Immunoglobulin-like PapD chaperone caps and uncaps interactive surfaces of nascently translocated pilus subunits.
Molecular chaperones are found in the cytoplasm of bacteria and in various cellular compartments in eukaryotes to maintain proteins in nonnative conformations that permit their secretion across membranes or assembly into oligomeric structures. Virtually nothing, however, has been reported about a similar requirement for molecular chaperones in the periplasm of Gram-negative bacteria. We used the well-characterized P pilus biogenesis system in Escherichia coli as a model to elucidate the mechanism of action of a periplasmic chaperone, PapD, which is specifically required for P pilus biogenesis. PapD probably associates with at least six P pilus subunits after their secretion across the cytoplasmic membrane, but PapD is not incorporated into the pilus. We used purified periplasmic complex that PapD forms with the PapG adhesin to investigate the function of interactions between the chaperone and its targets. We demonstrated that PapD binds to PapG to form a stable, discrete bimolecular complex and that, unlike cytoplasmic chaperones, the periplasmic PapD chaperone maintained PapG in a native-like conformation. Bound PapD in the complex was displaced by free PapD in vitro; however, the in vivo release of subunits to the nascent pilus is probably driven by an ATP-independent mechanism involving the outer membrane protein PapC. In addition, the binding of PapD to PapG in vitro prevented aggregation of PapG. We propose that the function of PapD and other periplasmic pilus chaperones is to partition newly translocated pilus subunits into assembly-competent complexes and thereby prevent nonproductive aggregation of the subunits in the periplasm. These data provide important information for understanding the mechanism of action of this general class of chaperones that function in the periplasmic space.


BRAF Inhibitors for BRAF V600E Mutant Colorectal Cancers: Literature Survey and Case Report.
The main method of fighting against colon cancer is targeted treatment. BRAF inhibitors, which are accepted as standard treatment for V600E mutant malign melanomas, are the newest approach for targeted treatment of V600E mutant colorectal cancers. In this case report, we share our experience about the use of BRAF inhibitor vemurafenib on a V600E mutant metastatic right colon adenocarcinoma patient. A 59-year-old male with only lung multiple metastatic V600E mutant right colon cancer presented to our clinic. The patient was evaluated and FOLFOX + bevacizumab treatment was initiated, which was then continued with vemurafenib. A remarkable response was achieved with vemurafenib treatment in which the drug resistance occurred approximately in the sixth month. Even though the patient benefited majorly from vemurafenib, he died on the 20th month of the diagnosis. The expected overall survival for metastatic V600E mutant colon adenocarcinoma patients is 4.7 months. BRAF inhibitors provide new treatment alternatives for V600E mutant colorectal cancers, with prolonged overall survival. BRAF inhibitors in combination with MEK inhibitors are reported as feasible treatment to overcome BRAF inhibitor drug resistance on which phase studies are still in progress. To conclude, BRAF inhibitors alone or in combination with other drugs provide a chance for curing BRAF V600E mutant colorectal cancer patients.


DNA sequence of the gene encoding the E alpha Ia polypeptide of the BALB/c mouse.
A 3.4-kilobase DNA fragment containing the gene coding for the E alpha chain of an Ia (I region-associated) antigen from the BALB/c mouse has been sequenced. It contains at least three exons, which correlate with the major structural domains of the E alpha chain-the two external domains alpha 1 and alpha 2, and the transmembrane-cytoplasmic domain. The coding sequence of the mouse E alpha gene shows striking homology to its counterpart at the DNA and protein levels. The translated alpha 2 exon demonstrates significant similarity to beta 2-microglobulin, to immunoglobulin constant region domains, and to certain domains of transplantation antigens. These observations and those of others suggest that the Ia antigen, transplantation antigen, and immunoglobulin gene families share a common ancestor.


Bromine-passivated Au(111) as a platform for the formation of organic self-assembled monolayers under electrochemical conditions.
Self-assembled monolayers of 5,10,15,20-tetra(4-pyridyl)porphyrin (TPyP) were formed by equilibrium adsorption from a perchloric acid solution onto Au(111) using an interposed adlayer of bromide. The passivating bromide adlayer was generated by addition of 150 microM KBr to the electrochemical cell and allowed monolayer ordering at positive potentials where a disordered TPyP monolayer would be found on a bare Au(111) surface. The TPyP monolayers were characterized in situ with electrochemical scanning tunneling microscopy (EC-STM) and cyclic voltammetry. They were successfully observed at working electrode potentials between 0.0 and +1.3 V vs Ag/AgCl. This wide potential window of usability for the bromide adlayer extends to potentials more positive than what has been achieved for similar observations using iodide-modified Au(111). Within the TPyP monolayers, isolated domains with differing geometries could be distinguished, suggesting dynamic monolayer rearrangements. These results demonstrate that the presence of a passivating bromide adlayer is conducive to the formation of highly ordered organic monolayers. Indeed, bromide is not only one of the few anions that are suitable for this purpose, but it may be superior to the more frequently used iodide.


The 'entangled' stent: a preventable cause of paravalvular leak of the Perceval bioprosthesis.
Despite the excellent early performance of the Perceval sutureless valve, there have been recent reports of stent infolding, followed by paravalvular leak that was linked to valve oversizing. The purpose of this study was to review published reports by assessing photographic and radiological images. An in vitro study was also conducted with stent twisting that may occur during the collapse of the valve, termed 'stent entanglement', demonstrating consecutive successful valve collapse and implantation. This result has led us to hypothesize that infolding is due to a number of triggers, e.g. distortion of the stent overlooked during the final visual inspection of the implanted valve, rather than to excessive oversizing of the prosthesis as the sole cause, as repeatedly suggested in previous reports.


Effect of atrial natriuretic factor on adenylate cyclase in various nephron segments.
The effects of rat synthetic atrial natriuretic factor (ANF) [Arg101, Tyr126] were studied on adenylate cyclase activity in various renal structures such as glomeruli, proximal tubules, loops of Henle, and collecting ducts from dog kidney. ANF inhibited adenylate cyclase activity in glomeruli, loops of Henle, and collecting ducts, but not in proximal tubules, in a concentration-dependent manner. The maximal inhibitions observed were approximately 45% in glomeruli and collecting ducts with an apparent Ki of 10(-10)-10(-9) M and 30% in loops of Henle with an apparent Ki of 10(-11)-5 X 10(-10) M. ANF also inhibited the stimulatory responses of various hormones and forskolin on adenylate cyclase in glomeruli, collecting ducts, and loops of Henle. However, the extent of inhibition varied in the three fractions. In addition, ANF showed an additive effect with the inhibitory response of angiotensin II on adenylate cyclase in glomeruli. These data indicate that ANF receptors coupled to adenylate cyclase are present in glomeruli, loops of Henle, and collecting ducts and not in proximal tubules, and it can be suggested that the inhibition of adenylate cyclase by ANF may be one of the mechanisms through which ANF regulates kidney functions.


[Antibody response of patients with severe acute respiratory syndrome (SARS) to nucleocapsid antigen of SARS-associated coronavirus].
To assess serum antibody responses of patients with severe acute respiratory syndrome (SARS) to nucleocapsid (N) antigen of SARS-associated coronavirus. The serum levels of IgM and IgG antibodies to N antigen were measured in 200 healthy blood donors and 13 SARS patients at different time points of acute and convalescent phases using indirect enzyme-linked immunosorbent assay (ELISA) with N fusion proteins of SARS-associated coronaviruses. The IgM positive critical value of 0.233 and IgG of 0.239 were selected as the threshold value for positive results that equals the product of 2.1 and the mean IgM and IgG levels of 200 healthy blood donors. In 13 patients with SARS, the antibody responses to N antigen were not detectable in the first week after the onset of symptoms. The IgM and IgG seroprotection rates were 83.3% and 66.7% respectively in the second week, both reaching 100% at the third week. IgM seroprotection rates was 61.5% in the second month, and 38.5% at third month. The IgG peaked one month after the onset and remained at high levels in the following 2 months. The antibody responses suggest that N protein of SARS is immunodominant and plays an important role in viral pathogenesis. This ELISA-based test for detecting anti- N antigen may be of significant value for SARS diagnosis.


[Changes in protein, lipid composition, DNA- and RNA- polymerase activity of the chromatin fraction and the nuclear matrix of the rat liver in hypovitaminosis E].
E-hypovitaminosis-induced antioxidant deficiency in rats causes changes in some properties of nuclear structures of the liver cells, i.e. fractions of transcriptionally active and repressed chromatin and nuclear matrix. Changes are found in the protein spectrum of the fraction of transcriptionally active chromatin and nuclear matrix. Lipids of transcriptionally active and repressed chromatin fractions may be peroxidated when this process is stimulated in the NADPH- and ascorbate-dependent systems. In antioxidant deficiency these processes are intensified in the fractions of repressed chromatin. E-hypovitaminosis leads to changes in the fatty acid spectrum of chromatin fractions which correlated with the shifts in the process of lipid peroxidation. Antioxidant deficiency produces changes in the activities of endogenous DNA- and RNA-polymerases in chromatin fractions and in the nuclear matrix. In the fraction of the transcriptionally active liver chromatin of E-deficient animals the endogenous total DNA-polymerase activity and the activity of DNA-polymerases alpha and beta decrease, while in the fractions of repressed chromatin the total RNA-polymerase activity increases. In E-hypovitaminosis the endogenous DNA- and RNA-polymerase activities in the nuclear matrix decrease. Addition of alpha-tocopherol to the preparations of the isolated nuclear matrix results in an increase of the DNA- and RNA-polymerase activities which is more vivid in preparations made of the E-hypovitaminous animal liver.


[Morphological diagnosis of plasmocytic myeloma in trephine biopsy (histological and immunohistochemical criteria)].
Histopathological features of multiple myeloma are reviewed with particular emphasis on its differential diagnosis with reactive plasmocytosis. An algorithm is proposed for examination of bone marrow trephine biopsy in multiple myeloma. Its prognostic factors are discussed. It is concluded that the diagnosis of myeloma in the pathology laboratory should consider cytopathological, histopathological and phenotypic data.


Proteasome inhibition alters glucose-stimulated (pro)insulin secretion and turnover in pancreatic {beta}-cells.
Metabolic labeling studies were conducted in freshly isolated mouse islets and a beta-cell line (MIN6) to examine the effects of proteasome inhibition on glucose-stimulated (pro)insulin synthesis and secretion. Glucose-stimulated (pro)insulin synthesis, as determined by the incorporation of [(3)H]tyrosine, decreased significantly by 90% in islets and 71% in MIN6 cells pretreated with the proteasome inhibitor lactacystin (10 microM) for 2 h. To follow the fate of newly synthesized (pro)insulin, islets were pulse-labeled with [(3)H]tyrosine (40 microCi) for 20 min and chased +/- lactacystin (10 microM) for up to 4 h. The release of newly synthesized (pro)insulin ([(3)H]tyrosine-labeled) was similar between lactacystin-treated and control islets despite a 51% decrease (p <0.05) in total immunoreactive (pro)insulin secretion by lactacystin-treated islets. The specific radioactivity of [(3)H]tyrosine-labeled (pro)insulin in the extracellular medium of lactacystin-treated islets (0.52 +/- 0.16 cpm/microunits) was 2-fold greater relative to control islets (0.25 +/- 0.06 cpm/microunits). Induction of the unfolded protein response by lactacystin, as evidenced by the up-regulation of endoplasmic reticulum (ER) chaperones (GRP78/BiP, GRP94, protein disulfide isomerase) and induction of the stress-inducible transcription factor C/EBP-homologous protein/GADD153 (CHOP/GADD153), likely contributed to the release of newly synthesized (pro)insulin to relieve ER stress. The present data indicate proteasome inhibition did not prevent, but increased (p <0.05), the intracellular degradation of [(3)H]tyrosine-labeled (pro-)insulin from 8 to 24% in islets. Collectively, these data indicate beta-cells may balance glucose-stimulated (pro)insulin synthesis and secretion with the activity of the proteasome to regulate protein concentrations in the ER.


Cutinase-Catalyzed Polyester-Polyurethane Degradation: Elucidation of the Hydrolysis Mechanism.
Polyurethanes (PU) are one of the most-used classes of synthetic polymers in Europe, having a considerable impact on the plastic waste management in the European Union. Therefore, they represent a major challenge for the recycling industry, which requires environmentally friendly strategies to be able to re-utilize their monomers without applying hazardous and polluting substances in the process. In this work, enzymatic hydrolysis of a polyurethane-polyester (PU-PE) copolymer using Humicola insolens cutinase (HiC) has been investigated in order to achieve decomposition at milder conditions and avoiding harsh chemicals. PU-PE films have been incubated with the enzyme at 50 °C for 168 h, and hydrolysis has been followed throughout the incubation. HiC effectively hydrolysed the polymer, reducing the number average molecular weight (Mn) and the weight average molecular weight (Mw) by 84% and 42%, respectively, as shown by gel permeation chromatography (GPC), while scanning electron microscopy showed cracks at the surface of the PU-PE films as a result of enzymatic surface erosion. Furthermore, Fourier Transform Infrared (FTIR) analysis showed a reduction in the peaks at 1725 cm-1, 1164 cm-1 and 1139 cm-1, indicating that the enzyme preferentially hydrolysed ester bonds, as also supported by the nuclear magnetic resonance spectroscopy (NMR) results. Liquid chromatography time-of-flight/mass spectrometry (LC-MS-Tof) analysis revealed the presence in the incubation supernatant of all of the monomeric constituents of the polymer, thus suggesting that the enzyme was able to hydrolyse both the ester and the urethane bonds of the polymer.


Insulin treatment normalizes retinal neuroinflammation but not markers of synapse loss in diabetic rats.
Diabetic retinopathy is one of the leading causes of blindness in developed countries, and a majority of patients with type I and type II diabetes will develop some degree of vision loss despite blood glucose control regimens. The effects of different insulin therapy regimens on early metabolic, inflammatory and neuronal retinal disease processes such as retinal neuroinflammation and synapse loss have not been extensively investigated. This study compared 3 months non-diabetic and streptozotocin (STZ)-induced diabetic Sprague Dawley rats. Diabetic rats received either no insulin treatment, systemic insulin treatment beginning after 1 week uncontrolled diabetes (early intervention, 11 weeks on insulin), or after 1.5 months uncontrolled diabetes (late intervention, 6 weeks on insulin). Changes in both whole animal metabolic and retinal inflammatory markers were prevented by early initiation of insulin treatment. These metabolic and inflammatory changes were also normalized by the later insulin intervention. Insulin treatment begun 1 week after diabetes induction ameliorated loss of retinal synapse markers. Synapse markers and presumably synapse numbers were equivalent in uncontrolled diabetes and when insulin treatment began at 1.5 months of diabetes. These findings are in agreement with previous demonstrations that retinal synapses are lost within 1 month of uncontrolled diabetes and suggest that synapses are not regained with glycemic control and restoration of insulin signaling. However, increased expression of metabolic and inflammatory markers associated with diabetes was reversed in both groups of insulin treatment. This study also emphasizes the need for insulin treatment groups in diabetic retinopathy studies to provide a more faithful modeling of the human condition.


Somatic cell genetics: a review of drug resistance, lectin resistance and gene transfer in mammalian cells in culture.
During the past decade development of selection procedures for isolating a large variety of altered stable phenotypes in mammalian cell culture has been extremely rapid. The list now includes temperature sensitive, auxotrophic, drug resistant and lectin resistant cell lines, as well as cultures containing altered products of differentiation. As a general class, the drug resistant mutants have been studied more often than any of the others because of the wide variety of very interesting and specifically altered mutants that can be isolated, and the ease with which they can usually be obtained. In this review we discuss the essential features of the best studied drug and lectin resistant systems. Also a section on gene transfer has been included since the new technology being developed in this area is certain to have great influence on our understanding of fundamental aspects of somatic cell variation.


Influence of refined cellulose on human bowel function and calcium and magnesium balance.
The effect of cellulose purified from wood pulp on wet and dry stool weights, gastrointestinal transit time (TT), frequency of defecation, and calcium and magnesium balances was tested. Seven healthy women consumed a low fiber diet of constant composition (percentage of total kcal: 23% protein, 30% fat, 47% carbohydrate) and the same metabolically controlled diet to which 16 g of refined cellulose (Solka Floc) was added. Each diet was consumed for approximately one month. The neutral detergent fiber contents of the two diets were 9.5 and 23.5 g, respectively. Cellulose consumption significantly increased mean daily wet stool weight from 74.6 +/- 23.4 (SD) to 130.5 +/- 29.4 g, mean daily dry fecal weight from 19.1 +/- 4.2 to 39.5 +/- 7.7 g, and frequency of defecatin from 0.85 +/- 0.2 to 1.10 +/- 0.29/day. Cellulose effectively shortened TT of two subjects with initially slow TT (7 days), but mean TT of all subjects was not significantly affected when fiber was added to the diet. Fecal excretions of calcium and magnesium were significantly greater when the diet containing cellulose was fed, and only calcium balance was significantly more negative. These results suggest that moderate levels of refined cellulose adversely increased fecal losses of calcium and magnesium. All other indices of bowel function remained within normal ranges.


Macrocyclic peptidomimetics as inhibitors of insulin-regulated aminopeptidase (IRAP).
Macrocyclic analogues of the linear hexapeptide, angiotensin IV (AngIV) have proved to be potent inhibitors of insulin-regulated aminopeptidase (IRAP, oxytocinase, EC 18.104.22.168). Along with higher affinity, macrocycles may also offer better metabolic stability, membrane permeability and selectivity, however predicting the outcome of particular cycle modifications is challenging. Here we describe the development of a series of macrocyclic IRAP inhibitors with either disulphide, olefin metathesis or lactam bridges and variations of ring size and other functionality. The binding mode of these compounds is proposed based on molecular dynamics analysis. Estimation of binding affinities (ΔG) and relative binding free energies (ΔΔG) with the linear interaction energy (LIE) method and free energy perturbation (FEP) method showed good general agreement with the observed inhibitory potency. Experimental and calculated data highlight the cumulative importance of an intact N-terminal peptide, the specific nature of the macrocycle, the phenolic oxygen and the C-terminal functionality.


The placebo effect and white coat effect in isolated systolic hypertension and systo-diastolic hypertension.
It is well recognised from many clinical trials that there is a blood pressure lowering effect when placebo is administered to patients with essential hypertension ("placebo effect"). The reduction in blood pressure, however, may also be partly due to loss of the alerting response ("white coat effect") as a result of familiarisation with the clinical environment. To investigate the hypothesis that there may be a more marked placebo effect and white coat effect in isolated systolic hypertension (ISH) compared with systo-diastolic hypertension (SDH), we studied 78 patients with hypertension: 34 had ISH and 44 patients had SDH. The 34 patients with ISH were older (68.7 vs 54.9 years), had a higher SBP (192.2 vs 169.6 mmHfg) and lower DBP (85.5 vs 102.0 mmHg) when compared to patients with SDH. Amongst the patients with ISH, there were no significant changes in mean blood pressures pre-placebo (paired t-test, p = NS). In the placebo period, there was a significant reduction in systolic blood pressures at all three points, and a significant reduction in diastolic blood pressures after 2 and 3 months placebo (paired t-test, p < 0.05). There was a mean reduction in mean systolic blood pressure at visit 1 by 5.2%, visit 2 by 5.1% and visit 3 by 4.6%, when compared to mean pre-placebo systolic blood pressures (p < 0.05). The mean reduction in diastolic blood pressure was 5.8% at visit 2 and 3.5% at visit 3, when compared to mean pre-placebo diastolic blood pressure (p < 0.05). At the 4-week visit after receiving placebo, the mean systolic blood pressure decreased by 9.4 mmHg (p = 0.003) and mean diastolic blood pressure by 2.7 mmHg (p = NS) in the patients with ISH. In patients with SDH, there were no statistically significant changes in recorded BP readings following the introduction of placebo. We suggest blood pressures in some patients with ISH may settle with careful follow up and initiation of treatment in these patients could potentially be delayed for at least 3 months, as therapy may not prove necessary.


Schwarz meets Schwann: design and fabrication of biomorphic and durataxic tissue engineering scaffolds.
Tissue engineering is a discipline at the leading edge of the field of computer assisted intervention. This multidisciplinary engineering science attempts to meet the reparative and regenerative needs of tissues and organs based on the notion of design and fabrication of scaffolds- porous, three-dimensional "trellis-like" biomimetic structures that, on implantation, provide a viable environment to recuperate and regenerate damaged cells. Existing scaffold fabrication strategies produce sub-optimal porous labyrinths with contra-naturam straight edges. The biomorphic geometry that mimics the secundam-naturam substrate would be one that is continuous through all space, partitioned into two not-necessarily-equal sub-spaces by a non-intersecting, two-sided surface. Minimal surface geometry is not only ideal to describe such a space but is also the preferentially assumed geometry in natural and pathological or manipulated cells. We present results on the premier attempt in computer-controlled fabrication, modulation, and mechanical characterization of tissue engineering scaffolds based on triply periodic minimal surfaces (TPMS). We also present novel strategies to realize coterminous seeding-feeding networks thereby guaranteeing blood/nutrient supply to the proliferating cells at close proximity. This initiative of linking Schwann's 1838 cell theory with Schwarz's 1865 discovery of TPMS is a significant step to fabricate the previously elusive optimal biomorphic tissue analogs.


Correlations of plasma growth hormone with somatostatin, gonadal steroid hormones and thyroid hormones in rainbow trout during sexual recrudescence.
The study explores the interrelationships among growth hormone (GH), somatostatin-14 (SRIF), non-esterified fatty acids (NEFA), gonadal steroid hormones and thyroid hormones (THs) in sexually recrudescent rainbow trout (Oncorhynchus mykiss) to examine aspects of the complex set of physiological changes associated with gonadal growth and maturation. Females exhibited significant decreases in plasma SRIF, NEFA and triiodo-L-thyronine (T3) concentrations, and a significant increase in plasma GH concentration associated with gonadal maturation, whereas in males, only SRIF and NEFA concentrations showed significant changes during testicular maturation. The declining SRIF levels during gonadal recrudescence may indicate a role for the hormone in the energy repartitioning processes that occur in both sexes at this time. Correlation analysis of plasma variables revealed a direct correlations between plasma NEFA and 17 beta-estradiol (E2) in females, an inverse correlation between NEFA and testosterone (T) in males, inverse correlations between GH and SRIF in both males and females, and inverse correlations between THs and SRIF concentrations in females. These marked gender differences in correlations likely reflect the different physiological challenges faced by the two sexes and emphasizes the need to consider gender, as well as maturity when studying the interactions of hormones.


[Recurrent significant bacteriuria and progression of IgA nephropathy].
Tubulointerstitial changes seems to be of decisive importance among factors influencing the prognosis of IgA nephropathy. In consequence of decreased protection ability of mucous membranes, in some cases masked urinary tract infections may stand in the background of the tubulointerstitial changes. In this study the connection between urinary tract infections, significant bacteriurias and the progression of IgA nephropathy was retrospectively investigated. The data and the progress of the disease of 19 IgA nephropathy patients with significant bacteriuria (microbiologically identified) were compared to 19 IgA nephropathy patients of similar age, sex and the time of follow-up without bacteriuria. During the follow-up (on the average 8.5 years), the renal function (values of serum creatinine) decreased significantly (p < 0.05) in both groups, but there was no significant difference between the two groups. Neither at start, nor at the end of the follow-up no significant difference was found in the two groups in the prevalence of proteinuria, haematuria, hypertension and between the values of serum parameters. On the basis of these data we assume, that with the help of frequent medical check up and adequate antibiotic treatment the unfavourable effects of urinary tract infections (chronic tubulointerstitial changes) can probably be fended off.


Long-term Thromboembolic Risk in Patients With Postoperative Atrial Fibrillation After Left-Sided Heart Valve Surgery.
New-onset postoperative atrial fibrillation (POAF) is a common complication of cardiac surgery. However, data on the long-term risk of thromboembolism in patients who develop POAF after heart valve surgery are conflicting. In addition, data on stroke prophylaxis in this setting are lacking. To assess the long-term risk of thromboembolism in patients developing new-onset POAF after isolated left-sided heart valve surgery relative to patients with nonsurgical, nonvalvular atrial fibrillation (NVAF). This observational cohort study was conducted from January 1, 2000, through December 31, 2015, using Danish nationwide registries and the Eastern Danish Heart Surgery Database. Patients who developed POAF after isolated left-sided heart valve surgery (bioprosthetic aortic or mitral valve replacement and/or aortic or mitral valve repair) from 2000 through 2015 were included. These patients were matched with patients with nonsurgical NVAF in a 1:3 ratio by age, sex, heart failure, hypertension, diabetes, a history of thromboembolism, ischemic heart disease, and year of diagnosis. Data analyses took place from January to March 2019. Rates of thromboembolism. Of the 1587 patients who underwent isolated left-sided heart valve surgery, 741 patients (46.7%) developed POAF during admission. Of the 712 patients with POAF who were eligible for matching, 675 patients were matched with 2025 patients with NVAF and made up the study population. In the matched study population, the median age was 71 (interquartile range, 65-77) years, and 1600 (59.3%) were men. Oral anticoagulation therapy was initiated within 30 days postdischarge in 420 patients with POAF (62.9%) and in 1030 patients with NVAF (51.4%). The crude incidence rates of thromboembolism were 21.9 (95% CI, 17.4-27.6) and 17.7 (95% CI, 15.2-20.6) events per 1000 person-years for patients with POAF and patients with NVAF, respectively. In the adjusted analysis, the long-term risk of thromboembolism was similar in patients with POAF and NVAF (hazard ratio, 1.22 [95% CI, 0.88-1.68]). Oral anticoagulation therapy during follow-up was associated with a lower risk of thromboembolic events in patients with POAF (hazard ratio, 0.45 [95% CI, 0.22-0.90]) as well as patients with NVAF (hazard ratio, 0.63 [95% CI, 0.45-0.87]) compared with no anticoagulation therapy. New-onset POAF after isolated left-sided heart valve surgery was associated with a similar long-term risk of thromboembolism as NVAF. These data warrant studies addressing the role of anticoagulation therapy in POAF after left-sided heart valve surgery.


The Effectiveness of Client-Centered Intervention With Telerehabilitation Method After Total Knee Arthroplasty.
There is known to be a decrease in quality of life and perceived occupational performance and satisfaction following total knee arthroplasty (TKA). This study was planned to examine the effectiveness of a client-centered (CC) intervention with the telerehabilitation (TR) method on the quality of life, perceived occupational performance, and satisfaction after TKA. A total of 38 patients who had undergone TKA were randomly assigned to the CC and control groups. A 12-day intervention program was applied to the CC group. The Nottingham Health Profile (NHP) and Canadian Occupational Performance Measure (COPM) were applied before and after intervention. The 12-day intervention showed a strong effect on all parameters in the CC group (p<.001). In the postintervention comparisons, a significant difference was found in favor of the CC group (p < .001). CC interventions with the TR method can be used in post-TKA interventions.


Women in academic psychiatry in Canada.
A comparison of numbers of women psychiatrists with faculty appointments and women residents in Departments of Psychiatry in Canada in 1975 and 1985 showed that the average percentage of women faculty has increased from 11.4% to 14.3% and of women residents from 23.5% to 43.4%. Some departments appeared to be oblivious to the special educational role of women faculty and had not discussed the discrepancy between the numbers of faculty and residents. Only two departments were actively recruiting women faculty. The study also demonstrated a continued concentration of women in the lower ranks. Barriers to recruiting women faculty include lack of academic role models, job advertising not specifically designed to attract women candidates, rigid requirements for appointments, women's lack of access to male corridors of power, pervasive underlying doubts about women's abilities and competence based on cultural stereotypes, female socialization which does not lend itself readily to roles of authority, assertiveness and leadership, and the role strain that ensues when women psychiatrists try to combine career, marriage and motherhood. If women psychiatrists are to fill some of the positions in Departments of Psychiatry, which will fall vacant over the next decade, much more attention must be paid to eliminating or diminishing the multiple obstacles for women who chose a career in academic psychiatry.


Incidence and determinants of antidepressant drug use in migraine patients.
The purpose of this retrospective, follow-up study was to characterise the use of antidepressant medication in a defined migraine population and evaluate the determinants thereof. Data was obtained from the PHARMO-RLS prescription database. Our migraine population (2,517 people) included patients having commenced specific migraine drugs, ergotamine or sumatriptan, for the first time from January 1 1992 to December 31 1998. The corresponding date was termed the 'index date'. Non-migraine patients, those not having used any medication specific for migraine, were selected and equally matched (n=2,517). The cumulative incidence of initiating antidepressant treatment was estimated during two-year observation periods prior to and after the index date. Several demographic and comedication characteristics were assessed as potential determinants of antidepressant drug use within the migraine population. Other determinants included usage patterns ("therapeutic intensity") of ergotamine and sumatriptan, defined as the absolute number of Defined Daily Doses (DDDs) dispensed per patient during one year prior to initiation of antidepressant therapy. A total of 300 migraine patients (11.9%) and 213 non-migraine patients (8.5%) had initiated antidepressant treatment in the two-year period prior to or in the two-year period after the index date (RR adj 1.4; 95% CI 1.2-1.7). The cumulative incidence of initiation of antidepressant treatment for the migraine population was 3.0% per year prior to and 3.2% per year after the initiation of specific migraine analgesia. The concomitant use of benzodiazepines (RR adj 4.7; 95% CI 3.5-6.3), migraine prophylactic medication (RR adj 2.1; 95% CI 1.6-2.8) and heavy therapeutic intensity use of specific migraine analgesia, defined as >/=150 DDDs per year were highly predictive of antidepressant drug use within the migraine population. In conclusion, compared to the non-migraine population, the initiation of antidepressant treatment was only slightly higher in the migraine population. A number of determinants within the latter were found to be strongly associated with antidepressant drug use, the nature of which most likely reflects an increased severity of migraine whereby therapeutic needs are higher.


Application of 3-D ultrasound in assisting the fitting procedure of spinal orthosis to patients with adolescent idiopathic scoliosis.
Spinal orthosis is generally applied to the patients with adolescent idiopathic scoliosis (AIS) during puberty to mechanically support the spine and prevent further deterioration. However, the optimum location of pressure is not easy to be determined and the X-ray taken is not a real time presentation of the spinal curvature. With the advancement of clinical ultrasound, tracing spinal processes along a scoliotic spine becomes possible, which means spinous process angle (SPA) can be obtained from ultrasound images. Moreover, SPA is found to be highly correlated with Cobb's angle. Since the outcome of orthotic intervention for AIS is considered to be associated with accurate orthosis fitting, this study seeks to apply three-dimensional (3-D) ultrasound in the fitting procedure of spinal orthosis for patients with AIS. The accuracy of pressure pad location in brace can help to improve the effectiveness of spinal orthosis treatment. By means of the ultrasound assessments, spinous process angle is examined and used as the parameter to evaluate the optimal location for pressure pad. The intra-rater reliability [ICC (1, 3)] for using ultrasound to measure SPA is >0.9 (p<0.05). Furthermore, the correlation between Cobb's angle estimated from the measurement of SPA in 3-D ultrasound images and Cobb's angle measured from X-ray is highly significant (R=0.98, p<0.01). According to these findings, ultrasound can be further developed as a non-invasive real-time assessment tool for spinal curvature especially in fitting stage to improve the treatment effect of the spinal orthosis.


Stoichiometry and coupling of active transport to oxidative metabolism in epithelial tissues.
A linear relationship has been observed between the rate of active ion transport and the oxygen consumption or lactate production rate in a variety of epithelia. Stoichiometries of ions transported per oxygen consumed or ATP utilized calculated from these relationships reflect actual properties of the active transport step when the following two conditions are met: 1) the basal metabolic rate, obtained in the absence of active transport, remains constant at all rates of active transport; and 2) all the net transport across the tissue considered in the calculation traverses through active (energy-dissipative) pathways. The nature of the cellular mechanism linking active transport and energy production is a fundamental physiological question. Experimental alterations in the rate of active transport elicit mitochondrial state transitions and/or changes in adenine nucleotide concentrations in various epithelia. These findings, obtained by optical and biochemical methods, indicate that ATP and its hydrolysis products constitute part of the coupling mechanism linking the turnover of transport ATPase and the aerobic metabolic rate in epithelia.


Investigating Italian Consumer Preferences for Different Characteristics of Provolone Valpadana Using the Conjoint Analysis Approach.
The objective of this paper was twofold. First, we estimated consumer preferences for an Italian cheese (Provolone Valpadana) with respect to several attributes and levels, such as price, origin certification, production system, 'free from' labelling, and brand. Second, we identified consumer clusters with similar preferences for various cheese characteristics. Preferences were estimated using the conjoint analysis method. Then, a cluster analysis was used to classify consumers into different (three) clusters followed by a market simulation. In all three clusters, the attribute most preferred by Italian consumers was the brand of the cheese: consumers preferred to purchase Provolone cheese having the lowest price, produced by Auricchio, bearing a European Union (EU) quality certification, produced organically, and non-lactose-free. The results of our study provide helpful information to food companies for better segmenting their market and targeting their consumers, as well as effectively promoting their products using brands, certifications as organic and lactose-free. This study contributes to the literature on consumer preference for the EU labelling scheme (voluntary and mandatory). To our knowledge, this is the first study to investigate this combination of multiple labels displayed on the front of Italian cheese packaging.


Intracranial metastases in patients with squamous cell carcinoma of the head and neck.
Intracranial metastases are rarely clinically diagnosed in patients with head and neck squamous cell carcinoma. Only 7 patients with metastases to the cavernous sinus from head and neck squamous cell carcinomas have been reported. A retrospective study revealed 13 patients with intracranial metastases of head and neck squamous cell carcinoma. In a 53-year-old woman a cavernous sinus metastasis of a laryngeal carcinoma was histologically diagnosed by using a CT-guided surgical navigation system and was treated with stereotactic radiotherapy. The mean survival was 4.3 months. Predictive factors for longer survival were absence of extracranial disease, age younger than 60 years, and treatment with radiotherapy. The prognosis for patients with intracranial disease is poor. The current development of computer-assisted stereotactic navigation and stereotactic radiotherapy may facilitate surgical diagnostic exploration and improve treatment, especially in patients without extracranial disease.


Effect of partial volume correction on estimates of the influx and cerebral metabolism of 6-[(18)F]fluoro-L-dopa studied with PET in normal control and Parkinson's disease subjects.
The poor spatial resolution of positron emission tomography (PET) is a limiting factor in the accurate assay of physiological processes investigated by compartmental modeling of tracer uptake and metabolism in living human brain. The radioactivity concentration in a region-of-interest is consequently altered by loss of signal from that structure and contamination from adjacent brain regions, phenomena known as partial volume effects. We now apply an MRI-based algorithm to compensate for partial volume effects in the special case of compartmental modeling of the cerebral uptake of 6-[(18)F]fluoro-L-dopa (FDOPA), an exogenous substrate of dopa decarboxylase. High-resolution MRI scans were obtained from normal volunteers (n = 4) and patients with Parkinson's disease (n = 4) in order to segment specific brain regions and calculate the partial volume correction factors. Dynamic 2D PET scans were acquired during 90 min following intravenous infusion of FDOPA. After partial volume correction, the apparent net blood-brain clearance of FDOPA (K(i)) was greatly increased in caudate and putamen of normal subjects and in caudate of Parkinson's disease patients. The equilibrium distribution volume of FDOPA (V(D)(e)) in cerebral cortex increased by 35% in all subjects. Using a two-compartment model, the relative activity of dopa decarboxylase with respect to FDOPA (k(D)(3)) in the basal ganglia was increased 2-3 times in normal subjects, to the range obtained previously in brain of living rat. The partial volume correction also increased the magnitude of k(D)(3) in caudate of Parkinson's disease patients, but did not alter k(D)(3) in putamen. A three-compartment model correcting for elimination of decarboxylated metabolites also yielded higher estimates of k(D)(3), but with a penalty in precision of the estimates. Together, these observations suggest that the limited spatial resolution of PET results in substantial underestimation of the true rate of FDOPA uptake and metabolism in vivo, and may also tend to obscure regional heterogeneity in the neurochemical pathology of Parkinson's disease.


Anti-leukemic effect of sodium metaarsenite (KML001) in acute myeloid leukemia with breaking-down the resistance of cytosine arabinoside.
Sodium metaarsenite (NaAs2O3: code name KML001) is an orally bioavailable arsenic compound with potential anti-cancer activity. However, the effect of KML001 has not been studied in acute myeloid leukemia (AML). We investigated the anti-leukemic effect of KML001 in AML, and determined the mode of action of KML001. KML001 inhibited the cellular proliferation in all AML cell lines and primary AML blasts as well as HL-60R (cytosine arabinoside-resistant HL-60) cells, while As2O3 was not effective in primary AML blasts and AML cell lines including HL-60R cells. KML001 induced G1 arrest and apoptosis in HL-60 and HL-60R cells. KML001 inhibited the activation of STAT (signal transducer and activator of transcription) 1, 3, 5, NF-κB, AKT and PI3K, while phosphorylated PTEN was upregulated. In addition, activation of ERK, p38 and JNK was observed in KML001-induced growth inhibition of HL-60 and HL-60R cells. Furthermore, KML001 induced telomeric terminal restriction fragment (TRF) length shortening in a time-dependent manner in HL-60 and HL-60R cells. Real‑time PCR with RNA extracted from KML001-treated HL-60 and HL-60R cells showed a significant reduction of catalytic subunit of telomerase, hTERT, in a time-dependent manner. Additionally, γ-H2AX, a sensitive molecular marker of DNA damage, in HL-60 and HL-60R cells was induced by KML001. These results suggest that KML001 inhibits the proliferation of AML cells including cytosine arabinoside-resistant AML cells via various mechanisms such as cell cycle arrest, induction of apoptosis, inhibition of JAK/STAT and PI3K pathways, activation of MAPK pathway and telomere targeting.


Numerical analysis of recurrence plots to detect effect of environmental-strength magnetic fields on human brain electrical activity.
Environmental magnetic fields may activate the neuroendocrine stressor system leading to some human diseases. The stressor theory predicts that the fields can trigger changes in brain electrical activity, like known stressors. We exposed subjects to 1 and 5 μT, 60 Hz while recording electroencephalograms (EEGs) from six derivations, and used a novel method based on numerical analysis of recurrence plots computed from the signals to detect brain electrical potentials evoked by onset and/or offset of the field. The EEGs were also analyzed using linear methods (time averaging). Evoked potentials occurred in all 22 subjects (family-wise error rate less than 0.05 for each subject); the average latency was 250 ms, as expected based on earlier studies using stronger magnetic fields. Field-induced changes in brain electrical activity were not found using time averaging. Control procedures and measurements obtained from electrical phantoms reasonably excluded recording artifacts or chance as explanations for the effects. Onset and offset of magnetic fields produced immediate changes in brain electrical activity, suggesting that the fields were detected by sensory transduction, like ordinary somatic stressors.


Selenium nanoparticles coated bacterial polysaccharide with potent antimicrobial and anti-lung cancer activities.
Bacterial exopolysaccharides are homopolymeric or heteropolymeric polysaccharides with large molecular weights (10-1000 kDa). Exopolysaccharides' functional uses and potential have revolutionized the industrial and medicinal industries. Hence, the aim of the present study was to optimize the production of bacterial exopolysaccharide and apply it as a capping agent for selenium nanoparticles synthesis. Exopolysaccharide (EPS) producing Lactic acid bacteria (LAB) were isolated from dairy products then biochemically characterized and assessed for their potential antimicrobial effect. The most potent EPS producer was identified as Lactiplantibacillus plantarum strain A2 with accession number OP218384 using 16S rRNA sequencing. Overall, FTIR data of the extracted EPS revealed similarity with amylopectin spectrum. 1H NMR spectrum revealed an α-anomeric configuration of the glycosidic linkage pattern in the polysaccharides while the 13C NMR spectrum can also be separated into two main portions, the anomeric carbons region (δ 98-102 ppm) and the non-anomeric carbons region (δ 60-81 ppm). Antimicrobial activity of the produced EPS showed maximum activity against Staphylococcus aureus, MRSA, Enterobacter aerogenes, Klebsiella pneumoniae and Candida albicans respectively. The EPS capsule layer surrounding the bacterial cells was detected by TEM study. Optimization of EPS production was evaluated using Taguchi design, trial 23 reported the highest biomass yield and EPS output (6.5 and 27.12 g/L respectively) with 2.4 and 3.3 folds increase (from the basal media) respectively. The optimized exopolysaccharide was used as a capping and stabilizing agent for selenium nanoparticles (EPS-SeNPs) synthesis. Zeta potential, size and PDI of the synthesized nanoparticles were - 19.7 mV, 45-65 nm and 0.446 respectively with strong bactericidal and fungicidal effect against the tested pathogens. Complete microbial growth eradication was recorded after 6, 8 and 10 h against Staphylococcus aureus, Candida albicans and Klebsiella pneumoniae respectively. EPS-SeNPs showed a potent antioxidant effect reached 97.4% and anticancer effect against A549 lung cancer cell line (IC50 reached 5.324 µg/mL). EPS-SeNPs inhibited cancerous cell growth at S phase. Moreover, molecular studies revealed the anti-apoptotic activity of Bcl2's was inhibited and Bax was activated. The present investigation successfully synthesized selenium nanoparticles through bacterial EPS with significantly high antimicrobial and anticancer activity.


Diabetes as an independent predictor of high atherosclerotic burden assessed by coronary computed tomography angiography: the coronary artery disease equivalent revisited.
(1) To study the prevalence and severity of coronary artery disease (CAD) in diabetic patients. (2) To provide a detailed characterization of the coronary atherosclerotic burden, including the localization, degree of stenosis and plaque composition by coronary computed tomography angiography (CCTA). Single center prospective registry including a total of 581 consecutive stable patients (April 2011-March 2012) undergoing CCTA (Dual-source CT) for the evaluation of suspected CAD without previous myocardial infarction or revascularization procedures. Different coronary plaque burden indexes and plaque type and distribution patterns were compared between patients with (n = 85) and without diabetes (n = 496). The prevalence of CAD (any plaque; 74.1 vs. 56%; p = 0.002) and obstructive CAD (≥50% stenosis; 31.8 vs. 10.3%; p < 0.001) were significantly higher in diabetic patients. The remaining coronary atherosclerotic burden indexes evaluated (plaque in LM-3v-2v with prox. LAD; SIS; SSS; CT-LeSc) were also significantly higher in diabetic patients. In the per segment analysis, diabetics had a higher percentage of segments with plaque in every vessel (2.6/13.1/7.5/10.5% for diabetics vs. 1.4/7.1/3.3/4.4% for nondiabetics for LM, LAD, LCx, RCA respectively; p < 0.001 for all) and of both calcified (19.3 vs. 9.2%, p < 0.001) and noncalcified or mixed types (14.4 vs. 7.0%; p < 0.001); the ratio of proximal-to-distal relative plaque distribution (calculated as LM/proximal vs. mid/distal/branches) was lower for diabetics (0.75 vs. 1.04; p = 0.009). Diabetes was an independent predictor of CAD and was also associated with more advanced CAD, evaluated by indexes of coronary atherosclerotic burden. Diabetics had a significantly higher prevalence of plaques in every anatomical subset and for the different plaque composition. In this report, the relative geographic distribution of the plaques within each subgroup, favored a more mid-to-distal localization in the diabetic patients.


Safety and effectiveness of MRE in comparison with CTE in diagnosis of adult Crohn's disease.
Background: Crohn's disease (CD) is a chronic inflammatory disease of the gastrointestinal tract that is characterized by recurrent attacks and frequent recovery. The lifelong course of this disease requires frequent assessment of the disease activity. The aim of this study was to compare the effectiveness and safety of computed tomography enterography (CTE) to magnetic resonance enterography (MRE) in adults with CD. Methods: A systematic review of the literatures was performed to evaluate the effectiveness and safety of CTE in comparison with MRE. PubMed, Cochrane Library, Scopus, Web of Science, and Embase were searched. Effectiveness outcomes included were sensitivity, specificity, diagnosis difference, diagnostic odds ratio, and positive and negative likelihood. Quality assessment of the studies was conducted using the QADAS score. Meta-analysis was done by RevMan 5.3 for selected outcomes. Results: Five studies had eligibility for analyzing effectiveness. The meta-analysis results showed that diagnosis difference of MRE and CTE, for diagnosing active CD (0.03 CI 95% -0.07-0.13), fistula (-0.01 CI 95% -0.09-0.07), and cramping (-0.02 CI 95% -0.1- 0.06) were not statistically significant. Six studies were finally selected for safety assessment. The results showed that people who are examined with CTE frequently are at increased risk of developing cancer significantly, as they receive more than 50 msv of radiation per year. Conclusion: There was no significant difference between MRE and CTE in diagnosis of Crohn's activity, detection of bowel obstruction, and detection of fistula and stenosis of the alimentary canal. However, the assessment of the safety profile of MRE and CTE showed that MRE is meaningfully safer than CTE for evaluating the recurrence of CD.


Clinicopathologic Features of Tissue Granulomas in Transplant Recipients: A Single Center Study in a Nontuberculosis Endemic Region.
There is a paucity of literature about tissue granulomas in transplant patients. To characterize the clinicopathologic features of granulomas in this population and develop a clinically judicious approach to their evaluation. We performed chart reviews of solid organ and allogeneic hematopoietic stem cell transplant recipients at Yale New Haven Hospital to identify patients with granulomas on biopsy obtained pathologic specimens. Pretransplant and posttransplant specimens were included. Data points included demographics, clinical presentation, epidemiologic risk factors, biopsy indication, location and timing, immunosuppression, histopathology, microbiology, and associated clinical diagnosis. Granuloma-related readmissions and mortality were recorded at 1, 3, and 12 months. Biopsy proven granulomas were identified in 56 of 2139 (2.6%) patients. Of 56, 16 (29%) were infectious. Common infectious etiologies were bartonellosis (n = 3) and cytomegalovirus hepatitis (n = 3). Tuberculosis was not identified. Clinical symptoms prompted tissue biopsy in 27 of 56 (48.2%) cases while biopsies were obtained for evaluation of incidental findings or routine disease surveillance in 29 of 56 (51.8%). Presence of symptoms was significantly associated with infectious etiologies; 11 of 27 (40.7%) symptomatic patients compared with 5 of 29 (17.2%) asymptomatic patients had infectious causes. One death from granulomatous cryptogenic organizing pneumonia occurred. In pretransplant asymptomatic patients, no episodes of symptomatic disease occurred posttransplantation. Granulomas were uncommon in a large transplant population; most were noninfectious but presence of symptoms was associated with infectious etiologies. Granulomas discovered pretransplant without clear infectious etiology likely do not require prolonged surveillance after transplantation. Symptomatology and epidemiologic risks factors should guide extent of microbiologic evaluation.


Refractive power and biometric properties of the nonhuman primate isolated crystalline lens.
Purpose. To characterize the age dependence of shape, refractive power, and refractive index of isolated lenses from nonhuman primates. Methods. Measurements were performed on ex vivo lenses from cynomolgus monkeys (cyno: n = 120; age, 2.7-14.3 years), rhesus monkeys (n = 61; age, 0.7-13.3 years), and hamadryas baboons (baboon: n = 16; age, 1.7-27.3 years). Lens thickness, diameter, and surface curvatures were measured with an optical comparator. Lens refractive power was measured with a custom optical system based on the Scheiner principle. The refractive contributions of the gradient, the surfaces, and the equivalent refractive index were calculated with optical ray-tracing software. The age dependence of the optical and biometric parameters was assessed. Results. Over the measured age range isolated lens thickness decreased (baboon: -0.04, cyno: -0.05, and rhesus: -0.06 mm/y) and equatorial diameter increased (logarithmically for the baboon and rhesus, and linearly for cyno: 0.07 mm/y). The isolated lens surfaces flattened and the corresponding refractive power from the surfaces decreased with age (-0.33, -0.48, and -0.68 D/y). The isolated lens equivalent refractive index decreased (only significant for the baboon, -0.001 D/y), and as a result the total isolated lens refractive power decreased with age (baboon: -1.26, cyno: -0.97, and rhesus: -1.76 D/y). Conclusions. The age-dependent trends in the optical and biometric properties, growth, and aging, of nonhuman primate lenses are similar to those of the pre-presbyopic human lens. As the lens ages, the decrease in refractive contributions from the gradient refractive index causes a rapid age-dependent decrease in maximally accommodated lens refractive power.


Molecular targeting of antiangiogenic factor 16K hPRL inhibits oxygen-induced retinopathy in mice.
To examine the ability and mechanism of the 16 kDa N-terminal fragment of human prolactin (16K hPRL) in the inhibition of abnormal retinal neovascularization. The 16K hPRL-encoding sequence was inserted into an adenoviral vector (16K-Ad). Western blot analysis verified the expression of 16K hPRL and inhibition of proliferation, confirming functional activity of the 16K hPRL in virus-infected adult bovine aortic endothelial (ABAE) cells. 16K hPRL inhibited retinal neovascularization in a mouse model of oxygen-induced retinopathy. The ability of recombinant 16K hPRL expressed in E. coli (r16K hPRL) was compared to that of endostatin in inducing apoptosis of cultured human retinal endothelial cells (HREC). 16K was expressed in virus-infected ABAE cells and resulted in a dose-dependent inhibition of cell proliferation. Eyes injected with 16K-Ad showed a reduction in preretinal neovascularization of 82.3 +/- 9.3% (P < 0.00001) when compared to uninjected controls. r16K hPRL was 100 times more potent than endostatin in inducing apoptosis in HRECs. Intravitreal administration of 16K hPRL inhibited neovascularization in the mouse model of oxygen-induced retinopathy. 16K hPRL stimulated apoptosis in HRECs and inhibited cell proliferation in ABAE cells. These results suggested a potential therapeutic role for 16K hPRL in the treatment of proliferative retinopathies.


[Balloon-assisted enteroscopy in surgical practice].
The authors analyze their experience with video-capsular enteroscopy and balloon-assisted enteroscopy in 184 patients. High diagnostic significance of enteroscopy and the possibility to perform minimally invasive operations are shown.


Time to chill: effects of simulated global change on leaf ice nucleation temperatures of subarctic vegetation.
We investigated the effects of long-term (7-yr) in situ CO(2) enrichment (600 μmol/mol) and increased exposure to UV-B radiation, the latter an important component of global change at high latitudes, on the ice nucleation temperatures of leaves of several evergreen and deciduous woody ericaceous shrubs in the subarctic (68° N). Three (Vaccinium uliginosum, V. vitis-idaea, and Empetrum hermaphroditum) of the four species of shrubs studied showed significantly higher ice nucleation temperatures throughout the 1999 growing season in response to CO(2) enrichment and increased exposure to UV-B radiation relative to the controls. The same species also showed a strong interactive effect when both treatments were applied together. In all cases, leaves cooled to below their ice nucleation temperatures failed to survive the damage resulting from intracellular ice formation. Our results strongly suggest that future global change on a decadal time scale (atmospheric CO(2) increases and polar stratospheric O(3) destruction) will lead to increased foliage damage of subarctic vegetation by severe late spring or early autumnal frosting events. Indeed, in support of our experimental findings, there is now some evidence that increases in atmospheric CO(2) concentration over the past three to four decades may already have acted in this manner on high-elevation arboreal plants in the Swedish Scandes. The implications for vegetation modeling in a future "greenhouse" world and palaeoclimate estimates from high-latitude plant fossils dating to the high-CO(2) environment of the Mesozoic are discussed.


Nursing management of chronic wounds: best practices across the continuum of care.
This article highlights the nurse's role within a holistic, interdisciplinary approach to chronic wound management. Best practices for chronic wound care are discussed, drawing on evidence-based science when it is available. The fundamentals of chronic wound care, including cleansing, irrigation, débridement, infection control, and topical treatment are addressed. New devices and technologies are briefly reviewed. Implementing these best practices across the continuum of care will result in greater advances in the management of chronic wounds.


Survival by histologic subtype in stage IV nonsmall cell lung cancer based on data from the Surveillance, Epidemiology and End Results Program.
The role of histology in the targeted management of nonsmall cell lung cancer (NSCLC) has garnered renewed attention in recent years. We provide contemporary population-based estimates of survival and an assessment of important prognostic factors in stage IV NSCLC by major histologic subtype. Using data from the Surveillance, Epidemiology and End Results (SEER) Program, we stratified 51,749 incident stage IV NSCLC patients (1988-2003 with follow-up through 2006) by major histologic subtype. We used Kaplan-Meier and Cox proportional hazards methods to describe overall survival and the prognostic influence of select patient, tumor, and treatment characteristics for each histologic subgroup. Survival was highest in patients with bronchioloalveolar adenocarcinoma (1-year survival: 29.1%) and lowest in those with large cell tumors (1-year survival: 12.8%). Diagnosis in later years, female gender, younger age, either Asian/Pacific Islander or Hispanic race/ethnicity, lower tumor grade, and surgery or beam radiation as part of first-line treatment were generally independently associated with a decreased risk of death, but the prognostic significance of some of these factors (age, ethnicity, tumor grade) varied according to histologic subtype. Findings demonstrate a poor prognosis across histologic subtypes in stage IV NSCLC patients but highlight differences in both absolute survival and the relative importance of select prognostic factors by histologic subclassification. More research using other sources of population-based data could help clarify the role of histology in the presentation, management, and prognosis of late-stage NSCLC.


Microbial hydrogen economy alleviates colitis by reprogramming colonocyte metabolism and reinforcing intestinal barrier.
With the rapid development and high therapeutic efficiency and biosafety of gas-involving theranostics, hydrogen medicine has been particularly outstanding because hydrogen gas (H2), a microbial-derived gas, has potent anti-oxidative, anti-apoptotic, and anti-inflammatory activities in many disease models. Studies have suggested that H2-enriched saline/water alleviates colitis in murine models; however, the underlying mechanism remains poorly understood. Despite evidence demonstrating the importance of the microbial hydrogen economy, which reflects the balance between H2-producing (hydrogenogenic) and H2-utilizing (hydrogenotrophic) microbes in maintaining colonic mucosal ecosystems, minimal efforts have been exerted to manipulate relevant H2-microbe interactions for colonic health. Consistent with previous studies, we found that administration of hydrogen-rich saline (HS) ameliorated dextran sulfate sodium-induced acute colitis in a mouse model. Furthermore, we demonstrated that HS administration can increase the abundance of intestinal-specific short-chain fatty acid (SCFA)-producing bacteria and SCFA production, thereby activating the intracellular butyrate sensor peroxisome proliferator-activated receptor γ signaling and decreasing the epithelial expression of Nos2, consequently promoting the recovery of the colonic anaerobic environment. Our results also indicated that HS administration ameliorated disrupted intestinal barrier functions by modulating specific mucosa-associated mucolytic bacteria, leading to substantial inhibition of opportunistic pathogenic Escherichia coli expansion as well as a significant increase in the expression of interepithelial tight junction proteins and a decrease in intestinal barrier permeability in mice with colitis. Exogenous H2 reprograms colonocyte metabolism by regulating the H2-gut microbiota-SCFAs axis and strengthens the intestinal barrier by modulating specific mucosa-associated mucolytic bacteria, wherein improved microbial hydrogen economy alleviates colitis.


[The comparative effectiveness of using basic preparations in the combined therapy of rheumatoid arthritis].
Comparison of the time-course of changes in the clinico-laboratory, x-ray and immunological findings in RA patients under the influence of the treatment with azathioprine (50 patients) sulfasalazine (42 patients) and their combination (48 patients) has demonstrated that the best effect (64.6%) may be provided by the use of combined therapy. Azathioprine and sulfasalazine should be administered in combination to patients with seropositive RA, systemic disease manifestations and a high laboratory activity as well as to patients with hormonal dependence. To reduce the number of untoward effects the indicated basic drugs should be applied in moderate doses.


Antitumor effects of ZD6474, a small molecule vascular endothelial growth factor receptor tyrosine kinase inhibitor, with additional activity against epidermal growth factor receptor tyrosine kinase.
Vascular endothelial growth factor (VEGF) is a major mitogen for endothelial cells and enhances vascular permeability. Enhanced VEGF secretion is found in human cancers and correlates with increased tumor neovascularization. ZD6474 is a p.o. bioavailable, VEGF flk-1/KDR receptor (VEGFR-2) tyrosine kinase inhibitor with antitumor activity in many human cancer xenografts and is currently in Phase I clinical development. We tested the effects of ZD6474 on EGFR phosphorylation in cell expressing functional epidermal growth factor receptor (EGFR) and the antiproliferative and the proapoptotic activity of ZD6474 alone or in combination taxanes in human cancer cell lines with functional EGFR but lacking VEGFR-2. The antitumor activity of this drug was also tested in nude mice bearing established GEO colon cancer xenografts. ZD6474 causes a dose-dependent inhibition of EGFR phosphorylation in mouse NIH-EGFR fibroblasts and human MCF-10A ras breast cancer cells, two cell lines that overexpress the human EGFR. ZD6474 treatment resulted in a dose-dependent inhibition of soft agar growth in seven human cell lines (breast, colon, gastric, and ovarian) with functional EGFR but lacking VEGFR-2. A dose-dependent supra-additive effect in growth inhibition and in apoptosis in vitro was observed by the combined treatment with ZD6474 and paclitaxel or docetaxel. ZD6474 treatment of nude mice bearing palpable GEO colon cancer xenografts (which are sensitive to inhibition of EGFR signaling) induced dose-dependent tumor growth inhibition. Immunohistochemical analysis revealed a significant dose-dependent reduction of neoangiogenesis. The antitumor activity of ZD6474 in GEO tumor xenografts was also found to be enhanced when combined with paclitaxel. Tumor regression was observed in all mice after treatment with ZD6474 plus paclitaxel, and it was accompanied by a significant potentiation in inhibition of angiogenesis. Six of 20 mice had no histological evidence of tumors after treatment with ZD6474 plus paclitaxel. This study suggests that in addition to inhibiting endothelial cell proliferation by blocking VEGF-induced signaling, ZD6474 may also be able to inhibit cancer cell growth by blocking EGFR autocrine signaling. These results provide also a rationale for the clinical evaluation of ZD6474 combined with taxanes in cancer patients.


S100A8∕A9 is a valuable biomarker and treatment target to detect and modulate neutrophil involvement in myocardial infarction.
Myocardial infarction (MI) leads to irreversible ischemic damage of the heart muscle and is the leading cause of heart failure. The ischemic cardiac injury triggers a potent local and systemic immune response. In the acute phase post-MI, neutrophils infiltrate the myocardium in large numbers and induce further cardiomyocyte death, expanding the infarcted area. The alarmin S100A8∕A9 is a proinflammatory mediator primarily produced by myeloid cells, with an emerging role in MI. We previously demonstrated that short-term inhibition of S100A8∕A9 during the inflammatory phase of the immune response to MI improves long-term cardiac function. In the present study, we investigated the effects of S100A8∕A9 blockade on myocardial inflammation and post-ischemic myocardial injury in a mouse model of coronary artery ligation. Immunohistochemical (IHC) staining revealed that the presence of S100A9 is strongly correlated with neutrophil infiltration in the myocardium on days 1 and 3 post-MI. A 3-day treatment with the S100A8∕A9 blocker ABR-238901 starting immediately after MI decreased the number of neutrophils and S100A9 presence in the myocardium and had a positive impact on cardiac damage, reducing infarction size. These findings promote S100A9 as an IHC biomarker of neutrophil infiltration and a promising immunomodulatory target to regulate neutrophil recruitment, reduce ischemic injury and promote long-term beneficial cardiac recovery after MI.


Evidence for an anabolic action of essential amino acid analogues in uremia and starvation.
Nitrogen-free analogues of essential amino acids, when administered with those essential amino acids for which analogues are ineffective or unavailable, exert three actions that may be beneficial in protein-deficient or protein-intolerant subjects. First, they bring about an increase in the concentrations of essential amino acids in the blood at the expense of the concentrations of certain non-essential amino acids, notably alanine and glutamine. This effect is most readily demonstrated in children with congenital defects of the urea cycle enzymes, but can also be seen during daily therapy of adults with portal-systemic encephalopathy. Second, these compounds promote nitrogen balance through their suppressive effect on urea synthesis (an effect not attributable to re-utilization of ammonia derived from urease action in the gut). This action is demonstrable in obese subjects who are already conserving nitrogen maximally at the end of a prolonged fast and can also be shown in the first week of fasting when the branched-chain keto acids alone are administered. In both situations, improved nitrogen conservation persists long after the analogues are metabolized, suggesting enzyme adaptations. In chronic uremics, nitrogen balance can be maintained in some (but not all) patients on very low nitrogen intakes. Third, these mixtures may delay or reverse the progressive decline in glomerular filtration rate characteristic of chronic renal failure in some cases: thus, for example, 5 of 6 patients taken off chronic dialysis have maintained lower serum urea concentrations without evidence of protein malnutrition for periods of 2-24 months.


New perspectives from microdialysis studies in freely-moving, spontaneously hypertensive rats on the pharmacology of drugs for the treatment of ADHD.
Attention deficit hyperactivity disorder (ADHD) is a common childhood psychiatric condition that is effectively treated by catecholaminergic drugs with a variety of different mechanisms and the SH rat is frequently used as a model of this disorder. In vivo microdialysis in freely-moving rats has been employed extensively to provide a better understanding of the pharmacodynamics of drugs at their sites of action. In this review, these three topics are brought together to explore the contribution of in vivo microdialysis studies in spontaneously hypertensive (SH) rats to our understanding of the neurochemical deficits in this rat strain and the actions of ADHD drugs on catecholaminergic function in the prefrontocortex (PFC), striatum and nucleus accumbens. What is revealed is that basal efflux of norepinephrine in the PFC is attenuated, whilst striatal and mesolimbic dopaminergic neurotransmission is hyperfunctional; the latter observation fits closely with the hyperactive phenotype of the SH rat. Furthermore, experiments performed with the enantiomers of amphetamine and threo-methylphenidate demonstrate that pharmacodynamic effects of drugs reported from experiments in outbred rat strains, e.g. Sprague-Dawleys, do not necessarily translate to the SH rat. When the findings are compared with the clinical efficacy of drugs used in treating ADHD, they indicate that the most efficacious drugs powerfully increase both norepinephrinergic and dopaminergic neurotransmission.


A bicistronic Epstein-Barr virus mRNA encodes two nuclear proteins in latently infected, growth-transformed lymphocytes.
EBNA2 is a nuclear protein expressed in all cells latently infected with and growth transformed by Epstein-Barr virus (EBV) infection (K. Hennessy and E. Kieff, Science 227:1230-1240, 1985). The nucleotide sequence of the EBNA2 mRNA (J. Sample, M. Hummel, D. Braun, M. Birkenbach, and E. Kieff, Proc. Natl. Acad. Sci. USA 83:5096-5100, 1986) revealed that it begins with a 924-base open reading frame that has an unusual potential translational initiation site (CAAATGG). This open reading frame is followed by 138 nucleotides with only one highly unlikely translational initiation site (TACATGC), which would translate a pentapeptide before the next stop codon. The last part of the mRNA is the open reading frame which encodes EBNA2. In this paper, we demonstrate that the 924-base open reading frame translates a 40-kilodalton protein in vitro or in murine cells transfected with the EBNA2 cDNA under control of the murine leukemia virus long terminal repeat. A protein of identical size was detected in EBV-transformed, latently infected human lymphocyte nuclei by using antibody specific for the leader open reading frame expressed in bacteria. Therefore, this is a rare example of a mRNA which translates two proteins from nonoverlapping open reading frames. Since the protein encoded by the leader of the EBNA mRNA is expressed in all nuclei of a latently infected cell line, it was designated EBNA-LP. EBNA-LP localizes to small intranuclear particles and differs in this respect from EBNA1, EBNA2, or EBNA3. EBNA-LP is not expressed in an EBV-transformed marmoset lymphocyte cell (B95-8) or in one EBV-infected Burkitt tumor cell line (Raji) but is expressed in three other Burkitt tumor cell lines (Namalwa, P3HR-1, and Daudi).


Pulmonary exacerbations and parent-reported outcomes in children <6 years with cystic fibrosis.
Pulmonary exacerbations (PEs) are used as clinical endpoints in infants and preschool children with cystic fibrosis (CF); however, their characteristics and impact in this age range are poorly understood. We used data from the Infant Study of Inhaled Saline, a multicenter trial of inhaled hypertonic versus isotonic saline, to describe PEs in children with CF <6 years and evaluate associations between PEs and parent-reported outcomes assessed by a weekly parent questionnaire (10 items) and three scales of the Cystic Fibrosis Questionnaire-Revised (CFQ-R), and other participant characteristics. There were 659 PEs among 253 of the 321 ISIS participants (mean age 2.3 years) during 287 participant-years follow-up. Of the 659 PEs, 636 (97%) were treated with oral and 45 (7%) with IV antibiotics (not mutually exclusive). Among 222 participants with PEs who had completed parent questionnaires during a PE and at baseline, 9 of the 10 symptoms were each present in a statistically significantly higher proportion of participants during a PE than at baseline. Lower (worse) baseline Respiratory Symptom and Physical Functioning CFQ-R scores were significantly associated with higher PE rate: rate ratio 1.08 (95%CI: 1.02, 1.14) and 1.21 (1.07, 1.36) per 10 point lower score in respective scale. A higher PE rate was also significantly associated with worse CFQ-R Respiratory Symptom and Physical Functioning scores at the end of the study, adjusted for baseline scores. Though most PEs did not require IV antibiotics, PEs appeared to have a negative impact on parent-reported health outcomes in infants and preschoolers with CF. Pediatr Pulmonol. 2015; 50:236-243. © 2014 Wiley Periodicals, Inc.


Effect of Tree-to-Shrub Type Conversion in Lower Montane Forests of the Sierra Nevada (USA) on Streamflow.
Higher global temperatures and increased levels of disturbance are contributing to greater tree mortality in many forest ecosystems. These same drivers can also limit forest regeneration, leading to vegetation type conversion. For the Sierra Nevada of California, little is known about how type conversion may affect streamflow, a critical source of water supply for urban, agriculture and environmental purposes. In this paper, we examined the effects of tree-to-shrub type conversion, in combination with climate change, on streamflow in two lower montane forest watersheds in the Sierra Nevada. A spatially distributed ecohydrologic model was used to simulate changes in streamflow, evaporation, and transpiration following type conversion, with an explicit focus on the role of vegetation size and aspect. Model results indicated that streamflow may show negligible change or small decreases following type conversion when the difference between tree and shrub leaf areas is small, partly due to the higher stomatal conductivity and the deep rooting depth of shrubs. In contrast, streamflow may increase when post-conversion shrubs have a small leaf area relative to trees. Model estimates also suggested that vegetation change could have a greater impact on streamflow magnitude than the direct hydrologic impacts of increased temperatures. Temperature increases, however, may have a greater impact on streamflow timing. Tree-to-shrub type conversion increased streamflow only marginally during dry years (annual precipitation < 800 mm), with most streamflow change observed during wetter years. These modeling results underscore the importance of accounting for changes in vegetation communities to accurately characterize future hydrologic regimes for the Sierra Nevada.


Initial evaluation of a hidden agenda method of teaching the interview.
A structured role-playing method of teaching the biopsychosocial interview using hidden agendas and videotape feedback was developed and evaluated. The teaching method significantly improved medical student interviewing skills as reflected by pre-post scores of 83 third-year students on the Facilitating Response Index. The teaching method is described in detail and recommendations for future research are presented.


Acute inflammation and infection maintain circulating phospholipid levels and enhance lipopolysaccharide binding to plasma lipoproteins.
Circulating lipoproteins are thought to play an important role in the detoxification of lipopolysaccharide (LPS) by binding the bioactive lipid A portion of LPS to the lipoprotein surface. It has been assumed that hypocholesterolemia contributes to inflammation during critical illness by impairing LPS neutralization. We tested whether critical illness impaired LPS binding to lipoproteins and found, to the contrary, that LPS binding was enhanced and that LPS binding to the lipoprotein classes correlated with their phospholipid content. Whereas low serum cholesterol was almost entirely due to the loss of esterified cholesterol (a lipoprotein core component), phospholipids (the major lipoprotein surface lipid) were maintained at near normal levels and were increased in a hypertriglyceridemic subset of septic patients. The levels of phospholipids found in the LDL and VLDL fractions varied inversely with those in the HDL fraction, and LPS bound predominantly to lipoproteins in the LDL and VLDL fractions when HDL levels were low. Lipoproteins isolated from the serum of septic patients neutralized the bioactivity of the LPS that had bound to them. Our results show that the host response to acute inflammation and infection tends to maintain lipoprotein phospholipid levels and that, despite hypocholesterolemia and reduced HDL levels, circulating lipoproteins maintain their ability to bind and neutralize an important bacterial agonist, LPS.


Regions of Rhodobacter sphaeroides cytochrome c2 required for export, heme attachment, and function.
Cytochrome c2 is a periplasmic redox protein involved in both the aerobic and photosynthetic electron transport chains of Rhodobacter sphaeroides. The process of cytochrome c2 maturation has been analyzed in order to understand the protein sequences involved in attachment of the essential heme moiety to the cytochrome c2 polypeptide and localization of the protein to the periplasm. To accomplish this, five different translational fusions which differ only in the cytochrome c2 fusion junction were constructed between cytochrome c2 and the Escherichia coli periplasmic alkaline phosphatase. All five of the fusion proteins are exported to the periplasmic space. The four fusion proteins that contain the NH2-terminal site of covalent heme attachment to cytochrome c2 are substrates for heme binding, suggesting that the COOH-terminal region of the protein is not required for heme attachment. Three of these hybrids possess heme peroxidase activity, which indicates that they are functional as electron carriers. Biological activity is possessed by one hybrid protein constructed five amino acids before the cytochrome c2 COOH terminus, since synthesis of this protein restores photosynthetic growth to a photosynthetically incompetent cytochrome c2-deficient derivative of R. sphaeroides. Biochemical analysis of these hybrids has confirmed CycA polypeptide sequences sufficient for export of the protein (A. R. Varga and S. Kaplan, J. Bacteriol. 171:5830-5839, 1989), and it has allowed us to identify regions of the protein sufficient for covalent heme attachment, heme peroxidase activity, docking to membrane-bound redox partners, or the capability to function as an electron carrier.


Genome-wide analysis of novel splice variants induced by topoisomerase I poisoning shows preferential occurrence in genes encoding splicing factors.
RNA splicing is required to remove introns from pre-mRNA, and alternative splicing generates protein diversity. Topoisomerase I (Top1) has been shown to be coupled with splicing by regulating serine/arginine-rich splicing proteins. Prior studies on isolated genes also showed that Top1 poisoning by camptothecin (CPT), which traps Top1 cleavage complexes (Top1cc), can alter RNA splicing. Here, we tested the effect of Top1 inhibition on splicing at the genome-wide level in human colon carcinoma HCT116 and breast carcinoma MCF7 cells. The RNA of HCT116 cells treated with CPT for various times was analyzed with ExonHit Human Splice Array. Unlike other exon array platforms, the ExonHit arrays include junction probes that allow the detection of splice variants with high sensitivity and specificity. We report that CPT treatment preferentially affects the splicing of splicing-related factors, such as RBM8A, and generates transcripts coding for inactive proteins lacking key functional domains. The splicing alterations induced by CPT are not observed with cisplatin or vinblastine and are not simply due to reduced Top1 activity, as Top1 downregulation by short interfering RNA did not alter splicing like CPT treatment. Inhibition of RNA polymerase II (Pol II) hyperphosphorylation by 5,6-dichloro-1-β-d-ribofuranosylbenzimidazole (DRB) blocked the splicing alteration induced by CPT, which suggests that the rapid Pol II hyperphosphorylation induced by CPT interferes with normal splicing. The preferential effect of CPT on genes encoding splicing factors may explain the abnormal splicing of a large number of genes in response to Top1cc.


Electrodeposited iridium oxide pH electrode for measurement of extracellular myocardial acidosis during acute ischemia.
In the present paper, fabrication, characterization, and physiological applications of a solid-state pH electrode are described. The pH sensing layer was based on an anodic electrodeposited iridium oxide film (AEIROF). Sputtered platinum electrodes (1 mm diameter) fabricated on flexible Kapton films or platinum wires were used as planar or cylindrical supports. Each electrode site was coated with Nafion to attenuate the interference of anionic redox species and to protect the electrode surface during in vivo measurements. Performance of the AEIROF was evaluated, for the first time, as a pH electrode and proved to have a slightly super-Nernstian response with slope of -63.5 +/- 2.2 mV/pH unit for both wire and planar sputtered platinum electrodes. Linear pH responses were obtained in the pH range 2-10. The electrodes have a working lifetime of at least 1 month with accuracy of about 0.02 pH unit and fast response time. The electrodes showed very low sensitivities for different species, such as Na+, K+, Li+, NH4+, Ca2+, Mg2+, dissolved oxygen, lactate, ascorbate, and urate, which are important for physiological applications. The electrodes were applied in extracellular pH measurements during brief regional ischemia in a swine heart and no-flow ischemia in an isolated rabbit papillary muscle. A first report on extracellular pH, K+, and lactate simultaneous measurements during no-flow ischemia using the AEIROF pH electrode and the previously described K+ and lactate electrodes is presented as well.


Acute liver failure induced by idiosyncratic reaction to drugs: Challenges in diagnosis and therapy.
Acute liver failure (ALF) requires urgent attention to identify etiology and determine prognosis, in order to assess likelihood of survival or need for transplantation. Identifying idiosyncratic drug-induced liver injury (iDILI) may be particularly difficult, but the illness generally follows a subacute course, allowing time to assess outcome and find a liver graft if needed. Not all drugs that cause iDILI lead to ALF; the most common are antibiotics including anti-tuberculous medications, non-steroidal anti-inflammatory agents and herbal and dietary supplements (HDS). Determining causality remains challenging particularly if altered mentation is present; identifying the causative agent depends in part on knowing the propensity of the drugs that have been taken in the proper time interval, plus excluding other causes. In general, iDILI that reaches the threshold of ALF will more often than not require transplantation, since survival without transplant is around 25%. Treatment consists of withdrawal of the presumed offending medication, consideration of N-acetylcysteine (NAC), as well as intensive care. Corticosteroids have not proven useful except perhaps in instances of apparent autoimmune hepatitis caused by a limited number of agents. Recently developed prognostic scoring systems may also aid in predicting outcome in this setting.


Restricting the Sale of Electronic Nicotine Delivery System Flavors.
Electronic nicotine delivery system use contributes to the epidemic of youth vaping. Regulations to curtail or prohibit the sale of flavored nicotine products aim to disrupt initiation of child nicotine use by reducing access to enticing nicotine flavorings. A total of 6 states and >300 localities have restricted or banned flavored nicotine product sales. In this case study, we outline the use of a localized town-based strategy, which offered 2 potential bills to incrementally restrict or prohibit sale of flavored vape products when county or state legislation was not politically feasible. Over the course of 18 months, these bills reduced the number of municipalities where these products could be sold or advertised until county, city, and statewide bans were effectively in place, ultimately making the passage of a bill in the statehouse palatable. Strong partnerships with officials who had expertise in local town government, local American Academy of Pediatrics chapter physician champions, and a diverse coalition were instrumental in motivating smaller governments, which often pass legislation faster than larger legislatures, to create child-protective tobacco policies.


Public Disaster Communication and Child and Family Disaster Mental Health: a Review of Theoretical Frameworks and Empirical Evidence.
Children have been identified as particularly vulnerable to psychological and behavioral difficulties following disaster. Public child and family disaster communication is one public health tool that can be utilized to promote coping/resilience and ameliorate maladaptive child reactions following an event. We conducted a review of the public disaster communication literature and identified three main functions of child and family disaster communication: fostering preparedness, providing psychoeducation, and conducting outreach. Our review also indicates that schools are a promising system for child and family disaster communication. We complete our review with three conclusions. First, theoretically, there appears to be a great opportunity for public disaster communication focused on child disaster reactions. Second, empirical research assessing the effects of public child and family disaster communication is essentially nonexistent. Third, despite the lack of empirical evidence in this area, there is opportunity for public child and family disaster communication efforts that address new domains.


Early diagnosis of spinal epidural metastases using out-patient computed tomographic myelography.
Twenty patients with known malignancies, back pain, abnormal roentgenograms of the spine, and normal neurological examinations were evaluated by outpatient computed tomographic (CT) myelography to determine the presence and extent of epidural tumor. Spinal CT following the intrathecal administration of low doses of water soluble contrast agents provided high quality diagnostic information. Three patients experienced adverse effects from this procedure which were mild and easily managed in the outpatient setting. Epidural tumor was identified in 15 of 20 (75%) patients. Patients were followed for 9-27 months following myelography. The 14 patients with epidural tumor treated with local radiation experienced pain relief and only one of these patients developed signs or symptoms of recurrent epidural tumor in the treated site. This study documents the high incidence of epidural tumor in selected patients without neurological deficits and the excellent palliative results of non-emergent, carefully planned radiation therapy. It also demonstrates that high resolution CT myelography can be performed safely in an outpatient setting in patients at high risk for epidural tumor. Outpatient myelography facilitates the early diagnosis of epidural tumor and provides needed information on the extent of the tumor for radiation treatment planning while conserving health care resources. For these reasons, outpatient CT myelography should be considered in selected patients with cancer who are at high risk for epidural metastases.


Hereditary Angio-Oedema for Dermatologists.
Among angio-oedema patients, hereditary angio-oedema (HAE) should not be overlooked. Besides skin swellings, these patients might have very painful abdominal attacks and potentially life-threatening angio-oedema of the upper airway. They will not respond to traditional anti-allergic therapy with antihistamines, corticosteroids, and adrenaline, and instead need specific drugs targeting the kallikrein-kinin pathway. Classically, patients with HAE have a quantitative or qualitative deficiency of the C1 inhibitor (C1INH) due to different mutations in SERPING1, although a new subtype with normal C1INH has been recognised more recently. This latter variant is diagnosed based on clinical features, family history, or molecular genetic testing for mutations in F12, ANGPT1,or PLG.The diagnosis of HAE is often delayed due to a general unfamiliarity with this orphan disease. However, undiagnosed patients are at an increased risk of unnecessary surgical interventions or life-threatening laryngeal swellings. Within the last decade, new and effective therapies have been developed and launched for acute and prophylactic therapy. Even more drugs are under evaluation in clinical trials. It is therefore of utmost importance that patients with HAE are diagnosed as soon as possible and offered relevant therapy with orphan drugs to reduce morbidity, prevent mortality, and improve quality of life.


Neural arbors are Pareto optimal.
Neural arbors (dendrites and axons) can be viewed as graphs connecting the cell body of a neuron to various pre- and post-synaptic partners. Several constraints have been proposed on the topology of these graphs, such as minimizing the amount of wire needed to construct the arbor (wiring cost), and minimizing the graph distances between the cell body and synaptic partners (conduction delay). These two objectives compete with each other-optimizing one results in poorer performance on the other. Here, we describe how well neural arbors resolve this network design trade-off using the theory of Pareto optimality. We develop an algorithm to generate arbors that near-optimally balance between these two objectives, and demonstrate that this algorithm improves over previous algorithms. We then use this algorithm to study how close neural arbors are to being Pareto optimal. Analysing 14 145 arbors across numerous brain regions, species and cell types, we find that neural arbors are much closer to being Pareto optimal than would be expected by chance and other reasonable baselines. We also investigate how the location of the arbor on the Pareto front, and the distance from the arbor to the Pareto front, can be used to classify between some arbor types (e.g. axons versus dendrites, or different cell types), highlighting a new potential connection between arbor structure and function. Finally, using this framework, we find that another biological branching structure-plant shoot architectures used to collect and distribute nutrients-are also Pareto optimal, suggesting shared principles of network design between two systems separated by millions of years of evolution.


Breast cancer metastasis to bone: it is not all about PTHrP.
Breast cancer shows a predilection for metastasis to bone. Interestingly, approximately 80% of patients with breast cancer also have bone metastases develop at some point during the course of their disease. Osteolytic breast cancer induces bonedestruction via the stimulation of osteoclasts. Breast cancer cells produce many known stimulators of bone resorption with significant research effort focused on the role of parathyroid hormone-related protein (PTHrP). However, a recent prospective clinical trial has questioned the primary role of PTHrP in this process. The overexpression of interleukin-8 (IL-8) in metastatic breast cancer cells prompted additional investigation of the role of IL-8 in osteolysis. Recombinant IL-8 induces the expression of RANKL mRNA and protein in osteoblastic cells and stimulates formation of bone resorbing osteoclasts, even in the absence of RANKL. The ability of IL-8 to directly stimulate osteoclastogenesis via RANKL dependent and independent mechanisms suggests it may play an important role in the process of osteoclast formation and function. Therefore, we propose that cytokines such as IL-8 are involved in the early stages of breast cancer metastasis and initiate the process of osteoclastic bone resorption. In this modified model of breast cancer metastasis to bone, PTHrP expression is induced later to stimulate the vicious cycle of bone destruction.


["Phylogenetic presumptions"--can jurisprudence terms promote comparative biology?].
The paper presents the results of a critical analysis of the "phylogenetic presumptions" conception by means of its comparison with the hypothetic-deductive method of the phylogeny reconstruction within the framework of the evolutionary systematics. Rasnitsyn (1988, 2002) suggested this conception by analogy with the presumption of innocence in jurisprudence, where it has only moral grounds. Premises of all twelve the "phylogenetic presumptions" are known for a long time as the criteria of character homology and polarity or as the criteria of relationship between organisms. Many of them are inductive generalizations based on a large body of data and therefore are currently accepted by most of taxonomists as criteria or corresponding rules, but not as presumptions with the imperative "it is true until the contrary is proved". The application of the juristic term "presumption" in phylogenetics introduces neither methodical profits, nor anything to gain a better insight of problems of the phylogenetic reconstruction. Moreover, it gives ill effects as, by analogy with a judicially charged person and his legal defense, it allows a researcher not to prove or substantiate his statements on characters and relationships. Some of Rasnitsyn's presumptions correspond to criteria, which have been recognized as invalid ones on the reason of their non-operationality (presumption "apomorphic state corresponds more effective adaptation") or insufficient ontological grounds (presumptions "are more complex structure is apomorphic", "the most parsimonious cladogram is preferable", and "one should considered every to be inherited").


Serum levels of soluble vascular cell adhesion molecule-1 (sVCAM-1) are elevated in advanced stages of non-Hodgkin's lymphomas.
The serum levels of soluble vascular cell adhesion molecule-1 (sVCAM-1) were measured in 116 patients with non-Hodgkin's lymphomas (NHL) tested previously for soluble intercellular adhesion molecule-1 (sICAM-1). In contrast to Hodgkin's disease and chronic lymphocytic leukaemia, the sVCAM-1 levels in NHL patients were not significantly different from the levels of healthy controls (n = 31). However, sVCAM-1 was elevated in advanced stage disease, i.e. stages III + IV. Elevated serum levels of sVCAM-1 were associated with significantly poorer disease-free (p = 0.024) and overall (p = 0.02) survival. sVCAM-1 correlated poorly with other known prognostic variables (LDH, sTK and beta 2m) and with sICAM-1. None of the tested markers added prognostic information for disease-free survival independently of Ann Arbor stage and B-symptoms. The expression of VCAM-1 and ICAM-1 in tumour biopsies from 15 patients representing 7 different histologies were examined and compared with the serum levels of the soluble adhesion molecules. No correlation was found between the adhesion molecule expression by vascular endothelium and the corresponding serum levels.