segmentation method, which is based on a cylindrical flux-based higher order tensor (HOT), is presented. On a vessel structure, the HOT naturally models branching points, which create challenges for vessel segmentation algorithms. In a general linear HOT model embedded in 3D, one has to work with an even order tensor due to an enforced antipodal-symmetry on the unit sphere. However, in scenarios such as in a bifurcation, the antipodally-symmetric tensor embedded in 3D will not be useful. In order to overcome that limitation, we embed the tensor in 4D and obtain a structure that can model asymmetric junction scenarios. During construction of a higher order tensor (e.g. third or fourth order) in 4D, the orientation vectors lie on the unit 3-sphere, in contrast to the unit 2-sphere in 3D tensor modeling. This 4D tensor is exploited in a seed-based vessel segmentation algorithm, where the principal directions of the 4D HOT is obtained by decomposition, and used in a HOT tractography approach. We demonstrate quantitative validation of the proposed algorithm on both synthetic complex tubular structures as well as real cerebral vasculature in Magnetic Resonance Angiography (MRA) datasets and coronary arteries from Computed Tomography Angiography (CTA) volumes.


The expression of human papillomavirus type 16 (HPV16 E7) induces cell cycle arrest and apoptosis in radiation and hypoxia resistant glioblastoma cells.
p53 is a widely known tumor-suppressor gene product that plays a key role in apoptotic cell death induced by DNA-damaging chemotherapeutic agents. Human glioma cells with functional p53 are known to be more resistant to γ-radiation. The aim of this study was to investigate whether the mutant glioblastoma cells (U87MG) transfected with human papilloma virus-type 16 E7 (HPV16 E7) genes were capable of increasing sensitivity towards irradiation and hypoxia-induced cell death. The pLXSN retroviral vector expressed HPV-16E7 genes and was infected into the p53 mutated U87MG cell line. A specific amplification band of HPV16 E7 genes was detected in E7 genes and transfected in the U87MG cell line using a reverse transcriptase polymerase chain reaction. The experimental groups included the mutant glioblastoma cell line (U87MG), empty vector (pLXSN) transfected to mutant glioblastoma cell line (U87MG-LXSN), and retrovirus carrying HPV16 E7 genes transfected to the mutant glioblastoma cell line (U87MG-E7). Hypoxic conditions were optimized using LDH assay and the subjects were exposed to hypoxia (16 and 20 h) and irradiation (9 h). Hoechst-propidium iodide (PI) staining results showed that hypoxia and irradiation increased the number of dead cells in the U87MG-E7 cells compared to U87MG and U87MG-LXSN cells. Results of the FACS analysis showed a similar pattern and recorded 80.44 and 58.94% of apoptotic cells in U87MG-E7 and U87MG cells, respectively. Cell cycle analysis by FACS revealed that, following irradiation and hypoxia, cells showed G2-M arrest. Additionally, the Western blot analysis results showed altered expression of E2F-1, Rb and p53 in the irradiation- and hypoxia-induced U87MG-E7 cells compared to U87MG and U87MG LXSN cells. In conclusion, the over-expression of HPV16 E7 genes in U87MG cell lines increasd cell apoptosis and E2F1 expression compared to the HPV non-infected U87MG cells following irradiation and hypoxia. These results indicate that tumor-specific therapies that increase sensitivity towards radiation and hypoxic conditions may be beneficial for suppression of cancers.


Japanese Cancer Association Meeting UICC International session--what is cost-effectiveness in cancer treatment?
The Japan National Committee for the Union for International Cancer Control (UICC) and UICC-Asia Regional Office (ARO) organized an international session as part of the official program of the 72nd Annual Meeting of the Japanese Cancer Association to discuss the topic "What is cost-effectiveness in cancer treatment? " Healthcare economics are an international concern and a key issue for the UICC. The presenters and participants discussed the question of how limited medical resources can be best used to support life, which is a question that applies to both developing and industrialized countries, given that cancer treatment is putting medical systems under increasing strain. The emergence of advanced yet hugely expensive drugs has prompted discussion on methodologies for Health Technology Assessment (HTA) that seek to quantify cost and effect. The session benefited from the participation of various stakeholders, including representatives of industry, government and academia and three speakers from the Republic of Korea, an Asian country where discussion on HTA methodologies is already advanced. In addition, the session was joined by a representative of National Institute for Health and Care Excellence (NICE) of the United Kingdom, which has pioneered the concept of cost-effectiveness in a medical context. The aim of the session was to advance and deepen understanding of the issue of cost-effectiveness as viewed from medical care systems in different regions.


Child's food consumption and physical exercise: Results from a Portuguese descriptive study.
To describe food consumption in Portuguese primary school children, to analyze the influence of food consumption on the body mass index (BMI), and to analyze the relationship between physical exercise and the child's food consumption. A quantitative, descriptive, exploratory, and cross-sectional study was conducted in 2 primary schools of the north of Portugal (n = 109 child). The use of a food register for 5 consecutive days and anthropometric evaluation of the children were used. The vast majority of children had a normal weight (65.10%). However, 34.90% of the children presented significant changes in their BMI (14.70% with low weight, 11.90% overweight, and 8.30% with obesity). Children who engage in physical activity drink more water and consume less sugary products. However, they also consume less meat, fish, and eggs than those who do not perform regular physical activity. The study highlights the emergence of new problems, such as the increasing prevalence of underweight children. The prevention of these problems, overweight, or underweight children, should be addressed among healthcare providers, local authorities, families, and teachers.


Tuning network topology and vibrational mode localization to achieve ultralow thermal conductivity in amorphous chalcogenides.
Amorphous chalcogenide alloys are key materials for data storage and energy scavenging applications due to their large non-linearities in optical and electrical properties as well as low vibrational thermal conductivities. Here, we report on a mechanism to suppress the thermal transport in a representative amorphous chalcogenide system, silicon telluride (SiTe), by nearly an order of magnitude via systematically tailoring the cross-linking network among the atoms. As such, we experimentally demonstrate that in fully dense amorphous SiTe the thermal conductivity can be reduced to as low as 0.10 ± 0.01 W m-1 K-1 for high tellurium content with a density nearly twice that of amorphous silicon. Using ab-initio simulations integrated with lattice dynamics, we attribute the ultralow thermal conductivity of SiTe to the suppressed contribution of extended modes of vibration, namely propagons and diffusons. This leads to a large shift in the mobility edge - a factor of five - towards lower frequency and localization of nearly 42% of the modes. This localization is the result of reductions in coordination number and a transition from over-constrained to under-constrained atomic network.


Prediction of right ventricular failure after ventricular assist device implant: systematic review and meta-analysis of observational studies.
Right ventricular failure (RVF) after left ventricular assist device (LVAD) implantation is associated with increased morbidity and mortality, but the identification of LVAD candidates at risk for RVF remains challenging. We undertook a systematic review and meta-analysis of observational studies of risk factors associated with RVF after LVAD implant. Thirty-six studies published between 1 January 1995 and 30 April 2015, comprising 995 RVF patients out of a pooled final population of 4428 patients, were identified. Meta-analysed prevalence of post-LVAD RVF was 35%. A need for mechanical ventilation [odds ratio (OR) 2.99], or continuous renal replacement therapy (CRRT; OR 4.61, area under the curve 0.78, specificity 0.91) were the clinical variables with the highest effect size (ES) in predicting RVF. International normalized ratio [INR; standardized mean difference (SMD) 0.49] and N-terminal pro-brain natriuretic peptide (NT-proBNP) (SMD 0.52) were the biochemical markers that best discriminated between RVF and No-RVF populations, though NT-proBNP was highly heterogeneous. Right ventricular stroke work index (RVSWI) and central venous pressure (CVP) (SMD -0.58 and 0.47, respectively) were the haemodynamic measures with the highest ES in identifying patients at risk of post-LVAD RVF; CVP was particularly useful in risk stratifying patients undergoing continuous-flow LVAD implant (SMD 0.59, P < 0.001, I2 = 20.9%). Finally, pre-implant moderate to severe right ventricular (RV) dysfunction, as assessed qualitatively (OR 2.82), or a greater RV/LV diameter ratio (SMD 0.51) were the standard echocardiographic measurements with the highest ES in comparing RVF with No-RVF patients. Longitudinal systolic strain of the RV free wall had the highest ES (SMD 0.73) but also the greatest heterogeneity (I2 = 74%) and was thus only marginally significant (P = 0.05). Patients on ventilatory support or CRRT are at high risk for post-LVAD RVF, similarly to patients with slightly increased INR, high NT-proBNP or leukocytosis. High CVP, low RVSWI, an enlarged right ventricle with concomitant low RV strain also identify patients at higher risk.


Theoretical studies on photo-induced cycloaddition and (6-4) reactions of the thymidine:4-thiothymidine dimer in a DNA duplex.
Thio-substituted nucleobases have received long-standing interest from experimental and theoretical scientists due to their potential applications in photodynamic therapy and crosslinking studies. Though the thymidine:4-thiothymidine dimer is an important structure in the DNA duplex, the molecular-level photoreaction mechanisms are still obscure. Herein, high-level QM/MM methods were adopted to investigate the photoinduced cycloaddition and (6-4) reactions of the thymidine:4-thiothymidine dimer in the DNA duplex, namely, d(ACCT(4ST)CGC:TGGAAGCG). Based on the calculated results, we identified five efficient nonadiabatic decay pathways to populate the T1 state from the initially occupied S2 state of Tp4ST via two crucial intersection structures, i.e., S2/S1 and S2/T2/S1/T1. Such photophysical processes are mainly localized on the 4-thiothymidine chromophore. After hopping to the T1 state, the light-induced [2+2] cycloaddition reaction could take place via a stepwise and nonadiabatic reaction pathway, which starts from Tp4ST via T1cc or T1cs intermediates in the T1 state and ends up with S5-thietane in the S0 state. By contrast, the concerted and thermal cycloaddition pathway in the ground state has a remarkable energy barrier, which is mechanistically less important. The subsequent generation of S5-(6-4) from S5-thietane is a concerted process in the S0 state with the simultaneous fission of the C4-S8 bond and the formation of the S8-H9 bond. In the end, we believe our present work will provide important mechanistic insights into photo-isomerization of thio-substituted nucleobases in DNA duplexes.


Investigating the impact of disease and health record duration on the eMERGE algorithm for rheumatoid arthritis.
The study sought to determine the dependence of the Electronic Medical Records and Genomics (eMERGE) rheumatoid arthritis (RA) algorithm on both RA and electronic health record (EHR) duration. Using a population-based cohort from the Mayo Clinic Biobank, we identified 497 patients with at least 1 RA diagnosis code. RA case status was manually determined using validated criteria for RA. RA duration was defined as time from first RA code to the index date of biobank enrollment. To simulate EHR duration, various years of EHR lookback were applied, starting at the index date and going backward. Model performance was determined by sensitivity, specificity, positive predictive value, negative predictive value, and area under the curve (AUC). The eMERGE algorithm performed well in this cohort, with overall sensitivity 53%, specificity 99%, positive predictive value 97%, negative predictive value 74%, and AUC 76%. Among patients with RA duration <2 years, sensitivity and AUC were only 9% and 54%, respectively, but increased to 71% and 85% among patients with RA duration >10 years. Longer EHR lookback also improved model performance up to a threshold of 10 years, in which sensitivity reached 52% and AUC 75%. However, optimal EHR lookback varied by RA duration; an EHR lookback of 3 years was best able to identify recently diagnosed RA cases. eMERGE algorithm performance improves with longer RA duration as well as EHR duration up to 10 years, though shorter EHR lookback can improve identification of recently diagnosed RA cases.


Post-Effort Changes in Activity of Traditional Diagnostic Enzymatic Markers in Football Players' Blood.
Long-term and intensive physical effort causes metabolic and biochemical adaptations for both athletic and non-athletic objectives. Knowing the importance of aerobic training in football players, the aim of this study was to evaluate changes in the activity of: creatinine kinase (CK), creatine kinase MB (CKMB), lactate dehydrogenase (LDH), α-hydroxybutyrate dehydrogenase (HBDH), cholinesterase (ChE) and alkaline phosphatase (ALP) in response to a semi-long distance outdoor run under aerobic conditions among both female and male football players. Sixteen participants aged 21.9±2 years (women) and 18.4±0.5 years (men), all of them voluntarily recruited football players, took part in an outdoor run, the women covering a distance of 7.4±0.3 km while men covered a distance of 10.7±1.0 km. Plasma activities of the studied enzymes were determined using an appropriate diagnostic assay kit. Our results indicate that total LDH activity could be a useful tool in evaluating physical fitness among athletes. We simultaneously established that ChE could not be a marker useful in assessing metabolic response to physical effort in athletes. Moreover, our results suggest that post-effort changes in ALP activity might be used to estimate early symptoms of certain vitamin deficiencies in an athlete's diet. We confirmed that the assessment of activity of selected traditional diagnostic enzymatic markers provides information about muscle state after physical effort.


Guided or self-guided internet-based cognitive-behavioural therapy (iCBT) for depression? Study protocol of an individual participant data network meta-analysis.
Although guided forms of internet-based cognitive-behavioural therapy (iCBT) result in a substantial reduction in depression, it seems that the most scalable way to deliver iCBT is without guidance. However, direct evidence on the comparison between guided and self-guided iCBT is scarce. Moreover, it is unclear which types of patients may benefit more from each of these two forms of iCBT. Network meta-analysis (NMA) using individual participant data (IPD) offers a way to assess the relative efficacy of multiple (>2) interventions. Moreover, it maximises our power to detect patient-level characteristics (covariates) that have an important effect on the efficacy of interventions. This protocol describes the procedures of an IPD-NMA, which aims at examining the relative efficacy of guided compared with self-guided iCBT and at identifying predictors and moderators of treatment outcome. We will use an existing database on psychotherapies for adult depression to identify eligible studies. This database has been updated up to 1 January 2018, through literature searches in PubMed, Embase, PsycINFO and Cochrane Library. The outcome of this IPD-NMA is reduction in depressive symptoms severity. We will fit the model in a Bayesian setting. After fitting the model, we will report the relative treatment effects for different types of patients, and we will discuss the clinical implications of our findings. Based on the results from the IPD-NMA model, we will develop and validate a personalised prediction model, aiming to provide patient-level predictions about the effects of the interventions. An ethical approval is not required for this study. The results will be published in a peer-review journal. These results will guide clinical decisions about the most efficient way to allocate iCBT resources, thereby increasing the scalability of this innovative therapeutic approach.


Implementation of Rao's one-sample polynomial growth curve model using SAS.
Longitudinal data are frequently treated with the classic analysis of variance and regression models. However, these models assume independence of observations. Hoel (1964) demonstrated that the use of least-squares methods on intercorrelated serial observations results in the rejection of the null hypothesis much too frequently. Although appropriate models for analyzing longitudinal data have been available for quite some time, they have remained inaccessible due to cumbersome matrix manipulations. We implement Rao's (1959) one-sample polynomial growth curve model using the programming capability and matrix language of SAS, which involves testing the goodness-of-fit and calculation of confidence bands for polynomial growth curves fit to data at equally spaced time points. Confidence intervals for the parameters themselves are also computed. The method and program (presented in the Appendix) are illustrated with examples involving mandibular ramus height in 12 young male rhesus monkeys. The data set, which spans a 4 year period (yearly observations), is fit adequately by a quadratic equation. The data spanning a 2 year period (half-year observations) are fit adequately by the linear equation. These examples illustrate the considerable widening of confidence bands that occurs when polynomial equations having more terms than are needed to meet the goodness-of-fit requirement are considered.


A double-blind trial of metoprolol in acute myocardial infarction. Effects on ventricular tachyarrhythmias.
During a double-blind trial in which patients with suspected myocardial infarction received metoprolol or placebo, we analyzed the occurrence of ventricular tachyarrhythmias. Metoprolol (15 mg intravenously) was given as soon as possible after admission, and thereafter 200 mg was given daily for three months. Antiarrhythmic drugs were given only for ventricular fibrillation and sustained ventricular tachycardia (greater than 60 beats per second). Definite acute myocardial infarction developed in 809 of the 1395 participants, and probable infarction in 162. Metoprolol did not influence the occurrence of premature ventricular contractions or short bursts of ventricular tachycardia. However, there were 17 cases of ventricular fibrillation in the placebo group (697 patients) and only 6 in the metoprolol group (698 patients, P less than 0.05). During the hospital stay significantly fewer patients receiving metoprolol (16) than placebo (38) (P less than 0.01) required lidocaine. In a separate analysis of 145 patients, metoprolol did not influence the occurrence of premature ventricular contractions or short bursts of ventricular tachycardia during the first 24 hours of treatment. Despite a lack of effect on less serious ventricular tachyarrhythmias, metoprolol had a prophylactic effect against ventricular fibrillation in acute myocardial infarction.


Visceral ischaemia and organ dysfunction after hybrid repair of complex thoraco-abdominal aneurysms.
The visceral hybrid repair of thoracoabdominal aneurysms (TAAAs) is a feasible and relatively safe alternative to traditional open repair in a cohort of patients at high surgical risk, averting the need for thoracotomy and supra-coeliac aortic cross clamping. The visceral ischaemia-reperfusion syndrome and organ dysfunction following visceral debranching is still unkown. This study investigates the relationship between visceral ischemia and multi system organ dysfunction. 18 consecutive patients undergoing elective, urgent and emergent hybrid repair of TAAAs between February 2005 and October 2007 were prospectively analyzed. Preoperative organ dysfunction and intraoperative risk factors (operating time, extent of the aneurysm, number of visceral vessels by passed) were assessed and compared with postoperative organ dysfunction (pulmonary, hepatic, renal, pancreatic and haematological disorders). Blood sampling for neutrophil CD 11b quantification was performed at baseline, on postoperative days 1, 3, 7 and before discharge. Perioperative Multi System Organ Dysfunction (MSOD) was diagnosed in 22.2% of patients (n = 4/18). Three of these patients died within 30 days (16.7%, n = 3/18). No relationship between preoperative organ dysfunction, blood loss, or operative time and postoperative organ dysfunction was observed. A significant correlation between the visceral retrograde revascularization and postoperative neutrophil expression in MSOD patients regardless of preoperative neutrophil baseline, TAAA extent and number of vessels by passed was present. Upregulation of neutrophils may be responsible for the higher incidence of MSOD and it may be an important marker predicting a severe multiple organ failure following visceral debranching in hybrid procedures.


Maternal depression and family adversity: Linked pathways to offspring depression?
There is conflicting evidence about the contribution of maternal depression and family adversity to depression experienced by offspring. Because maternal depression and family adversity are related, there is a need to determine how they independently contribute to offspring depression. Data are from a long-running prospective birth cohort study (Mater-University of Queensland Study of Pregnancy and its outcomes - MUSP). For this study some 2200 offspring were followed up at 30 years of age. We first examine the association between maternal depression and family adversity over the period from the pregnancy to the child reaching adulthood. Then we consider the extent to which maternal depression and family adversity trajectories over this period predict CIDI/DSM-IV episodes of depression in the offspring of these mothers at 30 years of age. We find a strong bi-directional association between maternal depression and family experiences of adverse life events over the entire period the child is at home. After adjustment, children reared in a family experiencing high levels of adverse life events are more likely to experience a lifetime ever DSM-IV diagnosis of depression, are more likely to have experienced multiple episodes of lifetime ever depression, and are more likely to report their first episode of depression was at a younger age. The findings suggest the association between maternal depression and offspring depression appears to be partly attributable to the higher levels of family adversity characteristic of depressed mothers.


FIRE: fractal indexing with robust extensions for image databases.
As already documented in the literature, fractal image encoding is a family of techniques that achieves a good compromise between compression and perceived quality by exploiting the self-similarities present in an image. Furthermore, because of its compactness and stability, the fractal approach can be used to produce a unique signature, thus obtaining a practical image indexing system. Since fractal-based indexing systems are able to deal with the images in compressed form, they are suitable for use with large databases. We propose a system called FIRE, which is then proven to be invariant under three classes of pixel intensity transformations and under geometrical isometries such as rotations by multiples of /spl pi//2 and reflections. This property makes the system robust with respect to a large class of image transformations that can happen in practical applications: the images can be retrieved even in the presence of illumination and/or color alterations. Additionally, the experimental results show the effectiveness of FIRE in terms of both compression and retrieval accuracy.


Watching diagnoses develop: Eye movements reveal symptom processing during diagnostic reasoning.
Finding a probable explanation for observed symptoms is a highly complex task that draws on information retrieval from memory. Recent research suggests that observed symptoms are interpreted in a way that maximizes coherence for a single likely explanation. This becomes particularly clear if symptom sequences support more than one explanation. However, there are no existing process data available that allow coherence maximization to be traced in ambiguous diagnostic situations, where critical information has to be retrieved from memory. In this experiment, we applied memory indexing, an eye-tracking method that affords rich time-course information concerning memory-based cognitive processing during higher order thinking, to reveal symptom processing and the preferred interpretation of symptom sequences. Participants first learned information about causes and symptoms presented in spatial frames. Gaze allocation to emptied spatial frames during symptom processing and during the diagnostic response reflected the subjective status of hypotheses held in memory and the preferred interpretation of ambiguous symptoms. Memory indexing traced how the diagnostic decision developed and revealed instances of hypothesis change and biases in symptom processing. Memory indexing thus provided direct online evidence for coherence maximization in processing ambiguous information.


Characterization and engineering of a two-enzyme system for plastics depolymerization.
Plastics pollution represents a global environmental crisis. In response, microbes are evolving the capacity to utilize synthetic polymers as carbon and energy sources. Recently, Ideonella sakaiensis was reported to secrete a two-enzyme system to deconstruct polyethylene terephthalate (PET) to its constituent monomers. Specifically, the I. sakaiensis PETase depolymerizes PET, liberating soluble products, including mono(2-hydroxyethyl) terephthalate (MHET), which is cleaved to terephthalic acid and ethylene glycol by MHETase. Here, we report a 1.6 Å resolution MHETase structure, illustrating that the MHETase core domain is similar to PETase, capped by a lid domain. Simulations of the catalytic itinerary predict that MHETase follows the canonical two-step serine hydrolase mechanism. Bioinformatics analysis suggests that MHETase evolved from ferulic acid esterases, and two homologous enzymes are shown to exhibit MHET turnover. Analysis of the two homologous enzymes and the MHETase S131G mutant demonstrates the importance of this residue for accommodation of MHET in the active site. We also demonstrate that the MHETase lid is crucial for hydrolysis of MHET and, furthermore, that MHETase does not turnover mono(2-hydroxyethyl)-furanoate or mono(2-hydroxyethyl)-isophthalate. A highly synergistic relationship between PETase and MHETase was observed for the conversion of amorphous PET film to monomers across all nonzero MHETase concentrations tested. Finally, we compare the performance of MHETase:PETase chimeric proteins of varying linker lengths, which all exhibit improved PET and MHET turnover relative to the free enzymes. Together, these results offer insights into the two-enzyme PET depolymerization system and will inform future efforts in the biological deconstruction and upcycling of mixed plastics.


Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism.
Autism spectrum disorder (ASD) is a complex developmental syndrome of unknown etiology. Recent studies employing exome- and genome-wide sequencing have identified nine high-confidence ASD (hcASD) genes. Working from the hypothesis that ASD-associated mutations in these biologically pleiotropic genes will disrupt intersecting developmental processes to contribute to a common phenotype, we have attempted to identify time periods, brain regions, and cell types in which these genes converge. We have constructed coexpression networks based on the hcASD "seed" genes, leveraging a rich expression data set encompassing multiple human brain regions across human development and into adulthood. By assessing enrichment of an independent set of probable ASD (pASD) genes, derived from the same sequencing studies, we demonstrate a key point of convergence in midfetal layer 5/6 cortical projection neurons. This approach informs when, where, and in what cell types mutations in these specific genes may be productively studied to clarify ASD pathophysiology.


A phase II study of YM155, a novel small-molecule suppressor of survivin, in castration-resistant taxane-pretreated prostate cancer.
YM155, a small-molecule survivin suppressor, showed modest single-agent activity in a phase I study of heavily pretreated patients. This study was conducted to determine the activity of YM155 in patients with castration-resistant prostate cancer (CRPC) who received prior taxane therapy. Patients received 4.8 mg/m(2)/day of YM155 over 168-h continuous i.v. infusion every 3 weeks. Study end points included prostate-specific antigen (PSA) response, objective tumor response, safety, progression-free survival (PFS) and overall survival (OS). Thirty-five patients were enrolled. Two of 32 (6.2%) assessable patients had a PSA response and 2 additional patients had PSA decrements >50% but not confirmed. One of 16 (6.2%) patients also had a partial response per RECIST V1. Median PFS and OS were 3.1 and 11.2 months, respectively. The most common adverse events were fatigue (63%), nausea (40%), anorexia (31%), constipation (31%), fever (26%) and vomiting (26%). YM155 has modest activity in taxane-pretreated CRPC with 25% of patients having prolonged stable disease (≥18 weeks). The regimen appears to be well tolerated. Based on the mechanism of action and preclinical evidence of synergy with docetaxel (Taxotere), YM155 combined with docetaxel is being evaluated in patients with CRPC.