The identification, impact and management of missing values and outlier data in nutritional epidemiology.
When performing nutritional epidemiology studies, missing values and outliers inevitably appear. Missing values appear, for example, because of the difficulty in collecting data in dietary surveys, leading to a lack of data on the amounts of foods consumed or a poor description of these foods. Inadequate treatment during the data processing stage can create biases and loss of accuracy and, consequently, misinterpretation of the results. The objective of this article is to provide some recommendations about the treatment of missing and outlier data, and orientation regarding existing software for the determination of sample sizes and for performing statistical analysis. Some recommendations about data collection are provided as an important previous step in any nutritional research. We discuss methods used for dealing with missing values, especially the case deletion method, simple imputation and multiple imputation, with indications and examples. Identification, impact on statistical analysis and options available for adequate treatment of outlier values are explained, including some illustrative examples. Finally, the current software that totally or partially addresses the questions treated is mentioned, especially the free software available.


[The diagnostic value of adenosine deaminase coefficient in patients with tuberculous exudative pleurisy].
The authors examined 51 patients aged 37.74 +/- 2.17 years who had tuberculous pleurisy and aged 49.8 +/- 4.6 years who had nonspecific pleurisy. Group 1 comprised 18 patients with isolated tuberculous exudative pleurisy. Group 2 included 13 patients with tuberculosis complicated by tuberculous pleurisy. Group 3 consisted of 10 patients with nonspecific exudative pleurisy. Catarrhal endobronchitis was the leading form of tracheo-broncheal tree lesion among patients with tuberculous exudative pleurisy (n = 20 (64.5%)). The activity of adenosine deaminase (ADA) was 2.18 +/- 0.73, 2.41 +/- 0.80, and 2.47 +/- 1.52 U/l in Groups 1, 2, and 3, respectively. Thus, the measurement of bronchoalveolar fluid ADA separately from other parameters is of no informative value in the differential diagnosis of the etiology of pleurisy. While analyzing the parameters, the authors introduced the coefficient of ADA (CADA) that was calculated using the formula: K(ADA) = ADA/cytosis. In patients with tuberculous pleurisy, K(ADA) was 0.65 +/- 0.17 (this was 0.52 +/-0.13 in isolated tuberculous exudative pleurisy and 0.84 +/- 0.36 in tuberculous exudative pleurisy complicated by pulmonary tuberculosis (p < 0.05), and 0.20 +/- 0.06 in nonspecific pleurisy (p < 0.05). The ADA coefficient of 0.52 or more confirms the tuberculous etiology in isolated pleurisies and permits a differential diagnosis to be made between specific and nonspecific pleurisy with and without lung changes.


"Let's get physical": advantages of a physical model over 3D computer models and textbooks in learning imaging anatomy.
Three-dimensional (3D) information plays an important part in medical and veterinary education. Appreciating complex 3D spatial relationships requires a strong foundational understanding of anatomy and mental 3D visualization skills. Novel learning resources have been introduced to anatomy training to achieve this. Objective evaluation of their comparative efficacies remains scarce in the literature. This study developed and evaluated the use of a physical model in demonstrating the complex spatial relationships of the equine foot. It was hypothesized that the newly developed physical model would be more effective for students to learn magnetic resonance imaging (MRI) anatomy of the foot than textbooks or computer-based 3D models. Third year veterinary medicine students were randomly assigned to one of three teaching aid groups (physical model; textbooks; 3D computer model). The comparative efficacies of the three teaching aids were assessed through students' abilities to identify anatomical structures on MR images. Overall mean MRI assessment scores were significantly higher in students utilizing the physical model (86.39%) compared with students using textbooks (62.61%) and the 3D computer model (63.68%) (P < 0.001), with no significant difference between the textbook and 3D computer model groups (P = 0.685). Student feedback was also more positive in the physical model group compared with both the textbook and 3D computer model groups. Our results suggest that physical models may hold a significant advantage over alternative learning resources in enhancing visuospatial and 3D understanding of complex anatomical architecture, and that 3D computer models have significant limitations with regards to 3D learning.


The Chemical, Microbiological and Volatile Composition of Kefir-like Beverages Produced from Red Table Grape Juice in Repeated 24-h Fed-Batch Subcultures.
The aim of this work was to study the production of kefir-like beverages via the fed-batch fermentation of red table grape juice at initial pHs of 3.99 (fermentation A) and 5.99 (fermentation B) with kefir grains during 4 repeated 24-h fed-batch subcultures. All kefir-like beverages (KLB) were characterized by low alcoholic grade (≤3.6%, v/v) and lactic and acetic acid concentrations. The beverages obtained from fermentation B had lower concentrations of sugars and higher microbial counts than the KLB obtained in fermentation A. Additionally, the KLB samples from fermentation B were the most aromatic and had the highest contents of alcohols, esters, aldehydes and organic acids, in contrast with the nonfermented juice and KLB from fermentation A. These results indicate the possibility of obtaining red table grape KLB with their own distinctive aromatic characteristics and high content in probiotic viable cells, contributing to the valorization of this fruit.


The Hip Fracture Patient on Warfarin: Evaluating Blood Loss and Time to Surgery.
To compare blood loss, delay of surgery, and short-term adverse events in (1) patients admitted on warfarin versus nonanticoagulated controls and (2) warfarin patients with day of surgery (DOS) international normalized ratio (INR) of 1.5 or greater versus below 1.5. Retrospective cohort. Academic Level I trauma center. One hundred twenty four patients treated surgically for hip fractures including patients presenting on warfarin (n = 62) and matched controls (n = 62). Cephalomedullary nailing (CMN), hemiarthroplasty, or total hip arthroplasty. The primary outcome was transfusion rate. Secondary outcomes included calculated blood loss, 30-day complication rate, and hours from emergency department presentation to surgery. There was no significant difference in blood transfusion rates between the warfarin and control groups (P = 0.86). Blood transfusion was required in 58.1% of patients in the warfarin group (48.3% of arthroplasties and 65.5% of CMNs) compared with 56.6% of controls (41.9% of arthroplasties and 73.3% of CMNs). There were also no significant differences in calculated blood loss or in complication rates. Patients on warfarin had significantly longer time to surgery (P < 0.01). Subanalysis of the warfarin group showed that patients with DOS INR at or above 1.5 had similar transfusion rates, blood loss, and complications compared with patients with INR below 1.5. Treatment with CMN was the only covariate that was found to be a significant independent predictor of transfusion on multivariable analysis (P = 0.048). Patients with hip fractures admitted on warfarin seem to be at similar risk of transfusion or adverse events compared with nonanticoagulated patients. Awaiting normalization of INR delayed surgery without reducing bleeding or preventing complications. Within reason, surgeons may consider proceeding with surgery in patients with INR above 1.5 if patients are otherwise medically optimized. The upper limit above which surgery causes increased blood loss is currently unknown. Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.


Deletion of the C-terminal domain of apolipoprotein A-I impairs cell surface binding and lipid efflux in macrophage.
The contribution of the amphipathic alpha-helices of apoA-I toward lipid efflux from human skin fibroblasts and macrophage was examined. Four apoA-I mutants were designed, each by deletion of a pair of predicted adjacent helices. Three mutants lacked two consecutive central alpha-helices [Delta(100-143), Delta(122-165), and Delta(144-186)], whereas the final mutant lacked the C-terminal domain [Delta(187-243)]. When compared to recombinant wild-type apoA-I and mutants with central domain deletions, Delta(187-243) exhibited a marked reduction in its ability to promote either cholesterol or phospholipid efflux from THP-1 macrophages. This mutant also demonstrated a decreased ability to bind lipids and to form lipoprotein complexes. In contrast, the four mutants and apoA-I equally supported cholesterol efflux from fibroblasts, albeit with a reduced capacity when compared to macrophages. Delta(187-243) bound poorly to the macrophage cell surface when compared to apoA-I, and competitive binding studies with the central domain and C-terminal deletions mutants showed that only Delta(187-243) did not compete effectively with [(125)I]apoA-I. Omission of PMA during cholesterol loading enhanced cholesterol efflux to both apoA-I (1.5-fold) and the C-terminal deletion mutant (2.5-fold). Inclusion of the Sandoz ACAT inhibitor (58-035) during loading and, in the absence of PMA, increased and equalized cholesterol efflux to apoA-I and Delta(187-243). Surprisingly, omission of PMA during cholesterol loading had minimal effects on the binding of apoA-I or Delta(187-243) to the THP-1 cell surface. Overall, these results show that cholesterol efflux from cells such as fibroblasts does not require any specific sequence between residues 100 and 243 of apoA-I. In contrast, optimal cholesterol efflux in macrophages requires binding of the C-terminal domain of apoA-I to a cell surface-binding site and the subsequent translocation of intracellular cholesterol to an efflux-competent pool.


The ethical considerations of outcome research.
Escalating costs have led to the increasing interest in outcome research in all areas of industry. In healthcare, providers, payors, and consumers are making every effort to improve the quality of patient care while managing costs. Because the overriding issue of cost is driving much of outcome research, it is increasingly important to recognize the fragile balance that exists between cost and quality. In addition, clinicians face a number of other ethical and legal concerns such as confidentiality, informed consent, and the needs of the underserved. This column describes outcome research, along with ethical principles that influence this research.


Somatization disorder and somatoform symptoms in systematically studied survivors of 10 disasters.
There is little agreement about the association of somatization with exposure to disaster trauma in the existing literature. Pre-disaster and post-disaster psychiatric disorders, somatization disorder, and individual somatoform (medically unexplained) symptoms were assessed with structured diagnostic interviews in 811 directly exposed survivors of 10 disasters. Only 1 individual met criteria for post-disaster somatization disorder; there were no incident cases. Only 21% of all somatic symptoms reported were somatoform symptoms. Although 29% of the sample had ≥1 post-disaster somatoform symptoms, only 13% of the sample had any incident somatoform symptoms, and only 1.5% of the sample had >1. Somatization disorder is not an observed outcome of disaster. Incidence of individual somatoform symptoms is relatively uncommon and represents a construct that is distinct from somatization disorder. Such symptoms appear to represent nonspecific distress or endemic symptoms in the population and are not necessarily causally related to the disaster. The only studies that have identified somatization symptoms in relation to disaster have used nondiagnostic symptom checklists. As illustrated by the findings from this study, nondiagnostic symptom checklists do not adequately substitute for structured diagnostic instruments in assessment of somatoform psychopathology.


Exploring architectures at the nanoscale: the interplay between hydrophobic twin lipid chains and head groups of designer peptide amphiphiles in the self-assembly process and application.
The self-assembly of peptide amphiphiles (PAs) is found to be governed by the hydrophobic interactions induced by the hydrophobic groups/number of alkyl chains and the hydrophilic head groups. In this study, an assessment of the nanostructures formed by the self-assembly of simple twin chained PAs was carried out and compared to their single chain/short analogues. The spectroscopic and microscopic analysis revealed the fact that the twin chained amphiphiles had a high inclination to form β-sheet nanofibers and further towards hydrogelation. The mixture of twin chained PAs also exhibited cooperative self-assembly with improved aggregation behavior, although not much augmentation in β-type structuring was found. In contrast, the single chain/short analogue containing PAs showed very less of β-sheet type structures to a lesser extent and no hydrogelating behavior but resulted in mostly random conformations. The increase in the number or alteration of polar head groups in double chained PAs induced higher extent of β-type conformation and better gelling capability due to the combined hydrophobic effect of the twin chains. The overall results delineated the dominance of hydrophobic interactions. Finally, calcium phosphate bio-mineralization was done in the hydrogels of twin chained PAs with the aim of developing future biomaterials.


Water under pressure
Water under pressure is investigated by first principles molecular dynamics, with a focus on the changes in hydrogen bonding and the oxygen network in the nondissociative regime. At a pressure of 10 GPa and a temperature of 600 K, which is close to the freezing point, no appreciable molecular dissociation is observed in the simulations. However, the structure of water is substantially altered from that at ambient conditions. The liquid exhibits a much larger coordination of oxygen atoms, an essential weakening of hydrogen bonding, and sizable changes in the density of electronic states close to the Fermi level. Our results provide new structural data for direct comparison with future experiments.


[Desensitisation to circumvent hypersensitivity reactions; treatment with docetaxel still possible].
A 57-year-old woman with advanced non-small cell lung carcinoma developed hypersensitivity reactions to docetaxel. Measures taken to attempt the re-administration of docetaxel failed. For the differential diagnosis, an IgE specific to docetaxel (in terms of cross-reactivity with Taxus baccata), the solubilizing agent polysorbate 80, as well as the possibility of the reaction being non-IgE-mediated, were all considered. The latter was thought to be most likely. Desensitisation has been reported to be safe and effective in protecting patients from severe hypersensitivity reactions in both IgE- and non-IgE-mediated reactions. Desensitisation in this context means the induction of temporary clinical unresponsiveness to the culprit drug. The gradual reintroduction of small doses of the drug at fixed time intervals eventually allows delivery of full therapeutic doses. Desensitisation to docetaxel was successfully carried out in a supervised setting a total of three times in this patient.


Decrease in plasma glucose concentration after microinjection of insulin into VMN.
The influence of insulin on hypothalamic regulation of blood sugar homeostatis was studied in anesthetized rats. Insulin was injected directly into the ventromedial hypothalamic nucleus (VMN), the lateral hypothalamic area (LHA), the parietal cortex, or the third cerebral ventricle, and changes in hepatic venous plasma glucose concentrations were studied. After injection of 100 microU insulin into the parietal cortex or the third ventricle, hepatic venous plasma glucose concentration did not differ from that of the control rats, which received saline injection into the same CNS regions. Saline injection into the LHA raised the hepatic venous plasma glucose concentration in control rats, where injection of 100 microU insulin into the LHA resulted in a modest but significant decrease of glycemia in the 2-, 5-, and 10-min postinjection samples. As little as 10 microU insulin injected into the VMN eliminated the hyperglycemic response seen in control rats after saline injection into this site. The divergence between insulin-treated rats and their saline-treated controls was further amplified, and an actual fall of plasma glucose was observed in rats given injections of 50 or 100 microU insulin into the VMN. Increasing quantities of insulin (from 10 to 100 microU) injected into the VMN resulted in graded decreases of hepatic venous plasma glucose concentrations, suggestive of a dose-response curve. These observations support the hypothesis that the VMN and the LHA are parts of an insulin-sensitive CNS glucoregulator system that exerts influences on the systemic blood glucose levels by causing rapid alterations in hepatic glucose metabolism.


Perceived support in sibling relationships and adolescent adjustment.
Siblings may support each other, but also reveal fierce rivalry and mutual aggression. Supportive sibling relationships have been linked to the development of psychosocial competence of children. In the present longitudinal study, we will focus on the development of perceived support in sibling dyads and on the influence of sibling support and sibling problem behavior on psychosocial adjustment in adolescence. In a three-wave longitudinal sample of 285 Dutch families with two adolescent children (11- to 15-year-olds), these two siblings judged the support perceived from each other. In addition, they themselves and their parents judged their internalizing and externalizing problem behaviors. The relation of sibling support and sibling problem behavior with internalizing and externalizing problem behaviors was examined while controlling for support from parents and friends and, over time, controlling for the autoregressive effects of problem behavior. Support perceived from a sibling is mostly negatively related to externalizing problems; sibling problem behavior is strongly related to internalizing problems. Differential developmental trajectories of adolescents' adjustment are associated with siblings' support and problem behavior. The results indicate that adolescents' relationships with both older and younger siblings are characterized by modeling processes.


Systemic candidiasis in premature infants experience with drug treatment.
Eleven premature infants with systemic candidiasis from 1981 to 1984 have been reported previously. The experience with antifungal drugs is presented. Amphotericin B at lower maintenance dose, together with 5 flucytosine (5FC), are the preferred drugs for treatment of systemic candidiasis at present.


Prevention of neonatal hyperbilirubinaemia in non-human primates by Zn-protoporphyrin.
Non-human primates were used as a model of human neonatal hyperbilirubinaemia and its chemotherapeutic suppression. High levels of haem oxygenase activity were detected in the liver and the spleen of neonatal rhesus (Macaca mulatta) and cynomolgus (Macaca irus) monkeys. When 1-day-old neonatal animals were given a single injection of Zn-protoporphyrin (40 mumol/kg, subcutaneously), serum bilirubin levels declined to nearly normal adult levels within 24 h and remained suppressed throughout the postnatal period (12 days). This treatment inhibited the activities of haem oxygenase and biliverdin reductase in the liver and the spleen, without affecting that of the brain. Zn-protoporphyrin treatment did not alter the activity of brain biliverdin reductase or increase brain bilirubin levels. The biological disposition of Zn-protoporphyrin was examined by measuring the biliary and urinary excretion of the metalloporphyrin complex, as well as its uptake and deposition in blood cells and tissues. Biliary excretion of the metalloporphyrin was minimal (0.12% over a 28 h period), and no evidence was detected for the urinary excretion of Zn-protoporphyrin. However, the concentration of metalloporphyrin in erythrocytes increased over the duration of the experiment (11 days) to such an extent that 46% of the administered compound was taken up by the cells. It appeared that the molecular basis for the sustained suppression of haem oxygenase activity and bilirubin production by Zn-protoporphyrin involved the release of the metalloporphyrin in the normal process of the degradation of fetal erythrocytes. The scope of the biological activity of Zn-protoporphyrin to alter haem-dependent processes appeared limited in nature, insofar as the microsomal contents of cytochrome P-450 and b5, as well as the aniline hydroxylase, were similar to those of the control animals. Also, the concentration of glutathione in the liver was unchanged. These findings suggest the potential usefulness of Zn-protoporphyrin in experimental and perhaps clinical conditions in which hyperbilirubinaemia occurs.


Vitamin D Signaling Suppresses Early Prostate Carcinogenesis in TgAPT121 Mice.
We tested whether lifelong modification of vitamin D signaling can alter the progression of early prostate carcinogenesis in studies using mice that develop high-grade prostatic intraepithelial neoplasia that is similar to humans. Two tissue-limited models showed that prostate vitamin D receptor (VDR) loss increased prostate carcinogenesis. In another study, we fed diets with three vitamin D3 levels (inadequate = 25 IU/kg diet, adequate for bone health = 150 IU/kg, or high = 1,000 IU/kg) and two calcium levels (adequate for bone health = 0.5% and high = 1.5%). Dietary vitamin D caused a dose-dependent increase in serum 25-hydroxyvitamin D levels and a reduction in the percentage of mice with adenocarcinoma but did not improve bone mass. In contrast, high calcium suppressed serum 1,25-dihydroxyvitamin D levels and improved bone mass but increased the incidence of adenocarcinoma. Analysis of the VDR cistrome in RWPE1 prostate epithelial cells revealed vitamin D-mediated regulation of multiple cancer-relevant pathways. Our data support the hypothesis that the loss of vitamin D signaling accelerates the early stages of prostate carcinogenesis, and our results suggest that different dietary requirements may be needed to support prostate health or maximize bone mass. SIGNIFICANCE: This work shows that disrupting vitamin D signaling through diet or genetic deletion increases early prostate carcinogenesis through multiple pathways. Higher-diet vitamin D levels are needed for cancer than bone.


Mitochondrial gene diversity in the common vole Microtus arvalis shaped by historical divergence and local adaptations.
The phylogeography of the common vole (Microtus arvalis) was examined by analysing mitochondrial DNA (mtDNA) sequence variation in 1044 base pairs (bp) of the cytochrome b (cytb) gene and in 322 bp of the control region (ctr) among 106 individuals from 58 locations. The geographical distribution of four previously recognized cytb evolutionary lineages in Europe was refined and a new lineage was found in southern Germany. All lineages were distributed allopatrically, except in one sample that was probably located in a contact zone. The occurrence of several lineages in the Alps is in keeping with their recent recolonization from distinct sources. The translation of 84 cytb DNA sequences produced 33 distinct proteins with relationships that differed from those of the DNA haplotypes, suggesting that the mtDNA lineages did not diverge in response to selection. In comparison with M. agrestis, a neutrality test detected no overall evidence for selection in the cytb gene, but a closer examination of a structural model showed that evolutionarily conserved and functionally important positions were often affected. A new phylogeographical test of random accumulation of nonsynonymous mutations generated significant results in three lineages. We therefore conclude that the molecular diversity of cytb in M. arvalis is overall the result of the demographic history of the populations, but that there have been several episodes of local adaptation to peculiar environments.


Surface plasmon resonance enhanced direct Z-scheme TiO2/ZnTe/Au nanocorncob heterojunctions for efficient photocatalytic overall water splitting.
Solar-driven photocatalytic overall water splitting is regarded as one of the ideal strategies to generate renewable hydrogen energy without the initiation of environmental issues. However, there are still a few remaining challenges to develop wide-light-absorption and stable photocatalysts for the simultaneous production of H2 and O2 in pure water without sacrificial reagents. Herein, we report the design and preparation of Z-scheme TiO2/ZnTe/Au nanocorncob heterojunctions by homogeneously decorating Au nanoparticles onto the surface of core-shell TiO2/ZnTe coaxial nanorods for highly efficient overall water splitting. With the appropriate band structure of TiO2/ZnTe heterojunctions and the surface plasmon resonance enhancement of Au nanoparticles, the well-designed TiO2/ZnTe/Au nanocorncob heterojunctions can synergistically make effective utilization of broad-range solar light illunimation and enhance the separation efficency of electron-hole pairs, as evidenced by UV-Vis absorption and time-resolved photoluminescence spectroscopy. Photoelectrochemical characterization confirms that the water-splitting reaction on TiO2/ZnTe/Au nanocorncobs is mainly carried out via a two-electron/two-electron transfer process with an intermediate product of H2O2. As a result, the TiO2/ZnTe/Au nanocorncob photocatalyst can generate H2 and O2 with a stoichiometric ratio of 2 : 1 under light irradiation without any sacrificial agents, exhibiting a high H2 production rate of 3344.0 μmol g-1 h-1 and a solar-to-hydrogen (STH) efficiency of 0.98%. Moreover, the TiO2/ZnTe/Au nanocorncob heterojunctions show high stability and well-preserved morphological integrity after long-term photocatalytic tests. This study provides a prototype route to produce clean hydrogen energy from only sunlight, pure water, and rationally-designed heterojunction photocatalysts.


EMB history to increase health technology literacy in the general public for improved health worldwide.
History provides common access to technology for both technical and non technical persons and for youngsters. Placed in an historical context complex health technology and health care can be more understandable and therefore more accessible to the general public; technical persons can understand past health technology advances to help propel the field. History is a reference for experts disguised as a story that anyone can understand and enjoy. This can be useful and effective at improving self advocate based health care.


N-terminal pro-brain natriuretic peptide testing in the emergency department: beneficial effects on hospitalization, costs, and outcome.
N-terminal pro-brain natriuretic peptide (NT-proBNP) is an established biomarker for heart failure. Assessment of this biomarker in patients with acute dyspnea presenting to the emergency department (ED) may aid diagnostic decision-making, resulting in improved patient care and reduced costs. In a prospective clinical trial, patients presenting with acute dyspnea to the ED of the Erasmus Medical College, Rotterdam, the Netherlands, were randomized for either rapid measurement or no measurement of NT-proBNP. For ruling out heart failure, cutoff values of 93 pg/mL in male and 144 pg/mL in female patients were used, and for ruling in heart failure, a cutoff value of 1,017 pg/mL was used. Time to discharge from the hospital and costs related to hospital admission were primary end points. Bootstrap analysis was used for comparison of costs and 30-day mortality between the NT-proBNP and control group. A total of 477 patients (54% male) was enrolled. The mean age was 59 years, with 44% of patients having a history of cardiac disease. Median time to discharge from the hospital was 1.9 days (interquartile range [IQR], 0.12-8.4 days) in the NT-proBNP group (n = 241) compared with 3.9 days (IQR, 0.16-11.0 days) in the control group (n = 236) (P = .04). Introduction of NT-proBNP testing resulted in a trend toward reduction in costs related to hospital admission and diagnostic investigations of $1,364 per patient (95% CI $-246 to $3,215), whereas 30-day mortality was similar (15 patients in the NT-proBNP and 18 patients in the control group). Introduction of NT-proBNP testing for heart failure in the ED setting reduces the time to discharge and is associated with a trend toward cost reduction.


A capture-sequencing strategy identifies IRF8, EBF1, and APRIL as novel IGH fusion partners in B-cell lymphoma.
The characterization of immunoglobulin heavy chain (IGH) translocations provides information on the diagnosis and guides therapeutic decisions in mature B-cell malignancies while enhancing our understanding of normal and malignant B-cell biology. However, existing methodologies for the detection of IGH translocations are labor intensive, often require viable cells, and are biased toward known IGH fusions. To overcome these limitations, we developed a capture sequencing strategy for the identification of IGH rearrangements at nucleotide level resolution and tested its capabilities as a diagnostic and discovery tool in 78 primary diffuse large B-cell lymphomas (DLBCLs). We readily identified IGH-BCL2, IGH-BCL6, IGH-MYC, and IGH-CCND1 fusions and discovered IRF8, EBF1, and TNFSF13 (APRIL) as novel IGH partners in these tumors. IRF8 and TNFSF13 expression was significantly higher in lymphomas with IGH rearrangements targeting these loci. Modeling the deregulation of IRF8 and EBF1 in vitro defined a lymphomagenic profile characterized by up-regulation of AID and/or BCL6, down-regulation of PRMD1, and resistance to apoptosis. Using a capture sequencing strategy, we discovered the B-cell relevant genes IRF8, EBF1, and TNFSF13 as novel targets for IGH deregulation. This methodology is poised to change how IGH translocations are identified in clinical settings while remaining a powerful tool to uncover the pathogenesis of B-cell malignancies.


TRPM2 contributes to inflammatory and neuropathic pain through the aggravation of pronociceptive inflammatory responses in mice.
Accumulating evidence suggests that neuroimmune interactions contribute to pathological pain. Transient receptor potential melastatin 2 (TRPM2) is a nonselective Ca²⁺-permeable cation channel that acts as a sensor for reactive oxygen species. TRPM2 is expressed abundantly in immune cells and is important in inflammatory processes. The results of the present study show that TRPM2 plays a crucial role in inflammatory and neuropathic pain. While wild-type and TRPM2 knock-out mice showed no difference in their basal sensitivity to mechanical and thermal stimulation, nocifensive behaviors in the formalin test were reduced in TRPM2 knock-out mice. In carrageenan-induced inflammatory pain and sciatic nerve injury-induced neuropathic pain models, mechanical allodynia and thermal hyperalgesia were attenuated in TRPM2 knock-out mice. Carrageenan-induced inflammation and sciatic nerve injury increased the expression of TRPM2 mRNA in the inflamed paw and around the injured sciatic nerve, respectively. TRPM2 deficiency diminished the infiltration of neutrophils and the production of chemokine (C-X-C motif) ligand-2 (CXCL2), a major chemokine that recruits neutrophils, but did not alter the recruitment of F4/80-positive macrophages in the inflamed paw or around the injured sciatic nerve. Microglial activation after nerve injury was suppressed in the spinal cord of TRPM2 knock-out mice. Furthermore, CXCL2 production and inducible nitric oxide synthase induction were diminished in cultured macrophages and microglia derived from TRPM2 knock-out mice. Together, these results suggest that TRPM2 expressed in macrophages and microglia aggravates peripheral and spinal pronociceptive inflammatory responses and contributes to the pathogenesis of inflammatory and neuropathic pain.


Breaking Free: The Genomics of Allopolyploidy-Facilitated Niche Expansion in White Clover.
The merging of distinct genomes, allopolyploidization, is a widespread phenomenon in plants. It generates adaptive potential through increased genetic diversity, but examples demonstrating its exploitation remain scarce. White clover (Trifolium repens) is a ubiquitous temperate allotetraploid forage crop derived from two European diploid progenitors confined to extreme coastal or alpine habitats. We sequenced and assembled the genomes and transcriptomes of this species complex to gain insight into the genesis of white clover and the consequences of allopolyploidization. Based on these data, we estimate that white clover originated ∼15,000 to 28,000 years ago during the last glaciation when alpine and coastal progenitors were likely colocated in glacial refugia. We found evidence of progenitor diversity carryover through multiple hybridization events and show that the progenitor subgenomes have retained integrity and gene expression activity as they traveled within white clover from their original confined habitats to a global presence. At the transcriptional level, we observed remarkably stable subgenome expression ratios across tissues. Among the few genes that show tissue-specific switching between homeologous gene copies, we found flavonoid biosynthesis genes strongly overrepresented, suggesting an adaptive role of some allopolyploidy-associated transcriptional changes. Our results highlight white clover as an example of allopolyploidy-facilitated niche expansion, where two progenitor genomes, adapted and confined to disparate and highly specialized habitats, expanded to a ubiquitous global presence after glaciation-associated allopolyploidization.


A prospective comparison of two measures of psychopathy in the prediction of institutional misconduct.
This study examined the predictive validity of two widely used measures of psychopathic traits, the Psychopathy Checklist--Revised (PCL-R; Hare, 2003) and the Psychopathic Personality Inventory (PPI; Lilienfeld & Andrews, 1996). Records of institutional infractions were obtained for a young adult sample of prison inmates (N = 46), who were followed for approximately two years following administration of these two scales. The PPI total and two factor scores predicted the total number of infractions committed (r ranging from .28 to .36). PPI Factor I showed some evidence of stronger associations with non-aggressive infractions (r = .36), whereas PPI Factor II was the strongest correlate of aggressive misconduct (r = .24). The total and facet scores of the PCL-R were not significantly predictive of any form of institutional misconduct, with effect sizes ranging from negligible to small (median r = .14, r ranging from -.01 to .21).


The In vitro anti-acne activity of two unani drugs.
Acne is the most common disorder treated by dermatologists. As many as 80-90% of all adolescents have some type of acne and 30% of them require medical treatment. It is an inflammatory disease of the pilosebaceous unit characterized by the formation of open and closed comedones, papules, pustules, nodules, and cysts. The present study was conducted to investigate the in vitro anti-acne activity of two Unani single drugs Darchini (Cinnamomum zeylanicum Bl.) and Tukhm Khashkhash (Papaver somniferum L. seeds). The antibacterial activity of aqueous, ethanolic and hydroalcoholic extracts of both drugs were investigated against two acne causing bacteria, i.e., Propionibacterium acne and Staphylococcus epidermidis using well diffusion method. The result showed that both drugs were active against the two bacteria. Against P. acne aqueous and ethanolic extract of Darchini and Tukhm Khashkhash showed the zone of inhibition of 18 ± 1.02 mm and 18 ± 1.6 mm and 13 ± 1.04 mm and 14 ± 1.8 mm, respectively. Against S. epidermidis aqueous, hydroalcoholic and ethanolic extracts of Darchini showed 22 ± 1.7 mm, 22 ± 1.2 mm and 15 ± 1.8 mm zone of inhibition respectively. Hydroalcoholic and ethanolic extracts of Tukhm Khashkhash showed 15 ± 1.09 mm and 13 ± 1.6 mm zone of inhibition respectively. This suggests that C. zeylanicum and P. somniferum have potential against acne causing bacteria and hence they can be used in topical anti-acne preparations and may address the antibiotic resistance of the bacteria.


Patient Perceptions of Dermatologic Photography: Scoping Review.
Medical photography is used extensively in dermatology to record disease progression, measure treatment response, and help teach patients about skin disease; such photos are also commonly utilized in teledermatology, medical education, research, and medical reference websites. Understanding patient perceptions of medical photographs obtained during dermatologic care in the clinic or hospital setting is critical to enable the delivery of high-quality, patient-centered medical care. The aims of this study were to elucidate patient perceptions of skin photos in dermatology and to explore possible next steps in improving the patient experience with medical photography in the hospital or clinic setting. A scoping review of the literature was performed using the PubMed database, with clinic- or hospital-based full-text publications in English spanning the last 10 years considered for inclusion. The majority of included studies (10/11, 91%) found positive patient attitudes toward medical photographs. The majority of patients (1197/1511, 79.2%) felt that medical photographs could improve medical care in the clinic setting. Written consent detailing all photo uses, including secondary uses (such as research or teaching), was preferred, apart from in 1 study. Patients preferred or found it acceptable for the photographer of their medical photos to be a physician (1301/1444, 90.1%). Clinic-owned cameras with departmental record storage were the preferred modality. Latinx and African American patients expressed less trust in the utility of medical photographs to improve care, compared with Asian and White patients. The minimal number of available publications on this topic and the inclusion of articles older than 5 years are limitations, since patient perceptions of medical photography may have rapidly changed during this time span, particularly in light of the COVID-19 pandemic and the subsequent increase in teledermatology visits. Patients reported positive perceptions of dermatologic photography for improving their medical care. Ethnic disparities in patient perceptions require further exploration to better elucidate nuances and develop interventions to improve the experience of marginalized patients. Building patient trust in nonphysician photographers may enhance clinic efficiency. Although clinic-owned cameras are well-accepted by patients, improved patient education surrounding the safety of electronic medical record phone applications is needed.


G-protein coupled progesterone receptors in the plasma membrane of fungus Rhizopus nigricans.
We have demonstrated simultaneous existence of progesterone receptors and GTPase activity in the membranes prepared from the filamentous fungus Rhizopus nigricans. The results obtained with pertussis toxin treated fungal mycelium suggest that these receptors do not couple to Gi-Go-proteins and play a role in the induction of steroid hydroxylating enzyme system by steroid substrates in the fungus.


Peroral video cholangioscopy to evaluate indeterminate bile duct lesions and preoperative mucosal cancerous extension: a prospective multicenter study.
Despite the development of peroral video cholangioscopy (PVCS), no prospective multicenter studies have been undertaken to investigate the diagnostic accuracy of PVCS in biliary tract diseases. Therefore, the aim of this study was to clarify the accuracy of PVCS in evaluating biliary tract lesions. This study was a prospective multicenter study at five tertiary referral centers in Japan and included 87 eligible patients with biliary tract diseases who underwent PVCS. The study evaluated the ability of PVCS to diagnose indeterminate biliary tract diseases, detect mucosal cancerous extension preoperatively in extrahepatic bile duct cancers, and predict adverse events. The use of PVCS appearance alone correctly distinguished benign from malignant indeterminate biliary lesions in 92.1 % of patients whereas biopsy alone was accurate in 85.7 %. In extrahepatic bile duct cancer, mucosal cancer extended histologically at least 20 mm in 34.7 % (17/49) of patients. The accuracy rate of PVCS to evaluate the presence or absence of mucosal cancerous extension by endoscopic retrograde cholangiography (ERC) alone, ERC with PVCS, and ERC with PVCS + biopsy were 73.5 %, 83.7 %, and 92.9 %, respectively. Adverse events were seen in 6.9 % of PVCS patients, but no serious complications were observed. PVCS enhanced the accurate diagnosis of biliary tract lesions by providing excellent resolution in combination with biopsy.


Kinetic and equilibrium analyses of [(123)I]epidepride binding to striatal and extrastriatal dopamine D(2) receptors.
Quantitative SPECT measures of dopamine D(2) like receptors with [(123)I]epidepride is complicated by its high affinity and lipophilic metabolites. The purpose of this study was to use both parent (P) and lipophilic metabolites (M) as input functions in a kinetic paradigm and in comparison to the results of equilibrium studies. Kinetic studies on eleven healthy human subjects, ages 32+/- 10 were performed following i.v. injection of approximately 370 MBq of [(123)I]epidepride. Images were acquired for 13.5+/-1.0 hours. Equilibrium studies were done on seven of eleven subjects with a bolus injection of approximately 140 MBq, bolus/infusion ratio of 10 hours, and infusion for 30-32 hours. High (striatum) and low (temporal cortex) density regions were studied. Two (P and M) and one (P) input function models were applied in the kinetic studies. In receptor-rich regions, the distribution volumes in nondisplaceable compartments were fixed to those in cerebellum. In addition, in the two input function model, K(1)(P)/K(1)(M) was fixed to the values in the cerebellum. The one input function model provided V'(3) values (=f(1)*B'(max)/K(D)) which were consistent with those obtained in equilibrium studies in both receptor-rich regions, while the two input function model provided consistent values only in striatum. Poor identifiability of the rate constants of metabolites seemed to be the source of errors in the two input function model. These results suggest that correct V'(3) values can be obtained with the one input function model both in high- and low-density regions.


Neonatal thrombo-embolism: risk factors, clinical features and outcome.
There are few data with respect to prothrombotic risk factors in neonates. To determine the associated risk factors, clinical features and outcome in newborn infants diagnosed with thrombo-embolism. Case records of 25 infants (17 full-term and eight preterm) diagnosed with thrombo-embolism between January 2005 and April 2008 in a neonatal intensive care unit were reviewed. Of the 25 infants, 18 cases of venous (72%) and seven of arterial (28%) thrombo-embolism were recorded; in 18 it was associated with central catheterisation. The sites of thrombosis were portal vein (15), right renal vein (one), right femoral vein (one), multiple veins (one), right femoral artery (3), right iliac artery (2), bilateral iliac and renal arteries (one) and left renal artery (one). Hereditary thrombotic mutations were detected in three patients and anticardiolipin antibody was detected in one, none of whom had been catheterised. The remaining three non-catheterised patients had perinatal risk factors. Venous catheter placement was undertaken in 12 patients (48%), eleven of whom had: umbilical venous catheterisation for exchange transfusion (9), partial exchange transfusion (one) and venous access (one), and one had femoral venous catheterisation for an angiographic study. Arterial catheterisation was undertaken in seven patients (28%) (one infant had both umbilical venous and arterial catheters) for angiographic studies (5) and blood sampling (2). Of the 18 catheterised patients (72%), thrombophilic studies were undertaken in 13 and none had abnormal results. Additional perinatal risk factors were present in 18 patients (72%) and included prematurity (8), congenital heart disease (8), septicaemia (5), dehydration (3), respiratory distress syndrome (3), polycythemia (2), meconium aspiration syndrome (one), pneumonia (one), maternal diabetes (one), necrotising enterocolitis (one) and perinatal asphyxia (one). Although most of the patients recovered after anticoagulant or fibrinolytic therapy, the five (20%) deaths were associated mainly with underlying diseases. The most important risk factor for thrombo-embolic events in neonates is placement of central catheters and some perinatal prothrombotic conditions. Nevertheless, hereditary or acquired thrombophilic risk factors may also be a cause of thrombo-embolism.


The yfhQ gene of Escherichia coli encodes a tRNA:Cm32/Um32 methyltransferase.
Naturally occurring tRNAs contain numerous modified nucleosides. They are formed by enzymatic modification of the primary transcripts during the complex RNA maturation process. In model organisms Escherichia coli and Saccharomyces cerevisiae most enzymes involved in this process have been identified. Interestingly, it was found that tRNA methylation, one of the most common modifications, can be introduced by S-adenosyl-L-methionine (AdoMet)-dependent methyltransferases (MTases) that belong to two structurally and phylogenetically unrelated protein superfamilies: RFM and SPOUT. As a part of a large-scale project aiming at characterization of a complete set of RNA modification enzymes of model organisms, we have studied the Escherichia coli proteins YibK, LasT, YfhQ, and YbeA for their ability to introduce the last unassigned methylations of ribose at positions 32 and 34 of the tRNA anticodon loop. We found that YfhQ catalyzes the AdoMet-dependent formation of Cm32 or Um32 in tRNASer1 and tRNAGln2 and that an E. coli strain with a disrupted yfhQ gene lacks the tRNA:Cm32/Um32 methyltransferase activity. Thus, we propose to rename YfhQ as TrMet(Xm32) according to the recently proposed, uniform nomenclature for all RNA modification enzymes, or TrmJ, according to the traditional nomenclature for bacterial tRNA MTases. Our results reveal that methylation at position 32 is carried out by completely unrelated TrMet(Xm32) enzymes in eukaryota and prokaryota (RFM superfamily member Trm7 and SPOUT superfamily member TrmJ, respectively), mirroring the scenario observed in the case of the m1G37 modification (introduced by the RFM member Trm5 in eukaryota and archaea, and by the SPOUT member TrmD in bacteria).


Universal Hitting Time Statistics for Integrable Flows.
The perceived randomness in the time evolution of "chaotic" dynamical systems can be characterized by universal probabilistic limit laws, which do not depend on the fine features of the individual system. One important example is the Poisson law for the times at which a particle with random initial data hits a small set. This was proved in various settings for dynamical systems with strong mixing properties. The key result of the present study is that, despite the absence of mixing, the hitting times of integrable flows also satisfy universal limit laws which are, however, not Poisson. We describe the limit distributions for "generic" integrable flows and a natural class of target sets, and illustrate our findings with two examples: the dynamics in central force fields and ellipse billiards. The convergence of the hitting time process follows from a new equidistribution theorem in the space of lattices, which is of independent interest. Its proof exploits Ratner's measure classification theorem for unipotent flows, and extends earlier work of Elkies and McMullen.


A3 adenosine receptor agonist IB-MECA reduces myocardial ischemia-reperfusion injury in dogs.
We examined the effect of the A3 adenosine receptor (AR) agonist IB-MECA on infarct size in an open-chest anesthetized dog model of myocardial ischemia-reperfusion injury. Dogs were subjected to 60 min of left anterior descending (LAD) coronary artery occlusion and 3 h of reperfusion. Infarct size and regional myocardial blood flow were assessed by macrohistochemical staining with triphenyltetrazolium chloride and radioactive microspheres, respectively. Four experimental groups were studied: vehicle control (50% DMSO in normal saline), IB-MECA (100 microg/kg iv bolus) given 10 min before the coronary occlusion, IB-MECA (100 microg/kg iv bolus) given 5 min before initiation of reperfusion, and IB-MECA (100 microg/kg iv bolus) given 10 min before coronary occlusion in dogs pretreated 15 min earlier with the ATP-dependent potassium channel antagonist glibenclamide (0.3 mg/kg iv bolus). Administration of IB-MECA had no effect on any hemodynamic parameter measured including heart rate, first derivative of left ventricular pressure, aortic pressure, LAD coronary blood flow, or coronary collateral blood flow. Nevertheless, pretreatment with IB-MECA before coronary occlusion produced a marked reduction in infarct size ( approximately 40% reduction) compared with the control group (13.0 +/- 3.2% vs. 25.2 +/- 3.7% of the area at risk, respectively). This effect of IB-MECA was blocked completely in dogs pretreated with glibenclamide. An equivalent reduction in infarct size was observed when IB-MECA was administered immediately before reperfusion (13.1 +/- 3.9%). These results are the first to demonstrate efficacy of an A3AR agonist in a large animal model of myocardial infarction by mechanisms that are unrelated to changes in hemodynamic parameters and coronary blood flow. These data also demonstrate in an in vivo model that IB-MECA is effective as a cardioprotective agent when administered at the time of reperfusion.


The International Collaboration for Cancer Classification and Research.
Gaps in the translation of research findings to clinical management have been recognized for decades. They exist for the diagnosis as well as the management of cancer. The international standards for cancer diagnosis are contained within the World Health Organization (WHO) Classification of Tumours, published by the International Agency for Research on Cancer (IARC) and known worldwide as the WHO Blue Books. In addition to their relevance to individual patients, these volumes provide a valuable contribution to cancer research and surveillance, fulfilling an important role in scientific evidence synthesis and international standard setting. However, the multidimensional nature of cancer classification, the way in which the WHO Classification of Tumours is constructed, and the scientific information overload in the field pose important challenges for the translation of research findings to tumour classification and hence cancer diagnosis. To help address these challenges, we have established the International Collaboration for Cancer Classification and Research (IC3 R) to provide a forum for the coordination of efforts in evidence generation, standard setting and best practice recommendations in the field of tumour classification. The first IC3 R meeting, held in Lyon, France, in February 2019, gathered representatives of major institutions involved in tumour classification and related fields to identify and discuss translational challenges in data comparability, standard setting, quality management, evidence evaluation and copyright, as well as to develop a collaborative plan for addressing these challenges.


[Epidemiology of stroke in Siberia].
Based on WHO MONICA methods and diagnostic criteria, it is shown that first-ever stroke incidence and mortality in Siberia (a total number of residents included in the analysis varied from 450,000 to about 800,000) that are among the highest in the world. In Novosibirsk, for the period from 1982 through 1991 there was a trend towards decreasing stroke incidence and mortality rates, but for the period from 1992 through 1997 there was a trend towards increasing there rates in both men and women. Age-standardized (US white population was used as a standard) stroke incidence rates increased from west to east and from south to north across Siberia, with a corresponding increase in the proportion of hemorrhagic strokes. In 1987-1988, age-adjusted stroke incidence rate in Novosibirsk was 212 per 100,000 residents per year, in Krasnoyarsk--325, in Tynda--329, in Anadyr--348. Stroke-case fatality rates ranged from 28% in Tynda to 41% in Anadyr. A multivariate regression analysis revealed that hypertension, left ventricular hypertrophy, ischemic heart disease. mitral valve disease, current cigarette smoking, excessing body mass index, winter season, and low ambient temperature are all significant and independent risk factors for the occurrence of ischemic stroke in Novosibirsk. A significant association between stroke occurrence and air pressure/geomagnetic activity change was found. Possible reasons for such unfavorable trends in stroke incidence in Siberia are discussed, and an optimal approach for improving organization of cerebrovascular disease care is suggested.


Long-term neurodevelopment of children exposed in utero to ciclosporin after maternal renal transplant.
Immunosuppressant therapy is essential in the prevention of organ transplant rejection. To evaluate the long-term neurodevelopmental outcomes of children following in utero ciclosporin (cyclosporine) exposure after maternal renal transplantation. A cohort study with matched controls using a prospectively collected database was conducted to assess neurocognitive and behavioral outcomes using standardized measures. Thirty-nine children exposed in utero to ciclosporin therapy following maternal renal transplantation were assessed (15 single pregnancies, 24 multiple pregnancies) and compared with 38 matched unexposed children. Intelligence, visuomotor abilities, and psychologic adjustment were measured using the Wechsler Preschool and Primary Scale of Intelligence-Revised (WPPSI-R), the Beery Developmental Test of Visual-Motor Integration (VMI-4) and the Wide Range Assessment of Visual Motor Abilities (WRAVMA), and the Child Behavior Checklist (CBCL), respectively. Statistical analysis, including regression, was performed to determine the significant predictors for the main outcome, full-scale IQ (FIQ). There were no significant differences in FIQ, verbal IQ (VIQ), performance IQ (PIQ) or behavioral outcomes between exposed and unexposed children or between single and multiple delivery groups. Thirty-three percent of exposed children were premature versus 0.5% in unexposed controls (p < 0.01). Prematurity was associated with low birthweight, high rates of perinatal complications, and instrumental deliveries. Relative to full-term children, premature, low birthweight children in the ciclosporin-exposed group had significantly lower FIQ and VIQ scores (101.04 vs 111.31 [p = 0.008] and 102.31 vs 113.08 [p = 0.021], respectively). Maternal IQ and socioeconomic status were positive and significant predictors for children's IQ (p < 0.001 and p = 0.03, respectively). There were no statistically significant differences in exposed children's IQ who were and were not breastfed. In this cohort, there was no association between in utero exposure to ciclosporin and long-term neurocognitive and behavioral development in children after maternal renal transplantation. Maternal IQ and socioeconomic status are positive predictors for children's intelligence. However, maternal renal transplantation and associated co-morbidity is associated with higher rates of premature delivery and consequent poorer neurocognitive and behavioral outcomes. Proper management of maternal morbidity and improved obstetric care may improve the child's profile.


Atrial myocardial deformation properties are temporarily reduced after cardioversion for atrial fibrillation and correlate well with left atrial appendage function.
This study was conducted to evaluate whether left atrial strain and strain rate correlate well with transesophageal parameters of stunning after atrial fibrillation. Twenty-two consecutive patients with chronic atrial fibrillation >/=3 months and <1 year were enrolled in the study. Transthoracic (TTE) and transesophageal (TEE) echocardiography with color Doppler myocardial imaging were performed before, 1 day after and 10 days after successful cardioversion. Left atrial transthoracic strain (S) and strain rate (SR) from lateral, inferior and anterior atrial walls, left atrial appendage tissue velocities, strain and strain rate values were measured with offline analysis. Left atrial appendage emptying (LAAEV) and filling (LAAFV) velocities were obtained from transesophageal echocardiography. Left atrial transthoracic, and left atrial appendage strain and strain rates were significantly lower following 1 day after cardioversion (TTE S/SR, 5.0 +/- 2.8%/2.3 +/- 1.0; TEE (septal) S/SR, 7.6 +/- 3.6%/1.6 +/- 0.7). There was a good correlation between these parameters and LAAEV (LA systolic strain and LAAEV, r = 0.73, P = 0.007). Left atrial and LAA strain and strain rate values improved over time, and correlated well with LAAEV, measured 10 days after cardioversion. Transthoracic atrial and TEE LAA strain and strain rate, which are quantitative measures of atrial function, are reduced after cardioversion, and recover subsequently. The good correlation between LAA function and TTE strain and strain rate suggests that TTE atrial parameters may help determine duration of anticoagulation.


Quantitative nested PCR for human cytomegalovirus DNA: analysis using NucleoScan 2001.
A quantitative nested DNA PCR for human cytomegalovirus (CMV) was developed using PCR mimic DNA as an internal standard. A combination of ultra-thin gel and enhanced detection of ethidium bromide-stained PCR bands allowed us to achieve a 25-fold increase in sensitivity over the conventional gel electrophoreses, down to 0.1 ng of DNA per band. When the technique was applied to measuring CMV load in CMV positive leucocyte DNA preparations its sensitivity spanned the range from single to hundreds of CMV DNA copies in 0.1 microg of total white blood cell DNA.


Copper-catalyzed asymmetric conjugate addition of organometallic reagents to extended Michael acceptors.
The copper-catalyzed asymmetric conjugate addition (ACA) of nucleophiles onto polyenic Michael acceptors represents an attractive and powerful methodology for the synthesis of relevant chiral molecules, as it enables in a straightforward manner the sequential generation of two or more stereogenic centers. In the last decade, various chiral copper-based catalysts were evaluated in combination with different nucleophiles and Michael acceptors, and have unambiguously demonstrated their usefulness in the control of the regio- and enantioselectivity of the addition. The aim of this review is to report recent breakthroughs achieved in this challenging field.


Effect of variable energy served on 24-hour energy intake in 16 preschools, Chicago, Illinois, 2007.
The effect of varying portion size in a natural environment on the self-regulation of 24-hour energy intake has not been evaluated. We studied students at 16 preschools in Chicago to determine the effect of meals with variable energy and macronutrients on the amount consumed over a 24-hour period (ie, at preschool and outside of preschool). The food items and portion sizes served at 16 preschools in the Chicago Public Schools early childhood education programs were observed for 3 to 8 days. Children were assessed for total energy and selected macronutrients consumed at preschool and outside of preschool for a 24-hour period; their data were pooled and reported by school. The students were predominantly African American (96%); on average, 32 students (range, 21-38) participated at each of the 16 preschools, and the age range of students was 4.0 to 4.5 years. The energy served at preschools ranged from 48% to 90% of the daily recommended energy allowance (REA). The mean energy intake at school was significantly higher (39% of REA) at 2 preschools, including 1 that served 90% of the REA. Mean energy consumption outside of preschool and total 24-hour energy consumption did not differ by preschool, adjusting for body mass index z score and sex. The preschools served meals that widely varied by portion size and energy; however, this variation did not result in differences in mean 24-hour nutrient intakes for the students attending these schools.


TBX4 is involved in the super-enhancer-driven transcriptional programs underlying features specific to lung fibroblasts.
Lung fibroblasts participate in the pathogenesis of respiratory diseases, including lung cancer and pulmonary fibrosis. Although fibroblasts are ubiquitous constituents of various organs, their cellular diversity among different organs has been poorly characterized. Here, we aimed to investigate the distinct gene signature of lung fibroblasts that represents its pulmonary origin and the underlying gene regulatory networks. Promoter-level differential expression analysis by cap analysis of gene expression (CAGE) sequencing revealed distinct gene expression patterns of fibroblasts derived from different anatomical sites and identified 88 coding genes with higher expression in lung fibroblasts relative to other fibroblasts. Multiple key transcription factors important for lung mesenchyme development, including the T-box transcription factors TBX2, TBX4, and TBX5 were enriched in this lung-specific signature and were associated with super-enhancers. TBX4 showed highly specific expression in lung fibroblasts and was required for cell proliferation and collagen gel contraction capacity. Transcriptome analysis revealed that TBX4 could broadly regulate fibroblast-related pathways and partly contribute to super-enhancer-mediated transcriptional programs. Of pathological importance, lung fibroblast-specific genes were globally downregulated in lung cancer-associated fibroblasts (CAFs). Notably, TBX2, TBX4, and TBX5 were downregulated and hypermethylated in lung CAFs, suggesting an association between epigenetic silencing of these factors and phenotypic alteration of lung fibroblasts in cancer. Our study highlights the importance of T-box transcription factors, especially TBX4, and super-enhancers in the roles of lung fibroblasts in pulmonary physiology and pathogenesis.


Antiphospholipid syndrome and cutaneous vasoocclusive disorders.
The antiphospholipid syndrome (characterized by the presence of circulating lupus anticoagulants or anticardiolipin antibodies) was first recognized in patients with systemic lupus erythematosus (SLE), but the syndrome can also exist in the absence of SLE. The clinical features include arterial or venous thrombosis, recurrent abortion, neurological problems, and various cutaneous disorders including thrombophlebitis, livedo reticularis, atrophie blanche, leg ulcers, and gangrene. In some cases, antiphospholipid antibodies may play a role with other recognized syndromes characterized by vascular occlusion, such as Sneddon's syndrome (livedo reticularis with cerebrovascular occlusion) and Degos' disease.


Mechanism of interaction of ticlopidine and its analogues with the energy-conserving mechanism in mitochondria.
It was shown recently that the antiaggregating agent ticlopidine and some of its analogues inhibit the energy-conserving mechanism in mitochondria [Abou-Khalil et al., Biochem. Pharmac. 33, 3893 (1984)]. In the present investigation, the mechanism of inhibition by these drugs was investigated by studying their effects on key reactions of oxidative phosphorylation. Liver mitochondria were isolated from Sprague-Dawley male rats, and the interactions of ticlopidine and six of its analogues with those key reactions were tested. We found: The transport of phosphate, glutamate and succinate into mitochondria was not affected significantly by ticlopidine or any of its analogues; however, it was inhibited by both mersalyl and N-ethylmaleimide as expected. There was no inhibitory effect of the tested drugs on the mitochondrial [3H]ADP translocation activity; rather, ticlopidine produced a concentration-dependent increase of that activity, reaching 54% with 20 micrograms/ml. Ticlopidine and its analogue, PCR 5325, increased the latent ATPase activity by about 400% and the DNP-dependent ATPase by about 50%. Also, PCR 4099 caused a 115% increase in the latent activity, whereas the effects of the remaining analogues varied from slight activation to slight inhibition. Under nonphosphorylation conditions, the mitochondrial H+ extrusion resulting from succinate oxidation was inhibited by ticlopidine in a concentration-dependent manner reaching a quasi total inhibition with 40 micrograms/ml. While PCR 5325 gave results similar to ticlopidine, PCR 4099 was less inhibitory and the other analogues were ineffective. These data indicate that the inhibitory action caused by ticlopidine and some of its analogues on oxidative phosphorylation does not reside at one particular site in the mitochondrial membrane; rather, the inhibition seems to be the outcome of profound alterations in mitochondrial ADP translocase, latent ATPase, and proton translocation in the respiratory chain.


Pharmacist comprehensive review of treatment compared with STOPP-START criteria to detect potentially inappropriate prescription in older complex patients.
To compare potentially inappropriate prescribing (PIP) according to the clinical judgement of the pharmacist with PIP according to explicit STOPP-START criteria in institutionalised and hospitalised patients with multiple pathologies. To describe and compare the main pharmacological groups involved and determine the factors associated with the detection of PIP in these patients. A prospective multicentre observational study of institutionalised and hospitalised multipathology patients aged >65 years. A specialised pharmacist used his best clinical judgement to detect PIP based on a comprehensive review of the complete chronic treatment of patients, which is an essential activity in interdisciplinary care. STOPP-START criteria were used as an aid tool to detect PIP. The main variable was the number of PIP incidents detected. Detected PIP incidents were analysed in 338 patients. Clinical judgement detected more PIP incidents (35%) than did STOPP-START criteria. More PIP incidents unrelated to these criteria were detected in institutionalised patients than in hospitalised patients. Clinical judgement mainly detected PIP incidents related to incorrect doses and drug interactions (p<0.001); however, STOPP-START criteria mainly detected PIP incidents related to drug duplication and insufficiently treated diagnosis or symptoms (p=0.001 and p<0.001). In total, 93.8% of the PIP incidents were detected in polypharmacy patients (≥5 drugs). Institutionalised and high-level polypharmacy (≥10 drugs) patients were at the highest risk of PIP. A large number of PIP incidents were detected in institutionalised and hospitalised patients with multiple pathologies. The inclusion of a pharmacist in the multidisciplinary team facilitated the detection of PIP incidents, particularly in the institutionalised population and patients treated with high-level polypharmacy which were not detected by explicit STOPP-START criteria.


[Tumor markers in C-cell cancer].
C-cell carcinoma (medullary thyroid carcinoma) is associated with increased serum calcitonin levels. In addition, increased serum levels of other tumour markers are also found: carcinoembryonic antigen (CEA), adrenocorticotrophic hormone (ACTH) and tissue polypeptide antigen (TPA). The relevance of these tumour markers as compared to calcitonin was evaluated in 46 patients with C-cell carcinoma. With decreasing frequency pathologically increased levels were found: calcitonin 93%, CEA 73%, TPA 17% and ACTH 8%. There was a positive correlation between calcitonin and CEA values. Calcitonin and CEA levels correlated with the clinical tumour stage. In selective venous catheterisation estimation of calcitonin is superior to estimation of CEA. Assessment of CEA supplements calcitonin measurements in follow-up controls and evaluation of success of treatment. As regards specificity and sensitivity calcitonin is superior to all other tested tumour markers in C-cell carcinoma.


Inhibition of mouse SP2/0 myeloma cell growth by the B7-H4 protein vaccine.
B7-H4 is a member of B7 family of co-inhibitory molecules and B7-H4 protein is found to be overexpressed in many human cancers and which is usually associated with poor survival. In this study, we developed a therapeutic vaccine made from a fusion protein composed of a tetanus toxoid (TT) T-helper cell epitope and human B7-H4IgV domain (TT-rhB7-H4IgV). We investigated the anti-tumor effect of the TT-rhB7-H4IgV vaccine in BALB/c mice and SP2/0 myeloma growth was significantly suppressed in mice. The TT-rhB7-H4IgV vaccine induced high-titer specific antibodies in mice. Further, the antibodies induced by TT-rhB7-H4IgV vaccine were capable of depleting SP2/0 cells through complement-dependent cytotoxicity (CDC) in vitro. On the other hand, the poor cellular immune response was irrelevant to the therapeutic efficacy. These results indicate that the recombinant TT-rhB7-H4IgV vaccine might be a useful candidate of immunotherapy for the treatment of some tumors associated with abnormal expression of B7-H4.


LSTrAP-Cloud: A User-Friendly Cloud Computing Pipeline to Infer Coexpression Networks.
As genomes become more and more available, gene function prediction presents itself as one of the major hurdles in our quest to extract meaningful information on the biological processes genes participate in. In order to facilitate gene function prediction, we show how our user-friendly pipeline, the Large-Scale Transcriptomic Analysis Pipeline in Cloud (LSTrAP-Cloud), can be useful in helping biologists make a shortlist of genes involved in a biological process that they might be interested in, by using a single gene of interest as bait. The LSTrAP-Cloud is based on Google Colaboratory, and provides user-friendly tools that process quality-control RNA sequencing data streamed from the European Nucleotide Archive. The LSTRAP-Cloud outputs a gene coexpression network that can be used to identify functionally related genes for any organism with a sequenced genome and publicly available RNA sequencing data. Here, we used the biosynthesis pathway of Nicotiana tabacum as a case study to demonstrate how enzymes, transporters, and transcription factors involved in the synthesis, transport, and regulation of nicotine can be identified using our pipeline.


Influence of transitional care on the clinical manifestations among patients with COVID‑19: A single‑center, double‑blinded, randomized survey.
Pneumonia and acute respiratory distress syndrome are the major complications of coronavirus disease 2019 (COVID-19). Transitional care is indispensable in successfully transitioning patients with COVID-19 from hospital to home and preventing adverse events of this disease. The purpose of the present study was to analyze the effects of transitional care on improvements in inflammation and pulmonary function in patients with COVID-19. Data of all hospitalized patients with COVID-19 (n=242) discharged from Mudanjiang Medical University (Mudanjiang, China) between May 2020 and October 2020 were retrospectively collected. Patients with COVID-19 had been hospitalized and assigned to receive transitional care (n=126) or usual care (n=116) and were followed up for 12 months. Hospital stay, inflammation and pulmonary function were compared in patients with COVID-19 between the transitional care and usual care group. Transitional care significantly improved physical symptoms, anxiety, depression and empathy of the patients for other patients affected. Compared to the usual care group, marked improvements in typical symptoms, including dyspnea, asthenia, cough, nausea, chest pain, myalgia, headache, fever, diarrhea, chest pain, dizziness, conjunctivitis, as well as disorders of smell and taste, were observed in the transitional care group. Patients in the transitional care group had a shorter hospital stay than those patients in the usual care group. Furthermore, transitional care decreased inflammation and ameliorated pulmonary function in patients with COVID-19. In conclusion, transitional care has an essential role in the improvement of physical symptoms, inflammation and pulmonary function in patients with COVID-19 [Chinese Clinical Trial Registry (ChiCTR) registration no. ChiCTR2200060295; 26.05.2022].


The evolution of extracellular matrix.
We present a perspective on the molecular evolution of the extracellular matrix (ECM) in metazoa that draws on research publications and data from sequenced genomes and expressed sequence tag libraries. ECM components do not function in isolation, and the biological ECM system or "adhesome" also depends on posttranslational processing enzymes, cell surface receptors, and extracellular proteases. We focus principally on the adhesome of internal tissues and discuss its origins at the dawn of the metazoa and the expansion of complexity that occurred in the chordate lineage. The analyses demonstrate very high conservation of a core adhesome that apparently evolved in a major wave of innovation in conjunction with the origin of metazoa. Integrin, CD36, and certain domains predate the metazoa, and some ECM-related proteins are identified in choanoflagellates as predicted sequences. Modern deuterostomes and vertebrates have many novelties and elaborations of ECM as a result of domain shuffling, domain innovations and gene family expansions. Knowledge of the evolution of metazoan ECM is important for understanding how it is built as a system, its roles in normal tissues and disease processes, and has relevance for tissue engineering, the development of artificial organs, and the goals of synthetic biology.


Circadian rhythms in Limulus photoreceptors. I. Intracellular studies.
The sensitivity of the lateral eye of the horseshoe crab, Limulus polyphemus, is modulated by efferent optic nerve impulses transmitted from a circadian clock located in the brain (Barlow, R. B., Jr., S. J. Bolanowski, and M. L. Brachman. 1977. Science. 197:86-89). At night, the efferent impulses invade the retinular, eccentric, and pigment cells of every ommatidium, inducing multiple anatomical and physiological changes that combine to increase retinal sensitivity as much as 100,000 times. We developed techniques for recording transmembrane potentials from a single cell in situ for several days to determine what circadian changes in retinal sensitivity originate in the primary phototransducing cell, the retinular cell. We found that the direct efferent input to the photoreceptor cell decreases its noise and increases its response. Noise is decreased by reducing the rate of spontaneous bumps by up to 100%. The response is increased by elevating photon catch (photons absorbed per flash) as much as 30 times, and increasing gain (response per absorbed photon) as much as 40%. The cellular mechanism for reducing the rate of spontaneous quantum bumps is not known. The mechanism for increasing gain appears to be the modulation of ionic conductances in the photoreceptor cell membrane. The mechanism for increasing photon catch is multiple changes in the anatomy of retinal cells. We combine these cellular events in a proposed scheme for the circadian rhythm in the intensity coding of single photoreceptors.


What are the core ideas behind the Precautionary Principle?
The Precautionary Principle is both celebrated and criticized. It has become an important principle for decision making, but it is also subject to criticism. One problem that is often pointed out with the principle is that is not clear what it actually says and how to use it. I have taken on this problem by performing an analysis of some of the most influential formulations of the principle in an attempt to identify the core ideas behind it, with the purpose of producing a formulation of the principle that is clear and practically applicable. It was found that what is called the Precautionary Principle is not a principle that tells us what do to achieve extra precaution or how to handle situations when extra precaution is called for. Instead, it was found to be a list of circumstances that each justify extra precaution. An analysis of some of the most common and influential formulations of the Precautionary Principle identified four such circumstances: (1) When we deal with important values that tend to be systematically downplayed by traditional decision methods - such as human health and the environment. (2) When we suspect that the decision might lead to irreversible and severe consequences and the values at stake are also irreplaceable, (3) When timing is at least as important as being right. (4) When it is more important to avoid false negatives than false positives. This interpretation of the Precautionary Principle does not say anything about what kind of actions to take when extra precaution is called for, but it does provide a clear and practically useful list of circumstances that call for extra precaution and that is not subject to the most common objections to the Precautionary Principle.


The effect of cicloxolone sodium on the replication of vesicular stomatitis virus in BSC-1 cells.
The effect of cicloxolone sodium (CCX) on the replication of vesicular stomatitis virus (VSV) was investigated. The drug was active during all stages of the virus replication cycle, indicating that it does not operate by the specific inhibition of any single essential virus gene product. The drug reduced the number of VSV particles assembled and released by 100- to 1000-fold. Infectious virus yield was reduced 1000- to 10000-fold, giving a 10-fold or greater increase in the particle/p.f.u. ratio. The reduced number of virus particles produced in the presence of CCX results from two superimposed effects: suppression of VSV secondary transcription and viral protein synthesis, and perturbation of virion assembly. The inhibition of VSV assembly is due to impairment of a Golgi apparatus function related to transport of VSV glycoprotein G to the cell surface, and is characterized by accumulation of viral G and M proteins within the cell. Incubation of VSV-infected cells in the presence of two glycosylation inhibitors, tunicamycin and monensin, similarly leads to intracellular accumulation of G and M proteins, suggesting a common mechanism of action affecting VSV virion assembly. The differential effect of CCX concentration on intracellular levels of the L, N and NS proteins was analysed. CCX also possesses a virucidal effect on mature infectious VSV particles in suspension, 300 microM reducing the VSV titre about 10-fold in 24 h at 4 degrees C or 37 degrees C. The mode of antiviral activity against VSV is compared with that against herpes simplex virus.


Birth cohort colorectal cancer (CRC): implications for research and practice.
Colorectal cancer (CRC) epidemiology is changing due to a birth cohort effect, first recognized by increasing incidence of early onset CRC (EOCRC, age < 50 years). In this paper, we define "birth cohort CRC" as the observed phenomenon, among individuals born 1960 and later, of increasing CRC risk across successive birth cohorts, rising EOCRC incidence, increasing incidence among individuals age 50-54 years, and flattening of prior decreasing incidence among individuals age 55-74 years. We demonstrate birth cohort CRC is associated with unique features, including increasing rectal cancer (greater than colon) and distant (greater than local) stage CRC diagnosis, and increasing EOCRC across all racial/ethnic groups. We review potential risk factors, etiologies, and mechanisms for birth cohort CRC, using EOCRC as a starting point and describing importance of viewing these through the lens of birth cohort. We also outline implications of birth cohort CRC for epidemiologic and translational research, as well as current clinical practice. We postulate that recognition of birth cohort CRC as an entity - including and extending beyond rising EOCRC - can advance understanding of risk factors, etiologies, and mechanisms, and address the public health consequences of changing CRC epidemiology.


Role of reactive oxygen species and antioxidants in plant disease resistance.
Membrane damage caused by the non-specific fungal toxin fusaric acid was less on pretreated than on control leaves when tobacco leaves were pretreated with anti-senescence plant hormones, such as kinetin, benzyladenine or the anti-ozonant N-[2-(2-oxo-1-imidazolidinyl)]ethyl-N'-phenylurea. Similarly, the necrosis caused by mercuric chloride was reduced by the above anti-senescence agents. In addition, in in vitro tests, leaves from selected paraquat-tolerant tobacco plants were less sensitive to Alternaria alternata (Fr) Keissler infection than those of the control paraquat-sensitive tobacco leaves. Paraquat-tolerant Conyza canadensis (L) Cronq weeds naturally selected in vineyards in Hungary showed similar inhibition of senescence to paraquat-tolerant tobacco, expressed as more green leaves and slower development. In accordance with this, the paraquat-tolerant Conyza leaves remained almost symptomless, while paraquat-sensitive plants showed severe symptoms after infection with Botrytis cinerea Pers. Oxidative burst (accumulation of hydrogen peroxide) was attenuated in TMV-infected leaves of Xanthi-nc tobacco as a result of treatment with salicylic acid or in leaves where systemic acquired resistance (SAR) had been induced by a previous TMV infection. Accordingly, superoxide dismutase (SOD) activity was higher in Xanthi tobacco leaves with SAR than without SAR. However, in NahG tobacco, in which SAR cannot develop, there was no augmentation of SOD activity. All the above data support the significance of delayed senescence and antioxidants in the resistance of plants to biotic and abiotic necrosis-inducing agents.


The Flexibility Scale: Development and Preliminary Validation of a Cognitive Flexibility Measure in Children with Autism Spectrum Disorders.
Flexibility is a key component of executive function, and is related to everyday functioning and adult outcomes. However, existing informant reports do not densely sample cognitive aspects of flexibility; the Flexibility Scale (FS) was developed to address this gap. This study investigates the validity of the FS in 221 youth with ASD and 57 typically developing children. Exploratory factor analysis indicates a five-factor scale: Routines/rituals, transitions/change, special interests, social flexibility, and generativity. The FS demonstrated convergent and divergent validity with comparative domains of function in other measures, save for the Generativity factor. The FS discriminated participants with ASD and controls. Thus, this study suggests the FS may be a viable, comprehensive measure of flexibility in everyday settings.


The effect of exposure duration on the biological activity of mobile telephony radiation.
In the present experiments we studied the effects of different durations of a single (continuous), daily exposure, ranging from 1 min up to 21 min, to the two established systems of digital mobile telephony radiation that are commonly used in Europe, viz. GSM 900 MHz (Global System for Mobile telecommunications) and DCS 1800 MHz (Digital Cellular System-referred to also as GSM 1800 MHz), on a well-tested biological model, the reproductive capacity of the insect Drosophila melanogaster. The insects were exposed to each type of radiation at an intensity of about 10 microW/cm(2), corresponding to a distance of 20 or 30 cm from the antenna of a DCS 1800 or a GSM 900 mobile phone handset, respectively. At these distances the bioactivity of mobile telephony radiation was found to be at a maximum due to the existence of a "window" of increased bioactivity around this value, as we have shown recently [1-4]. The results show that the reproductive capacity decreases almost linearly with increasing exposure duration to both GSM 900 and DCS 1800 radiation, suggesting that short-term exposures to these radiations have cumulative effects on living organisms. Additionally, our results show again that GSM 900 MHz radiation is slightly more bioactive than DCS 1800 MHz radiation, at the same exposure durations and under equal radiation intensities, as shown in our previous experiments [5].


Target volume and position variations during intensity-modulated radiotherapy for patients with nasopharyngeal carcinoma.
Considerable anatomical changes occur during intensity-modulated radiotherapy (IMRT) for nasopharyngeal carcinoma (NPC). This study aimed to quantify volumetric and positional variations of the target volume during IMRT. Twenty patients with locally advanced NPC who received concurrent (13 patients) or sequential (seven patients) chemoradiotherapy were prospectively recruited and underwent planning computed tomography (CT) and six repeat CTs (every five fractions). Each repeat CT was rigidly registered to the planning CT. Gross tumor volume (GTV) and elective clinical target volume (CTV) were manually delineated on each axial CT image. CTVs of the primary tumor and lymph nodes were expanded with 5 mm margins to corresponding GTVs, with necessary modifications. Volume loss, system and random errors, and the mean and three-dimensional vector displacements were calculated and compared statistically. Volumes of the primary tumor and small (>1 cm, ≤3 cm) and large (>3 cm) positive neck lymph nodes decreased at a rate of 2.6%, 3.7%, and 3.9% per treatment day, respectively. CTVs of the primary tumor, lymph nodes, and elective region decreased 1.5%, 2.3%, and 0.3% per treatment day, respectively. Average displacements of the GTVs and CTVs were <1.3 mm in all directions. GTVs and CTVs of the large and small lymph nodes shifted medially by 0.8-1.3 and 0.6-1.2 mm, respectively, on average. Average three-dimensional displacements of the GTVs and CTVs were 3.4-4.3 mm and 2.5-3.7 mm, respectively. Volume loss and displacements in most directions were significantly larger in patients receiving concurrent chemoradiotherapy than in those receiving sequential therapy. Volume loss and displacements of the GTV of large nodes and elective CTV were significantly larger in male than in female patients. Volumetric and positional changes of the target volume were considerable, and volume loss increased as treatment time elapsed during IMRT for NPC.


Determinants of harmful use of alcohol among urban slum dwelling adults in Kenya.
Harmful alcohol use is a public health problem associated with negative health and socio-economic impacts. However, patterns and dynamics of alcohol use among slum-dwellers in Kenya are poorly understood. To establish determinants of harmful alcohol use among adults in an urban slum setting in Kenya. Cross-sectional study involving a consecutively selected sample (N=215) from Githurai, in Nairobi. A pre-tested questionnaire that captured data on socio-demographics, drinking patterns, type, reasons, initiator, and support system. Of the respondents, those above 31 years, married, separated/divorced/widowed, of high education, earning above 50 USD, and from dysfunctional families consumed more alcohol. Low earners consumed (p < 0.05) unrecorded while high earners drank (p< 0.001) recorded alcohol. Adults from families with a drinking father and sibling consumed more alcohol (p=0.001). Single, low educational attainment/earners, and those in dysfunctional families (p <0.05) drank due to stress and reported alcohol-related problems. Young, unmarried, and casual laborers were introduced (p < 0.05) to alcohol by friends. Socio-demographic, economic, familial, social interactions, and stress are associated with harmful alcohol use among adults from slums calling for interventions targeting these factors.


Impacts of serum P-selectin on blood pressure control after PCI in patients with coronary heart disease complicated with hypertension.
We analyzed the impact of potent anti-hypertension or anti-thrombotic therapy after PCI in patients with coronary heart disease complicated with hypertension, whilst to reflect the prognosis by testing P-selectin. A total of 177 patients with coronary heart disease (CHD) complicated with hypertension was continuously enrolled in this study and randomly divided into traditional anti-hypertension group (group A: 130/80 mm Hg ≤ BP ≤ 140/90 mm Hg; anti-hypertensive drugs: β blockers and angiotensin converting enzyme inhibitor, n=84) and potent anti-hypertension group (group B: BP <130/80 mm Hg; dosage and frequency in group B > group A, n=93). This study was approved by the Ethics Committee of Shaoxing People's Hospital. Signed written informed consents were obtained from all participants before the study. Patients who need a stent placed (CAG shows narrowed vascular diameter ≥75%) have to continuously be followed-up for one year. Standard anti-hypertension (fluctuation of BP <5 mm Hg measured for 3 successive days) was detected respectively at admission and inpatient. The blood pressure, low-density lipoprotein cholesterin (LDL-C), high-sensitivity C-reactive protein (hs-CRP) and P-selectin levels were tested 1 month and 1 year after discharge; the time of adverse events (AEs) was also recorded. There were no statistical differences between the occurrence times of AEs between group A and B (p=0.946). The P-selectin [(83±21) vs. (69±16) μg/L, p=0.038], systolic pressure [(134±8) vs. (119±13) mm Hg, p<0.001] and diastolic pressure [(85±6) vs. (70±5) mm Hg] in group A were higher (p=0.001) than those of group B. Compared with P-selectin ≥50.00 μg/L, the median survival time (>12 vs. 10 months, χ2=3.621, p=0.047) of P-selectin <50.00 μg/L was longer. By comparing P-selectin in different SBP grading (<120 mm Hg, 120-130 mm Hg, 130-140 mm Hg), the difference was statistically significant (χ2=12.912, p=0.002). Potent anti-hypertension may influence the occurrence time of AEs after PCI in patients with coronary heart disease complicated hypertension. P-selectin can be a sensitive indicator. SBP has an apparent "J-curve effect" and an appropriate anti-hypertensive scope (120-130 mm Hg).


Chemical cognition: chemoconnectomics and convergent evolution of integrative systems in animals.
Neurons underpin cognition in animals. However, the roots of animal cognition are elusive from both mechanistic and evolutionary standpoints. Two conceptual frameworks both highlight and promise to address these challenges. First, we discuss evidence that animal neural and other integrative systems evolved more than once (convergent evolution) within basal metazoan lineages, giving us unique experiments by Nature for future studies. The most remarkable examples are neural systems in ctenophores and neuroid-like systems in placozoans and sponges. Second, in addition to classical synaptic wiring, a chemical connectome mediated by hundreds of signal molecules operates in tandem with neurons and is the most information-rich source of emerging properties and adaptability. The major gap-dynamic, multifunctional chemical micro-environments in nervous systems-is not understood well. Thus, novel tools and information are needed to establish mechanistic links between orchestrated, yet cell-specific, volume transmission and behaviors. Uniting what we call chemoconnectomics and analyses of the cellular bases of behavior in basal metazoan lineages arguably would form the foundation for deciphering the origins and early evolution of elementary cognition and intelligence.


The changing face of functional foods.
Consumers began to view food from a radically different vantage point in the 1990s. This 'changing face' of food has evolved into an exciting area of the food and nutrition sciences known as functional foods. Functional foods can be defined as those providing health benefits beyond basic nutrition and include whole, fortified, enriched or enhanced foods which have a potentially beneficial effect on health when consumed as part of a varied diet on a regular basis at effective levels. Interest in functional foods skyrocketed in the last decade due to a number of key factors, including the growing self-care movement, changes in food regulations and overwhelming scientific evidence highlighting the critical link between diet and health. The interest in functional foods has resulted in a number of new foods in the marketplace designed to address specific health concerns, particularly as regards chronic diseases of aging. In addition to new foods designed specifically to enhance health, however, functional foods can also include those traditional, familiar foods for which recent research findings have highlighted new health benefits or dispelled old dogma about potential adverse health effects. An excellent example is the American egg-Nature's original functional food. Eggs have not traditionally been regarded as a functional food, primarily due to concerns about their adverse effects on serum cholesterol levels. Furthermore, it is now known that there is little if any connection between dietary cholesterol and blood cholesterol levels and consuming up to one or more eggs per day does not adversely affect blood cholesterol levels. Finally, eggs are an excellent dietary source of many essential (e.g., protein, choline) and non-essential (e.g., lutein/zeaxanthin) components which may promote optimal health. Nutrition in the new millennium will be dramatically different than it was in the 20th century. Completion of the human genome project will facilitate the identification of humans predisposed to diet-related diseases. Targeted or 'prescription' nutrition will become the norm, enabling the food and medical industries to provide timely and individualized approaches to disease prevention and health promotion. The egg will continue to play an important role in the changing face of functional foods.


Fasciola gigantica, F. hepatica and Fasciola intermediate forms: geometric morphometrics and an artificial neural network to help morphological identification.
Fasciola hepatica and F. gigantica cause fascioliasis in both humans and livestock. Some adult specimens of Fasciola sp. referred to as "intermediate forms" based on their genetic traits, are also frequently reported. Simple morphological criteria are unreliable for their specific identification. In previous studies, promising phenotypic identification scores were obtained using morphometrics based on linear measurements (distances, angles, curves) between anatomical features. Such an approach is commonly termed "traditional" morphometrics, as opposed to "modern" morphometrics, which is based on the coordinates of anatomical points. Here, we explored the possible improvements that modern methods of morphometrics, including landmark-based and outline-based approaches, could bring to solving the problem of the non-molecular identification of these parasites. F. gigantica and Fasciola intermediate forms suitable for morphometric characterization were selected from Thai strains following their molecular identification. Specimens of F. hepatica were obtained from the Liverpool School of Tropical Medicine (UK). Using these three taxa, we tested the taxonomic signal embedded in traditional linear measurements versus the coordinates of anatomical points (landmark- and outline-based approaches). Various statistical techniques of validated reclassification were used, based on either the shortest Mahalanobis distance, the maximum likelihood, or the artificial neural network method. Our results revealed that both traditional and modern morphometric approaches can help in the morphological identification of Fasciola sp. We showed that the accuracy of the traditional approach could be improved by selecting a subset of characters among the most contributive ones. The influence of size on discrimination by shape was much more important in traditional than in modern analyses. In our study, the modern approach provided different results according to the type of data: satisfactory when using pseudolandmarks (outlines), less satisfactory when using landmarks. The different reclassification methods provided approximately similar scores, with a special mention to the neural network, which allowed improvements in accuracy by combining data from both morphometric approaches. We conclude that morphometrics, whether traditional or modern, represent a valuable tool to assist in Fasciola species recognition. The general level of accuracy is comparable among the various methods, but their demands on skills and time differ. Based on the outline method, our study could provide the first description of the shape differences between species, highlighting the more globular contours of the intermediate forms.


Mechanisms of muscle degeneration, regeneration, and repair in the muscular dystrophies.
To withstand the rigors of contraction, muscle fibers have specialized protein complexes that buffer against mechanical stress and a multifaceted repair system that is rapidly activated after injury. Genetic studies first identified the mechanosensory signaling network that connects the structural elements of muscle and, more recently, have identified repair elements of muscle. Defects in the genes encoding the components of these systems lead to muscular dystrophy, a family of genetic disorders characterized by progressive muscle wasting. Although the age of onset, affected muscles, and severity vary considerably, all muscular dystrophies are characterized by muscle necrosis that overtakes the regenerative capacity of muscle. The resulting replacement of muscle by fatty and fibrous tissue leaves muscle increasingly weak and nonfunctional. This review discusses the cellular mechanisms that are primarily and secondarily disrupted in muscular dystrophy, focusing on membrane degeneration, muscle regeneration, and the repair of muscle.