Description of a new species of Anagyrus Howard (Hymenoptera: Chalcidoidea: Encyrtidae), a promising biological control agent of the invasive Madeira mealybug, Phenacoccus madeirensis Green (Hemiptera: Sternorrhyncha: Pseudococcidae).
Anagyrus amnestos sp. n. (Hymenoptera: Encyrtidae), a promising parasitoid of the invasive Madeira mealybug, Phenacoccus madeirensis Green (Hemiptera: Pseudococcidae), is described based on material collected from India. This parasitoid was identified as Anagyrus sp. nov. nr. sinope Noyes & Menezes in recent literature, and was initially collected in Georgia, USA. It was found to be a specific parasitoid of the Madeira mealybug and its biological attributes and potential as a biological control agent of this pest were studied. In what appears to be a case of fortuitous introduction, we detected this parasitoid in large numbers on Madeira mealybugs from the southern Indian state of Karnataka, where the mealybug is a recently introduced invasive pest. In view of its economic importance as a potential biological control agent of the Madeira mealybug, it is formally described and illustrated here. Comparative accounts of the new species vis-a-vis its close relatives in India and the Americas are provided.


Welfare Genome Project: A Participatory Korean Personal Genome Project With Free Health Check-Up and Genetic Report Followed by Counseling.
The Welfare Genome Project (WGP) provided 1,000 healthy Korean volunteers with detailed genetic and health reports to test the social perception of integrating personal genetic and healthcare data at a large-scale. WGP was launched in 2016 in the Ulsan Metropolitan City as the first large-scale genome project with public participation in Korea. The project produced a set of genetic materials, genotype information, clinical data, and lifestyle survey answers from participants aged 20-96. As compensation, the participants received a free general health check-up on 110 clinical traits, accompanied by a genetic report of their genotypes followed by genetic counseling. In a follow-up survey, 91.0% of the participants indicated that their genetic reports motivated them to improve their health. Overall, WGP expanded not only the general awareness of genomics, DNA sequencing technologies, bioinformatics, and bioethics regulations among all the parties involved, but also the general public's understanding of how genome projects can indirectly benefit their health and lifestyle management. WGP established a data construction framework for not only scientific research but also the welfare of participants. In the future, the WGP framework can help lay the groundwork for a new personalized healthcare system that is seamlessly integrated with existing public medical infrastructure.


Nanoimprinted distributed feedback lasers of solution processed hybrid perovskites.
Hybrid perovskite materials have considerable potential for light emitting devices such as LEDs and lasers. We combine solution processed CH3NH3PbI3 perovskite with UV nanoimprinted polymer gratings to fabricate distributed feedback (DFB) lasers. The lead acetate deposition route is shown to be an effective method for fabricating low-loss waveguides (loss coefficient ~6 cm-1) and highly compatible with the polymer grating substrates. The nanoimprinted perovskite exhibited single-mode band-edge lasing, confirmed by angle-dependent transmission measurements. Depending on the excitation pulse duration the lasing threshold shows a value of 110 μJ/cm2 under nanosecond pumping and 4 μJ/cm2 under femtosecond pumping. We demonstrate further that this laser has excellent stability with a lifetime of 108 pulses.


The Impact of Cesarean and Vaginal Delivery on Results of Psychological Cognitive Test in 5 Year Old Children.
Background and objectives: The impact of cesarean and vaginal delivery on cognitive development was analyzed in 5 year old children. Materials and Methods: Two cohorts of 5 year old children born in the years 2013 and 2014 in Karvina (Northern Moravia) and Ceske Budejovice (Southern Bohemia) were studied for their cognitive development related to vaginal (n = 117) and cesarean types of delivery (n = 51). The Bender Visual Motor Gestalt Test (BG test) and the Raven Colored Progressive Matrices (RCPM test) were used as psychological tests. Results: In the comparison of vaginal delivery vs. cesarean section, the children delivered by cesarean section scored lower and, therefore, achieved poorer performance in cognitive tests compared to those born by vaginal delivery, as shown in the RCPM (p < 0.001) and in the BG test (p < 0.001). When mothers' education level was considered, the children whose mothers achieved a university degree scored higher in both the RCPM test (p < 0.001) and the BG test (p < 0.01) compared to the children of mothers with lower secondary education. When comparing mothers with a university degree to those with higher secondary education, there was a significant correlation between level of education and score achieved in the RCPM test (p < 0.001), but not in the BG test. Conclusions: According to our findings, the mode of delivery seems to have a significant influence on performance in psychological cognitive tests in 5 year old children in favor of those who were born by vaginal delivery. Since cesarean-born children scored notably below vaginally born children, it appears possible that cesarean delivery may have a convincingly adverse effect on children's further cognitive development.


A few upstream bifurcations drive the spatial distribution of red blood cells in model microfluidic networks.
The physics of blood flow in small vessel networks is dominated by the interactions between Red Blood Cells (RBCs), plasma and blood vessel walls. The resulting couplings between the microvessel network architecture and the heterogeneous distribution of RBCs at network-scale are still poorly understood. The main goal of this paper is to elucidate how a local effect, such as RBC partitioning at individual bifurcations, interacts with the global structure of the flow field to induce specific preferential locations of RBCs in model microfluidic networks. First, using experimental results, we demonstrate that persistent perturbations to the established hematocrit profile after diverging bifurcations may bias RBC partitioning at the next bifurcations. By performing a sensitivity analysis based upon network models of RBC flow, we show that these perturbations may propagate from bifurcation to bifurcation, leading to an outsized impact of a few crucial upstream bifurcations on the distribution of RBCs at network-scale. Based on measured hematocrit profiles, we further construct a modified RBC partitioning model that accounts for the incomplete relaxation of RBCs at these bifurcations. This model allows us to explain how the flow field results in a single pattern of RBC preferential location in some networks, while it leads to the emergence of two different patterns of RBC preferential location in others. Our findings have important implications in understanding and modeling blood flow in physiological and pathological conditions.


Sex-biased phoretic mite load on two seaweed flies: Coelopa frigida and Coelopa pilipes.
Two hypotheses explain male-biased parasitism. Physiological costs of male sexually selected characteristics can reduce immunocompetence. Alternatively, ecological differences could generate male-biased parasitism. One method of comparing the importance of the two theories is to investigate patterns of phoresy, which are only likely to be generated by ecological rather than immunological differences between the sexes. Here we studied the pattern of phoresy of the mite, Thinoseius fucicola, on two species of seaweed fly hosts, Coelopa frigida and Coelopa pilipes. We found a highly male-biased pattern of phoresy of T. fucicola on both species. These are the first reported instances of sex-biased phoresy in a solely phoretic parasite. We also show the first two cases of size-biased phoresy. We suggest that ecological factors, particularly, male mate searching, generated male biased patterns of phoresy. We highlight the potential importance of studies of phoresy in determining the relative roles of the immunocompetence and ecological theories in generating male-biased parasitism. We suggest that more studies of patterns of phoresy are carried out to allow detailed comparisons with patterns of parasitism.


Treatment of Ankylosing Spondylitis With a Bushen-Qiangdu-Zhilv Decoction: A Case Report With a 3-year Follow-up.
Context • Ankylosing spondylitis (AS) is a refractory rheumatic disease, characterized by sacroiliitis and structural damage, and over decades, it can lead to joint fusion, frequently followed by significant spinal deformity and disability. However, to date, no method has been found to be effective in relieving or blocking structural damage to joints. Objective • The study intended to show that a decoction of Bushen-Qiangdu-Zhilv (BQZ), a therapy used in traditional Chinese medicine (TCM), can provide an alternative treatment for AS patients. Design • The research team performed a case study. Setting • The study was conducted at Guangdong Provincial Hospital of TCM in Guangzhou, China. Participant • The case study involved a 33-y-old male patient with active AS who visited the research team's clinic. Intervention • The patient took the BQZ orally 2 ×/d at 30 min after breakfast and 30 min after dinner. The patient returned to the clinic for consultation monthly. The patient took 2 servings/d for 10 mo and then received continuous BQZ treatment of the maintenance dosage for a period of approximately 3 y until December 2013. The maintenance dosage of BQZ was 3 or 4 decoctions per wk. Outcome Measures • The study used a number of measurements to evaluate the outcomes of treatment: (1) disease activity-the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI); (2) functional condition-the Bath Ankylosing Spondylitis Functional Index (BASFI); (3) inflammation-ratings of morning stiffness and night pain, serum C-reactive protein (CRP) concentration measured by means of particle-enhanced immunonephelometry, and erythrocyte sedimentation rate (ESR) value as detected using the Westergren method; (4) spinal mobility-the Bath Ankylosing Spondylitis Metrology Index (BASMI); and (5) global assessments by patient and physician. Results • The participant showed improvements in inflammatory symptoms and recovery from structural damage after receiving the TCM therapy for 3 y. Conclusions • The study has shown that the long-term use of BQZ not only can lead to an improvement in inflammatory symptoms and quality of life but also can help to restore function after structural damage in AS patients.


In vitro antiviral interaction of lopinavir with other protease inhibitors.
The in vitro inhibition of wild-type human immunodeficiency virus (HIV) by combinations of lopinavir and six other protease inhibitors over a range of two-drug combination ratios was evaluated. Combinations of lopinavir with indinavir, nelfinavir, amprenavir, tipranavir, and BMS-232632 generally displayed an additive relationship. In contrast, a consistent, statistically significant synergistic inhibition of HIV type 1 replication with combinations of lopinavir and saquinavir was observed. Analysis of the combination indices indicated that lopinavir with saquinavir was synergistic over the entire range of drug combination ratios tested and at all levels of inhibition in excess of 40%. Cellular toxicity was not observed at the highest drug concentrations tested. These results suggest that administration of combinations of the appropriate dose of lopinavir with other protease inhibitors in vivo may result in enhanced antiviral activity with no associated increase in cellular cytotoxicity. More importantly, the observed in vitro synergy between lopinavir and saquinavir provides a theoretical basis for the clinical exploration of a novel regimen of lopinavir-ritonavir and saquinavir.


Measurement of pressure at the wavy gas-liquid interface.
A method for measuring the pressure in gas at the wave surface has been developed and is presented here. This method utilizes a sensor which follows the wave surface; the pressure fluctuations usually present under such conditions have been minimized by the use of a swivel joint and special tubing configuration.


Interaction of Hsp90 with the nascent form of the mutant epidermal growth factor receptor EGFRvIII.
EGFRvIII is a mutant epidermal growth factor that promotes aggressive growth of glioblastomas. We made a plasmid that directed the expression of an EGFRvIII with three copies of the Flag epitope at its amino terminus. Flag-tagged EGFRvIII was expressed at the same levels as unmodified EGFRvIII, and showed the same subcellular localization. However, the Flag epitope could only be detected on EGFRvIII present in the endoplasmic reticulum; the epitope was covalently modified during trafficking of the receptor through the Golgi so that it was no longer recognized by anti-Flag antibody. This property was exploited to selectively purify nascent EGFRvIII from glioblastoma cells. Nascent EGFRvIII was found to copurify with a set of other proteins, identified by mass spectrometry as the two endoplasmic reticulum chaperones Grp94 and BiP, and the two cytosolic chaperones Hsc70 and Hsp90. The Hsp90-associated chaperone Cdc37 also co-purified with EGFRvIII, suggesting that Hsp90 binds EGFRvIII as a complex with this protein. Geldanamycin and radicicol, two chemically unrelated inhibitors of Hsp90, decreased the expression of EGFRvIII in glioblastoma cells. These studies show that nascent EGFRvIII in the endoplasmic reticulum associates with Hsp90 and Cdc37, and that the Hsp90 association is necessary to maintain expression of EGFRvIII.


Endocrine organ metastases in subjects with lobular carcinoma of the breast.
To define the frequency and pattern of endocrine organ metastases in patients dying of invasive lobular carcinoma. Postmortem microscopic evaluation of the ovaries and adrenal, pituitary, thyroid, and parathyroid glands for breast cancer metastases. Roswell Park Cancer Institute, Buffalo, NY, between 1971 and 1990. One hundred eighteen subjects who died of their cancer: 86 had infiltrating ductal carcinoma; 32, invasive lobular carcinoma. Quantitative measurements to allow frequency determinations and statistical comparisons. Endocrine organ metastases were found in 91% of the subjects with invasive lobular carcinoma vs 58% of subjects with infiltrating ductal carcinoma. The adrenal gland was most frequently involved. Multiple endocrine metastases were most common in the group with invasive lobular carcinoma. A relationship exists between invasive lobular carcinoma and endocrine metastases. This indicates that antemortem endocrine evaluation may subsequently improve quality-of-life treatment.


Vaginal cytology in women using oral contraceptives.
The present study was undertaken to assess the effect of a known synthetic steroid on vaginal epithelium as a diagnostic and prognostic tool. Biweekly vaginal smears from 10 multiparous, normally menstruating Indian females ages 21-40 were studied for 3 consecutive cycles, during which time they received Voldy's 21 oral contraceptive which contained both estrogen and progesterone. 7 of these cases acted as controls for themselves since their daily smears had been studied prior to the medication. In general, all smears had present a large number of leukocytes and Doderlein bacilli. There was a loss of cyclic pattern normally seen by midzonal maturation index, low karyopyknotic index, and the appearance of navicular cells with marked curling and folding of cells. The appearance of occasional cells having larger than a 5 micron-sized nucleus during the 2nd and 3rd cycles of medication may be suggestive of some significant effect with regard to the prolonged use of this oral contraceptive.


The bacterial 'enigma': cracking the code of cell-cell communication.
In recent years it has become clear that the production of N-acyl homoserine lactones (N-AHLs) is widespread in Gram-negative bacteria. These molecules act as diffusible chemical communication signals (bacterial pheromones) which regulate diverse physiological processes including bioluminescence, antibiotic production, plasmid conjugal transfer and synthesis of exoenzyme virulence factors in plant and animal pathogens. The paradigm for N-AHL production is in the bioluminescence (lux) phenotype of Photobacterium fischeri (formerly classified as Vibrio fischeri) where the signalling molecule N-(3-oxohexanoyl)-L-homoserine lactone (OHHL) is synthesized by the action of the LuxI protein. OHHL is thought to bind to the LuxR protein, allowing it to act as a positive transcriptional activator in an autoinduction process that physiologically couples cell density (and growth phase) to the expression of the bioluminescence genes. Based on the growing information on LuxI and LuxR homologues in other N-AHL-producing bacterial species such as Erwinia carotovora, Pseudomonas aeruginosa, Yersinia enterocolitica, Agrobacterium tumefaciens and Rhizobium leguminosarum, it seems that analogues of the P. fischeri lux autoinducer sensing system are widely distributed in bacteria. The general physiological function of these simple chemical signalling systems appears to be the modulation of discrete and diverse metabolic processes in concert with cell density. In an evolutionary sense, the elaboration and action of these bacterial pheromones can be viewed as an example of multicellularity in prokaryotic populations.


Analysis of glucose-6-phosphate translocase and hexose-6-phosphate phosphohydrolase, the two obligatory components of microsomal glucose-6-phosphatase system, in rat liver.
A membrane filter procedure developed by Igarashi et al. (1984) for the measurement of glucose 6-phosphate uptake by the microsomes has been demonstrated to be a good method for assaying glucose-6-phosphate translocase, an obligatory component of the microsomal glucose-6-phosphatase system. When glucose-6-phosphate translocase was assayed in developing and diabetic rat livers independently of hexose-6-phosphate phosphohydrolase, another obligatory component of the glucose-6-phosphatase system, the two activities were found to undergo alterations, whose profiles, however, were quite distinct from each other. The profile of the microsomal glucose-6-phosphatase activity resembles the profile of the phosphohydrolase activity rather than that of the translocase activity, suggesting that the phosphohydrolase may be rate-limiting at least under these conditions. AH-109A, a strain of transplantable rat ascites hepatoma, was found to lack both glucose-6-phosphate translocase and hexose-6-phosphate phosphohydrolase activities.


Intuition: a critical review of the research and rhetoric.
This paper will explore the concept of intuition in nursing from an acute care and community nursing perspective. It will consider definitions of intuition and examine the research which can inform our understanding of this important component of decision making. In the current health service climate, which demands measurable research-based evidence, the involvement of intuition as an element of judgement is often denigrated. The result is that many nurses are being forced to be covert in their use of this crucial aspect of judgement and focus solely on the conscious elements of decision-making. However, research evidence would suggest that intuition occurs in response to knowledge, is a trigger for action and/or reflection and thus has a direct bearing on analytical processes in patient/client care. The authors therefore argue that the essential nature of intuition cannot be ignored in the practice, management, education and research of nursing.


Improving the representation of peptide-like inhibitor and antibiotic molecules in the Protein Data Bank.
With the accumulation of a large number and variety of molecules in the Protein Data Bank (PDB) comes the need on occasion to review and improve their representation. The Worldwide PDB (wwPDB) partners have periodically updated various aspects of structural data representation to improve the integrity and consistency of the archive. The remediation effort described here was focused on improving the representation of peptide-like inhibitor and antibiotic molecules so that they can be easily identified and analyzed. Peptide-like inhibitors or antibiotics were identified in over 1000 PDB entries, systematically reviewed and represented either as peptides with polymer sequence or as single components. For the majority of the single-component molecules, their peptide-like composition was captured in a new representation, called the subcomponent sequence. A novel concept called "group" was developed for representing complex peptide-like antibiotics and inhibitors that are composed of multiple polymer and nonpolymer components. In addition, a reference dictionary was developed with detailed information about these peptide-like molecules to aid in their annotation, identification and analysis. Based on the experience gained in this remediation, guidelines, procedures, and tools were developed to annotate new depositions containing peptide-like inhibitors and antibiotics accurately and consistently.


Renal tolerability of three commonly employed non-steroidal anti-inflammatory drugs in elderly patients with osteoarthritis.
The primary endpoint of this study was to compare the renal tolerability of amtolmetin guacyl (AMG), diclofenac and rofecoxib in elderly patients with symptomatic osteoarthritis (OA). The assessment of efficacy was the secondary endpoint. 90 patients who satisfied the American College of Rheumatology classification criteria for hand, hip or knee OA were randomly assigned to 3 treatment groups receiving either: AMG 1,200 mg over thefirst 3 days and and 600 mg/day thereafter; diclofenac 150 mg/day; or rofecoxib 25 mg/day for 2 weeks. At baseline and after therapy patients were clinically assessed by the same examiner who was unaware of the treatment arm assignement. Serum and urinary parameters of renal function and the outcome measures of efficacy were evaluated before (t(0)) and after therapy (t(1)). Diclofenac produced a significant reduction in creatinine clearance (t(0) = 88.93 +/- 11.59; t(1) = 75.90 +/- 16.32; p: < 0.001) and in the daily urine volume (t(0) = 1,337.93 +/- 202.07; t(1) = 1,027.59 +/- 249.14; p: < 0.001). In the same treatment group a significant increase in serum creatinine, blood urea nitrogen, uric acid and potassium were observed. Rofecoxib treated patients showed a significant increase in body weight (t(0) = 75.31 +/- 4.26; t(1) = 76.54 +/- 4.84; p: < 0.001), systolic blood pressure (t(0) = 144 +/- 10.86; t(1) = 154 +/- 11.8; p < 0.001), diastolic blood pressure (t(0) = 80 +/- 6.05; t(1) = 89 +/- 7.66; p < 0.001) and serum sodium (t(0) = 138.73 +/- 1.28; t(1) = 140.12 +/- 1.80; p < 0.005) associated with a significant decrease in the daily urine volume (t(0) = 1294.64 +/- 205.21; t, = 1,115.48 +/- 238.47; p < 0.001) and creatinine clearance (t(0)= 86.73 +/- 8.14; t(1) = 83.15 +/- 7.96; p < 0.01). No significant changes in the clinical and humoral parameters were recorded in AMG treated patients. Diclofenac was more efficacious than the other 2 drugs (p < 0.001). No differences were observed between AMG and rofecoxib. Side effects related to altered kidney function were significantly higher in the rofecoxib group (p < 0.005). Diclofenac mainly impaired blood renal flow and the glomerularfiltration rate, while rofecoxib negatively influenced the renal sodium-water exchange. AMG demonstrated a renal sparing effect, although the eract mechanism is unclear


Annexin A5 regulates surface αvβ5 integrin for retinal clearance phagocytosis.
Diurnal clearance phagocytosis by the retinal pigment epithelium (RPE) is a conserved efferocytosis process whose binding step is mediated by αvβ5 integrin receptors. Two related annexins, A5 (ANXA5) and A6 (ANXA6), share an αvβ5 integrin-binding motif. Here, we report that ANXA5, but not ANXA6, regulates the binding capacity for spent photoreceptor outer segment fragments or apoptotic cells by fibroblasts and RPE. Similar to αvβ5-deficient RPE, ANXA5-/- RPE in vivo lacks the diurnal burst of phagocytosis that follows photoreceptor shedding in wild-type retina. Increasing ANXA5 in cells lacking αvβ5 or increasing αvβ5 in cells lacking ANXA5 does not affect particle binding. Association of cytosolic ANXA5 and αvβ5 integrin in RPE in culture and in vivo further supports their functional interdependence. Silencing ANXA5 is sufficient to reduce levels of αvβ5 receptors at the apical phagocytic surface of RPE cells. The effect of ANXA5 on surface αvβ5 and on particle binding requires the C-terminal ANXA5 annexin repeat but not its unique N-terminus. These results identify a novel role for ANXA5 specifically in the recognition and binding step of clearance phagocytosis, which is essential to retinal physiology.This article has an associated First Person interview with the first author of the paper.


A possible tumor suppressor gene for parathyroid adenomas.
Many short sequence repeat polymorphisms (SSRP) have been reported recently. There have been few reports of loss of heterozygosity (LOH) in tumors, employing these SSRP markers. The author examined loss of heterozygosity in 19 MEN-1 tumors and 43 sporadic parathyroid adenomas. All 19 (100%) MEN-1 tumors showed allelic loss on chromosome 11q. 15 out of 43 (34.9%) sporadic parathyroid adenomas showed allelic loss at the same locus on chromosome 11 as MEN-1 tumors. There was no significant allelic loss region on other chromosomes. These results suggest that the MEN-1 gene, which plays the role of a tumor suppressor gene in parathyroid tissue, has been localized telomeric to PYGM and centromeric INT2 loci on chromosome 11q13 and that the MEN-1 gene can be a tumor suppressor gene for sporadic parathyroid adenomas.


Ras-induced activation of Raf-1 is dependent on tyrosine phosphorylation.
Although Rafs play a central role in signal transduction, the mechanism(s) by which they become activated is poorly understood. Raf-1 activation is dependent on the protein's ability to bind Ras, but Ras binding is insufficient to activate Raf-1 tyrosine phosphorylation to this Ras-induced activation, in the absence of an over-expressed tyrosine kinase. We demonstrate that Raf-1 purified form Sf9 cells coinfected with baculovirus Ras but not Src could be inactivated by protein tyrosine phosphatase PTP-1B. 14-3-3 and Hsp90 proteins blocked both the tyrosine dephosphorylation and inactivation of Raf-1, suggesting that Raf-1 activity is phosphotyrosine dependent. In Ras-transformed NIH 3T3 cells, a minority of Raf-1 protein was membrane associated, but essentially all Raf-1 activity and Raf-1 phosphotyrosine fractionated with plasma membranes. Thus, the tyrosine-phosphorylated and active pool of Raf-1 constitute a membrane-localized subfraction which could also be inactivated with PTP-1B. By contrast, B-Raf has aspartic acid residues at positions homologous to those of the phosphorylated tyrosines (at 340 and 341) of Raf-1 and displays a high basal level of activity. B-Raf was not detectably tyrosine phosphorylated, membrane localized, or further activated upon Ras transformation, even though B-Raf has been shown to bind to Ras in vitro. We conclude that tyrosine phosphorylation is an essential component of the mechanism by which Ras activates Raf-1 kinase activity and that steady-state activated Ras is insufficient to activate B-Raf in vivo.


I want to move, but cannot: characteristics of involuntary stayers and associations with health among Canadian seniors.
The purpose of this study was to investigate characteristics of seniors in the Canadian population who are involuntary stayers and to assess associations with health. Data come from the 1994 Canadian National Population Health Survey, with the sample restricted to those 65 and older (N = 2,551). Nearly 1 in 10 seniors identified as an involuntary stayer. Seniors with few socioeconomic resources, poor health, greater need for assistance, and low social involvement were more likely to identify as an involuntary stayer. Furthermore, seniors who were involuntary stayers report significantly more distress and greater odds of low self-rated health than other seniors. This study brings into visibility an understudied segment of the elderly population: seniors who are unable to move from their present location despite their desire to do so. Further research and policy responses assisting seniors to age in a setting of their own choosing are needed.


[Ultrasonic cleavage of DNA in complexes with Ag(I), Cu(II), Hg(II)].
We investigated a phenomenon of ultrasonic cleavage of DNA complexed with transition metal cations Ag(I), Cu(II) and Hg(II). We found the statistically significant dependence of relative intensity of cleavage on cation type and concentration. Each cation may cause two different types of distortion in the DNA double-helix depending on whether it binds to major or minor DNA groove. The intensity of ultrasonic cleavage decreases if cation binds to the major DNA groove; the intensity of cleavage increases if cation binds to the minor DNA groove and disturbs the hydrogen bonds of complementary base pairs or it intercalates between bases. Both types of DNA distortion can affect the intensity of N-S interconversion of deoxyribose.


Regional and cell-type-specific effects of DAMGO on striatal D1 and D2 dopamine receptor-expressing medium-sized spiny neurons.
The striatum can be divided into the DLS (dorsolateral striatum) and the VMS (ventromedial striatum), which includes NAcC (nucleus accumbens core) and NAcS (nucleus accumbens shell). Here, we examined differences in electrophysiological properties of MSSNs (medium-sized spiny neurons) based on their location, expression of DA (dopamine) D1/D2 receptors and responses to the μ-opioid receptor agonist, DAMGO {[D-Ala(2)-MePhe(4)-Gly(ol)(5)]enkephalin}. The main differences in morphological and biophysical membrane properties occurred among striatal sub-regions. MSSNs in the DLS were larger, had higher membrane capacitances and lower Rin (input resistances) compared with cells in the VMS. RMPs (resting membrane potentials) were similar among regions except for D2 cells in the NAcC, which displayed a significantly more depolarized RMP. In contrast, differences in frequency of spontaneous excitatory synaptic inputs were more prominent between cell types, with D2 cells receiving significantly more excitatory inputs than D1 cells, particularly in the VMS. Inhibitory inputs were not different between D1 and D2 cells. However, MSSNs in the VMS received more inhibitory inputs than those in the DLS. Acute application of DAMGO reduced the frequency of spontaneous excitatory and inhibitory postsynaptic currents, but the effect was greater in the VMS, in particular in the NAcS, where excitatory currents from D2 cells and inhibitory currents from D1 cells were inhibited by the largest amount. DAMGO also increased cellular excitability in the VMS, as shown by reduced threshold for evoking APs (action potentials). Together the present findings help elucidate the regional and cell-type-specific substrate of opioid actions in the striatum and point to the VMS as a critical mediator of DAMGO effects.


The Pedicled Buccal Fat Pad: Anatomical Study of the New Flap for Skull Base Defect Reconstruction After Endoscopic Endonasal Transpterygoid Surgery.
Objectives To evaluate the efficacy and safety of using a buccal fat pad for endoscopic skull base defect reconstruction. Design Descriptive anatomical study with an illustrative case presentation. Setting Anatomical study was performed on 12 fresh human cadaver specimens with injected arteries (24 sides). Internal carotid artery was exposed in the coronal plane via the endoscopic transpterygoid approach. The pedicled buccal fat pad was used for reconstruction. Participants: 12 human cadaver head specimens; one patient operated using the proposed technique. Main outcome measures: Proximity of the buccal fat pad flap to the defect, compliance of the flap, comfort and safety of harvesting procedure, and compatibility with the Hadad-Bassagasteguy nasoseptal flap. Results: Harvesting procedure was performed using anterior transmaxillary corridor. The pedicled buccal fat pad flap can be used to pack the sphenoid sinus or cover the internal carotid artery from cavernous to upper parapharyngeal segment. Conclusion The buccal fat pad can be safely harvested through the same approach without external incisions and is compliant enough to conform to the skull base defect. The proposed pedicled flap can replace free abdominal fat in central skull base reconstruction. The volume of the buccal fat pad allows obliteration of the sphenoid sinus or upper parapharyngeal space.


Catalyst free annulative thioboration of unfunctionalized olefins.
A direct and catalyst-free annulative thioboration of unfunctionalized olefins has been developed. In the presence of BCl3 as the sole boron source, the boryl group and thiol group are added to the C-C double bonds simultaneously. The boronic acids obtained can be protected to form synthetically ubiquitous pinacol boronate esters.


[A case of malignant thymoma associated with myasthenia gravis, pure red cell aplasia and high serum level of SCC antigen].
We present a case of 43-year-old man with pure red cell aplasia appearing 8 years after thymothymectomy. He underwent an operation and postoperative radiotherapy for malignant thymoma associated with myasthenia gravis in 1983. In 1991 high serum level of SCC antigen was noted and a metastatic tumor was found in the retroperitoneal region. After removal of the tumor pure red cell aplasia developed, which responded to steroid therapy. The serum level of SCC antigen is still abnormally high.


Human immunodeficiency virus type 1 replication and regulation of APOBEC3G by peptidyl prolyl isomerase Pin1.
APOBEC3G (A3G) is a cytidine deaminase that restricts human immunodeficiency virus type 1 (HIV-1) replication. HIV-1 synthesizes a viral infectivity factor (Vif) to counter A3G restriction. Currently, it is poorly understood how A3G expression/activity is regulated by cellular factors. Here, we show that the prolyl isomerase Pin1 protein modulates A3G expression. Pin1 was found to be an A3G-interacting protein that reduces A3G expression and its incorporation into HIV-1 virion, thereby limiting A3G-mediated restriction of HIV-1. Intriguingly, HIV-1 infection modulates the phosphorylation state of Pin1, enhancing its ability to moderate A3G activity. These new findings suggest a potential Vif-independent way for HIV-1 to moderate the cellular action of A3G.


Online sample concentration and analysis of drugs of abuse in human urine by micelle to solvent stacking in capillary zone electrophoresis.
A sensitive and rapid CZE-UV method was developed to determine drugs and their metabolites' presence in human urine. Ten drugs of abuse were analyzed including four amphetamines, cocaine, cocaethylene, heroin, morphine, 6-monoacetylmorphine, and 4-methylmethcathinone. An MSS (micelle to solvent stacking) approach was evaluated to enhance method sensitivity. This method considers composition of the micellar sample solution matrix and the injection time. Several analytical conditions influencing the resolution of the drugs mixture as pH and buffer concentration, organic solvent content, were also investigated. The base-line separation of all studied analytes in the same run was achieved within 18 min in an uncoated fused silica capillary (50 μm id × 60 cm) using a background solution containing 50 mM phosphate buffer pH 2.5 and 30% ACN v/v. Other experimental parameters such as applied voltage and capillary temperature were set up at 20 kV and 20°C, respectively. LOD values ranging between 15 and 75 ng/mL for all studied compounds were obtained. From a comparison with conventional CZE, the proposed method provides an increase of sensitivity (39- to 55-fold enhancement factor). Under optimal MSS-CZE conditions, good linearity was achieved (R2 ≤ 0.9998). The method was finally applied to the analysis of urine samples spiked with a standard mixture after a sample pretreatment, reaching satisfactory recovery values.


AIDS and cancer registry linkage: measurement and enhancement of registry completeness. The National AIDS/Cancer Match Study Group.
To measure AIDS registry completeness for Kaposi's sarcoma (KS) and cancer registry completeness for KS and non-Hodgkin's lymphoma (NHL), we linked AIDS and cancer registries at selected health departments. We found 10,350 people with KS: 1,935 reported only to the AIDS registry, 1,428 reported only to the cancer registry, and 6,987 reported to both. Ninety-three cases of non-HIV-associated KS were expected. For KS, AIDS registry completeness was 84% [6,987/(6,987 + 1,428 - 93)] and cancer registry completeness was 78% [6,987/(6,987 + 1,935)]. Cancer registry completeness for AIDS-related NHL was 76%. If this linking were conducted nationally, about 5,700 additional cases of AIDS and 10,000 additional cases of AIDS-related cancers would be recorded.


Control of Cross Talk between Angiogenesis and Inflammation by Mesenchymal Stem Cells for the Treatment of Ocular Surface Diseases.
Angiogenesis is beneficial in the treatment of ischemic heart disease and peripheral artery disease. However, it facilitates inflammatory cell filtration and inflammation cascade that disrupt the immune and angiogenesis privilege of the avascular cornea, resulting in ocular surface diseases and even vision loss. Although great progress has been achieved, healing of severe ocular surface injury and immunosuppression of corneal transplantation are the most difficult and challenging step in the treatment of ocular surface disorders. Mesenchymal stem cells (MSCs), derived from various adult tissues, are able to differentiate into different cell types such as endothelial cells and fat cells. Although it is still under debate whether MSCs could give rise to functional corneal cells, recent results from different study groups showed that MSCs could improve corneal disease recovery through suppression of inflammation and modulation of immune cells. Thus, MSCs could become a promising tool for ocular surface disorders. In this review, we discussed how angiogenesis and inflammation are orchestrated in the pathogenesis of ocular surface disease. We overviewed and updated the knowledge of MSCs and then summarized the therapeutic potential of MSCs via control of angiogenesis, inflammation, and immune response in the treatment of ocular surface disease.


High pressure liquid chromatography of zearalenone and zearalenols in rat urine and liver.
A high pressure liquid chromatographic technique with internal standardization has been developed for determining zearalenone and metabolites in rat urine and liver. Following extraction with methylene chloride and solvent partition, samples are cleaned up by applying the extract to a Sephadex LH-20 column and eluting with a mixture of benzene-methanol (85 + 15). Compounds were resolved on 2 Part-isil-10 columns (25 cm x 4.6 mm id) in series with a mobile phase of isooctane-chloroform-methanol (35 + 25 + 3), and detected at 280 nm. The internal standard was 6'alpha-acetoxyzearalane. Limits of detection were about 2.0 ng for zearalenone and 5.0 ng for zearalenols (6'-hydroxyzearalane). Zearalenone and zearalenols were excreted mainly in free form with relatively little glucuronide conjugation. Metabolism of zearalenone to free zearalenol was minor compared with formation of bound forms.


Changes in Social Capital and Cigarette Smoking Behavior Over Time: A Population-Based Panel Study of Temporal Relationships.
Identifying factors that influence individuals' smoking behavior remains a huge public health concern. This study aimed to investigate changes in individuals' cigarette smoking while considering well-known smoking determinants, including social capital, its presence being postulated to reduce smoking. From British Household Panel Survey data, two baseline smoking cohorts were created ("smoking" and "not smoking"). The same individuals from this nationally representative sample (NT = 8114, aged 16-91 years) were interviewed on four occasions between years 2000 and 2007 to investigate changes in cigarette smoking behavior. Logistic regression models with random effects compensated for within-individual behavior over time. Temporal pathways were investigated by lagging independent variables (t - 1) in relation to our cigarette-use outcome at time (t). Active social participation at (t - 1) was positively associated with smoking cessation at (t) (odds ratio [OR] = 1.39; 95% confidence interval [CI] [1.07-1.82]). Separating from one's spouse at (t - 1) increased risk for smoking relapse/initiation at (t) (OR = 6.63; 95% CI [1.70-28.89]). Conversely, being married protected against smoking cigarettes (OR = 1.87; 95% CI [1.15-3.04]). These associations held in our robustness checks. Initial marital breakdown predicted a high risk of smoking relapse/initiation. The timing of this life event provides a critical window where adverse smoking behavior might occur. Conversely, the positive effects of active social participation on cigarette cessation remained consistent, its absence further predicting smoking relapse/initiation. Robustness of results confirms the important role that active participation has on cigarette smoking behavior. Group smoking cessation interventions could harness participatory elements to better achieve their goals. By investigating temporal relationships between well-known smoking determinants and cigarette smoking outcomes, we identified that being "separated" (not "divorced") at time (t) predicted a higher risk of smoking relapse/initiation at (t). Tailored health messages could be employed to highlight the increased risk of cigarette smoking relapse/initiation during this stressful life event. Conversely, active social participation (a common social capital proxy) consistently predicted smoking cessation over time. Future group smoking cessation interventions could be designed explicitly to harness participatory elements to better achieve their goals.


Acetyl L-carnitine protects motor neurons and Rohon-Beard sensory neurons against ketamine-induced neurotoxicity in zebrafish embryos.
Ketamine, a non-competitive antagonist of N-methyl-D-aspartate (NMDA) type glutamate receptors is commonly used as a pediatric anesthetic. Multiple studies have shown ketamine to be neurotoxic, particularly when administered during the brain growth spurt. Previously, we have shown that ketamine is detrimental to motor neuron development in the zebrafish embryos. Here, using both wild type (WT) and transgenic (hb9:GFP) zebrafish embryos, we demonstrate that ketamine is neurotoxic to both motor and sensory neurons. Drug absorption studies showed that in the WT embryos, ketamine accumulation was approximately 0.4% of the original dose added to the exposure medium. The transgenic embryos express green fluorescent protein (GFP) localized in the motor neurons making them ideal for evaluating motor neuron development and toxicities in vivo. The hb9:GFP zebrafish embryos (28 h post fertilization) treated with 2 mM ketamine for 20 h demonstrated significant reductions in spinal motor neuron numbers, while co-treatment with acetyl L-carnitine proved to be neuroprotective. In whole mount immunohistochemical studies using WT embryos, a similar effect was observed for the primary sensory neurons. In the ketamine-treated WT embryos, the number of primary sensory Rohon-Beard (RB) neurons was significantly reduced compared to that in controls. However, acetyl L-carnitine co-treatment prevented ketamine-induced adverse effects on the RB neurons. These results suggest that acetyl L-carnitine protects both motor and sensory neurons from ketamine-induced neurotoxicity.


Young and burgess type I lateral compression pelvis fractures: a comparison of anterior and posterior pelvic ring injuries.
The goals of this study were to find associations between anterior and posterior ring injuries, provide a descriptive comparison of pelvic ring disruptions as assessed by plain radiography, and compare the value of computed tomography (CT) over plain radiography in evaluating anterior and posterior structures. A retrospective review of radiographic reports and records identified 142 patients with pubic ramus fractures as observed by plain radiography. A statistical analysis was performed to test the associations between anterior ring injury as assessed by plain radiography and posterior ring injury as assessed by CT. Forty-five point five percent of patients with bilateral ramus fractures and 42.0% of patients with dual-ramus fractures had concomitant sacral fractures not observed on plain radiographs. These occult sacral fractures were found in only 11.1% of patients with inferior ramus fractures. The type of pubic injury on plain radiographs may be predictive of posterior ring injury, and therefore may help determine injury energy and severity, determine the need for further imaging studies, and help guide clinical management. Although CT is highly sensitive in identifying both anterior and posterior pubic ring injuries, elderly patients with simple fractures of a single pubic ramus are less likely to suffer from pelvic instability and thus may not benefit from CT.


Language barriers and access to care.
The purpose of this chapter is to examine how language barriers contribute to health disparities among ethnic and racial minorities in the United States. A literature search was systematically conducted using selected computer databases (MEDLINE and CINAHL). Searches were limited to English-language-published research in the years from 1985 to 2003. A total of 47 published articles were included in this review. Overall these studies indicate that language barriers are associated with longer visit time per clinic visit, less frequent clinic visits, less understanding of physician's explanation, more lab tests, more emergency room visits, less follow-up, and less satisfaction with health services. The results also indicate that people who are older, poorer, and female tend to have severe language barriers compared to those who are younger, wealthier, and male. Improvement of communication between patients and providers in relation to health disparity consists of cultural competency and communication skills. Implications of these studies for practice and further research are outlined.


Non-Coding RNAs: Prevention, Diagnosis, and Treatment in Myocardial Ischemia-Reperfusion Injury.
Recent knowledge concerning the role of non-coding RNAs (ncRNAs) in myocardial ischemia/reperfusion (I/R) injury provides new insight into their possible roles as specific biomarkers for early diagnosis, prognosis, and treatment. MicroRNAs (miRNAs) have fewer than 200 nucleotides, while long ncRNAs (lncRNAs) have more than 200 nucleotides. The three types of ncRNAs (miRNAs, lncRNAs, and circRNAs) act as signaling molecules strongly involved in cardiovascular disorders (CVD). I/R injury of the heart is the main CVD correlated with acute myocardial infarction (AMI), cardiac surgery, and transplantation. The expression levels of many ncRNAs and miRNAs are highly modified in the plasma of MI patients, and thus they have the potential to diagnose and treat MI. Cardiomyocyte and endothelial cell death is the major trigger for myocardial ischemia-reperfusion syndrome (MIRS). The cardioprotective effect of inflammasome activation in MIRS and the therapeutics targeting the reparative response could prevent progressive post-infarction heart failure. Moreover, the pharmacological and genetic modulation of these ncRNAs has the therapeutic potential to improve clinical outcomes in AMI patients.


Ventricular tachycardia/fibrillation: therapeutic alternatives.
It is now clear that no single therapy is appropriate for a consecutive series of patients with ventricular tachycardia or ventricular fibrillation (VT/VF). Drug responders by electrophysiological studies, patients who are not inducible following surgery, and patients treated with an implantable cardioverter defibrillator (ICD) all can have similarly low sudden death rates and virtually identical long-term mortality. However, many patients fail to respond to drugs, and surgical risks are excessive in others, and always higher than for an ICD implant. Nevertheless, overall survival in each of these groups (and probably for patients treated with antitachycardia pacers and ablation) is about 60% at 60 months. Major challenges now are: (1) choosing therapy to maximize risk-benefit ratio; and (2) treatment of the pump failure and progressive disease that now accounts for most cardiac mortality.


The role and potential therapeutic application of myeloid-derived suppressor cells in TNBS-induced colitis.
MDSCs, a heterogeneous population of cells that expand during many pathogenic conditions, have remarkable abilities to suppress T cell responses. Their role in murine colitis, induced by TNBS and therapeutic application, remains unclear. Murine colitis was induced through intrarectally administrating TNBS, twice. MDSCs in spleen and colonic LPMCs were identified using flow cytometric analysis. In adoptive transfer, MDSCs were isolated from spleen after TNBS challenges by using microbeads or generated in vitro by coculturing bone marrow cells with HSCs and then transferred into naïve mice. Two hours later, mice were then challenged with TNBS, once/week for 2 weeks. The mice were killed four days after the second TNBS delivery, and intestinal inflammation and cytokine levels and MDSC percentages were evaluated. The percentages of CD11b+Gr-1+MDSCs and subsets (CD11b+Ly6C+ and CD11b+Ly6G+MDSCs) were increased in spleen and/or colonic LPMCs in colitis mice and also correlated with the severity of intestinal inflammation. MDSCs isolated from colitis mice suppressed the proliferation of splenocytes in vitro. Adoptive transfer of MDSCs, isolated from colitis mice or generated in vitro, decreased intestinal inflammation, levels of IFN-γ, IL-17, and TNF, and percentages of spleen MDSCs when compared with controls. MDSCs that have inhibitory function in vitro and in vivo are increased and correlated with intestinal inflammation, suggesting that they may be used as a biomarker of disease activity and a cell-based biotherapy in IBD.


Modulation of TCR-mediated signaling pathway by thymic shared antigen-1 (TSA-1)/stem cell antigen-2 (Sca-2).
Thymic shared antigen-1 (TSA-1) is a glycosyl-phosphatidylinositol (GPI)-anchored differentiation Ag expressed on murine lymphocytes, and is identical to stem cell Ag-2 (Sca-2). Using newly established mAb against TSA-1/Sca-2, we have previously shown that surface TSA-1 expression is induced upon activation in T cells, and that anti-TSA-1 inhibits IL-2 production induced by anti-CD3 stimulation in T cell hybridomas. In the present study, we have analyzed the functional role of TSA-1 during T cell activation using normal T cells, T cell hybridomas, and transfected Jurkat cell lines that expressed either GPI-anchored or transmembrane form of TSA-1. Anti-TSA-1 inhibited IL-2 production from normal T cells stimulated with soluble anti-CD3 plus accessory cells. Anti-TSA-1 exhibited the inhibitory effect on T cells, but not on accessory cells, because anti-TSA-1 inhibited IL-2 production in Jurkat cells transfected with TSA-1 cDNA, but not in control transfectant. A transmembrane form of TSA-1 was expressed in Jurkat cells by fusing the extracellular portion of TSA-1 to the transmembrane and cytoplasmic regions of the class 1 Db. The analysis using this transfectant revealed that anti-TSA-1-mediated inhibition of IL-2 production did not require the GPI anchor of TSA-1. Finally, in addition to the inhibition of IL-2 production, tyrosine phosphorylation of CD3 zeta-chains observed following TCR stimulation, one of the important early activation events, was markedly reduced by anti-TSA-1. These results imply that TSA-1/Sca-2 plays an important regulatory role in the TCR signaling pathway of activated T cells in addition to its role in T cell differentiation.


Expression of vascular endothelial growth factor does not promote transformation but confers a growth advantage in vivo to Chinese hamster ovary cells.
Vascular endothelial growth factor (VEGF) is a mitogen with a specificity for endothelial cells in vitro and an angiogenic inducer in vivo. We tested the hypothesis that VEGF may confer on expressing cells a growth advantage in vivo. Dihydrofolatereductase--Chinese hamster ovary cells were transfected with expression vectors which direct the constitutive synthesis of VEGF. Neither the expression nor the exogenous administration of VEGF stimulated anchorage-dependent or anchorage-independent growth of Chinese hamster ovary cells in vitro. However, VEGF-expressing clones, unlike control cells, demonstrated an ability to proliferate in nude mice. Histologic examination revealed that the proliferative lesions were compact, well vascularized, and nonedematous. Ultrastructural analysis revealed that capillaries within the lesions were of the continuous type. These findings indicate that the expression of VEGF may confer on cells the ability to grow in vivo in the absence of transformation by purely paracrine mechanisms. Since VEGF is a widely distributed protein, this property may have relevance for a variety of physiological and pathological proliferative processes.


Aspects of the effect of bile salts on Candida albicans.
Cholic acid, chenodeoxycholic acid, deoxycholic acid, glycocholic acid, glycodeoxycholic acid, hyodeoxycholic acid and lithocholic acid as their sodium salts, were fungistatic to the growth of Candida albicans. Of the compounds tested, cholic acid, deoxycholic acid and chenodeoxycholic acid were the most active. In combination with other antifungal agents only cholic acid exhibited synergism with amphotericin B, whilst the imidazole antifungal agents inhibited the action of the bile salts. The bile salt minimal inhibitory concentrations were close to the critical micelle concentrations. Even though the compounds are surface active they did not cause loss of intracellular K+ and were without effect on oxygen consumption. The bile salts, particularly cholic acid, produced morphological changes that gave rise to swollen cells.


Toward organometallic (99m)Tc imaging agents: synthesis of water-stable (99)Tc-NHC complexes.
(99)Tc(V)O2-NHC complexes containing monodentate and bidentate N-heterocyclic carbenes (NHCs) have been prepared by the reactions of [TcO(glyc)2](-) (glyc = ethyleneglycolato) with 1,3-dimethylimidazoline-2-ylidene (L1), 1,1'-methylene-3,3'-dimethyl-4,4'-diimidazoline-2,2'-diylidene (L2), and 1,1'-methylene-3,3'-diethyl-4,4'-diimidazoline-2,2'-diylidene (L3) in THF. The resulting complexes were fully characterized and their stabilities investigated. While complexes with monodentate NHCs only are hydrolytically unstable, complexes containing bidentate NHCs are water-stable over a broad pH range. The high water stability allows interconversion of the {(99)Tc(V)O2}(+) core into {(99)Tc(V)OCl}(2+) with HCl as the H(+) and Cl(-) source. An alternative procedure to obtain (99)Tc(V)O2-NHC complexes is the in situ deprotonation of imidazolium salts, enabling the preparation of (99)Tc(V)O2-NHC compounds without free NHCs, thus increasing the scope of NHC ligands drastically. The remarkable stability and pH-controllable reactivity of the new complexes underlines the potential of NHCs as stabilizing ligands for (99)Tc complexes and paves the way for the first (99m)Tc-NHC complexes in the future.


Functional knockout of the adenosine 5'-phosphosulfate reductase gene in Physcomitrella patens revives an old route of sulfate assimilation.
The reduction of adenosine 5'-phosphosulfate (APS) to sulfite catalyzed by adenosine 5'-phosphosulfate reductase is considered to be the key step of sulfate assimilation in higher plants. However, analogous to enteric bacteria, an alternative pathway of sulfate reduction via phosphoadenosine 5'-phosphosulfate (PAPS) was proposed. To date, the presence of the corresponding enzyme, PAPS reductase, could be neither confirmed nor excluded in plants. To find possible alternative routes of sulfate assimilation we disrupted the adenosine 5'-phosphosulfate reductase single copy gene in Physcomitrella patens by homologous recombination. This resulted in complete loss of the correct transcript and enzymatic activity. Surprisingly, the knockout plants grew on sulfate as the sole sulfur source, and the concentration of thiols in the knockouts did not differ from the wild type plants. However, when exposed to a sublethal concentration of cadmium, the knockouts were more sensitive than wild type plants. When fed [(35)S]sulfate, the knockouts incorporated (35)S in thiols; the flux through sulfate reduction was approximately 50% lower than in the wild type plants. PAPS reductase activity could not be measured with thioredoxin as reductant, but a cDNA and a gene coding for this enzyme were detected in P. patens. The moss Physcomitrella patens is thus the first plant species wherein PAPS reductase was confirmed on the molecular level and also the first organism wherein both APS- and PAPS-dependent sulfate assimilation co-exist.


Takotsubo cardiomyopathy: a rare complication of acute viral gastroenteritis.
Takotsubo Cardiomyopathy (TCM) is characterized by a transient but reversible ventricular dysfunction in post-menopausal females following, but not always, a recent emotional or physical stress. Typically, chest pain is reported as a presenting symptom in the majority of patients. The severe diarrheal illness secondary to acute viral gastroenteritis is not commonly reported as the stressor event prior to TCM. We report a unique case of a middle-aged male presented with syncope shortly after loose bowel movements. He was diagnosed with TCM and was successfully managed with supportive care. The purpose of this case is to make clinicians aware of this rare association.


A Multivariate Analysis of Unilateral Cleft Lip and Palate Facial Skeletal Morphology.
Unilateral cleft lip and palate (UCLP) occurs when the maxillary and nasal facial prominences fail to fuse correctly during development, resulting in a palatal cleft and clefted soft and hard tissues of the dentoalveolus. The UCLP deformity may compromise an individual's ability to eat, chew, and speak. In this retrospective cross-sectional study, cone beam computed tomography (CBCT) images of 7-17-year-old individuals born with UCLP (n = 24) and age- and sex-matched controls (n = 24) were assessed. Coordinate values of three-dimensional anatomical landmarks (n = 32) were recorded from each CBCT image. Data were evaluated using principal coordinates analysis (PCOORD) and Euclidean distance matrix analysis (EDMA). Approximately 40% of morphometric variation is captured by PCOORD axes 1-3, and the negative and positive ends of each axis are associated with specific patterns of morphological differences. Approximately 36% of facial skeletal measures significantly differ by confidence interval testing (α = 0.10) between samples. Although significant form differences occur across the facial skeleton, strong patterns of morphological differences were localized to the lateral and superioinferior aspects of the nasal aperture, particularly on the clefted side of the face. The UCLP deformity strongly influences facial skeletal morphology of the midface and oronasal facial regions, and to a lesser extent the upper and lower facial skeletons. The pattern of strong morphological differences in the oronasal region combined with differences across the facial complex suggests that craniofacial bones are integrated and covary, despite influences from the congenital cleft.


Application of computer modelling and lead field theory in developing multiple aimed impedance cardiography measurements.
Conventional impedance cardiography (ICG) methods estimate parameters related to the function of the heart from a single waveform that reflects an integrated combination of complex sources. We have previously developed methods and tools for calculating measurement sensitivity distributions of ICG electrode configurations. In this study, the methods were applied to investigate the prospects of recording multiple aimed ICG waveforms utilizing the 12-lead electrocardiography (ECG) electrode locations. Three anatomically realistic volume conductor models were used: one based on Visible Human Man cryosection data and two on magnetic resonance (MR) images representing end diastolic and end systolic phases of the cardiac cycle. Based on the sensitivity distributions obtained, 236 electrode configurations were selected for preliminary clinical examination on 12 healthy volunteers and 9 valvular patients. The model study suggested that a variety of configurations had clearly enhanced sensitivity to the cardiovascular structures as compared to conventional ICGs. Simulation data and clinical experiments showed logical correspondence supporting the theoretically predicted differences between the configurations. Recorded 12-lead ICG signals had characteristic waveforms and landmarks not coinciding with those of conventional ICG. Furthermore, configurations showing resemblance to invasive data and morphological variations in disease are of interest. The results indicate the applicability of the modelling approach in developing ICG measurement configurations. However, the level of clinical relevance and potential of the 12-lead method remains to be explored in studies employing dynamic modelling and acquisition of invasive reference data.


Origin of stereocontrol in the construction of the 12-oxatricyclo[188.8.131.52(2,7)]dodecane ring system by Prins-pinacol reactions.
Polycyclic products containing the 12-oxatricyclo[220.127.116.11(2,7)]dodecane moiety having either the trans (8a-e) or cis (9a-e) relative configuration of the oxacyclic bridge and the cis angular substituents are formed stereospecifically by Prins-pinacol cyclizations of unsaturated alpha-dithianyl acetals 14a-e or 15a-e. These results show that the topography (boat or chair) of the Prins cyclization of the sulfur-stabilized oxocarbenium ions generated from acetals 14a-e or 15a-e is controlled by the stereoelectronic influence of the allylic substituents, with steric effects playing a minor role. A complex molecular rearrangement that is terminated by a thio-Prins-pinacol reaction is also identified.


Endohepatology - current status.
This article discusses the most recent studies regarding the emerging field of endohepatology - the use of diagnostic and therapeutic endoscopic tools for the management of patients with liver disease and portal hypertension. New research has shown that liver biopsy specimens obtained by each Endoscopic ultrasound (EUS)-guidance, the percutaneous approach, and the transjugular approach contained sufficient portal triads to adequately analyzed by experienced pathologists - suggesting that any of these routes of liver biopsy is clinically acceptable; further, all had similar rates of adverse events. An initial prospective study showed that EUS guided portal pressure measurement was safe, effective, and accurate. A recent metanalysis showed that EUS-guided cyanoacrylate injection and coil embolization was statistically more efficacious and with less complications than EUS guided cyanoacrylate injection and EUS guided coil injection alone, suggesting that combination therapy appears to be the preferred approach for gastric varices (GV) bleeding. A prospective study evaluating focal liver lesions showed that the use of artificial intelligence had up to 100% sensitivity and 81% specificity for identifying malignant focal liver lesions. EUS guided liver biopsy is safe and enables accurate diagnosis of underlying liver disease. EUS guided portal pressure measurement is also safe and is accurate. Combination therapy of EUS guided cyanoacrylate injection and coil embolization is more efficacious and has less complications than injection or coil therapy alone when used for GV bleeding. Artificial intelligence is highly sensitive and specific when used in conjunction with EUS in the diagnosis of malignant focal liver lesions. Endohepatology is a rapidly expanding field with great potential.


Relationship between anaerobic capacity estimated using a single effort and 30-s tethered running outcomes.
The purpose of the current study was to investigate the relationship between alternative anaerobic capacity method (MAODALT) and a 30-s all-out tethered running test. Fourteen male recreational endurance runners underwent a graded exercise test, a supramaximal exhaustive effort and a 30-s all-out test on different days, interspaced by 48h. After verification of data normality (Shapiro-Wilk test), the Pearson's correlation test was used to verify the association between the anaerobic estimates from the MAODALT and the 30-s all-out tethered running outputs. Absolute MAODALT was correlated with mean power (r = 0.58; P = 0.03), total work (r = 0.57; P = 0.03), and mean force (r = 0.79; P = 0.001). In addition, energy from the glycolytic pathway (E[La-]) was correlated with mean power (r = 0.58; P = 0.03). Significant correlations were also found at each 5s interval between absolute MAODALT and force values (r between 0.75 and 0.84), and between force values and E[La-] (r between 0.73 to 0.80). In conclusion, the associations between absolute MAODALT and the mechanical outputs from the 30-s all-out tethered running test evidenced the importance of the anaerobic capacity for maintaining force during the course of time in short efforts.


Prediction of dental arch width increase in the early mixed dentition using craniofacial parameters.
The dimensions of the dental arch have considerable impact on treatment planning. Since the dental arch development has a relationship with the craniofacial growth, we designed a cohort study to find a regression model for predicting the mandibular arch width increase using craniofacial parameters. A total of 148 children, all in early mixed dentition, were selected randomly from primary schools by cluster sampling. Craniofacial anthropometric parameters were measured by a caliper bow and intercanine and intermolar widths were assessed on each subject's dental casts by a digital caliper at baseline and after 12 months. Data were analyzed with SPSS v. 15. Student's t-test and linear regression test were applied separately for girls and boys. Out of 153 children, 148 returned for one-year follow-up meeting the inclusion criteria. The results of regression analysis showed a significant inverse correlation between intercanine width and facial index. The bigonial dimension showed a high correlation with both the intermolar width and the intercanine width increase. We found that the arch width increase in the early mixed dentition could be predicted precisely based on certain craniofacial parameters.


Norepinephrine stimulation of adenylate cyclase potentiates protein kinase C action: electrophysiological studies in the dentate gyrus.
Protein kinase C and norepinephrine-stimulated adenylate cyclase have been linked to formation of long-term potentiation in the dentate gyrus. However, little is known about second messenger system interactions regulating synaptic transmission. In electrophysiological studies of the dentate gyrus, we observe synergistic interactions between norepinephrine and phorbol esters, activators of protein kinase C. Norepinephrine markedly potentiates the block of adenosine's inhibitory action by phorbol esters. Norepinephrine's action is mimicked by the beta-adrenoceptor agonist isoproterenol and blocked by the beta-adrenoceptor antagonists timolol and propranolol. Forskolin also mimicks norepinephrine's action. Accordingly, norepinephrine's potentiation of protein kinase C appears to be mediated by the cyclic AMP second messenger system. This mechanism may contribute to norepinephrine's facilitation of long-term potentiation in the dentate gyrus.


[Angioscopic evaluation of atherosclerosis].
Recently, percutaneous transluminal angioscopy has been clinically used. We describe the evaluation of atherosclerosis by angioscopy. In observation of aortic and peripheral arteries, color of the luminal surface is yellow in the lesion without endothelial fibrosis, whereas, it is white with endothelial fibrosis. A variety of findings such as endothelial flap, endothelial thickening, mural bleeding, mural or occlusive thrombi are observed in the atherosclerotic lesions. It is difficult to detect these findings by angiography. In observation of coronary arteries, color of the luminal surface is yellow or white and often associates spiral folds in the early stage of atherosclerosis. Plaques are classified to two categories. One is the complex plaque characterised by endothelial flap, rupture of atheroma, ulceration, mural thrombus and usually observed in patients with unstable angina or myocardial infarction. Another is the regular plaque without those findings and observed in patients with stable angina. Angioscopy is useful for evaluation of atherosclerosis.


Effects of quercetin nanoliposomes on C6 glioma cells through induction of type III programmed cell death.
Quercetin has been shown to induce apoptosis in a number of cancer cell lines, but a quercetin-loaded nanoliposomal formulation with enhanced antitumor activity in C6 glioma cells and its effect on cancer cell death has not been well studied. The aim of this study was to examine if quercetin-loaded liposomes (QUE-NL) has enhanced cytotoxic effects and if such effects involve type III programmed cell death in C6 glioma cells. C6 glioma cells were treated with QUE-NL and assayed for cell survival, apoptosis, and necrosis. Levels of reactive oxygen species production and loss of mitochondrial membrane potential (ΔΨm) were also determined by flow cytometry assay to assess the effects of QUE-NL. ATP levels and lactate dehydrogenase activity were measured, and Western blotting was used to assay cytochrome C release and caspase expression. QUE-NL induced type III (necrotic) programmed cell death in C6 glioma cells in a dose-dependent and time-dependent manner. High concentrations of QUE-NL induced cell necrosis, which is distinct from apoptosis and autophagy, whereas liposomes administered alone induced neither significant apoptosis nor necrosis in C6 glioma cells. QUE-NL-induced ΔΨm loss and cytochrome C release had no effect on caspase activation, but decreased ATP levels and increased lactate dehydrogenase activity indicated that QUE-NL stimulated necrotic cell death. C6 glioma cells treated with QUE-NL showed a cellular pattern associated with necrosis without apoptosis and was independent of caspase activity. Nonapoptotic cell death induced by high concentrations of QUE-NL for controlling caspase-independent type III programmed cell death may provide the basis for novel therapeutic approaches to overcome avoidance of apoptosis by malignant cells.


[Problems of tobacco smoke and positive effects of quit-smoking on human health].
Cigarette smoking dominates among Japanese smokers. A smoker takes a small amount of nicotine into the body by one aspiration of cigarette; this amount is not large enough to cause acute symptoms. The way of consuming one cigarette by about 10 aspirations may supply a sufficient amount of nicotine to the body without producing unpleasant symptoms of acute toxicity. Cigarette is very effective goods of nicotine delivery to increase the nicotine-dependent patients. In addition, owing to the tricky image strategy by a tobacco company, the citizens in Japan have not become sufficiently aware of hazards of tobacco. For health hazards of smoking, people do not fully understand cigarette smoking may affect the whole body because of the strong impression of "cancer" particularly "lung cancer" as the disease of smoking. Therefore, we, healthcare professionals, should treat diseases with accurate knowledge of tobacco hazards and also should play a positive role to enlighten people about the truth of tobacco hazards, which do not mean cancer alone.


Ofatumumab for B cell depletion therapy in ANCA-associated vasculitis: a single-centre case series.
B cell depletion is an effective treatment strategy in ANCA-associated vasculitis (AAV). Ofatumumab is a fully humanized anti-CD20 mAb that has shown efficacy in the treatment of haematological malignancy and RA. The use of ofatumumab in the treatment of AAV has not previously been reported. This study was based on a case series of eight patients who received ofatumumab, in conjunction with low-dose CYC and oral steroids, in the treatment of AAV. Eight patients received ofatumumab: seven for remission induction in active disease (three relapsing; four with new disease) and one for remission maintenance. B cell depletion was achieved in all patients by 1 month, and was sustained for at least 6 months. All patients with active disease achieved clinical remission (BVAS of zero, or BVAS ⩽5 if all scores due to persistent urinary abnormalities in the presence of stable or improving renal function) by 3 months. This was associated with a rapid fall in ANCA titres, reduced inflammatory responses and improvements in renal function. At 12 months, three patients had repopulated B cells associated with the recurrence of circulating ANCAs, although no patients experienced major clinical relapse in the first 24 months. No unexpected side effects were observed. Treatment with ofatumumab resulted in similar serological and clinical responses to those seen in previous cohorts treated at our centre with a comparable CS, CYC and rituximab-based regimen. Ofatumumab should be considered an alternative B cell depleting agent in patients who are intolerant of, or unresponsive to, rituximab.


Poly (ionic liquid)-Based Breath Figure Films: A New Kind of Honeycomb Porous Films with Great Extendable Capability.
In this work, we reported a new method for the convenient fabrication of various functional porous films, which cannot be directly generated using breath figures (BFs). A series of polystyrene-b-poly (ionic liquid) (PS-b-PIL) block copolymers were employed for BFs process for the first time. It was found that PS-b-PIL could form well-defined BFs porous structure. Remarkably, the described PS-b-PIL copolymers are prone to form hierarchical structure, and the formed pore structure is strongly dependent on the used experimental parameters. Importantly, we found that the anion exchange could provide as an effective means, by which the porous films could be further and facilely converted into other functional films. As a demonstration, in our case, porous films with different surface (hydrophilic and hydrophobic) property, porous polydopamine films decorated with Au nanoparticles or glutathione and porous SiO2 films were prepared by using different counteranions as well as further conversion. Due to the unlimited combination of cation and anion in ionic liquid moiety, all the results indicate that the BFs films generated by using PS-PIL could serve as a platform to access various functional porous films by a simple counteranion exchange, showing a great extendable capability.


Deranged early T cell development in immunodeficient strains of nonobese diabetic mice.
NOD mice exhibit defects in T cell functions that have been postulated to contribute to diabetes susceptibility in this strain. However, early T cell development in NOD mice has been largely unexplored. NOD mice with the scid mutation and Rag1 deficiency were analyzed for pre-T cell development in the NOD genetic background. These strains reveal an age-dependent, programmed breakdown in beta selection checkpoint enforcement. At 5-8 wk of age, even in the absence of TCRbeta expression, CD4+ and CD4+CD8+ blasts appear spontaneously. However, these breakthrough cells fail to restore normal thymic cellularity. The breakthrough phenotype is recessive in hybrid (NODxB6)F1-scid and -Rag1null mice. The breakthrough cells show a mosaic phenotype with respect to components of the beta selection program. They mimic normal beta selection by up-regulating germline TCR-Calpha transcripts, CD2, and Bcl-xL and down-regulating Bcl-2. However, they fail to down-regulate transcription factors HEB-alt and Hes1 and initially express aberrantly high levels of Spi-B, c-kit (CD117), and IL-7Ralpha. Other genes examined distinguish this form of breakthrough from previously reported models. Some of the abnormalities appear first in a cohort of postnatal thymocytes as early as the double-negative 2/double-negative 3 transitional stage. Thus, our results reveal an NOD genetic defect in T cell developmental programming and checkpoint control that permits a subset of the normal outcomes of pre-TCR signaling to proceed even in the absence of TCRbeta rearrangement. Furthermore, this breakthrough may initiate thymic lymphomagenesis that occurs with high frequency in both NOD-scid and -Rag1null mice.


Unilateral Acute Macular Toxoplasmic Chorioretinitis Associated with White Dot-Like Choroidal Involvement Demonstrated on Indocyanine Green Angiography
A 9-year-old otherwise healthy boy was examined due to a 4-day history of visual decline in his right eye. Ophthalmological examination revealed an area of active retinochoroiditis in the right macula. Indocyanine green angiography (ICGA) demonstrated multiple hypocyanescent dots surrounding the active lesion extending 360 degrees towards the equator. Optical coherence tomography angiography (OCTA) exhibited dark dots on the choriocapillaris slab over areas corresponding to the hypocyanescent dots detected with ICGA. Full systemic examination and laboratory investigations were carried out. Toxoplasma gondii serology was positive. The diagnosis of toxoplasmic chorioretinitis with white dot-like choroidal involvement was made. Trimethoprim/sulfamethoxazole, azithromycin, and oral prednisolone were administered orally. On repeated ICGA 2 weeks later, the scattered hypocyanescent dots were significantly fewer in number. A month later, right visual acuity was improved, the macular chorioretinitis focus had become inactive, an epiretinal membrane had formed, and the dark dots on the choriocapillaris slab of OCTA were markedly diminished. ICGA may be helpful to observe possible, subtle choroidal involvement in patients with toxoplasmic chorioretinitis.


Urokinase-type plasminogen activator-induced monocyte adhesion is modulated by kininogen, kallikrein, factor XII, and plasminogen.
Urokinase-type plasminogen activator (u-PA) was found to induce monocyte adhesion through a u-PA receptor (u-PAR)-mediated cAMP-dependent signal transduction pathway (J. Biol. Chem. 270, 30282-30285, 1995). In the present study, the effects of kininogen, kallikrein, factor XII, and plasminogen on u-PA-induced monocyte adhesion were examined since these proteins are abundant in plasma and closely related to u-PA in fibrinolysis and inflammation. Monocyte adhesion to a standard plastic surface by u-PA was shown to be inhibited by the activated, two-chain forms of kininogen (HKa) and kallikrein. The latter occurred only at higher, though physiological, concentrations and was dependent on its catalytic activity. Monocyte adhesion was promoted by factor XII and plasminogen via a noncatalytic mechanism. The findings indicated that u-PA-induced monocyte adhesion was downregulated by HKa and kallikrein and upregulated by factor XII and plasminogen at physiological concentrations. Therefore, these contact system proteins may be important modulators of u-PA-induced monocyte adhesion, a process which is involved in many pathophysiological events.


Immediate rehabilitation of the edentulous jaws with full fixed prostheses supported by four implants: interim results of a single cohort prospective study.
The purpose of this study was to prospectively evaluate the clinical and radiographic outcomes of immediately loaded full-arch fixed prostheses supported by a combination of axially and non-axially positioned implants in a large cohort of patients with completely edentulous jaws, up to 5 years of function. One hundred and seventy-three edentulous patients (80 males and 93 females) were enrolled according to specific selection criteria. Each patient received a full-arch fixed prosthesis supported by two distal tilted implants and two anterior axially placed implants. The provisional functional acrylic prosthesis was delivered the same day as surgery in all cases. All cases were finalized 4-6 months later. The patients were scheduled for follow-up at 6 and 12 months of function, and annually up to 5 years. At each follow-up plaque and bleeding score was assessed and radiographic evaluation of marginal bone level was performed. The overall follow-up range was 4-59 months. A total of 154 immediately loaded prostheses (61 in the maxilla and 93 in the mandible) were in function for at least 1 year and were considered for the analysis. Four axially placed implants failed in the maxilla and one tilted implant in the mandible, all within 6 months of loading. No further implant failure occurred to date. Implant survival at 1 year was 98.36% and 99.73% for the maxilla and the mandible, respectively. Marginal bone loss at 1 year averaged 0.9+/-0.7 mm in the maxilla (204 implants) and 1.2+/-0.9 mm in the mandible (292 implants). No difference was found in marginal bone loss between axial and tilted implants. Plaque and bleeding scores progressively improved from 6 to 12 months. Fracture of the acrylic prosthesis occurred in 14% of total cases. The present preliminary results from a relatively large sample size suggest that the present technique can be considered a viable treatment option for the immediate rehabilitation of both mandible and maxilla.


How will climate novelty influence ecological forecasts? Using the Quaternary to assess future reliability.
Future climates are projected to be highly novel relative to recent climates. Climate novelty challenges models that correlate ecological patterns to climate variables and then use these relationships to forecast ecological responses to future climate change. Here, we quantify the magnitude and ecological significance of future climate novelty by comparing it to novel climates over the past 21,000 years in North America. We then use relationships between model performance and climate novelty derived from the fossil pollen record from eastern North America to estimate the expected decrease in predictive skill of ecological forecasting models as future climate novelty increases. We show that, in the high emissions scenario (RCP 8.5) and by late 21st century, future climate novelty is similar to or higher than peak levels of climate novelty over the last 21,000 years. The accuracy of ecological forecasting models is projected to decline steadily over the coming decades in response to increasing climate novelty, although models that incorporate co-occurrences among species may retain somewhat higher predictive skill. In addition to quantifying future climate novelty in the context of late Quaternary climate change, this work underscores the challenges of making reliable forecasts to an increasingly novel future, while highlighting the need to assess potential avenues for improvement, such as increased reliance on geological analogs for future novel climates and improving existing models by pooling data through time and incorporating assemblage-level information.


Delivery and Measurement of High-Value Care in Standardized Patient Encounters.
Residencies have incorporated high-value care (HVC) training to contain health care expenditures. Assessment methods of HVC curricula are limited. In our clinical skills laboratory, we evaluated the effectiveness of HVC curricula using standardized patients (SPs) to determine if there is a correlation with performance in counseling, history and physical, HVC knowledge, and demographics. Through ambulatory cases, SPs evaluated postgraduate year 2 (PGY-2) residents using checklists to determine if they obtained the chief complaint, medical and social history, focused physical examination, and conveyed information regarding patient management. Investigators scored knowledge-based questions on the need for imaging in low back pain, annual stress testing in coronary artery disease, and chest x-ray for gastroesophageal reflux disease. Univariate analysis was used to calculate percentage distribution of residents' ordering of inappropriate tests. All 56 PGY-2 residents participated in the study and completed at least 2 of 3 HVC cases. Analysis showed that 48% (27 of 56) ordered at least 1 inappropriate test. Residents who ordered unnecessary testing had similar performance in history and physical as well as knowledge of HVC. Inappropriate ordering was significantly associated with poorer performance in counseling (mean percentage counseling score of 68% versus 56% for those who ordered inappropriately, P < .001) and communication skills (mean percentage communication score of 74% versus 71% for those who ordered inappropriately, P < .003). There were no patterns for ordering by demographics. Our evaluation of residents during SP encounters found a correlation between the use of inappropriate testing and lower counseling and communication skills.


Allogeneic marrow transplantation in a cat with acute myeloid leukemia.
A listless, anorectic 2-year-old cat was found to have a normocytic, nonregenerative anemia. A diagnosis of acute myeloid leukemia type M6Er was made. Because the cat was young, had negative FeLV and feline immunodeficiency virus test results, had a sibling that could be used as a bone marrow donor, had received only 1 transfusion, and was in good health other than being anemic, allogeneic bone marrow transplantation (BMT) was attempted using marrow from the cat's sibling. The most life-threatening complication following BMT was hemorrhage caused by severe thrombocytopenia. Complete hematopoietic engraftment was evident 36 days after BMT. The cat then was discharged to its owner. In the first year, the cat continued to improve with the exception of an intractable dermatophytosis, which resolved eventually. The cat continues to do well 4 years after BMT. To our knowledge, this represents the first report of successful allogeneic BMT for a cat with acute myeloid leukemia.


Preparedness to implement national enteral nutritional therapy practice guidelines: An observational study of primary health care institutions in South Africa.
Despite the long-term consequences of malnutrition in hospitalised patients, nutritional practice guidelines for adults, particularly in the recovery phase are rarely implemented in community based primary health care settings. This study aimed at assessing the current practice to establish preparedness for effective implementation of the 2016 South African Enteral Nutrition Practice Guidelines for Adults. This study was conducted in a district hospital in KwaZulu-Natal, a community health centre, two primary health care (PHC) clinics and one household. Non-participant observations were conducted to observe 10 purposefully selected health care professionals involved in nutritional therapy provision to adults, a patient on home enteral nutrition (HEN) and a family caregiver. Content analysis helped identify predominant themes that emerged in the study. Observation results showed that the national enteral nutritional (EN) therapy practice guidelines were not available in all health care institutions. Health care professionals were not aware of them and the care users confirmed that they attended HEN related follow-up care at institutions that prescribed and inserted their feeding tubes. Two major themes that emerged in this study include positive factors and negative factors that influence implementation of the guideline. The study identified factors that can have significant influence on the implementation of the national enteral nutritional therapy practice guidelines, a necessary step for changing clinical practice and thus clinical outcomes of patients. The EN/HEN training and the provision of necessary resources are needed to improve the situation. More research on the strategies for the dissemination of guidelines is essential to improve awareness and thus adoption and implementation.


MRI Susceptibility Changes Suggestive of Iron Deposition in the Thalamus after Ischemic Stroke.
Iron accumulation has been linked to neuronal injury following cerebral ischemia. In animals, a hypointense signal on T2*-weighted (T2*-w) MRI correlated with iron deposits in remote brain regions following ischemic stroke. We aim to assess whether such signal changes are present in remote brain structures following ischemic stroke in humans. We analyzed T2*-w images of 36 patients with unilateral ischemic stroke and 36 healthy controls. Regions of interest (ROIs) consisted of the thalamus, putamen, globus pallidus, caudate nucleus and white matter. To quantify signal intensity in ROIs ipsilateral to the infarct, signal intensity was measured in the ROIs in both hemispheres and a ratio of signal intensity was calculated. Signal asymmetry was compared between patients and controls and its relation with time after stroke onset was assessed. In 34 (94%) patients, the thalamus ipsilateral to the infarct was hypointense compared to the contralateral thalamus. Ipsilateral thalamic signal hypointensity was significantly different between patients and controls (p < 0.001) and was present as early as 1 day after stroke onset. In other ROIs, no difference was found between patients and controls. No association was found between intensity asymmetry and time. We demonstrated that, as early as days after ischemic stroke, T2*-w signal intensity was decreased in the ipsilateral thalamus. This finding might indicate pathophysiologic changes in regions outside the infarcted area, possibly reflecting toxic iron accumulation.


Serum peptidome patterns that distinguish metastatic thyroid carcinoma from cancer-free controls are unbiased by gender and age.
Serum peptidomics is a special form of functional proteomics. The small number of blood proteins that are the source of most prominent peptides in human serum serve as a substrate pool for commonly occurring and/or cancer-derived proteases. Exoprotease activities in particular, when superimposed on the ex vivo coagulation and complement degradation pathways, contribute to generation of not only cancer-specific but also "cancer type"-specific serum peptides. Following development of a unique, semiautomated serum peptide profiling platform and after completing investigations to eliminate common experimental bias, we have now studied possible effects of gender and age on serum peptidomes of 200 healthy men and women, ages 20-80, and of 60 patients (30 men and 30 women) with metastatic thyroid carcinomas. Extensive MALDI-TOF MS and data analysis suggested negligible contributions of both age and gender to the serum peptidome patterns except that healthy men and women under 35 years, but not older individuals, could be distinguished with approximately 70% accuracy. Considering the more advanced age of most patients, this finding is unlikely to interfere with peptidomics analysis of most cancers. By examining patient samples and age/gender-matched controls followed by variability analysis of either demographic or disease (versus control) groups, we could conclusively rule out demographic bias. An optimized, 12-peptide ion thyroid cancer signature was then developed, enabling classification of an independent validation set with 95% sensitivity and 95% specificity (binomial confidence intervals, 75.1-99.9%). Ten of these peptides had previously been assigned to signature patterns of other solid tumor cancers. One of the two newly discovered peptides was dehydro-Ala(3)-fibrinopeptide A. As we expand this study to include hundreds of thyroid cancer patients, the peptide signature will be adjusted, further validated, and then evaluated in a clinical setting used either independently or in combination with existing markers.


SSeCKS/Gravin/AKAP12 inhibits cancer cell invasiveness and chemotaxis by suppressing a protein kinase C- Raf/MEK/ERK pathway.
SSeCKS/Gravin/AKAP12 ("SSeCKS") encodes a cytoskeletal protein that regulates G(1) --> S progression by scaffolding cyclins, protein kinase C (PKC) and PKA. SSeCKS is down-regulated in many tumor types including prostate, and when re-expressed in MAT-LyLu (MLL) prostate cancer cells, SSeCKS selectively inhibits metastasis by suppressing neovascularization at distal sites, correlating with its ability to down-regulate proangiogenic genes including Vegfa. However, the forced re-expression of VEGF only rescues partial lung metastasis formation. Here, we show that SSeCKS potently inhibits chemotaxis and Matrigel invasion, motility parameters contributing to metastasis formation. SSeCKS suppressed serum-induced activation of the Raf/MEK/ERK pathway, resulting in down-regulation of matrix metalloproteinase-2 expression. In contrast, SSeCKS had no effect on serum-induced phosphorylation of the Src substrate, Shc, in agreement with our previous data that SSeCKS does not inhibit Src kinase activity in cells. Invasiveness and chemotaxis could be restored by the forced expression of constitutively active MEK1, MEK2, ERK1, or PKCalpha. SSeCKS suppressed phorbol ester-induced ERK1/2 activity only if it encoded its PKC binding domain (amino acids 553-900), suggesting that SSeCKS attenuates ERK activation through a direct scaffolding of conventional and/or novel PKC isozymes. Finally, control of MLL invasiveness by SSeCKS is influenced by the actin cytoskeleton: the ability of SSeCKS to inhibit podosome formation is unaffected by cytochalasin D or jasplakinolide, whereas its ability to inhibit MEK1/2 and ERK1/2 activation is nullified by jasplakinolide. Our findings suggest that SSeCKS suppresses metastatic motility by disengaging activated Src and then inhibiting the PKC-Raf/MEK/ERK pathways controlling matrix metalloproteinase-2 expression and podosome formation.


Endothelin-1 as an autocrine/paracrine apoptosis survival factor for endothelial cells.
Endothelin-1 (ET-1), an endothelium-derived vasoactive peptide, functions as a potent vasoconstrictor as well as mitogen. We show here a novel role for ET-1 as an apoptosis survival factor for cultured rat endothelial cells. When we rendered endothelial cells obtained from rat aorta quiescent by serum starvation, significant portions of cultured cells underwent apoptotic death as demonstrated by nucleosomal laddering on agarose gel electrophoresis, flow cytometry analysis with FACS, and the TdT-mediated dUTP biotin nick-end labeling (TUNEL) method. ET-1 dose-dependently (10[-12] to 10[-6] mol/L) suppressed the apoptosis induced by serum starvation. The ET(B) receptor antagonist (BQ788; 10[-6] mol/L) and ET(A/B) receptor antagonists (PD142893 and PD145065; 10[-6] mol/L), but not the ET(A) receptor antagonist (BQ123; 10[-6] mol/L), blocked the apoptosis protective effect of 10[-7] mol/L ET-1. Nonimmune rabbit serum reduced the apoptotic event induced by serum deprivation, whereas neutralization of endogenous ET-1 by polyclonal anti-ET-1 antiserum abrogated this protective effect. The ET(B) receptor antagonist (BQ788; 10[-8] to 10[-6] mol/L), but not the ET(A) receptor antagonist (BQ123; 10[-8] to 10[-6] mol/L), significantly inhibited proliferation of endothelial cells. These data suggest that ET-1, as well as mitogen, functions as an apoptosis survival factor for endothelial cells in an autocrine/paracrine manner via the ET(B) receptor.


RCSB Protein Data Bank: Sustaining a living digital data resource that enables breakthroughs in scientific research and biomedical education.
The Protein Data Bank (PDB) is one of two archival resources for experimental data central to biomedical research and education worldwide (the other key Primary Data Archive in biology being the International Nucleotide Sequence Database Collaboration). The PDB currently houses >134,000 atomic level biomolecular structures determined by crystallography, NMR spectroscopy, and 3D electron microscopy. It was established in 1971 as the first open-access, digital-data resource in biology, and is managed by the Worldwide Protein Data Bank partnership (wwPDB; wwpdb.org). US PDB operations are conducted by the RCSB Protein Data Bank (RCSB PDB; RCSB.org; Rutgers University and UC San Diego) and funded by NSF, NIH, and DoE. The RCSB PDB serves as the global Archive Keeper for the wwPDB. During calendar 2016, >591 million structure data files were downloaded from the PDB by Data Consumers working in every sovereign nation recognized by the United Nations. During this same period, the RCSB PDB processed >5300 new atomic level biomolecular structures plus experimental data and metadata coming into the archive from Data Depositors working in the Americas and Oceania. In addition, RCSB PDB served >1 million RCSB.org users worldwide with PDB data integrated with ∼40 external data resources providing rich structural views of fundamental biology, biomedicine, and energy sciences, and >600,000 PDB101.rcsb.org educational website users around the globe. RCSB PDB resources are described in detail together with metrics documenting the impact of access to PDB data on basic and applied research, clinical medicine, education, and the economy.


A novel pH-sensitive (±)-α-tocopherol-5-fluorouracil adduct with antioxidant and anticancer properties.
A novel pH-sensitive (±)-α-tocopherol-5-fluorouracil (VE-5-FU) adduct with antioxidant and anticancer properties for antioxidant-based cancer chemoprevention was synthesized and utilized for selective drug release in the stomach.