Temperature, larval diet, and density effects on development rate and survival of Aedes aegypti (Diptera: Culicidae).
Many environmental factors, biotic and abiotic interact to influence organismal development. Given the importance of Aedes aegypti as a vector of human pathogens including dengue and yellow fever, understanding the impact of environmental factors such as temperature, resource availability, and intraspecific competition during development is critical for population control purposes. Despite known associations between developmental traits and factors of diet and density, temperature has been considered the primary driver of development rate and survival. To determine the relative importance of these critical factors, wide gradients of conditions must be considered. We hypothesize that 1) diet and density, as well as temperature influence the variation in development rate and survival, 2) that these factors interact, and this interaction is also necessary to understand variation in developmental traits. Temperature, diet, density, and their two-way interactions are significant factors in explaining development rate variation of the larval stages of Ae. aegypti mosquitoes. These factors as well as two and three-way interactions are significantly associated with the development rate from hatch to emergence. Temperature, but not diet or density, significantly impacted juvenile mortality. Development time was heteroskedastic with the highest variation occurring at the extremes of diet and density conditions. All three factors significantly impacted survival curves of experimental larvae that died during development. Complex interactions may contribute to variation in development rate. To better predict variation in development rate and survival in Ae. aegypti, factors of resource availability and intraspecific density must be considered in addition, but never to the exclusion of temperature.


Relationship of lipoproteins to cardiovascular events: the AIM-HIGH Trial (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides and Impact on Global Health Outcomes).
This study sought to examine the relationship between niacin treatment, lipoproteins, and cardiovascular (CV) outcomes in this secondary analysis of the AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides and Impact on Global Health Outcomes) trial. During a 3-year follow-up in 3,414 patients with established CV disease and low high-density lipoprotein cholesterol (HDL-C) levels, combined niacin + low-density lipoprotein cholesterol (LDL-C)-lowering therapy did not reduce CV events compared with LDL-C-lowering therapy alone. Subjects taking simvastatin and/or ezetimibe were randomized to receive extended-release (ER) niacin 1,500 to 2,000 mg or minimal immediate-release niacin (≤ 150 mg) as placebo at bedtime. LDL-C levels in both groups were maintained from 40 to 80 mg/dl. Hazard ratios were estimated by using Cox proportional hazards models for relationships between lipoproteins and the composite endpoint of CV death, myocardial infarction, acute coronary syndrome, ischemic stroke, or symptom-driven revascularization. CV outcomes were not associated with ER niacin in any baseline lipoprotein tertile. In a subset of patients in both the highest triglyceride (≥ 198 mg/dl) and lowest HDL-C (<33 mg/dl) tertiles, ER niacin showed a trend toward benefit (hazard ratio: 0.74, p = 0.073). In-trial LDL-C levels, non-HDL-C levels, and the total cholesterol/HDL-C ratio were positively associated with CV events in the control group, but these relationships were absent in the ER niacin group. Baseline lipoprotein tertiles did not predict differential benefit or harm with ER niacin added to LDL-C-lowering therapy, but a small dyslipidemic subgroup may benefit. ER niacin attenuated expected relationships of lipoprotein risk factors with CV events, raising the possibility that nonlipoprotein actions of niacin could affect risk. (Niacin Plus Statin to Prevent Vascular Events [AIM-HIGH]; NCT00120289).


The clamshell osteotomy: a new technique to correct complex diaphyseal malunions.
The treatment of complex diaphyseal malunions is challenging, requiring extensive preoperative planning and precise operative technique. We have developed a simpler method to treat some of these deformities. Ten patients with complex diaphyseal malunions (including four femoral and six tibial malunions) underwent a clamshell osteotomy. The indications for surgery included pain at adjacent joints and deformity. After surgical exposure, the malunited segment was transected perpendicular to the normal diaphysis proximally and distally. The transected segment was again osteotomized along its long axis and was wedged open, similar to opening a clamshell. The proximal and distal segments of the diaphysis were then aligned with use of an intramedullary rod as an anatomic axis template and with use of the contralateral extremity as a length and rotation template. The patients were assessed clinically and radiographically at a mean of thirty-one months (range, six to fifty-two months) after the osteotomy. Complete angular correction was achieved in each case; the amount of correction ranged from 2 degrees to 20 degrees in the coronal plane, from 0 degrees to 32 degrees in the sagittal plane, and from 0 degrees to 25 degrees in the axial plane (rotation). Correction of length ranged from 0 to 5 cm, and limb length was restored to within 2 cm in all patients. All osteotomy sites were healed clinically by six months. While no deep infections occurred, superficial wound dehiscence occurred in two patients along the approach for the longitudinal portion of the osteotomy, emphasizing the importance of careful soft-tissue handling and patient selection. The clamshell osteotomy provides a useful way to correct many forms of diaphyseal malunion by realigning the anatomic axis of the long bone with use of a reamed intramedullary rod as a template. This technique provides an alternative that could decrease preoperative planning time and complexity as well as decrease the need for intraoperative osteotomy precision in a correctly chosen subset of patients with diaphyseal deformities.


Polymeric receptors for the recognition of folic acid and related compounds via substructure imprinting.
A range of 2-acrylamidopyridines, showing subtle differences in solution binding toward carboxylic acids, has been investigated as functional monomers in molecular imprinting. Imprinting of N-Z-L-glutamic acid with one such monomer is shown to be effective in the creation of a molecularly imprinted polymer (MIP) with recognition properties for its template and also for larger molecules containing glutamic acid residues. In comparison to a MIP prepared via a more "traditional" approach, the new polymeric receptors exhibit reduced nonspecific binding. The new receptors are compared with previously reported urea-based receptors targeting the glutamic acid residue and receptors targeting the pteridine substructure of folic acid.


Countries' response to WHO's travel recommendations during the 2013-2016 Ebola outbreak.
To determine how, during the 2013-2016 Ebola outbreak in western Africa, States Parties to the World Health Organization's (WHO) 2005 International Health Regulations (IHR) followed the IHR's international travel recommendations. In 2015, we used the Google search engine to investigate the 196 States Parties to the 2005 IHR. Information detailing Ebola-related travel regulations or restrictions of each State Party was sourced first from official government websites and then from travel and news websites. When limited, conflicting or no relevant information was found on a government website, an email inquiry was sent to a corresponding embassy in an Anglophone country. We collected relevant and non-conflicting data for each of 187 States Parties. Of these, 43 (23.0%) prohibited the entry of foreigners who had recently visited a country with widespread Ebola transmission and another 15 (8.0%) imposed other substantial restrictions on such travellers: the requirement to produce a medical certificate documenting no infection with Ebola (n = 8), mandatory quarantine (n = 6) or other restrictions (n = 1). In responding to the 2013-2016 Ebola outbreak, countries had variable levels of adoption of the 2005 IHR's international travel recommendations. We identified 58 (31.0%) States Parties that exceeded or disregarded the recommendations. There is a need for more research to understand and minimize deviations from such recommendations.


SDH mutations in cancer.
The SDHA, SDHB, SDHC, SDHD genes encode the four subunits of succinate dehydrogenase (SDH; mitochondrial complex II), a mitochondrial enzyme involved in two essential energy-producing metabolic processes of the cell, the Krebs cycle and the electron transport chain. Germline loss-of-function mutations in any of the SDH genes or assembly factor (SDHAF2) cause hereditary paraganglioma/phaeochromocytoma syndrome (HPGL/PCC) through a mechanism which is largely unknown. Owing to the central function of SDH in cellular energy metabolism it is important to understand its role in tumor suppression. Here is reported an overview of genetics, clinical and molecular progress recently performed in understanding the basis of HPGL/PCC tumorigenesis.


Plastids unleashed: their development and their integration in plant development.
Derived by endosymbiosis from ancestral cyanobacteria, chloroplasts integrated seamlessly into the biology of their host cell. That integration involved a massive transfer of genes to the cell's nucleus, with the modification of pre-existing processes, like plastid division and the operation of the plastid genetic machinery and the emergence of new ones, like the import of proteins translated in the cytoplasm. The uncovering in molecular detail of several of these processes reveals a merger of mechanisms of symbiont and host origin. Chloroplasts acquired roles as part of the biology of land plants by differentiating into a variety of interconvertible plastid forms according to the cell type. How these conversions take place, or how new problems, like the regulation of the plastid population size in cells, have been solved, is barely starting to be understood. Like the whole plant and as a result of the requirements and dangers associated with photosynthetic activity, chloroplasts in particular are under the control of environmental cues. Far from being passive targets of cellular processes, plastids are sources of signals of plastid-nuclear communication, which regulate activities for their own biogenesis. Plastids are also sources of developmental signals, in whose absence tissue architecture or cell differentiation are aberrant, in a cell-autonomous fashion. Over evolutionary time, plastids also contributed many genes for activities that are no longer directly associated with them (like light perception or hormone function). The overall picture is one in which plastids are at both the receiving and the acting ends in plant development, in both ontogenic and evolutionary terms.


Self peptides isolated from MHC glycoproteins of non-obese diabetic mice.
The non-obese diabetic (NOD) mouse spontaneously develops an insulin-dependent diabetes mellitus that resembles human type I diabetes. This disease can be transferred by purified T cells or cloned T cell lines, implicating an autoimmune T cell attack on the pancreatic beta cells of the islets of Langerhans. As all T cell responses involve recognition of peptides bound to MHC molecules displayed at the cell surface, we have examined self peptides binding to the MHC molecules on spleen cells of the NOD mouse. Peptides eluted from the MHC class I molecule Kd have sequences that conform to known motifs for peptides binding this molecule in other strains of mice. The NOD mouse expresses the unique MHC class II molecule I-Ag7. Peptides eluted from I-Ag7 have sequences that implicate an acidic residue in the C terminus of the peptide as important for binding. The role of this residue in binding has been confirmed by direct peptide-binding analysis. This C-terminal acidic amino acid may interact with an arginine residue in the MHC class II alpha-chain that is exposed when beta-chain residue 57 is mutated to serine, or to the unique beta-chain residue histidine 56. These data may provide valuable insights into the nature of autoantigenic peptides presented by NOD mouse MHC molecules by defining the nature of I-Ag7-peptide binding.


Drosophila importin-7 functions upstream of the Elmo signaling module to mediate the formation and stability of muscle attachments.
Establishment and maintenance of stable muscle attachments is essential for coordinated body movement. Studies in Drosophila have pioneered a molecular understanding of the morphological events in the conserved process of muscle attachment formation, including myofiber migration, muscle-tendon signaling, and stable junctional adhesion between muscle cells and their corresponding target insertion sites. In both Drosophila and vertebrate models, integrin complexes play a key role in the biogenesis and stability of muscle attachments through the interactions of integrins with extracellular matrix (ECM) ligands. We show that Drosophila importin-7 (Dim7) is an upstream regulator of the conserved Elmo-Mbc→Rac signaling pathway in the formation of embryonic muscle attachment sites (MASs). Dim7 is encoded by the moleskin (msk) locus and was identified as an Elmo-interacting protein. Both Dim7 and Elmo localize to the ends of myofibers coincident with the timing of muscle-tendon attachment in late myogenesis. Phenotypic analysis of elmo mutants reveal muscle attachment defects similar to those previously described for integrin mutants. Furthermore, Elmo and Dim7 interact both biochemically and genetically in the developing musculature. The muscle detachment phenotype resulting from mutations in the msk locus can be rescued by components in the Elmo signaling pathway, including the Elmo-Mbc complex, an activated Elmo variant, or a constitutively active form of Rac. In larval muscles, the localization of Dim7 and activated Elmo to the sites of muscle attachment is attenuated upon RNAi knockdown of integrin heterodimer complex components. Our results show that integrins function as upstream signals to mediate Dim7-Elmo enrichment to the MASs.


Supplementation with progestogens in the first trimester of pregnancy to prevent miscarriage in women with unexplained recurrent miscarriage: a systematic review and meta-analysis of randomized, controlled trials.
To investigate whether treatment with progestogens in the first trimester of pregnancy would decrease the incidence of miscarriage in women with a history of unexplained recurrent miscarriage. Systematic review and meta-analysis. Not applicable. Women with a history of unexplained recurrent miscarriage. Randomized, controlled trials were identified by searching electronic databases. We included randomized, controlled trials comparing supplementation with progestogens (i.e., intervention group) in the first trimester of pregnancy with control (either placebo or no treatment) in women with a history of recurrent miscarriage. All types of progestogens, including natural P and synthetic progestins, were analyzed. The primary outcome was the incidence of miscarriage. The summary measures were reported as relative risk (RR) with 95% confidence interval (CI). Ten trials including 1,586 women with recurrent miscarriage were analyzed. Eight studies used placebo as control and were double-blind. Regarding the intervention, two RCTs used natural P, whereas the other eight studies used progestins: medroxyprogesterone, cyclopentylenol ether of progesterone, dydrogesterone, or 17-hydroxyprogesterone caproate. Pooled data from the 10 trials showed that women with a history of unexplained recurrent miscarriage who were randomized to the progestogens group in the first trimester and before 16 weeks had a lower risk of recurrent miscarriage (RR 0.72, 95% CI 0.53-0.97) and higher live birth rate (RR 1.07, 95% CI 1.02-1.15) compared with those who did not. No statistically significant differences were found in the other secondary outcomes, including preterm birth (RR 1.09, 95% CI 0.71-1.66), neonatal mortality (RR 1.80, 95% CI 0.44-7.34), and fetal genital abnormalities (RR 1.68, 95% CI 0.22-12.62). Our findings provide evidence that supplementation with progestogens may reduce the incidence of recurrent miscarriages and seem to be safe for the fetuses. Synthetic progestogens, including weekly IM 17-hydroxyprogesterone caproate, but not natural P, were associated with a lower risk of recurrent miscarriage. Given the limitations of the studies included in our meta-analysis, it is difficult to recommend route and dose of progestogen therapy. Further head-to-head trials of P types, dosing, and route of administration are required.


UGT2B17 minor histocompatibility mismatch and clinical outcome after HLA-identical sibling donor stem cell transplantation.
Minor histocompatibility Ags (mHags) have been implicated in the pathogenesis of GVHD after allogeneic hematopoietic stem cell transplantation (HSCT). Uridine diphospho-glucuronosyltransferase 2B17 (UGT2B17) gene deletion may act as a mHag and its association with acute GVHD (aGVHD) has been described. We retrospectively studied the clinical impact of a UGT2B17 mismatch in a cohort of 1127 patients receiving a HSCT from an HLA-identical sibling donor. UGT2B17 mismatch was present in 69 cases (6.1%). Incidence of severe aGVHD was higher in the UGT2B17 mismatched pairs (22.7% vs 14.6%), but this difference was not statistically significant (P: 0.098). We did not detect differences in chronic GVHD, overall survival, relapse-free survival, transplant-related mortality or relapse. Nevertheless, when we analyzed only those patients receiving grafts from a male donor (616 cases), aGVHD was significantly higher in the UGT2B17 mismatched group (25.1% vs 12.8%; P: 0.005) and this association was confirmed by the multivariate analysis (P: 0.043; hazard ratio: 2.16, 95% confidence interval: 1.03-4.57). Overall survival was worse for patients mismatched for UGT2B17 (P: 0.005). We conclude that UGT2B17 mismatch has a negative clinical impact in allogeneic HSCT from HLA-identical sibling donors only when a male donor is used. These results should be confirmed by other studies.


Prevalence, awareness, treatment and control of hypertension in four Middle East countries.
We report the prevalence, awareness, treatment, and control of hypertension across four Middle Eastern countries (Iran, Occupied Palestinian Territory, Saudi Arabia, and United Arab Emirates), using a standardized and uniform method. The Prospective Urban Rural Epidemiology study enrolled participants from 52 urban and 35 rural communities from four countries in the Middle East. We report results using definitions of hypertension, prevalence, awareness, treatment, and control, and the standards for uniform reporting of hypertension in adults as recently recommended by the World Hypertension League expert committee. Data for analyses were available on 10 516 participants, of whom 5082 (48%) were men. The mean age was 49 (±9.4) years for men and 48 (±9.3) years among women. A total of 3270 participants had hypertension (age-standardized rates, 33%), and n = 1807 (49%) of these participants were aware of their diagnosis. Of those with hypertension, n = 1754, (47%) were treated and only n = 673, (19%) had controlled blood pressure levels. Only 17% (n = 541) of those treated for hypertension received two or more blood pressure-lowering medications and 15% (n = 499) received statins. The prevalence, awareness, treatment, and control of blood pressure were higher among women and older (50-69 years) participants compared with men and younger individuals (30-49 years) (P < 0.0001 for all). The prevalence was higher in rural communities; however, awareness, treatment, and control were significantly higher among urban dwellers. Findings from this study indicate the need for improvements in hypertension diagnosis and treatment in the Middle East, especially in rural communities, men and younger individuals.


Waist circumference, abdominal obesity, and depression among overweight and obese U.S. adults: National Health and Nutrition Examination Survey 2005-2006.
Obesity is associated with an increased risk of mental illness; however, evidence linking body mass index (BMI)-a measure of overall obesity, to mental illness is inconsistent. The objective of this study was to examine the association of depressive symptoms with waist circumference or abdominal obesity among overweight and obese U.S. adults. A cross-sectional, nationally representative sample from the 2005-2006 National Health and Nutrition Examination Survey was used. We analyzed the data from 2,439 U.S. adults (1,325 men and 1,114 nonpregnant women) aged ≥ 20 years who were either overweight or obese with BMI of ≥ 25.0 kg/m2. Abdominal obesity was defined as waist circumference of > 102 cm for men and > 88 cm for women. Depressive symptoms (defined as having major depressive symptoms or moderate-to-severe depressive symptoms) were assessed by the Patient Health Questionnaire-9 diagnostic algorithm. The prevalence and the odds ratios (ORs) with 95% confidence intervals (CIs) for having major depressive symptoms and moderate-to-severe depressive symptoms were estimated using logistic regression analysis. After multivariate adjustment for demographics and lifestyle factors, waist circumference was significantly associated with both major depressive symptoms (OR: 1.03, 95% CI: 1.01-1.05) and moderate-to-severe depressive symptoms (OR: 1.02, 95% CI: 1.01-1.04), and adults with abdominal obesity were significantly more likely to have major depressive symptoms (OR: 2.18, 95% CI: 1.35-3.59) or have moderate-to-severe depressive symptoms (OR: 2.56, 95% CI: 1.34-4.90) than those without. These relationships persisted after further adjusting for coexistence of multiple chronic conditions and persisted in participants who were overweight (BMI: 25.0-< 30.0 kg/m2) when stratified analyses were conducted by BMI status. Among overweight and obese U.S. adults, waist circumference or abdominal obesity was significantly associated with increased likelihoods of having major depressive symptoms or moderate-to-severe depressive symptoms. Thus, mental health status should be monitored and evaluated in adults with abdominal obesity, particularly in those who are overweight.


The receptor for immunoglobulin E on rat basophilic leukemia cells: effect of ligand binding on receptor expression.
We have evaluated the effect of ligand binding on expression of the receptor for IgE on rat basophilic leukemia (RBL) cells. RBL cells were grown in the presence or absence of 131I-labeled IgE and sometimes were also surface labeled with 125I. We found that cells grown in the presence of IgE continued to accumulate receptors at the surface and thus the apparent amount of cell-associated IgE continued to increase. The results obtained suggest that, in the presence of IgE, the elimination of the receptor from the surface was halted or slowed significantly (approximately equal to 80%) while insertion into the membrane of previously synthesized receptor continued.


Association between genetic variants in VEGF, ERCC3 and occupational benzene haematotoxicity.
Benzene is an established human haematotoxin, with substantial interindividual variation in benzene-induced toxicity. To further examine if genetic variation contributes to benzene haematotoxicity, we analysed 1023 tagSNPs in 121 gene regions important for benzene metabolism, haematopoiesis, leukaemia and lymphoma among 250 workers exposed to benzene and 140 unexposed controls in a cross-sectional study carried out in China. Linear regression was used to analyse the relationship between genetic polymorphisms and total white blood cell (WBC) count and its subtypes, adjusting for potential confounders and occupational exposure to benzene and toluene among exposed workers. The minp test assessed the association on the gene region level. The false discovery rate method was used to control for multiple comparisons. VEGF (minp = 0.0030) and ERCC3 (minp = 0.0042) were the most significantly associated gene regions with altered WBC counts among benzene-exposed workers, after accounting for multiple comparisons. Highly significant changes were also found for WBC subtype counts, including granulocytes, CD4+ T cells and lymphocytes for VEGF and granulocytes and NK cells for ERCC3. Further, in workers exposed to <1 ppm, a SNP in VEGF was associated with changes in WBC and granulocyte counts, and SNPs in ERCC3 were associated with changes in WBC, NK cell and granulocyte counts. Our findings suggest that genetic variation in VEGF, which plays an important role in blood vessel growth, and ERCC3, which is a member of the DNA repair pathway and is responsible for repairing bulky DNA adducts formed by chemicals, may contribute to individual susceptibility to benzene-induced haematotoxicity at relatively low levels of benzene exposure.


The emerging role of d-2-hydroxyglutarate as an oncometabolite in hematolymphoid and central nervous system neoplasms.
Approximately 20% of unselected cases and 30% cytogenetically diploid cases of acute myeloid leukemia (AML) and 80% of grade II-III gliomas and secondary glioblastomas carry mutations in the isocitrate dehydrogenase (IDH) 1 and 2 genes. IDH1/2 mutations prevent oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG) and modulate the function of IDH (neomorphic activity) thereby facilitating reduction of α-KG to D-2-hydroxyglutarate (D-2HG), a putative oncometabolite. D-2HG is thought to act as a competitive inhibitor of α-KG-dependent dioxygenases that include prolyl hydroxylases and chromatin-modifying enzymes. The end result is a global increase of cellular DNA hypermethylation and alterations of the cellular epigenetic state, which has been proposed to play a role in the development of a variety of tumors. In this review, we provide an update on potential molecular mechanisms linking IDH1/2 mutations and the resulting oncometabolite, D-2HG, with malignant transformation. In addition, in patients with AML and glioma we focus on the associations between IDH1/2 mutations and clinical, morphologic, cytogenetic, and molecular characteristics.


Detection of formestane abuse by mass spectrometric techniques.
Formestane (4-hydroxy-androstenedione) is an aromatase inhibitor prohibited in sports and included, since 2004, in the list of prohibited substances updated yearly by the World Anti-Doping Agency (WADA). Since the endogenous production of formestane has been described, it is mandatory for the anti-doping laboratories to use isotope ratio mass spectrometry (IRMS) to establish the exogenous origin before issuing an adverse analytical finding. The described IRMS methods for formestane detection are time-consuming, requiring usually two consecutive liquid chromatographic sample purifications in order to have final extracts of adequate purity before the mass spectrometric analysis. After establishing a procedure for the determination of the origin of formestane by IRMS without the need of derivatization, and integrated in the overall analytical strategy of the laboratory for pseudo-endogenous steroids, a mass spectrometric analysis by gas chromatography-mass spectrometry (GC-MS) and gas chromatography-tandem mass spectrometry (GC-MS/MS) of formestane metabolites was carried out in order to investigate whether other biomarkers of formestane abuse could be integrated in order to avoid time-consuming and expensive IRMS confirmations for formestane. From the metabolic studies performed, the inclusion of 3β,4α-dihydroxy-5α-androstan-17-one (4α-hydroxy-epiandosterone) in the routine GC-MS procedures has demonstrated to be diagnostic in order to reduce the number of unnecessary confirmations of the endogenous origin of formestane.


Lung Cancer Susceptibility and hOGG1 Ser326Cys Polymorphism: A Meta-Analysis.
Recent lung cancer studies have focused on identifying the effects of single nucleotide polymorphisms (SNPs) in candidate genes, among which DNA repair genes are increasingly being studied. Genetic variations in DNA repair genes are thought to modulate DNA repair capacity and are suggested to be related to lung cancer risk. In this study, we tried to assess reported studies of association between polymorphism of human 8-oxoguanine DNA glycosylase 1 (hOGG1) Ser326Cys and lung cancer. We conducted MEDLINE, Current Contents and Web of Science searches using "hOGG1", "lung cancer" and "polymorphism" as keywords to search for papers published (from January 1995 through August 2010). Data were combined using both a fixed effects (the inverse variance-weighted method) and a random effects (DerSimonian and Laird method) model. The Cochran Q test was used for the assessment of heterogeneity. Publication bias was assessed by both Begg's and Egger's tests. We identified 20 case-control studies in 21 different ethnic populations. As two studies were not in the Hardy-Weinberg equilibrium, 18 case-control studies in 19 different ethnic populations (7,792 cases and 9,358 controls) were included in our meta-analysis. Summary frequencies of the Cys allele among aucasians and Asians based on the random effects model were 20.9% (95% confidence interval (CI) = 18.9-22.9) and 46.1% (95% CI = 40.2-52.0), respectively. The distribution of the Cys allele was significantly different between Asians and Caucasians (P < 0.001). The Cys/Cys genotype was significantly associated with lung cancer risk in Asian populations (odds ratio = 1.27, 95% CI = 1.09-1.48) but not in Caucasian populations. This ethnic difference in lung cancer risk may be due to environmental factors such as cigarette smoking and dietary factors. Although the summary risk for developing lung cancer may not be large, lung cancer is such a common malignancy that even a small increase in risk can translate to a large number of excess lung cancer cases. As lung cancer is a multifactorial disease, further investigations of the gene-gene and gene-environment interactions on the hOGG1 polymorphism-associated lung cancer risk may help to better understand of the molecular pathogenesis of human lung cancer.


Patient factors in the selection of operative versus nonoperative treatment for posterior tibial tendon dysfunction.
The influence of demographic, medical history, and treatment variables on the maintenance of nonoperative care or progression to operative intervention in Posterior Tibial Tendon Dysfunction (PTTD) was explored. This retrospective study compared demographic, medical history and treatment variables between operative and nonoperative care in subjects with PTTD. Charts with the ICD-9 codes (726.72, 726.90) and brace distribution records for 2005 and 2006 were used to identify subjects. From these, 166 of 606 charts included documentation of PTTD. Variables were grouped into three categories including demographics (Age, body mass index, gender and working status), medical (stage, symptom duration, pain at initial evaluation, and past treatments) and treatment (initial brace, length of care episode, and brace change). Statistical comparisons between subjects treated nonoperatively and operatively were made. Significant variables were entered into a logistic regression analysis. Accuracy (sensitivity/specificity) was assessed by examining the success of predicting which subjects were treated operatively or nonoperatively. Of the 166 subjects, 125 (75.4%) received nonoperative care and 41 (24.6%) operative care. Nine variables distinguished the operative from the nonoperative group (p<0.05): including BMI, work status, stage, symptom duration, prior orthotic use, prior injection, custom brace, brace changes, and length of care episode. The logistic regression model identified BMI, symptom duration, prior cortisone injections, and prior orthotic use as significant and resulted in a specificity of 95.4% and sensitivity of 38.2%. This retrospective analysis provides a patient profile of factors in the success of nonoperative care in PTTD.


Higher dietary magnesium intake is associated with lower body mass index, waist circumference and serum glucose in Mexican adults.
Obesity and diabetes mellitus (DM) are public health concerns in Mexico of top-level priority due to their high prevalence and their growth rate in recent decades. The accumulation of adipose tissue leads to an unbalanced release of pro-oxidant factors, which causes cellular damage and favors the development of comorbidities. Recent evidence suggests that oxidative stress also promotes the accumulation of adipose tissue and the development of insulin resistance. The objective of this study is to evaluate the association between usual intake of antioxidant nutrients, specifically vitamins A, C, E and magnesium with body mass index (BMI), waist circumference (WC) and serum glucose concentrations in a representative sample of Mexican adults. We analyzed data on diet, BMI, WC and serum glucose from the Mexican National Health and Nutrition Survey 2012. Analysis included 20- to 65-year-old adults without a known diagnosis of DM (n = 1573). Dietary information was obtained using the five-step multiple-pass method developed by the United States Department of Agriculture and adapted to the Mexican context. Nutrient usual intake distributions were estimated using the Iowa State University method, through the "Software for Intake Distribution Estimation" (PC-Side) v.1.02. Associations were analyzed using multivariate regression models. Higher dietary magnesium intake was associated with lower markers of adiposity, so that an increase in 10 mg per 1000 kcal/day of magnesium was associated with an average decrease in BMI of 0.72% (95% CI: -1.36, - 0.08) and 0.49 cm (95% CI: -0.92, - 0.07) of WC. Additionally, in women with normal glucose concentrations, an increase in magnesium intake was associated with an average decrease in serum glucose by 0.59% (95% CI: -1.08, - 0.09). The results suggest that magnesium intake is associated with lower BMI, WC and serum glucose in Mexican population. However, more studies are required to elucidate the nature of this association.


Towards better definition, quantification and treatment of fibrosis in heart failure. A scientific roadmap by the Committee of Translational Research of the Heart Failure Association (HFA) of the European Society of Cardiology.
Fibrosis is a pivotal player in heart failure development and progression. Measurements of (markers of) fibrosis in tissue and blood may help to diagnose and risk stratify patients with heart failure, and its treatment may be effective in preventing heart failure and its progression. A lack of pathophysiological insights and uniform definitions has hampered the research in fibrosis and heart failure. The Translational Research Committee of the Heart Failure Association discussed several aspects of fibrosis in their workshop. Early insidious perturbations such as subclinical hypertension or inflammation may trigger first fibrotic events, while more dramatic triggers such as myocardial infarction and myocarditis give rise to full blown scar formation and ongoing fibrosis in diseased hearts. Aging itself is also associated with a cardiac phenotype that includes fibrosis. Fibrosis is an extremely heterogeneous phenomenon, as several stages of the fibrotic process exist, each with different fibrosis subtypes and a different composition of various cells and proteins - resulting in a very complex pathophysiology. As a result, detection of fibrosis, e.g. using current cardiac imaging modalities or plasma biomarkers, will detect only specific subforms of fibrosis, but cannot capture all aspects of the complex fibrotic process. Furthermore, several anti-fibrotic therapies are under investigation, but such therapies generally target aspecific aspects of the fibrotic process and suffer from a lack of precision. This review discusses the mechanisms and the caveats and proposes a roadmap for future research.


Attention-deficit hyperactive disorder in school-aged children in Saudi Arabia.
The current study was designed to explore the prevalence of attention-deficit hyperactive disorder (ADHD) in primary schools in Saudi Arabia. The study collected data from both teachers and parents for 708 primary school pupils attending grades 1-3 (7-9 years old), using DSM-IV criteria of ADHD. The result showed that the overall rate of ADHD was 2.7%, and in particular, the rate of attention types, 2.0%; hyperactive/impulsivity type, 1.4% and combined type, 0.7%. Teachers reported ADHD in a higher frequency than parents. However, applying a combination of reports from teachers and parents, screening of ADHD is likely to be more accurate. These findings highlight the importance of detecting ADHD in pupils at an early age and to develop a specific set of psychological clinical interventions for helping them.


The hygiene hypothesis, the COVID pandemic, and consequences for the human microbiome.
The COVID-19 pandemic has the potential to affect the human microbiome in infected and uninfected individuals, having a substantial impact on human health over the long term. This pandemic intersects with a decades-long decline in microbial diversity and ancestral microbes due to hygiene, antibiotics, and urban living (the hygiene hypothesis). High-risk groups succumbing to COVID-19 include those with preexisting conditions, such as diabetes and obesity, which are also associated with microbiome abnormalities. Current pandemic control measures and practices will have broad, uneven, and potentially long-term effects for the human microbiome across the planet, given the implementation of physical separation, extensive hygiene, travel barriers, and other measures that influence overall microbial loss and inability for reinoculation. Although much remains uncertain or unknown about the virus and its consequences, implementing pandemic control practices could significantly affect the microbiome. In this Perspective, we explore many facets of COVID-19-induced societal changes and their possible effects on the microbiome, and discuss current and future challenges regarding the interplay between this pandemic and the microbiome. Recent recognition of the microbiome's influence on human health makes it critical to consider both how the microbiome, shaped by biosocial processes, affects susceptibility to the coronavirus and, conversely, how COVID-19 disease and prevention measures may affect the microbiome. This knowledge may prove key in prevention and treatment, and long-term biological and social outcomes of this pandemic.


Optimizing Tactical Medical Performance: The Effect of Light Hue on Vision Testing.
Red and blue are the historical tactical lighting hues of choice to ensure light discipline and to preserve dark adaptation. As yet, no scientifically ideal hue for use in Special Operations medicine has been identified. We propose red/green polychromatic light as a superior choice that preserves visual function for tactical medical tasks in austere settings. Thirty participants were enrolled in this institutional review board-approved study. Participants completed four vision tasks in low-light settings under various lighting conditions. The Pelli-Robson Near Contrast Sensitivity test (PR), tumbling E visual acuity test, Farnsworth D-15 color-vision test (FD15), and pseudoisochromatic plate (PiP) testing was performed under white, green, or red light illumination and also red/green and red/green/yellow lights. PR and tumbling E tests were performed using blue and blue/red lights. The test results for each light were compared against a white-light standard. Contrast sensitivity as measured by PR testing showed no statistical difference when white light was used compared with red/green or red/green/yellow light, and the differences between red, green, blue, and blue/red all were statistically different from when white light was used. When measuring visual acuity, blue light was the only color for which there was a statistically significant decrease in visual acuity in comparison with white. There was no reduction in visual acuity with any other lights compared with white. Performance on FD15 testing with all single-hue and multihue lights was significantly worse than with white light for measuring color-vision perception. Color discrimination as measured by PiP testing showed red and green light was significantly worse than with white light, whereas test results when green/red and green/red/yellow lights were used were not statistically different from white. Red/Green/yellow and red/green were superior light sources and performance results only were worse than white light on FD15 testing.


Early-Onset Sepsis Among Very Preterm Infants.
To determine the epidemiology and microbiology of early-onset sepsis (EOS) among very preterm infants using a nationally representative cohort from academic and community hospitals to inform empirical antibiotic guidance, highlight risk factors for infection, and aid in prognostication for infected infants. Prospective observational study of very preterm infants born weighing 401 to 1500 g or at 22 to 29 weeks' gestational age from January 2018 to December 2019 in 753 Vermont Oxford Network centers. EOS was defined as a culture-confirmed bacterial infection of the blood or cerebrospinal fluid in the 3 days after birth. Demographics, clinical characteristics, and outcomes were compared between infants with and without EOS. Of 84 333 included infants, 1139 had EOS for an incidence rate of 13.5 per 1000 very preterm births (99% confidence interval [CI] 12.5-14.6). Escherichia coli (538 of 1158; 46.5%) and group B Streptococcus (218 of 1158; 18.8%) were the most common pathogens. Infected infants had longer lengths of stay (median 92 vs 66 days) and lower rates of survival (67.5% vs 90.4%; adjusted risk ratio 0.82 [95% CI 0.79-0.85]) and of survival without morbidity (26.1% vs 59.4%; adjusted risk ratio 0.66 [95% CI 0.60-0.72]). In a nationally representative sample of very preterm infants with EOS from 2018 to 2019, approximately one-third of isolates were neither group B Streptococcus nor E coli. Three-quarters of all infected infants either died or survived with a major medical morbidity. The profoundly negative impact of EOS on very preterm infants highlights the need for novel preventive strategies.


Using sketch-map coordinates to analyze and bias molecular dynamics simulations.
When examining complex problems, such as the folding of proteins, coarse grained descriptions of the system drive our investigation and help us to rationalize the results. Oftentimes collective variables (CVs), derived through some chemical intuition about the process of interest, serve this purpose. Because finding these CVs is the most difficult part of any investigation, we recently developed a dimensionality reduction algorithm, sketch-map, that can be used to build a low-dimensional map of a phase space of high-dimensionality. In this paper we discuss how these machine-generated CVs can be used to accelerate the exploration of phase space and to reconstruct free-energy landscapes. To do so, we develop a formalism in which high-dimensional configurations are no longer represented by low-dimensional position vectors. Instead, for each configuration we calculate a probability distribution, which has a domain that encompasses the entirety of the low-dimensional space. To construct a biasing potential, we exploit an analogy with metadynamics and use the trajectory to adaptively construct a repulsive, history-dependent bias from the distributions that correspond to the previously visited configurations. This potential forces the system to explore more of phase space by making it desirable to adopt configurations whose distributions do not overlap with the bias. We apply this algorithm to a small model protein and succeed in reproducing the free-energy surface that we obtain from a parallel tempering calculation.


The use of cost-benefit analysis in road assessments: a methodological inquiry.
Cost-benefit analysis is a useful tool for priority setting in road safety. The value of statistical life (VOSL) is a metric used to estimate the benefits of road interventions in cost-benefit analyses. The International Road Assessment Program (iRAP), for example, created a rule-of-thumb to calculate VOSL benefits of road infrastructure when performing cost-benefit assessments in countries where data on VOSL are sparse. To evaluate the rapid assessment metric developed by iRAP and provide suggestions for improvement in these methods. We replicated iRAP calculations in order to make a critical assessment of the sources, results and conclusions. We found the iRAP metric a good example for highlighting some relevant aspects that should be considered in any VOSL estimation in order to enhance its use as a guiding principle for assessing road interventions. Specifically, we recommend the explicit disclosure of the assumptions, the use of sensitivity analysis and the avoidance of omitted variables bias.


Characteristics of utility cyclists in Queensland, Australia: an examination of the associations between individual, social, and environmental factors and utility cycling.
Initiatives to promote utility cycling in countries like Australia and the US, which have low rates of utility cycling, may be more effective if they first target recreational cyclists. This study aimed to describe patterns of utility cycling and examine its correlates, among cyclists in Queensland, Australia. An online survey was administered to adult members of a state-based cycling community and advocacy group (n=1813). The survey asked about demographic characteristics and cycling behavior, motivators and constraints. Utility cycling patterns were described, and logistic regression modeling was used to examine associations between utility cycling and other variables. Forty-seven percent of respondents reported utility cycling: most did so to commute (86%). Most journeys (83%) were >5 km. Being male, younger, employed full-time, or university-educated increased the likelihood of utility cycling (P<.05). Perceiving cycling to be a cheap or a convenient form of transport was associated with utility cycling (P<.05). The moderate rate of utility cycling among recreational cyclists highlights a potential to promote utility cycling among this group. To increase utility cycling, strategies should target female and older recreational cyclists and focus on making cycling a cheap and convenient mode of transport.


A Small Insulinomimetic Molecule Also Improves Insulin Sensitivity in Diabetic Mice.
Dramatic increase of diabetes over the globe is in tandem with the increase in insulin requirement. This is because destruction and dysfunction of pancreatic β-cells are of common occurrence in both Type1 diabetes and Type2 diabetes, and insulin injection becomes a compulsion. Because of several problems associated with insulin injection, orally active insulin mimetic compounds would be ideal substitute. Here we report a small molecule, a peroxyvanadate compound i.e. DmpzH[VO(O2)2(dmpz)], henceforth referred as dmp, which specifically binds to insulin receptor with considerable affinity (KD-1.17μM) thus activating insulin receptor tyrosine kinase and its downstream signaling molecules resulting increased uptake of [14C] 2 Deoxy-glucose. Oral administration of dmp to streptozotocin treated BALB/c mice lowers blood glucose level and markedly stimulates glucose and fatty acid uptake by skeletal muscle and adipose tissue respectively. In db/db mice, it greatly improves insulin sensitivity through excess expression of PPARγ and its target genes i.e. adiponectin, CD36 and aP2. Study on the underlying mechanism demonstrated that excess expression of Wnt3a decreased PPARγ whereas dmp suppression of Wnt3a gene increased PPARγ expression which subsequently augmented adiponectin. Increased production of adiponectin in db/db mice due to dmp effected lowering of circulatory TG and FFA levels, activates AMPK in skeletal muscle and this stimulates mitochondrial biogenesis and bioenergetics. Decrease of lipid load along with increased mitochondrial activity greatly improves energy homeostasis which has been found to be correlated with the increased insulin sensitivity. The results obtained with dmp, therefore, strongly indicate that dmp could be a potential candidate for insulin replacement therapy.


Utilizing in vitro and PBPK tools to link ADME characteristics to plasma profiles: case example nifedipine immediate release formulation.
One of the most prominent food-drug interactions is the inhibition of intestinal cytochrome P450 (CYP) 3A enzymes by grapefruit juice ingredients, and, as many drugs are metabolized via CYP 3A, this interaction can be of clinical importance. Calcium channel-blocking agents of the dihydropyridine type, such as felodipine and nifedipine, are subject to extensive intestinal first pass metabolism via CYP 3A, thus resulting in significantly enhanced in vivo exposure of the drug when administered together with grapefruit juice. Physiologically based pharmacokinetic (PBPK) modeling was used to simulate pharmacokinetics of a nifedipine immediate release formulation following concomitant grapefruit juice ingestion, that is, after inhibition of small intestinal CYP 3A enzymes. For this purpose, detailed data about CYP 3A levels were collected from the literature and implemented into commercial PBPK software. As literature reports show that grapefruit juice (i) leads to a marked delay in gastric emptying, and (ii) rapidly lowers the levels of intestinal CYP 3A enzymes, inhibition of intestinal first pass metabolism following ingestion of grapefruit juice was simulated by altering the intestinal CYP 3A enzyme levels and simultaneously decelerating the gastric emptying rate. To estimate the in vivo dispersion and dissolution behavior of the formulation, dissolution tests in several media simulating both the fasted and fed state stomach and small intestine were conducted, and the results from the in vitro dissolution tests were used as input function to describe the in vivo dissolution of the drug. Plasma concentration-time profiles of the nifedipine immediate release formulation both with and without simultaneous CYP 3A inhibition were simulated, and the results were compared with data gathered from the literature. Using this approach, nifedipine plasma profiles could be simulated well both with and without enzyme inhibition. A reduction in small intestinal CYP 3A levels by 60% was found to yield the best results, with simulated nifedipine concentration-time profiles within 20% of the in vivo observed results. By additionally varying the dissolution input of the PBPK model, a link between the dissolution characteristics of the formulation and its in vivo performance could be established.


Coronary Computed Tomography Angiography-Specific Definitions of High-Risk Plaque Features Improve Detection of Acute Coronary Syndrome.
Background High-risk plaque (HRP) features as detected by coronary computed tomography angiography (CTA) predict acute coronary syndrome (ACS). We sought to determine whether coronary CTA-specific definitions of HRP improve discrimination of patients with ACS as compared with definitions from intravascular ultrasound (IVUS). Methods and Results In patients with suspected ACS, randomized to coronary CTA in the ROMICAT II (Rule Out Myocardial Infarction/Ischemia Using Computer Assisted Tomography II) trial, we retrospectively performed semiautomated quantitative analysis of HRP (including remodeling index, plaque burden as derived by plaque area, low computed tomography attenuation plaque volume) and degree of luminal stenosis and analyzed the performance of traditional IVUS thresholds to detect ACS. Furthermore, we derived CTA-specific thresholds in patients with ACS to detect culprit lesions and applied those to all patients to calculate the discriminatory ability to detect ACS in comparison to IVUS thresholds. Of 472 patients, 255 patients (56±7.8 years; 63% men) had coronary plaque. In 32 patients (6.8%) with ACS, culprit plaques (n=35) differed from nonculprit plaques (n=172) with significantly greater values for all HRP features except minimal luminal area (significantly lower; all P<0.01). IVUS definitions showed good performance while minimal luminal area (odds ratio: 6.82; P=0.014) and plaque burden (odds ratio: 5.71; P=0.008) were independently associated with ACS but not remodeling index (odds ratio: 0.78; P=0.673). Optimized CTA-specific thresholds for plaque burden (area under the curve: 0.832 versus 0.676) and degree of stenosis (area under the curve: 0.826 versus 0.721) showed significantly higher diagnostic performance for ACS as compared with IVUS-based thresholds (all P<0.05) with borderline significance for minimal luminal area (area under the curve: 0.817 versus 0.742; P=0.066). Conclusions CTA-specific definitions of HRP features may improve the discrimination of patients with ACS as compared with IVUS-based definitions. CLINICAL TRIAL REGISTRATION URL: https://www.clinicaltrials.gov . Unique identifier: NCT01084239.


Care for the caregivers: a review of self-report instruments developed to measure the burden, needs, and quality of life of informal caregivers.
Significant demands are being placed on the informal caregivers of chronically ill patients, including those suffering from cancer. Health care professionals need to be aware of these demands, and they need effective tools to assess the impact these demands place on the caregivers. Over the past 25 years, researchers have developed self-report instruments to assess informal caregivers. These instruments assess various aspects of the caregiving experience, including caregiver burden, needs, and quality of life. The purpose of this review was to identify and critically evaluate these instruments. MEDLINE and PUBMED were searched from 1966 to 2002. After an extensive literature search and review, and utilizing specific inclusion criteria, 28 instruments were identified and evaluated in terms of their development, content, and psychometric properties. In addition, a history of the construct and measurement development in the areas of caregiver burden, needs, and quality of life are discussed. Although some further development and refinement of instruments could benefit the field, depending on the questions researchers or clinicians seek to pursue, there are many proven tools available for their use. Future research needs to use these instruments to assess the effectiveness of interventions aimed at improving the care of the caregivers.


The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria.
This evidence- and consensus-based guideline was developed following the methods recommended by Cochrane and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group. The conference was held on 1 December 2016. It is a joint initiative of the Dermatology Section of the European Academy of Allergology and Clinical Immunology (EAACI), the EU-founded network of excellence, the Global Allergy and Asthma European Network (GA²LEN), the European Dermatology Forum (EDF) and the World Allergy Organization (WAO) with the participation of 48 delegates of 42 national and international societies. This guideline was acknowledged and accepted by the European Union of Medical Specialists (UEMS). Urticaria is a frequent, mast cell-driven disease, presenting with wheals, angioedema, or both. The lifetime prevalence for acute urticaria is approximately 20%. Chronic spontaneous urticaria and other chronic forms of urticaria are disabling, impair quality of life and affect performance at work and school. This guideline covers the definition and classification of urticaria, taking into account the recent progress in identifying its causes, eliciting factors and pathomechanisms. In addition, it outlines evidence-based diagnostic and therapeutic approaches for the different subtypes of urticaria.


The anemia of chronic renal failure in sheep. Response to erythropoietin-rich plasma in vivo.
The hypoproliferative anemia in chronic renal failure has been assumed to be the result of decreased erythropoietin (Ep) production by the damaged kidney and of the shortening of erythrocyte survival. However, many in vitro studies suggest that erythropoietic inhibitors in uremic plasma may contribute to the anemia. To determine the in vivo relevance of uremic inhibitors, increasing amounts of Ep as Ep-rich plasma were infused into six uremic sheep, and their erythropoietic responses were compared with those of nine normal sheep receiving similar amounts of Ep-rich plasma. Three sheep were studied in both normal and uremic states. Ep-rich plasma was obtained from phenylhydrazine- and phlebotomy-induced anemic sheep. Stable uremia was created by subtotal nephrectomy. Erythropoiesis was quantitated by reticulocyte response, ferrokinetics (plasma iron turnover and marrow transit time), and by hemoglobin C synthesis. Ep-rich plasma stimulated erythropoiesis similarly in uremic and normal sheep, regardless of the degree of uremia. Nondialyzed uremic sheep responded as well as dialyzed animals. The anemia was corrected in the uremic dialyzed animals. The anemia was corrected in the uremic sheep after 15-40 daily infusions of Ep-rich plasma, the total dosage depending on the severity of the anemia. Polycythemia was induced when the infusions were continued. Reticulocytes, plasma iron turnover, and erythrocyte mass changes increased as the amount of Ep-rich plasma was increased. These dose-response effects, coupled with the identical erythropoietic response in normal and uremic sheep given the same amount of Ep-rich plasma, imply that there are no physiologically significant erythropoietic inhibitors in uremia.


Color constancy in a scene with bright colors that do not have a fully natural surface appearance.
Theoretical and experimental approaches have proposed that color constancy involves a correction related to some average of stimulation over the scene, and some of the studies showed that the average gives greater weight to surrounding bright colors. However, in a natural scene, high-luminance elements do not necessarily carry information about the scene illuminant when the luminance is too high for it to appear as a natural object color. The question is how a surrounding color's appearance mode influences its contribution to the degree of color constancy. Here the stimuli were simple geometric patterns, and the luminance of surrounding colors was tested over the range beyond the luminosity threshold. Observers performed perceptual achromatic setting on the test patch in order to measure the degree of color constancy and evaluated the surrounding bright colors' appearance mode. Broadly, our results support the assumption that the visual system counts only the colors in the object-color appearance for color constancy. However, detailed analysis indicated that surrounding colors without a fully natural object-color appearance had some sort of influence on color constancy. Consideration of this contribution of unnatural object color might be important for precise modeling of human color constancy.


Fruit and vegetable consumption and its contribution to inequalities in life expectancy and disability-free life expectancy in ten European countries.
To assess to what extent educational differences in total life expectancy (TLE) and disability-free life expectancy (DFLE) could be reduced by improving fruit and vegetable consumption in ten European countries. Data from national census or registries with mortality follow-up, EU-SILC, and ESS were used in two scenarios to calculate the impact: the upward levelling scenario (exposure in low educated equals exposure in high educated) and the elimination scenario (no exposure in both groups). Results are estimated for men and women between ages 35 and 79 years. Varying by country, upward levelling reduced inequalities in DFLE by 0.1-1.1 years (1-10%) in males, and by 0.0-1.3 years (0-18%) in females. Eliminating exposure reduced inequalities in DFLE between 0.6 and 1.7 years for males (6-15%), and between 0.1 years and 1.8 years for females (3-20%). Upward levelling of fruit and vegetable consumption would have a small, positive effect on both TLE and DFLE, and could potentially reduce inequalities in TLE and DFLE.


Sublobar resections for small-sized stage Ia lung adenocarcinoma: a Sino-Japanese multicenter study.
Segmentectomy for small-sized stage Ia non-small cell lung cancer (NSCLC) may be comparable to lobectomy regarding prognosis and local recurrence. However, the clinical results of wedge resection for such patients are still under debate. In this international multicenter study, we retrospectively studied surgical outcomes of sublobar resections for patients with small-sized stage Ia adenocarcinoma to elucidate whether wedge resection is inferior to segmentectomy for such patients. Between March 2000 and August 2011, 173 patients underwent segmentectomy (group I), and 181 patients underwent wedge resection (group II) at three institutions in Japan and China. The tumor was defined as Ground glass opacity (GGO) type when the proportion of GGO was equal or more than 50% in HRCT, while solid type was defined as the proportion of GGO less than 50%. Clinicopathologic factors, local recurrence rate, and survival were compared. The two groups were similar in sex, comorbidity rate, and composition of Noguchi type. There was no in-hospital death. Postoperative morbidity rate of group I was significantly higher than that of group II (11.0% vs. 2.2%, P=0.016). Local recurrence rates were similar between group I (4.0%) and group II (4.4%), while no patient with GGO type tumors had local recurrence. Overall and lung cancer-specific survivals were of no significant difference between the two groups. Lung cancer-specific survival rates at 10 years were significantly better in patients with GGO type tumors than in those with solid type tumors (100% vs. 76.9%, P<0.001). In multivariate Cox regression analyses of lung cancer-specific survival of all patients, GGO type turned out to be an independent prognostic factor, while extent of resection did not have any influence. Our data suggests that sublobar resection is an acceptable procedure for small lung adenocarcinomas without nodal involvement, and wedge resection may not be inferior to segmentectomy for small GGO type tumors. Our study also demonstrates that GGO type is an independent prognostic factor of disease-free survival for small-sized (diameter ≤2.0 cm) stage Ia lung adenocarcinomas.


Melatonin in epilepsy: first results of replacement therapy and first clinical results.
At a single evening dose of 5-10 mg, melatonin (MLT), the pineal gland hormone, can exert a positive effect on the frequency of epileptic attacks in children with sleep disturbances of various etiologies. We have shown that the sleep behavior can be normalized and an existing epilepsy can be favorably influenced. Pretherapeutic MLT secretion profiles can provide new information concerning the origin and treatment of these disturbances. In vitro experiments suggest that this effect might be the result of the interaction between MLT and MLT-specific receptors in the neocortex. Due to its favorable safety profile, MLT can be liberally administered in the specified doses and be considered as a useful antiepileptic drug.


Study of 2009 H1N1 Pandemic Influenza Virus as a Possible Causative Agent of Diabetes.
Recent studies have suggested that influenza A virus (IAV) might be involved in the etiology of diabetes. To address this question, we tested the ability of H1N1 pandemic IAV to infect, replicate, and damage human β cells/pancreatic islets in vitro and induce pancreatic damage and/or glucose metabolism alterations in chemical and autoimmune models of β cell damage in vivo. Moreover, we looked for direct and/or indirect evidence of correlation between IAV infection and autoimmunity/diabetes in humans. Human H1N1 A/California/2009-derived viruses infected human pancreatic islets in vitro, inducing a proinflammatory response associated with substantial increases of CXCL9 and CXCL10 release. In vivo, infected mice showed a clear susceptibility to the virus, with its localization also found in extrapulmonary organs, including the pancreas. Infection was able to induce mild modifications of glycemia in C57B6 mice after chemical damage of islets but did not modulate the autoimmune damage of islets in NOD mice. One of 69 nasopharyngeal swabs collected from patients at the onset of type 1 diabetes yielded positive results for IAV. Pancreas sections from 17 organ donors available from the Network for Pancreatic Organ Donors With Diabetes showed the persistence of CXCL10-positive cells in islet autoimmunity-positive subjects; however, extremely rare cells stained for viral RNA and not preferentially in autoimmune subjects. Influenza H1N1 pdm strains are able to infect and replicate in mammalian pancreatic cells both in vitro and in vivo but did not cause any functional impairment consistent with diabetes.


A radically configurable six-state compound.
Most organic radicals possess short lifetimes and quickly undergo dimerization or oxidation. Here, we report on the synthesis by radical templation of a class of air- and water-stable organic radicals, trapped within a homo[2]catenane composed of two rigid and fixed cyclobis(paraquat-p-phenylene) rings. The highly energetic octacationic homo[2]catenane, which is capable of accepting up to eight electrons, can be configured reversibly, both chemically and electrochemically, between each one of six experimentally accessible redox states (0, 2+, 4+, 6+, 7+, and 8+) from within the total of nine states evaluated by quantum mechanical methods. All six of the observable redox states have been identified by electrochemical techniques, three (4+, 6+, and 7+) have been characterized by x-ray crystallography, four (4+, 6+, 7+, and 8+) by electron paramagnetic resonance spectroscopy, one (7+) by superconducting quantum interference device magnetometry, and one (8+) by nuclear magnetic resonance spectroscopy.


The impact of the COVID-19 pandemic on cancer deaths due to delays in diagnosis in England, UK: a national, population-based, modelling study.
Since a national lockdown was introduced across the UK in March, 2020, in response to the COVID-19 pandemic, cancer screening has been suspended, routine diagnostic work deferred, and only urgent symptomatic cases prioritised for diagnostic intervention. In this study, we estimated the impact of delays in diagnosis on cancer survival outcomes in four major tumour types. In this national population-based modelling study, we used linked English National Health Service (NHS) cancer registration and hospital administrative datasets for patients aged 15-84 years, diagnosed with breast, colorectal, and oesophageal cancer between Jan 1, 2010, and Dec 31, 2010, with follow-up data until Dec 31, 2014, and diagnosed with lung cancer between Jan 1, 2012, and Dec 31, 2012, with follow-up data until Dec 31, 2015. We use a routes-to-diagnosis framework to estimate the impact of diagnostic delays over a 12-month period from the commencement of physical distancing measures, on March 16, 2020, up to 1, 3, and 5 years after diagnosis. To model the subsequent impact of diagnostic delays on survival, we reallocated patients who were on screening and routine referral pathways to urgent and emergency pathways that are associated with more advanced stage of disease at diagnosis. We considered three reallocation scenarios representing the best to worst case scenarios and reflect actual changes in the diagnostic pathway being seen in the NHS, as of March 16, 2020, and estimated the impact on net survival at 1, 3, and 5 years after diagnosis to calculate the additional deaths that can be attributed to cancer, and the total years of life lost (YLLs) compared with pre-pandemic data. We collected data for 32 583 patients with breast cancer, 24 975 with colorectal cancer, 6744 with oesophageal cancer, and 29 305 with lung cancer. Across the three different scenarios, compared with pre-pandemic figures, we estimate a 7·9-9·6% increase in the number of deaths due to breast cancer up to year 5 after diagnosis, corresponding to between 281 (95% CI 266-295) and 344 (329-358) additional deaths. For colorectal cancer, we estimate 1445 (1392-1591) to 1563 (1534-1592) additional deaths, a 15·3-16·6% increase; for lung cancer, 1235 (1220-1254) to 1372 (1343-1401) additional deaths, a 4·8-5·3% increase; and for oesophageal cancer, 330 (324-335) to 342 (336-348) additional deaths, 5·8-6·0% increase up to 5 years after diagnosis. For these four tumour types, these data correspond with 3291-3621 additional deaths across the scenarios within 5 years. The total additional YLLs across these cancers is estimated to be 59 204-63 229 years. Substantial increases in the number of avoidable cancer deaths in England are to be expected as a result of diagnostic delays due to the COVID-19 pandemic in the UK. Urgent policy interventions are necessary, particularly the need to manage the backlog within routine diagnostic services to mitigate the expected impact of the COVID-19 pandemic on patients with cancer. UK Research and Innovation Economic and Social Research Council.


Comparative Effect of Curcumin and Nanocurcumin on Nephroprotection at Cisplatin-induced Rats.
Cisplatin is a first-line chemotherapeutic agent for various solid tumors including ovarian and breast cancer. Thereby, it has been proven effective as an antineoplastic agent, but its clinically use is limited because of its nephrotoxicity side effect. This study aimed to investigate curcumin as a renoprotector agent against cisplatin nephrotoxicity. The samples used were curcumin and its nanoparticles formulated using ionic gelation method. The nephrotoxicity was investigated through several parameters such as serum creatinine, blood urea nitrogen, serum albumin, kidney weight ratio, and histopathology. These parameters were tested on rats and divided into the following four groups: normal group, negative control group that administered cisplatin with doses amount of 7 mg/kg body weight (BW) intraperitoneally, nanocurcumin group (cisplatin + nanocurcumin) and curcumin group (cisplatin + curcumin). The agents were administered at a dose of 100 mg/kg BW every day in 9 days before cisplatin administration. The sample of blood serum and kidneys organ were taken 48h after cisplatin administration. The negative control group showed a significant increase in serum creatinine, blood urea nitrogen, and kidney weight ratio, whereas it showed a significant decrease in serum albumin. The administration of sample agents showed a significant decrease in serum creatinine, blood urea nitrogen, and kidney weight ratio and an increase in the albumin level as compared to negative control group. Nanocurcumin showed significant improvement in kidneys more than curcumin. In contrast, histopathological examination verified the necrosis in negative control group, suggesting the renoprotection effect of nanocurcumin against nephrotoxicity on cisplatin-induced rats.


Treatment fidelity: its importance and reported frequency in aphasia treatment studies.
Treatment fidelity is a measure of the reliability of the administration of an intervention in a treatment study. It is an important aspect of the validity of a research study, and it has implications for the ultimate implementation of evidence-supported interventions in typical clinical settings. Aphasia treatment studies published in the last 10 years in 3 journals were reviewed using coding techniques that were adapted from Gresham, Gansle, Noell, Cohen, and Rosenblum (1993). The following items were noted: identifying information, study design, description of both the dependent and independent variables, and whether a measure of treatment fidelity was explicitly included. Of the aphasia treatment studies published in the last 10 years, 14% explicitly reported treatment fidelity. Most studies reporting treatment fidelity used checking of videotaped sessions by independent raters. Of the reviewed studies, 45% provided sufficient treatment description to support replication. Treatment fidelity is widely acknowledged as being critical to research validity and is a foundation for the implementation of evidence-based practices, but only a small percentage of aphasia treatment studies published in the last 10 years explicitly reported treatment fidelity. Recommendations for research practices include increased attention to matters of treatment fidelity in the peer review process and explicit incorporation of 3 levels of treatment fidelity in treatment research.


Pineal gland calcification and defective sense of direction.
Calcification of the pineal gland is shown to be closely related to defective sense of direction. In a tricentre prospective study of 750 patients lateral skull radiographs showed that 394 had calcified pineal glands. Sense of direction was assessed by subjective questioning and objective testing and the results noted on a scale of 0-10 (where 10 equals perfect sense of direction). The average score for the 394 patients with pineal gland calcification was 3.7 (range 0-8), whereas the 356 patients without pineal gland calcification had an average score of 7.6 (range 2-10). This difference was highly significant (p less than 0.01). A smaller parallel study in pigeons showed that pineal calcification also leads to a reduction in homing abilities. The findings suggested that the pineal gland plays an important part in directional sense and that damage to the gland, as indicated by calcification, causes defective sense of direction - perhaps by altering the intrinsic intracranial electromagnetic environment and thus affecting the magnetite response mechanism.


Aspirin: an unexpected side effect on prostacyclin synthesis in cultured vascular smooth muscle cells.
Monolayer cultures of rat aorta smooth muscle cells synthesized the anti-aggregatory substance prostacyclin via the cyclooxygenase pathway from 14C-labeled arachidonic acid. The product was identified both by bioassay and by mass spectrometry. Labeled cells produced prostacyclin only when exposed to the initiator thrombin: treatment with therapeutic concentrations of aspirin (0.2 millimolar) for 30 minutes completely destroyed the cells' ability to synthesize prostacyclin. Prostacyclin synthesis from exogenous arachidonic acid recovered fully within 1 to 2 hours by a cycloheximide-sensitive process. Thrombin responsivness, which was permanently impaired in confluent nondividing cultures, recovered substantially and within 24 hours only when cells were stimulated to divide by subculturing. These results indicate that resting vascular cells can rapidly synthesize new cyclooxygenase, but that aspirin destroys additional components of the prostacyclin system which can only be replaced during cell division.


Wheat streak mosaic virus: a century old virus with rising importance worldwide.
Wheat streak mosaic virus (WSMV) causes wheat streak mosaic, a disease of cereals and grasses that threatens wheat production worldwide. It is a monopartite, positive-sense, single-stranded RNA virus and the type member of the genus Tritimovirus in the family Potyviridae. The only known vector is the wheat curl mite (WCM, Aceria tosichella), recently identified as a species complex of biotypes differing in virus transmission. Low rates of seed transmission have been reported. Infected plants are stunted and have a yellow mosaic of parallel discontinuous streaks on the leaves. In the autumn, WCMs move from WSMV-infected volunteer wheat and other grass hosts to newly emerged wheat and transmit the virus which survives the winter within the plant, and the mites survive as eggs, larvae, nymphs or adults in the crown and leaf sheaths. In the spring/summer, the mites move from the maturing wheat crop to volunteer wheat and other grass hosts and transmit WSMV, and onto newly emerged wheat in the fall to which they transmit the virus, completing the disease cycle. WSMV detection is by enzyme-linked immunosorbent assay (ELISA), reverse transcription-polymerase chain reaction (RT-PCR) or quantitative RT-PCR (RT-qPCR). Three types of WSMV are recognized: A (Mexico), B (Europe, Russia, Asia) and D (USA, Argentina, Brazil, Australia, Turkey, Canada). Resistance genes Wsm1, Wsm2 and Wsm3 have been identified. The most effective, Wsm2, has been introduced into several wheat cultivars. Mitigation of losses caused by WSMV will require enhanced knowledge of the biology of WCM biotypes and WSMV, new or improved virus detection techniques, the development of resistance through traditional and molecular breeding, and the adaptation of cultural management tactics to account for climate change.


A systems biology consideration of the vasculopathy of sickle cell anemia: the need for multi-modality chemo-prophylaxsis.
Much of the morbidity and mortality of sickle cell anemia is accounted for by a chronic vasculopathy syndrome. There is currently no identified therapy, interventional or prophylactic, for this problem. For two reasons, development of an effective therapeutic approach will require a systems biology level perspective on the vascular pathobiology of sickle disease. In the first place, multiple biological processes contribute to the pathogenesis of vasculopathy: red cell sickling, inflammation and adhesion biology, coagulation activation, stasis, deficient bioavailability and excessive consumption of NO, excessive oxidation, and reperfusion injury physiology. The probable hierarchy of involvement of these disparate sub-biologies places inflammation caused by reperfusion injury physiology as the likely, proximate, linking pathophysiological factor. In the second place, most of these sub-biologies overlap with each other and, in any case, have multiple points of potential interaction and transactivation. Consequently, an approach modeled upon chemotherapy for cancer is needed. This would be a truly multi-modality approach that hopefully could be achieved via employment of relatively few drugs. It is proposed here that the specific combination of a statin with suberoylanilide hydroxamic acid would provide a suitable, broad, multi-modality approach to chemo-prophylaxis for sickle vasculopathy.


Implants inserted into homografts bearing fixed restorations.
In the last decade several studies have evaluated the clinical outcome of implants inserted into autografts and rehabilitated with fixed restorations in either one- or two-step surgical protocols. However, no study has investigated implants placed into homografts; thus, a case series analysis was performed to verify the clinical outcome of implants inserted into fresh frozen bone (FFB) and bearing fixed prosthetic restorations. Fifty-eight patients underwent iliac crest homograft transplants and 238 implants were inserted. Seventy-one double-etched, 19 sandblasted and acid-etched-1 (SLA1), 10 grit-blasted and acid-etched, 73 anodic oxidized, 39 CaPo4 ceramic-blasted, 19 SLA2, and seven additional implants of various types were used. Implant diameter and length ranged from 3 to 5 mm and from 7 to 16 mm, respectively. Implants were inserted to replace 15 incisors, 14 canines, 102 premolars, and 107 molars. A total of 111 restorations were performed. No implants were lost. Cox regression analysis showed that implant type and type of edentulism directly correlated with a lower bone resorption and thus had a better clinical outcome and success rate. Implants bearing fixed restorations and inserted into FFB have higher survival and succes rates compared to those placed in nongrafted and grafted jaws reported in previous studies.


Profiles of brain metastases: Prioritization of therapeutic targets.
We sought to compare the tumor profiles of brain metastases from common cancers with those of primary tumors and extracranial metastases in order to identify potential targets and prioritize rational treatment strategies. Tumor samples were collected from both the primary and metastatic sites of nonsmall cell lung cancer, breast cancer and melanoma from patients in locations worldwide, and these were submitted to Caris Life Sciences for tumor multiplatform analysis, including gene sequencing (Sanger and next-generation sequencing with a targeted 47-gene panel), protein expression (assayed by immunohistochemistry) and gene amplification (assayed by in situ hybridization). The data analysis considered differential protein expression, gene amplification and mutations among brain metastases, extracranial metastases and primary tumors. The analyzed population included: 16,999 unmatched primary tumor and/or metastasis samples: 8,178 nonsmall cell lung cancers (5,098 primaries; 2,787 systemic metastases; 293 brain metastases), 7,064 breast cancers (3,496 primaries; 3,469 systemic metastases; 99 brain metastases) and 1,757 melanomas (660 primaries; 996 systemic metastases; 101 brain metastases). TOP2A expression was increased in brain metastases from all 3 cancers, and brain metastases overexpressed multiple proteins clustering around functions critical to DNA synthesis and repair and implicated in chemotherapy resistance, including RRM1, TS, ERCC1 and TOPO1. cMET was overexpressed in melanoma brain metastases relative to primary skin specimens. Brain metastasis patients may particularly benefit from therapeutic targeting of enzymes associated with DNA synthesis, replication and/or repair.


Evaluation of an Environmental Monitoring Program for the Microbial Safety of Air and Surfaces in a Dairy Plant Environment.
Microbiological hazards can occur when foodstuffs come into contact with contaminated surfaces or infectious agents dispersed by air currents in the manufacturing environment. An environmental monitoring program (EMP) is a critical aspect of sustainable and safe food manufacturing used to evaluate the effectiveness of the microbial controls in place. An effective EMP should be based on risk analysis, taking into account previous sampling history to determine the selection of the sampling points, the scope of the test, and the frequency of analysis. This study involved evaluation of the environmental monitoring regime and microbiological status of a medium-sized dairy plant manufacturing food ingredients, e.g., proteins, milk powders, and dairy fats. The data specific to microbial tests ( n = 3,468), recorded across 124 fixed sampling locations over a 2-year period (2014 to 2015) from air ( n = 1,787) and surfaces ( n = 1,681) were analyzed. The aim of this study was to highlight the strengths and weaknesses of the EMP in a select dairy processing plant. The results of this study outline the selection of sampling locations, the scope of the test, and the frequency of analysis. An analysis of variance revealed subsections of the manufacturing areas with high risk factors, especially the packaging subsection specified for bulk packaging, the atomizer, and the fluidized bed. The temporal and spatial analysis showed the potential to reduce or relocate the monitoring effort, most notably related to total coliforms and Staphylococcus aureus, across the dairy plant due to homogeneity across the sampling subsections with little or no deviations. The results suggest a need to reevaluate the current EMP and the corrective action plan, especially with regard to detection of pathogens. Recommendations for optimization of the EMP are presented to assist the dairy industry with reviewing and revising the control measures and hazard assessment with regard to existing contamination issues.


Factors associated with biochemical remission after microscopic transsphenoidal surgery for acromegaly.
Objectives To analyze surgical outcomes and predictive factors of disease remission in acromegaly patients who underwent microscopic transsphenoidal surgery (TSS) for a growth hormone (GH)-secreting adenoma. Design A 6-year retrospective review of 86 consecutive acromegaly surgeries. Setting Procedures performed at a single institution by a single surgeon. Participants Seventy acromegaly patients. Main Outcome Measures Demographic information, preoperative laboratory values, tumor imaging data, and morphological and immunohistochemical data were collected. Predictive values using the latest and most stringent biochemical remission criteria were determined using univariate and multivariate statistical analyses. Results Remission rate for 59 (18 males) acromegaly patients meeting the study inclusion criteria was 52.5%. Remission rates for micro- and macroadenomas were 81.8% and 45.8%, respectively. Patients of older age, with a smaller tumor, lower Knosp grade, lower preoperative GH, and insulinlike growth factor 1 levels were more likely to achieve remission. Remission rate decreased significantly with repeat surgeries. Those patients with adenomas that stained positive for somatostatin receptor subtype 2A were less likely to experience tumor recurrence and more likely to respond to medical treatment with persistent or elevated GH hypersecretion. Conclusions Microscopic TSS continues to be a viable means for treating acromegaly patients. Patients should be followed long term.


What has been learnt from the thrombin-activatable fibrinolysis inhibitor-deficient mouse?
Thrombin-activatable fibrinolysis inhibitor (TAFI) is a circulating zymogen that is activated physiologically by the thrombin/thrombomodulin complex to activated TAFI (TAFIa) which is a basic carboxypeptidase. Substrates include fibrin, leading to a reduction in rate of plasmin generation, and several proinflammatory mediators such as bradykinin, thrombin-cleaved osteopontin and complement factor C5a. TAFI-deficient mice have no phenotype without being challenged and TAFIa appears to play a limited role in physiological fibrinolysis in vivo. In several disease models, the TAFI-deficient mice have different outcomes from the wild type (WT), but whether the difference is beneficial or an exacerbation of the disease depends on the model. The consequences of TAFI deficiency include increased plasmin as a result of enhanced incorporation of plasminogen and tissue plasminogen activator into the fibrin clot, but also loss of its ability to degrade other substrates, with the resultant up-regulation of several proinflammatory mediators, including C5a. Criteria are recommended to demonstrate that a substrate is a physiological substrate of TAFIa.


Genetic manipulation of antibiotic-producing microorganisms.
The application of directed selection techniques and genetic engineering methods for manipulation of antibiotic-producing microorganisms is generating a new era in industrial microbiology. Modern methods, based on advances in the knowledge of the biosynthetic pathways and regulatory mechanisms involved in the induction and repression of genes involved in antibiotic synthesis, provide a means of increasing antibiotic activity. Hence, recombinant DNA and protoplast fusion methods are used to alter the genetics of antibiotic producers in a semirandom fashion for the development of novel hybrid antibiotics. Directed mutation and selection, protoplast fusion, and both semirandom and specific recombinant DNA methods are examples of alternative procedures for manipulating the biosynthetic pathways of microorganisms for strain improvement and for new hybrid antibiotic synthesis.


Gimatecan and other camptothecin derivatives poison Leishmania DNA-topoisomerase IB leading to a strong leishmanicidal effect.
The aim of this work is the in vitro and ex vivo assessment of the leishmanicidal activity of camptothecin and three analogues used in cancer therapy: topotecan (Hycantim®), gimatecan (ST1481) and the pro-drug irinotecan (Camptosar®) as well as its active metabolite SN-38 against Leishmania infantum. The activity of camptothecin and its derivatives was studied on extracellular L. infantum infrared-emitting promastigotes and on an ex vivo murine model of infected splenocytes with L. infantum fluorescent amastigotes. In situ formation of SDS/KCl precipitable DNA-protein complexes in Leishmania promastigotes indicated that these drugs are DNA topoisomerase IB poisons. The inhibitory potency of camptothecin derivatives on recombinant L. infantum topoisomerase IB was assessed in vitro showing that gimatecan is the most active compound preventing the relaxation of supercoiled DNA at submicromolar concentrations. Cleavage equilibrium assays in Leishmania topoisomerase IB show that gimatecan changes the equilibrium towards cleavage at much lower concentrations than the other camptothecin derivatives and that this effect persists over time. Gimatecan and camptothecin were the most powerful compounds preventing cell growth of free-living L. infantum promastigotes within the same concentration range. All these compounds killed L. infantum splenocyte-infecting amastigotes within the nanomolar range. The amastigote form showed higher sensitivity to topoisomerase IB poisons (with high therapeutic selectivity indexes) than free-living promastigotes. All the compounds assayed poisoned L. infantum DNA topoisomerase IB leading to a strong leishmanicidal effect. Camptothecin derivatives are suitable for reducing the parasitic burden of ex vivo infected splenocytes. The selectivity index of gimatecan makes it a promising drug against this neglected disease.


Bifurcation into functional niches in adaptation.
One of the central questions in evolutionary biology concerns the dynamics of adaptation and diversification. This issue can be addressed experimentally if replicate populations adapting to identical environments can be investigated in detail. We have studied 501 such replicas using digital organisms adapting to at least two fundamentally different functional niches (survival strategies) present in the same environment: one in which fast replication is the way to live, and another where exploitation of the environment's complexity leads to complex organisms with longer life spans and smaller replication rates. While these two modes of survival are closely analogous to those expected to emerge in so-called r and K selection scenarios respectively, the bifurcation of evolutionary histories according to these functional niches occurs in identical environments, under identical selective pressures. We find that the branching occurs early, and leads to drastic phenotypic differences (in fitness, sequence length, and gestation time) that are permanent and irreversible. This study confirms an earlier experimental effort using microorganisms, in that diversification can be understood at least in part in terms of bifurcations on saddle points leading to peak shifts, as in the picture drawn by Sewall Wright.


Polymeric hydrogels for novel contact lens-based ophthalmic drug delivery systems: a review.
Only about 5% of drugs administrated by eye drops are bioavailable, and currently eye drops account for more than 90% of all ophthalmic formulations. The bioavailability of ophthalmic drugs can be improved by a soft contact lens-based ophthalmic drug delivery system. Several polymeric hydrogels have been investigated for soft contact lens-based ophthalmic drug delivery systems: (i) polymeric hydrogels for conventional contact lens to absorb and release ophthalmic drugs; (ii) polymeric hydrogels for piggyback contact lens combining with a drug plate or drug solution; (iii) surface-modified polymeric hydrogels to immobilize drugs on the surface of contact lenses; (iv) polymeric hydrogels for inclusion of drugs in a colloidal structure dispersed in the lens; (v) ion ligand-containing polymeric hydrogels; (vi) molecularly imprinted polymeric hydrogels which provide the contact lens with a high affinity and selectivity for a given drug. Polymeric hydrogels for these contact lens-based ophthalmic drug delivery systems, their advantages and drawbacks are critically analyzed in this review.


Intranuclear retention of ribosomal RNAs in response to herpes simplex virus type 1 infection.
The localization of ribosomal RNA (rRNA) was investigated at the ultrastructural level in herpes simplex virus type 1 infected HeLa cells using three distinct biotinylated probes which bind in sequence to three different segments of the ribosomal genes. Comparison of the above with the signal levels obtained from non-infected cells reveals information about the effects of HSV-1 infection on ribosome biogenesis. A probe specific for the 5' end portion of pre-rRNA labeled all nucleoli of both non-infected and infected cells in the same way, that is, it mainly labeled the dense fibrillar component and the border of the fibrillar centers but only slightly labeled the granular component. This indicates that the initial cleavage of pre-rRNA in herpes infection still occurs in the 5' region of the 5' external transcribed spacer. However, a probe specific for 18 S rRNA labeled the granular component of the nucleoli more intensely after infection. In addition, significant amounts of rRNA molecules were present within the intranuclear viral region, except over the enclosed viral dense bodies, and within the virus-enlarged clusters of interchromatin granules. The data indicate that the still enigmatic viral dense bodies, which are nucleolus-related structures, are excluded from the marked intranuclear retention of ribosomal RNAs and, in addition, reveal a possible role for the interchromatin granules of infected cells in the regulation of the export of the ribosomal subunits towards the cytoplasm.


Effect of Diet Quality and Genetic Predisposition on Hemoglobin A1c and Type 2 Diabetes Risk: Gene-Diet Interaction Analysis of 357,419 Individuals.
To assess the interactions between diet quality and genetic predisposition to incident type 2 diabetes (T2D). Between 2006 and 2010, 357,419 participants with genetic and complete dietary data from the UK Biobank were enrolled and prospectively followed up to 2017. The genetic risk score (GRS) was calculated on the basis of 424 variants associated with T2D risk, and a higher GRS indicates a higher genetic predisposition to T2D. The adherence to a healthy diet was assessed by a diet quality score comprising 10 important dietary components, with a higher score representing a higher overall diet quality. There were 5,663 incident T2D cases documented during an average of 8.1 years of follow-up. A significant negative interaction was observed between the GRS and the diet quality score. After adjusting for major risk factors, per SD increment in the GRS and the diet quality score was associated with a 54% higher and a 9% lower risk of T2D, respectively. A simultaneous increment of 1 SD in both the diet quality score and GRS was additionally associated with a 3% lower T2D risk due to the antagonistic interaction. In categorical analyses, a sharp reduction of 23% in T2D risk associated with a 1-SD increment in the diet quality score was detected among participants in the extremely high GRS group (GRS >95%). We also observed a strong negative interaction between the GRS and the diet quality score on the blood HbA1c level at baseline (P < 0.001). The adherence to a healthy diet was associated with more reductions in blood HbA1c levels and subsequent T2D risk among individuals with a higher genetic risk. Our findings support tailoring dietary recommendations to an individual's genetic makeup for T2D prevention.


Differential Kinetics of Coagulation Factors and Natural Anticoagulants in Patients with Liver Cirrhosis: Potential Clinical Implications.
Advanced liver diseases are associated with profound alterations of the coagulation system increasing the risk not only of bleeding, but also of thromboembolic complications. A recent milestone study has shown that prophylactic anticoagulation in liver cirrhosis patients results in a reduced frequency of hepatic decompensation. Yet, INR measurement, one of the most widely applied tests to assess liver function, only inaccurately predicts the risk of hepatic decompensation related to alterations of the coagulation system. To assess the relationship between selected coagulation factors / natural anticoagulants with INR, MELD score, and hepatic decompensation, we performed the present pilot study. A total number of 92 patients with various stages of liver cirrhosis were included and prospectively followed for at least 6 months. We found that important natural anticoagulants, namely antithrombin and protein C, as well as factor XI (which may also serve as an anticoagulant) decreased earlier and by a larger magnitude than one would expect from classical coagulation test results. The correlation between these factors and INR was only moderate. Importantly, reduced plasma activities of natural anticoagulants but not INR or MELD score were independent predictors of hepatic encephalopathy (P = 0.013 and 0.003 for antithrombin and protein C, respectively). In patients with liver cirrhosis plasma activities of several natural anticoagulants are earlier and stronger affected than routine coagulation tests. Reduced activities of natural anticoagulants may be predictive for the development of hepatic encephalopathy.