Update: Ongoing Zika Virus Transmission - Puerto Rico, November 1, 2015-April 14, 2016.
Zika virus is a flavivirus transmitted primarily by Aedes species mosquitoes, and symptoms of infection can include rash, fever, arthralgia, and conjunctivitis (1).* Zika virus infection during pregnancy is a cause of microcephaly and other severe brain defects (2). Infection has also been associated with Guillain-Barré syndrome (3). In December 2015, Puerto Rico became the first U.S. jurisdiction to report local transmission of Zika virus, with the index patient reporting symptom onset on November 23, 2015 (4). This report provides an update to the epidemiology of and public health response to ongoing Zika virus transmission in Puerto Rico. During November 1, 2015-April 14, 2016, a total of 6,157 specimens from suspected Zika virus-infected patients were evaluated by the Puerto Rico Department of Health (PRDH) and CDC Dengue Branch (which is located in San Juan, Puerto Rico), and 683 (11%) had laboratory evidence of current or recent Zika virus infection by one or more tests: reverse transcription-polymerase chain reaction (RT-PCR) or immunoglobulin M (IgM) enzyme-linked immunosorbent assay (ELISA). Zika virus-infected patients resided in 50 (64%) of 78 municipalities in Puerto Rico. Median age was 34 years (range = 35 days-89 years). The most frequently reported signs and symptoms were rash (74%), myalgia (68%), headache (63%), fever (63%), and arthralgia (63%). There were 65 (10%) symptomatic pregnant women who tested positive by RT-PCR or IgM ELISA. A total of 17 (2%) patients required hospitalization, including 5 (1%) patients with suspected Guillain-Barré syndrome. One (<1%) patient died after developing severe thrombocytopenia. The public health response to the outbreak has included increased laboratory capacity to test for Zika virus infection (including blood donor screening), implementation of enhanced surveillance systems, and prevention activities focused on pregnant women. Vector control activities include indoor and outdoor residual spraying and reduction of mosquito breeding environments focused around pregnant women's homes. Residents of and travelers to Puerto Rico should continue to employ mosquito bite avoidance behaviors, take precautions to reduce the risk for sexual transmission (5), and seek medical care for any acute illness with rash or fever.


Cryptococcus neoformans: paradigm for the role of antibody immunity against fungi?
Cryptococcus neoformans is an encapsulated fungus that is a frequent cause of life-threatening infections in patients with AIDS. C. neoformans has many similarities with encapsulated bacteria such as S. pneumoniae and H. influenzae for which antibody immunity is important in protection. However the role of antibody immunity in protection against C. neoformans has been controversial. Experiments with polyclonal sera have produced conflicting evidence for and against the importance of antibody immunity in host defense. Experiments with monoclonal antibodies (mAb) to the C. neoformans capsular polysaccharide (CPS) have revealed the existence of protective, non-protective and disease-enhancing mAbs, suggesting that the divergent results obtained with polyclonal preparations may be a result of relative proportion of protective and non-protective antibodies in immune sera. Administration of protective mAbs can prolong survival, decrease organ fungal burden, and reduce serum polysaccharide antigen. In vitro experiments suggests that protective mAbs modify the course of infection by enhancing effector cell function against C. neoformans. Addition of mAb to antifungal drugs enhances their efficacy against C. neoformans in vivo and in vitro. Human-mouse chimeric antibodies with activity against C. neoformans have been constructed. A highly immunogenic capsular polysaccharide-protein vaccine has been synthesized that elicits protective antibodies in mice. Antibody immunity elicited by conjugate vaccines or provided by passive administration may be useful in the prevention treatment of human cryptococcal infections.


Genetic analysis of EphA-dependent signaling mechanisms controlling topographic mapping in vivo.
Ephrin/Eph ligands and receptors are best known for their prominent role in topographic mapping of neural connectivity. Despite the large amount of work centered on ephrin/Eph-dependent signaling pathways in various cellular contexts, the molecular mechanisms of action of Eph receptors in neural mapping, requiring dynamic interactions between complementary gradients of ephrins and Eph receptors, remain largely unknown. Here, we investigated in vivo the signaling mechanisms of neural mapping mediated by the EphA4 receptor, previously shown to control topographic specificity of thalamocortical axons in the mouse somatosensory system. Using axon tracing analyses of knock-in mouse lines displaying selective mutations for the Epha4 gene, we determined for the first time which intracellular domains of an Eph receptor are required for topographic mapping. We provide direct in vivo evidence that the tyrosine kinase domain of EphA4, as well as a tight regulation of its activity, are required for topographic mapping of thalamocortical axons, whereas non-catalytic functional modules, such as the PDZ-binding motif (PBM) and the Sterile-alpha motif (SAM) domain, are dispensable. These data provide a novel insight into the molecular mechanisms of topographic mapping, and constitute a physiological framework for the dissection of the downstream signaling cascades involved.


Red cell alloimmunization among antenatal women attending a tertiary care hospital in south India.
Detection of maternal alloimmunization against red cell antigens is vital in the management of haemolytic disease of the foetus and newborn (HDFN). This study was conducted to measure the presence of allosensitization to blood group antibodies in the antenatal women attending a tertiary care hospital and to observe the proportion of minor blood group antibodies to assess the benefit of screening for the same. All antenatal women registered in the hospital between January 2008 and January 2009, were screened for irregular antibodies using a commercial 3-cell antibody screening panel. Antibody identification was performed on samples found positive using a commercial 11 cell-panel. Screening was performed on 5347 women, 339 (6.34%) of whom were Rh negative. Allosensitization was found in 79 women (1.48%; confidence interval 1.17 -1.84). In 29 of these 79 (37%) women the allo-antibodies could not be identified. In the remaining 50 women, 54 antibodies were characterized. A total of 40 clinically significant antibody specificities were identified among 36 women, of whom four were Rh(D) positive. Allosensitization with clinically significant antibodies was found in 9.43 per cent (confidence interval 6.55-13.06) Rh(D) negative and in 0.08 per cent (confidence interval .02-0.2) Rh(D) positive women. Anti D was the most frequent antibody found in 8.85 per cent Rh(D) negative women. The remaining clinically significant antibodies identified included anti-C, c, E, Jk(a), Jk(b), M and S. In Rh(D) negative women, anti-D and antibodies of the Rh system contributed 83.3 and 94.4 per cent of clinically significant antibodies. However, in Rh(D) positive women, non-Rh antibodies comprised three out of four clinically significant antibodies. The presence of alloimmunization in our study corroborated with data reported from India. The most frequent antibody was anti-D. However, a significant fraction was non-D. Alloimmunization among Rh(D) positive women though low as compared to Rh(D) negative women, included clinically significant antibodies, and most of these were non Rh.


A cross-sectional pilot study of compassion fatigue, burnout, and compassion satisfaction in pediatric palliative care providers in the United States.
Compassion fatigue (CF) is secondary traumatic distress experienced by providers from contact with patients' suffering. Burnout (BO) is job-related distress resulting from uncontrollable workplace factors that manifest in career dissatisfaction. Compassion satisfaction (CS) is emotional fulfillment derived from caring for others. The literature on BO in healthcare providers is extensive, whereas CF and CS have not been comprehensively studied. Because of ongoing exposure to patient and family distress, pediatric palliative care (PPC) providers may be at particular risk for CF. We conducted a cross-sectional pilot study of CF, BO, and CS among PPC providers across the United States. The Compassion Fatigue and Satisfaction Self-Test for Helpers and a questionnaire of professional and personal characteristics were distributed electronically and anonymously to PPC physicians and nurses. Logistic and linear regression models for CF, BO, and CS as a function of potential risk factors were constructed. The survey response rate was 39%, primarily consisting of female, Caucasian providers. The prevalence of CF, BO, and CS was 18%, 12%, and 25%, respectively. Distress about a "clinical situation," physical exhaustion, and personal loss were identified as significant determinants of CF. Distress about "coworkers," emotional depletion, social isolation, and "recent involvement in a clinical situation in which life-prolonging activities were not introduced" were significant determinants of BO. Physical exhaustion, personal history of trauma, "recent involvement in a clinical situation in which life-prolonging activities were not introduced," and not discussing distressing issues were significant predictors of lower CS scores.Significance of resultsCF and BO directly influence the well-being and professional performance of PPC providers. To provide effective compassionate care to patients, PPC providers must be attentive to predictors of these phenomena. Further work is needed to explore additional causes of CF, BO, and CS in PPC providers as well as potential interventions.


Comparison of microarray and sage techniques in gene expression analysis of human glioblastoma.
To enhance glioblastoma (GB) marker discovery we compared gene expression in GB with human normal brain (NB) by accessing SAGE Genie web site and compared obtained results with published data. Nine GB and five NB SAGE-libraries were analyzed using the Digital Gene Expression Displayer (DGED), the results of DGED were tested by Northern blot analysis and RT-PCR of arbitrary selected genes. Review of available data from the articles on gene expression profiling by microarray-based hybridization showed as few as 35 overlapped genes with increased expression in GB. Some of them were identified in four articles, but most genes in three or even in two investigations. There was found also some differences between SAGE results of GB analysis. Digital Gene Expression Displayer approach revealed 676 genes differentially expressed in GB vs. NB with cut-off ratio: twofold change and P < or = 0.05. Differential expression of selectedgenes obtained by DGED was confirmed by Northern analysis and RT-PCR. Altogether, only 105 of 955 genes presented in published investigations were among the genes obtained by DGED. Comparison of the results obtained by microarrays and SAGE is very complicated because authors present only the most prominent differentially expressed genes. However, even available data give quite poor overlapping of genes revealed by microarrays. Some differences between results obtained by SAGE in different investigations can be explained by high dependence on the statistical methods used. As for now, the best solution to search for molecular tumor markers is to compare all available results and to select only those genes, which significant expression in tumor combined with very low expression in normal tissues was reproduced in several articles. 105 differentially expressed genes, common to both methods, can be included in the list of candidates for the molecular typing of GBs. Some genes, encoded cell surface or extra-cellular proteins may be useful for targeting gliomas with antibody-based therapy.


Age and site of Colonic Neoplastic Lesions: Implications of screening in South Asia.
Objective : To evaluate the Age of patients and the site of Colonic Neoplastic Lesions (CNL) and to determine the appropriate screening strategy for Colorectal Carcinoma (CRC) (sigmoidoscopy versus colonoscopy) in our population. Methods : This is a cross sectional study. Data of all patients more than 16 years of age who underwent full colonoscopic examination at the Aga Khan University hospital between January 2011 till December 2013 and were diagnosed to have CRC or advanced adenomas (defined as polyp more than 1 cm and/or having villous morphology on histology) was recorded. Lesions found distal to the splenic flexure were characterized as distal lesions and while lesions found between the splenic flexure and the cecum were characterized as proximal lesions. During the study period colonic neoplastic lesions were found in 217 patients; 186 (85.7%) patients had CRC and 31(14.3%) patients had advanced adenomatous polyps. Mean age was 55.8±14 years and amongst them 72 (33.2%) patients were less than 50 years of age while 145 (66.8%) were more than 50 years. In 144 (66.4%) patients lesions were located in the distal colon, 65 (30%) had lesions in the proximal colon while in 8 (3.7%) patients the neoplastic lesions were found both in the proximal and distal colon. The predominant symptoms were bleeding per rectum in 39.6% of patients followed by weight loss in 31.8% of patients. Only 3 patients had familial syndromes with multiple polyps. When patients younger than 50 years of age were compared with patients more than 50 years there was no statistically significant difference between the site of neoplastic lesion as well as the presenting symptoms. (p value 0.85). Colonic Neoplastic Lesions presented at younger age in our study population and one third of the lesions were found in the right sided colon. Hence screening for CNLs should be implied at an earlier age preferably with colonoscopy. More population based data is required to further validate our results.


Prevalence, patterns and correlates of alcohol consumption and its' association with tobacco smoking among Sri Lankan adults: a cross-sectional study.
Most studies on alcohol consumption carried out in Sri Lanka are limited to single/few provinces in the island. The objective of this study was to determine the prevalence, patterns and correlates of alcohol consumption among a larger sample of adults in Sri Lanka. This cross-sectional study was conducted in seven of all nine provinces in Sri Lanka, between 2005 and 2006. A nationally representative sample of 5000 adults aged ≥18 years was selected using multi-stage random cluster sampling. Data of 4532 participants were collected using an interviewer administered questionnaire. Data analysis included chi-squared test, multiple logistic regression analysis and Spearman correlation using Stata/SE 10.0 (StataCorp LP., Texas, USA) software package. Males were 40%; mean age was 46.1 years (±15.1). The overall, urban and rural prevalence (95% CI) of current drinking was 23.7% (21.7 - 25.7), 29.5% (25.7 - 33.3) and 22.2% (19.8 - 24.7) respectively (p = 0.001). Current (M: 48.1%, F: 1.2%, p < 0.0001) and former (M: 21.4%, F: 0.7%, p < 0.0001) drinking was much higher in males. The highest prevalence of drinking in males (58.9%) and females (2.2%) was in the 30 - 39 and <20 year age groups respectively. Lowest prevalence in men (24.6%) and women (0%) was in the >70 years age-group. Hazardous drinking was seen in 5.2% of men and 0.02% of women. Male sex, urban living and current smoking correlated with both current and hazardous drinking. Lower level of education, and age >70 years positively correlated with hazardous drinking. Alcohol is predominantly a problem in Sri Lankan males. In males, both current and hazardous drinking positively correlated with urban living, white collar occupation, Burgher ethnicity and current smoking. Hazardous drinking positively correlated with lower level of education and older age. The data shown here are useful in planning interventions simultaneously targeting alcohol and tobacco.


Development and preliminary evaluation of student-authored electronic cases.
In medical education, virtual patients are now widely used to support and enhance clinical teaching. However, there is still only a limited adoption of similar methods in veterinary education. This paper describes an initiative at the Royal Veterinary College (RVC) in London to develop student-authored cases during clinical rotations that were subsequently adapted for self-directed learning in the undergraduate curriculum as virtual patients. This approach was designed to enhance the quality of the clinical learning experience, assist in the development of clinical reasoning skills, and complement the existing teaching caseload. The creation of virtual patients involved a two-stage process. In the first stage, students compiled clinical case data and media from patients admitted to the teaching hospitals. They then used these resources to develop electronic cases using a customized Microsoft PowerPoint template that were presented at grand rounds to clinicians and other students. In the second stage, selected cases were further developed with the integration of self-assessment and additional media to create virtual patients for use in teaching. A survey was used to gather feedback on students' experiences in creating and using electronic cases. It was completed by 163 final-year students (81%) and the results indicated that all respondents had created electronic cases on one or more rotations (mean=4.3 rotations, range=1-9). Overall, the feedback suggested that the students found creating and using these cases useful and that the experience improved their approach to a case.


Effects of a Potato Spindle Tuber Viroid Tomato Strain on the Symptoms, Biomass, and Yields of Classical Indicator and Currently Grown Potato and Tomato Cultivars.
The Chittering strain of potato spindle tuber viroid (PSTVd) infects solanaceous crops and wild plants in the subtropical Gascoyne Horticultural District of Western Australia. Classical PSTVd indicator hosts tomato cultivar Rutgers (R) and potato cultivar Russet Burbank (RB) and currently widely grown tomato cultivars Petula (P) and Swanson (S) and potato cultivars Nadine (N) and Atlantic (A) were inoculated with this strain to study its pathogenicity, quantify fruit or tuber yield losses, and establish whether tomato strains might threaten potato production. In potato foliage, infection caused spindly stems, an upright growth habit, leaves with ruffled margins and reduced size, and upward rolling and twisting of terminal leaflets (RB, A, and N); axillary shoot proliferation (A); severe plant stunting (N and RB); and necrotic spotting of petioles and stems (RB). Tubers from infected plants were tiny (N) or small and "spindle shaped" with (A) or without (RB) cracking. Potato foliage dry weight biomass was decreased by 30 to 44% in A and RB and 37% in N, whereas tuber yield was diminished by 50 to 89% in A, 69 to 71% in RB, and 90% in N. In tomato foliage, infection caused epinasty and rugosity in apical leaves, leaf chlorosis, and plant stunting (S, P, and N); cupped leaves (S and P); and reduced leaf size, flower abortion, and necrosis of midribs, petioles, and stems (R). Mean tomato fruit size was greatly decreased in all three cultivars. Tomato foliage dry weight biomass was diminished by 40 to 53% (P), 42% (S), and 37 to 51% (R). Tomato fruit yield was decreased by 60 to 76% (P), 52% (S), and 64 to 89% (R), respectively. Thus, the tomato strain studied was highly pathogenic to classical indicator and representative current tomato and potato cultivars, causing major losses in fruit and tuber yields. Tomato PSTVd strains, therefore, pose a threat to tomato and potato industries worldwide.


Responses to Quadrivalent Influenza Vaccine Reveal Distinct Circulating CD4+CXCR5+ T Cell Subsets in Men Living with HIV.
T cell help for B cells may be perturbed in people living with HIV (PLWH), even when HIV is suppressed, as evidenced by reports of suboptimal responses to influenza vaccination. We investigated cTFH responses to the 2017-18 inactivated quadrivalent influenza vaccine (QIV) in men living with antiretroviral therapy (ART)-suppressed HIV infection who were treated in the early or chronic phase of infection, and control subjects. Here we show that seroprotective antibody responses in serum and oral fluid correlated with cTFH activation and were equivalent in all three groups, irrespective of when ART was started. These responses were attenuated in those reporting immunisation with influenza vaccine in the preceding three years, independent of HIV infection. Measurement of influenza-specific IgG in oral fluid was closely correlated with haemagglutination inhibition titre. T-SNE and two-dimensional analysis revealed a subset of CD4+CXCR3+CXCR5+ cTFH activated at one week after vaccination. This was distinguishable from cTFH not activated by vaccination, and a rare, effector memory CD4+CXCR5hiCD32hi T cell subset. The data support the use of QIV for immunisation of PLWH, reveal distinct circulating CD4+CXCR5+ T cell subsets and demonstrate oral fluid sampling for influenza-specific IgG is an alternative to phlebotomy.


Efficacy of Intravenous Ketamine in Adolescent Treatment-Resistant Depression: A Randomized Midazolam-Controlled Trial.
Adolescent depression is prevalent and is associated with significant morbidity and mortality. Although intravenous ketamine has shown efficacy in adult treatment-resistant depression, its efficacy in pediatric populations is unknown. The authors conducted an active-placebo-controlled study of ketamine's safety and efficacy in adolescents. In this proof-of-concept randomized, double-blind, single-dose crossover clinical trial, 17 adolescents (ages 13-17) with a diagnosis of major depressive disorder received a single intravenous infusion of either ketamine (0.5 mg/kg over 40 minutes) or midazolam (0.045 mg/kg over 40 minutes), and the alternate compound 2 weeks later. All participants had previously tried at least one antidepressant medication and met the severity criterion of a score >40 on the Children's Depression Rating Scale-Revised. The primary outcome measure was score on the Montgomery-Åsberg Depression Rating Scale (MADRS) 24 hours after treatment. A single ketamine infusion significantly reduced depressive symptoms 24 hours after infusion compared with midazolam (MADRS score: midazolam, mean=24.13, SD=12.08, 95% CI=18.21, 30.04; ketamine, mean=15.44, SD=10.07, 95% CI=10.51, 20.37; mean difference=-8.69, SD=15.08, 95% CI=-16.72, -0.65, df=15; effect size=0.78). In secondary analyses, the treatment gains associated with ketamine appeared to remain 14 days after treatment, the latest time point assessed, as measured by the MADRS (but not as measured by the Children's Depression Rating Scale-Revised). A significantly greater proportion of participants experienced a response to ketamine during the first 3 days following infusion as compared with midazolam (76% and 35%, respectively). Ketamine was associated with transient, self-limited dissociative symptoms that affected participant blinding, but there were no serious adverse events. In this first randomized placebo-controlled clinical trial of intravenous ketamine in adolescents with depression, the findings suggest that it is well tolerated acutely and has significant short-term (2-week) efficacy in reducing depressive symptoms compared with an active placebo.Reprinted from Am J Psychiatry 2021; 178:352-362 with permission from American Psychiatric Association Publishing.


Superficiality in forensic psychiatric patients is related to superior phonological, semantic and syntactic skills.
Psychopaths are reported to have unusual language processing, and they have been suggested to have better phonological awareness than do non-psychopaths. Phonological processing skills have not been studied among psychopathic persons, and it is unclear how the degree of psychopathy is related to such skills. One aim of the present study was to investigate this relationship. An additional aim was to investigate how affective-interpersonal traits and antisocial lifestyle of psychopaths are related to verbal skills such as reading and spelling, as well as to phonological processing skills. Forty (80% male) forensic psychiatric patients participated. They were all Swedish speaking and their mean age was 36 years. The patients performed reading and spelling tests as well as a battery of tasks assessing phonological processing. The patients were also assessed using the Psychopathy Checklist: Screening Version (PCL:SV). The patients' scores on Factor 1 (affective and interpersonal traits) of the PCL:SV were significantly positively correlated with results on decoding of sentences and reading speed tests as well as with phonological processing skills. However, the only item that was significantly related to phonological processing skills as well as semantic and syntactic skills was Superficial. In general, psychopaths easily shift conversational topics, and it may be due to a certain cognitive skill such as rapid automatized naming. We suggest that further studies focus on rapid automatized naming in psychopaths to clarify whether their superficial character might be related to rapid naming.


THE EVOLVING CONSEQUENCES OF OXYCONTIN REFORMULATION ON DRUG OVERDOSES.
Recent evidence suggests that the short-term transition of the opioid crisis from prescription opioids to heroin can be attributed to the reformulation of OxyContin, which substantially reduced access to abusable prescription opioids. In this paper, we find that over a longer time horizon, reformulation stimulated illicit drug markets to grow and evolve. We compare overdose trajectories in areas more exposed to reformulation, defined as states with higher rates of nonmedical OxyContin use before reformulation, to less exposed areas. More exposed areas experienced disproportionate increases in fatal overdoses involving synthetic opioids (fentanyl) and nonopioid substances like cocaine, suggesting that these new epidemics are related to the same factors driving the rise in heroin deaths. Instead of just short-term substitution from prescription opioid to heroin overdoses, the transition to illicit markets spurred by reformulation led to growth in the overall overdose rate to unprecedented levels.


The role of calcium influx pathways in phospholipase D activation in bovine adrenal glomerulosa cells.
The steroid hormone aldosterone maintains sodium homeostasis and is therefore important in the control of blood volume and pressure. Angiotensin II (AngII) and elevated extracellular potassium concentrations ([K(+)](e)), the prime physiologic regulators of aldosterone secretion from adrenal glomerulosa cells, activate phospholipase D (PLD) in these cells. The role of Ca(2+) in the activation by these agents is unknown, although nitrendipine, a voltage-dependent Ca(2+) channel antagonist, does not inhibit AngII-elicited PLD activation, despite the fact that this compound blocked elevated [K(+)](e)-stimulated PLD activity. PLD activation triggered by AngII was also unaffected by the T-type calcium channel inhibitor nickel. Nevertheless, Ca(2+) influx was required for AngII-induced PLD activation in both primary cultures of bovine adrenal glomerulosa cells and a glomerulosa cell model, the NCI H295R adrenocortical carcinoma cell line. The involvement of store-operated Ca(2+) (SOC) influx and Ca(2+) release-activated Ca(2+) (CRAC) influx pathways in PLD activation was investigated using thapsigargin, an endoplasmic reticulum Ca(2+) pump inhibitor that empties the store to induce SOC influx, and the SOC inhibitor YM-58483 (BTP2), as well as a CRAC inhibitor, tyrphostin A9. In bovine glomerulosa cells, tyrphostin A9 inhibited AngII-induced PLD activation without affecting elevated [K(+)](e)-stimulated enzyme activity. On the other hand, differences were observed between the bovine adrenal glomerulosa and H295R cells in the involvement of Ca(2+) influx pathways in PLD activation, with the involvement of the SOC pathway suggested in the H295R cells. In summary, our results indicate that Ca(2+) entry only through certain Ca(2+) influx pathways is linked to PLD activation.


Conserved structural regions involved in the catalytic mechanism of Escherichia coli K-12 WaaO (RfaI).
Escherichia coli K-12 WaaO (formerly known as RfaI) is a nonprocessive alpha-1,3 glucosyltransferase, involved in the synthesis of the R core of lipopolysaccharide. By comparing the amino acid sequence of WaaO with those of 11 homologous alpha-glycosyltransferases, four strictly conserved regions, I, II, III, and IV, were identified. Since functionally related transferases are predicted to have a similar architecture in the catalytic sites, it is assumed that these four regions are directly involved in the formation of alpha-glycosidic linkage from alpha-linked nucleotide diphospho-sugar donor. Hydrophobic cluster analysis revealed a conserved domain at the N termini of these alpha-glycosyltransferases. This domain was similar to that previously reported for beta-glycosyltransferases. Thus, this domain is likely to be involved in the formation of beta-glycosidic linkage between the donor sugar and the enzyme at the first step of the reaction. Site-directed mutagenesis analysis of E. coli K-12 WaaO revealed four critical amino acid residues.


A new non-exercise-based Vo2max prediction equation for aerobically trained men.
The purposes of the present study were to (a) modify previously published Vo(2)max equations using the constant error (CE = mean difference between actual and predicted Vo(2)max) values from Malek et al. (28); (b) cross-validate the modified equations to determine their accuracy for estimating Vo(2)max in aerobically trained men; (c) derive a new non- exercise-based equation for estimating Vo(2)max in aerobically trained men if the modified equations are not found to be accurate; and (d) cross-validate the new Vo(2)max equation using the predicted residual sum of squares (PRESS) statistic and an independent sample of aerobically trained men. One hundred and fifty-two aerobically trained men (Vo(2)max mean +/- SD = 4,154 +/- 629 ml.min(-1)) performed a maximal incremental test on a cycle ergometer to determine actual Vo(2)max. An aerobically trained man was defined as someone who had participated in continuous aerobic exercise 3 or more sessions per week for a minimum of 1 hour per session for at least the past 18 months. Nine previously published Vo(2)max equations were modified for use with aerobically trained men. The predicted Vo(2)max values from the 9 modified equations were compared to actual Vo(2)max by examining the CE, standard error of estimate (SEE), validity coefficient (r), and total error (TE). Cross-validation of the modified non-exercise-based equations on a random subsample of 50 subjects resulted in a %TE > or = 13% of the mean of actual Vo(2)max. Therefore, the following non-exercise-based Vo(2)max equation was derived from a random subsample of 112 subjects: Vo(2)max (ml.min(-1)) = 27.387(weight in kg) + 26.634(height in cm) - 27.572(age in years) + 26.161(h.wk(-1) of training) + 114.904(intensity of training using the Borg 6-20 scale) + 506.752(natural log of years of training) - 4,609.791 (R = 0.82, R(2) adjusted = 0.65, and SEE = 378 ml.min(-1)). Cross-validation of this equation on the remaining sample of 40 subjects resulted in a %TE of 10%. Therefore, the non-exercise-based equation derived in the present study is recommended for estimating Vo(2)max in aerobically trained men.


Total, caffeinated and decaffeinated coffee and tea intake and gastric cancer risk: results from the EPIC cohort study.
Prospective studies examining the association between coffee and tea consumption and gastric cancer risk have shown inconsistent results. We investigated the association between coffee (total, caffeinated and decaffeinated) and tea consumption and the risk of gastric cancer by anatomical site and histological type in the European Prospective Investigation into Cancer and Nutrition study. Coffee and tea consumption were assessed by dietary questionnaires at baseline. Adjusted hazard ratios (HRs) were calculated using Cox regression models. During 11.6 years of follow up, 683 gastric adenocarcinoma cases were identified among 477,312 participants. We found no significant association between overall gastric cancer risk and consumption of total coffee (HR 1.09, 95%-confidence intervals [CI]: 0.84-1.43; quartile 4 vs. non/quartile 1), caffeinated coffee (HR 1.14, 95%-CI: 0.82-1.59; quartile 4 vs. non/quartile 1), decaffeinated coffee (HR 1.07, 95%-CI: 0.75-1.53; tertile 3 vs. non/tertile 1) and tea (HR 0.81, 95%-CI: 0.59-1.09; quartile 4 vs. non/quartile 1). When stratified by anatomical site, we observed a significant positive association between gastric cardia cancer risk and total coffee consumption per increment of 100 mL/day (HR 1.06, 95%-CI: 1.03-1.11). Similarly, a significant positive association was observed between gastric cardia cancer risk and caffeinated coffee consumption (HR 1.98, 95%-CI: 1.16-3.36, p-trend=0.06; quartile 3 vs. non/quartile 1) and per increment of 100 mL/day (HR 1.09, 95%-CI: 1.04-1.14). In conclusion, consumption of total, caffeinated and decaffeinated coffee and tea is not associated with overall gastric cancer risk. However, total and caffeinated coffee consumption may be associated with an increased risk of gastric cardia cancer. Further prospective studies are needed to rule out chance or confounding.


Vitamin D and mortality: meta-analysis of individual participant data from a large consortium of cohort studies from Europe and the United States.
To investigate the association between serum 25-hydroxyvitamin D concentrations (25(OH)D) and mortality in a large consortium of cohort studies paying particular attention to potential age, sex, season, and country differences. Meta-analysis of individual participant data of eight prospective cohort studies from Europe and the US. General population. 26,018 men and women aged 50-79 years. All-cause, cardiovascular, and cancer mortality. 25(OH)D concentrations varied strongly by season (higher in summer), country (higher in US and northern Europe) and sex (higher in men), but no consistent trend with age was observed. During follow-up, 6695 study participants died, among whom 2624 died of cardiovascular diseases and 2227 died of cancer. For each cohort and analysis, 25(OH)D quintiles were defined with cohort and subgroup specific cut-off values. Comparing bottom versus top quintiles resulted in a pooled risk ratio of 1.57 (95% CI 1.36 to 1.81) for all-cause mortality. Risk ratios for cardiovascular mortality were similar in magnitude to that for all-cause mortality in subjects both with and without a history of cardiovascular disease at baseline. With respect to cancer mortality, an association was only observed among subjects with a history of cancer (risk ratio, 1.70 (1.00 to 2.88)). Analyses using all quintiles suggest curvilinear, inverse, dose-response curves for the aforementioned relationships. No strong age, sex, season, or country specific differences were detected. Heterogeneity was low in most meta-analyses. Despite levels of 25(OH)D strongly varying with country, sex, and season, the association between 25(OH)D level and all-cause and cause-specific mortality was remarkably consistent. Results from a long term randomised controlled trial addressing longevity are being awaited before vitamin D supplementation can be recommended in most individuals with low 25(OH)D levels.


Fitness efficacy of vibratory exercise compared to walking in postmenopausal women.
In this study, we compared the efficacy of 8 months of low-frequency vibration and a walk-based program in health-related fitness. Twenty-seven postmenopausal women were randomly assigned into two groups: whole-body vibration (WBV) group (n = 18) performed three times/week a static exercise on a vibration platform (6 sets of 1-min with 1 min of rest, with a 12.6 Hz of frequency and an amplitude of 3 mm); walk-based program (WP) group (n = 18) performed three times/week a 60-min of walk activity at 70-75% of maximal heart rate. A health-related battery of tests was applied. Maximal unilateral concentric and eccentric isokinetic torque of the knee extensors was recorded by an isokinetic dynamometer. Physical fitness was measured using the following tests: vertical jump test, chair rise test and maximal walking speed test over 4 m. Maximal unilateral isokinetic strength was measured in the knee extensors in concentric actions at 60 and 300 degrees /s, and eccentric action at 60 degrees /s. After 8 months, the WP improved the time spent to walk 4 m (20%) and to perform the chair rise test (12%) compared to the WBV group (P = 0.006, 0.002, respectively). In contrast, the comparison of the changes in vertical jump showed the higher effectiveness of the vibratory exercise in 7% (P = 0.025). None of exercise programs showed change on isokinetic measurements. These results indicate that both programs differed in the main achievements and could be complementary to prevent lower limbs muscle strength decrease as we age [ISRCTN76235671].


Practicality of Acute and Transitional Care and its consequences in the era of SwissDRG: a focus group study.
Switzerland recently introduced Acute and Transitional Care (ATC) as a new financing option and a preventive measure to mitigate potential side effects of Swiss Diagnosis Related Group (SwissDRG). The goal of ATC was to support patients who after acute treatment at a hospital require temporary increased professional care. However, evidence is lacking as to the practicality of ATC. Using qualitative focus group methodology, we sought to understand the implementation and use of ATC. A purposive sample of forty-two professionals from five Swiss cantons participated in this study. We used a descriptive thematic approach to analyse the data. Our findings first reveal that ATC's implementation differs in the five cantons (i.e. federal states). In two cantons, only ambulatory variant of ATC is used; in one canton only stationary ATC has been created, and two cantons had both ambulatory and stationary ATC but preferred the latter. Second, there are intrinsic practical challenges associated with ATC, which include physicians' lack of familiarity with ATC and its regulatory limitations. Finally, participants felt that due to shorter hospital stays because of SwissDRG, premature discharge of patients with complex care needs to stationary ATC takes place. This development does not fit the nursing home concept of care tailored to long-term patients. This empirical study underscores that there is a strong need to improve ATC so that it is uniformly implemented throughout the country and its application is streamlined. In light of the newness of ATC as well as SwissDRG, their impact on the quality of care received by patients is yet to be fully understood. Empirical evidence is necessary to improve these two measures.


Antithrombotic therapy in neonates and children: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).
This chapter about antithrombotic therapy in neonates and children is part of the Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Grade 1 recommendations are strong and indicate that the benefits do, or do not, outweigh risks, burden, and costs, and Grade 2 suggests that individual patient values may lead to different choices (for a full understanding of the grading, see Guyatt et al in this supplement, pages 123S-131S). In this chapter, many recommendations are based on extrapolation of adult data, and the reader is referred to the appropriate chapters relating to guidelines for adult populations. Within this chapter, the majority of recommendations are separate for neonates and children, reflecting the significant differences in epidemiology of thrombosis and safety and efficacy of therapy in these two populations. Among the key recommendations in this chapter are the following: In children with first episode of venous thromboembolism (VTE), we recommend anticoagulant therapy with either unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) [Grade 1B]. Dosing of IV UFH should prolong the activated partial thromboplastin time (aPTT) to a range that corresponds to an anti-factor Xa assay (anti-FXa) level of 0.35 to 0.7 U/mL, whereas LMWH should achieve an anti-FXa level of 0.5 to 1.0 U/mL 4 h after an injection for twice-daily dosing. In neonates with first VTE, we suggest either anticoagulation or supportive care with radiologic monitoring and subsequent anticoagulation if extension of the thrombosis occurs during supportive care (Grade 2C). We recommend against the use of routine systemic thromboprophylaxis for children with central venous lines (Grade 1B). For children with cerebral sinovenous thrombosis (CSVT) without significant intracranial hemorrhage (ICH), we recommend anticoagulation initially with UFH, or LMWH and subsequently with LMWH or vitamin K antagonists (VKAs) for a minimum of 3 months (Grade 1B). For children with non-sickle-cell disease-related acute arterial ischemic stroke (AIS), we recommend UFH or LMWH or aspirin (1 to 5 mg/kg/d) as initial therapy until dissection and embolic causes have been excluded (Grade 1B). For neonates with a first AIS, in the absence of a documented ongoing cardioembolic source, we recommend against anticoagulation or aspirin therapy (Grade 1B).


Spine surgery outcome in patients who sought compensation after a motor vehicle accident: a retrospective cohort study.
Back and neck pain are common after road traffic injury and are treated by spine surgery in some cases. This study aimed to describe the outcomes of spine surgery in people who made an insurance claim after road traffic accidents without an associated spinal fracture or dislocation. This study was a retrospective cohort based on insurers' data of Compulsory Third Party (CTP) claims. File audit and data extraction were undertaken using a study-specific proforma. Primary outcomes were ongoing pain and symptoms, complications, return to work and pre-injury duties, and ongoing treatment 2 years following spine surgery. Secondary outcomes were health care costs based on data provided by the insurers. After screening 766 files, 90 cases were included (female: 48; mean age: 46 years). Among the subjects who were working prior the injury, the rate of return to work was 37% and return to pre-injury duties was 23% 2 years following the surgery. The average number of appointments with health care professionals in the 1 year after surgery was 21, compared to 10 for the 1 year prior to surgery (p = 0.03). At 2 years following the initial surgery, 21% of claimants had undergone revision spine surgery; 68% reported ongoing back pain and 41% had ongoing radicular symptoms. The difference between costs 1 year before and after surgery (excluding surgical costs) was statistically significant (p = 0.04). Fusions surgery was associated with higher total costs than decompression alone. After adjusting for surgery type, lumbar surgery was associated with higher costs in the 1 year after surgery and total surgical costs compared to cervical surgery. The majority of claimants continued having clinical symptoms, continued using health care and did not return to work despite undertaking spine surgery.


Effects of nonionic surfactant C12E5 on the cooperative dynamics of water.
A dielectric relaxation study of binary mixtures of nonionic surfactant C12E5 + water has been made as a function of temperature in the isotropic micellar, lamellar, and hexagonal regions of the phase diagram. Two dielectric dispersion steps were found and could be assigned to the intermolecular cooperative dynamics of water at the micellar interface and in the bulk water domains. A quantitative analysis is given. The relaxation amplitudes were used to determine effective hydration numbers. The activation energies of water relaxation were calculated from the relaxation times. The data indicate weaker surfactant-water and water-water interactions near the micellar interface compared to those of bulk liquid water. Further analysis revealed the presence of water clusters large enough to show a cooperative relaxation mode even at high surfactant concentrations. However, the relaxation time of this mode is larger compared to that of pure water. This points out the importance of confinement effects on water dynamics.


Transcriptional selectors, masters, and combinatorial codes: regulatory principles of neural subtype specification.
The broad range of tissue and cellular diversity of animals is generated to a large extent by the hierarchical deployment of sequence-specific transcription factors and co-factors (collectively referred to as TF's herein) during development. Our understanding of these developmental processes has been facilitated by the recognition that the activities of many TF's can be meaningfully described by a few functional categories that usefully convey a sense for how the TF's function, and also provides a sense for the regulatory organization of the developmental processes in which they participate. Here, we draw on examples from studies in Caenorhabditis elegans, Drosophila melanogaster, and vertebrates to discuss how the terms spatial selector, temporal selector, tissue/cell type selector, terminal selector and combinatorial code may be usefully applied to categorize the activities of TF's at critical steps of nervous system construction. While we believe that these functional categories are useful for understanding the organizational principles by which TF's direct nervous system construction, we however caution against the assumption that a TF's function can be solely or fully defined by any single functional category. Indeed, most TF's play diverse roles within different functional categories, and their roles can blur the lines we draw between these categories. Regardless, it is our belief that the concepts discussed here are helpful in clarifying the regulatory complexities of nervous system development, and hope they prove useful when interpreting mutant phenotypes, designing future experiments, and programming specific neuronal cell types for use in therapies.


Spirochetal antigens and lymphoid cell surface markers in Lyme synovitis. Comparison with rheumatoid synovium and tonsillar lymphoid tissue.
Using monoclonal antibodies to spirochetal antigenes and lymphoid cell surface markers, we examined the synovial lesions of 12 patients with Lyme disease, and compared them with rheumatoid synovium and tonsillar lymphoid tissue. The synovial lesions of Lyme disease patients and rheumatoid arthritis patients were similar and often consisted of the elements found in normal organized lymphoid tissue. In both diseases, T cells, predominantly of the helper/inducer subset, were distributed diffusely in subsynovial lining areas, often with nodular aggregates of tightly intermixed T and B cells. IgD-bearing B cells were scattered within the aggregates, and a few follicular dendritic cells and activated germinal center B cells were sometimes present. Outside the aggregates, many plasma cells, high endothelial venules, scattered macrophages, and a few dendritic macrophages were found. HLA-DR and DQ expression was intense throughout the lesions. In 6 of the 12 patients with Lyme arthritis, but in none of those with rheumatoid arthritis, a few spirochetes and globular antigen deposits were seen in and around blood vessels in areas of lymphocytic infiltration. Thus, in Lyme arthritis, a small number of spirochetes are probably the antigenic stimulus for chronic synovial inflammation.


miwi, a murine homolog of piwi, encodes a cytoplasmic protein essential for spermatogenesis.
The piwi family genes are crucial for stem cell self-renewal, RNA silencing, and translational regulation in diverse organisms. However, their function in mammals remains unexplored. Here we report the cloning of a murine piwi gene (miwi) essential for spermatogenesis. miwi encodes a cytoplasmic protein specifically expressed in spermatocytes and spermatids. miwi(null) mice display spermatogenic arrest at the beginning of the round spermatid stage, resembling the phenotype of CREM, a master regulator of spermiogenesis. Furthermore, mRNAs of ACT (activator of CREM in testis) and CREM target genes are downregulated in miwi(null) testes. Whereas MIWI and CREM do not regulate each other's expression, MIWI complexes with mRNAs of ACT and CREM target genes. Hence, MIWI may control spermiogenesis by regulating the stability of these mRNAs.


Morphine Reward Promotes Cue-Sensitive Learning: Implication of Dorsal Striatal CREB Activity.
Different parallel neural circuits interact and may even compete to process and store information: whereas stimulus-response (S-R) learning critically depends on the dorsal striatum (DS), spatial memory relies on the hippocampus (HPC). Strikingly, despite its potential importance for our understanding of addictive behaviors, the impact of drug rewards on memory systems dynamics has not been extensively studied. Here, we assessed long-term effects of drug- vs food reinforcement on the subsequent use of S-R vs spatial learning strategies and their neural substrates. Mice were trained in a Y-maze cue-guided task, during which either food or morphine injections into the ventral tegmental area (VTA) were used as rewards. Although drug- and food-reinforced mice learned the Y-maze task equally well, drug-reinforced mice exhibited a preferential use of an S-R learning strategy when tested in a water-maze competition task designed to dissociate cue-based and spatial learning. This cognitive bias was associated with a persistent increase in the phosphorylated form of cAMP response element-binding protein phosphorylation (pCREB) within the DS, and a decrease of pCREB expression in the HPC. Pharmacological inhibition of striatal PKA pathway in drug-rewarded mice limited the morphine-induced increase in levels of pCREB in DS and restored a balanced use of spatial vs cue-based learning. Our findings suggest that drug (opiate) reward biases the engagement of separate memory systems toward a predominant use of the cue-dependent system via an increase in learning-related striatal pCREB activity. Persistent functional imbalance between striatal and hippocampal activity could contribute to the persistence of addictive behaviors, or counteract the efficiency of pharmacological or psychotherapeutic treatments.


Epidemiology of patients hospitalized for ocular trauma in the Chaoshan region of China, 2001-2010.
The burden and pattern of ocular trauma in China are poorly known and not well studied. We aimed at studying the epidemiological characteristics of patients hospitalized for ocular trauma at major ophthalmology departments in the largest industrial base of plastic toys in China. A retrospective study of ocular trauma cases admitted to 3 tertiary hospitals in China from 1st January 2001 to 31st December 2010 was performed. The study included a total of 3,644 injured eyes from 3,559 patients over the 10-year period: 2,008 (55.1%) open-globe injuries, 1,580 (43.4%) closed-globe injuries, 41 (1.1%) chemical injuries, 15 (0.4%) thermal injuries and 678 (18.6%) ocular adnexal injuries. The mean age of the patients was 29.0±16.8 years with a male-to-female ratio of 5.2∶1 (P = 0.007). The most frequent types of injury were work-related injuries (1,656, 46.5%) and home-related injuries (715, 20.1%). The majority of injuries in males (56.2%) and females (36.0%) occurred in the 15-44 age group and 0-14 age group, respectively. The final visual acuity correlated with the initial visual acuity (Spearman's correlation coefficient = 0.659; P<0.001). The Ocular Trauma Score also correlated with the final visual acuity (Spearman's correlation coefficient = 0.655; P<0.001). This analysis provides an epidemiological study of patients who were hospitalized for ocular trauma. Preventive efforts are important for both work-related and home-related eye injuries.


Growth and Tissue Formation from Single, Isolated Tobacco Cells in Microculture.
Single, isolated cells of tobacco divided and grew to form small colonies of over 50 cells in microcultures with a medium containing fresh liquid coconut milk, but in the absence of neighboring cells or nurse tissue. Subsequently, the mass of cells obtained from the single cell, when transferred to agar coconut milk medium, established itself as a clone of callus tissue. Some of these single-cell clones showed differentiation of many tracheid-like cells and shoots with small leaves.


Bioactive products formed in humans from fish oils.
Resolvins, maresins, and protectins can be formed from fish oils. These specialized pro-resolving mediators (SPMs) have been implicated in the resolution of inflammation. Synthetic versions of such SPMs exert anti-inflammatory effects in vitro and when administered to animal models. However, their importance as endogenous products formed in sufficient amounts to exert anti-inflammatory actions in vivo remains speculative. We biased our ability to detect SPMs formed in healthy volunteers by supplementing fish oil in doses shown previously to influence blood pressure and platelet aggregation under placebo-controlled conditions. Additionally, we sought to determine the relative formation of SPMs during an acute inflammatory response and its resolution, evoked in healthy volunteers by bacterial lipopolysaccharide (LPS). Bioactive lipids, enzymatic epoxyeicosatrienoic acids (EETs), and free radical-catalyzed prostanoids [isoprostanes (iPs)] formed from arachidonic acid and the fish oils, served as comparators. Despite the clear shift from ω-6 to ω-3 EETs and iPs, we failed to detect a consistent signal, in most cases, of SPM formation in urine or plasma in response to fish oil, and in all cases in response to LPS on a background of fish oil. Our results question the relevance of these SPMs to the putative anti-inflammatory effects of fish oils in humans.


Determinants of multimethod contraceptive use in a sample of adolescent women diagnosed with psychological disorders.
Despite recommendations for concurrent use of contraceptives and condoms to prevent unintended pregnancy and STIs, multimethod contraceptive use among women is poor. This study examined individual-, interpersonal-, and environmental-level factors that predict multimethod use among sexually active adolescent women diagnosed with psychological disorders. This multisite study analyzed data from 288 sexually active adolescent women who provided sociodemographic, psychosocial, and behavioral data related to birth control and condom use. 34.7% of the participants reported multimethod use in the past three months. Controlling for empirically and theoretically relevant covariates, a multivariable logistic regression identified self-efficacy, multiple partners, pregnancy history, parental communication, parental norms about sex, and neighborhood cohesion as significant predictors of multimethod use. While continued targeted messages about multi-method contraceptive use are imperative at the individual level, an uptake in messages targeting interpersonal- and environmental-level factors such as adolescents' parents and the broader community is urgently needed.


Global associations between birds and vane-dwelling feather mites.
Understanding host-symbiont networks is a major question in evolutionary ecology. Birds host a great diversity of endo- and ectosymbiotic organisms, with feather mites (Arachnida: Acariformes: Analgoidea, Pterolichoidea) being among the most diverse of avian symbionts. A global approach to the ecology and evolution of bird-feather-mite associations has been hampered because of the absence of a centralized data repository. Here we present the most extensive data set of associations between feather mites and birds. Data include 12 036 records of 1887 feather mite species located on the flight feathers of 2234 bird species from 147 countries. Feather mites typically located inside quills, on the skin, or on downy body feathers are not included. Data were extracted from 493 published sources dating from 1882 to 2015. Data exploration shows that although most continents and bird families are represented, most bird species remain unexplored for feather mites. Nevertheless, this is the most comprehensive data set available for enabling global macroecological analyses of feather mites and their hosts, such as ecological network analyses. This metadata file outlines the structure of these data and provides primary references for all records used.


HIV Infection, risk factors and health services use among male-to-female transgender sex workers: a cross-sectional study in Portugal.
Male-to-female transgender sex workers (TSW) have been identified as a key population at risk for HIV. This study examined risk behaviors and HIV prevalence among TSW, and described health services use. A participatory cross-sectional survey was conducted with 125 TSW recruited in locations and networks where sex workers congregate. HIV-risk behaviors were common among participants. Inconsistent condom use with clients in the previous month was reported by 12.0% of participants and was associated with Portuguese nationality, inconsistent condom use with non-paying partners and not been reached by HIV prevention programs in the previous year. Ever use of psychoactive substances was reported by 61.6% of participants and was associated with being non-employed, doing full-time sex work, having higher number of non-paying partners and having never used health services. Also, ever use of psychoactive substances was negatively associated with older age and Portuguese nationality. About 34% of the participants reported having not been tested in the previous 12 months; 20.2% never used the health services. Overall, 14.9% (95%CI: 8.0-21.0%) reported being HIV-positive. Of those, 22.2% (95%CI: 1.0-43.5%) had unprotected sex with clients in the previous month, 26.7% (95%CI: 1.3-52.0%) had unprotected sex with non-paying partners in the previous year, 13.3% (95%CI: 0.0-33.0%) had ever injected drugs, 60.0% (95%CI: 23.0-97.0%) reported a past STI and 33.3% (95%CI: 2.0-64.6%) had currently HIV/STI co-infection. The socioeconomic, relational or partnering, and structural contexts conducive to increased risk are warranting further investigation. This knowledge would be valuable to inform prevention programs. HIV interventions, including secondary prevention, should address specific needs of TSW. Outreach initiatives aimed to reach TSW who are difficult to access can play a role in promoting access to health services and reducing HIV infection and transmission.


Quantum effects in the understanding of consciousness.
This paper presents a historical perspective on the development and application of quantum physics methodology beyond physics, especially in biology and in the area of consciousness studies. Quantum physics provides a conceptual framework for the structural aspects of biological systems and processes via quantum chemistry. In recent years individual biological phenomena such as photosynthesis and bird navigation have been experimentally and theoretically analyzed using quantum methods building conceptual foundations for quantum biology. Since consciousness is attributed to human (and possibly animal) mind, quantum underpinnings of cognitive processes are a logical extension. Several proposals, especially the Orch OR hypothesis, have been put forth in an effort to introduce a scientific basis to the theory of consciousness. At the center of these approaches are microtubules as the substrate on which conscious processes in terms of quantum coherence and entanglement can be built. Additionally, Quantum Metabolism, quantum processes in ion channels and quantum effects in sensory stimulation are discussed in this connection. We discuss the challenges and merits related to quantum consciousness approaches as well as their potential extensions.


Nuclear envelope expansion is crucial for proper chromosomal segregation during a closed mitosis.
Here, we screened a 10,371 library of diverse molecules using a drug-sensitive fission yeast strain to identify compounds which cause defects in chromosome segregation during mitosis. We identified a phosphorium-ylide-based compound Cutin-1 which inhibits nuclear envelope expansion and nuclear elongation during the closed mitosis of fission yeast, and showed that its target is the β-subunit of fatty acid synthase. A point mutation in the dehydratase domain of Fas1 conferred in vivo and in vitro resistance to Cutin-1. Time-lapse photomicrography showed that the bulk of the chromosomes were only transiently separated during mitosis, and nucleoli separation was defective. Subsequently sister chromatids re-associated leading to chromosomal mis-segregation. These segregation defects were reduced when the nuclear volume was increased and were increased when the nuclear volume was reduced. We propose that there needs to be sufficient nuclear volume to allow the nuclear elongation necessary during a closed mitosis to take place for proper chromosome segregation, and that inhibition of fatty acid synthase compromises nuclear elongation and leads to defects in chromosomal segregation.


Pain perception following epithelialized gingival graft harvesting: a randomized clinical trial.
The aim of this study was to compare the effects of a hemostatic collagen sponge and a collagen sponge sealed with a bio-adhesive material on the palatal donor sites with the purpose of minimizing postoperative pain after epithelialized gingival graft (EGG) harvesting. The present study consisted of 44 EGGs harvested in 44 patients. In the control group, a hemostatic collagen sponge was applied over the palatal wound, while the test group was treated with additional cyanoacrylate. Patients were observed for 14 days, evaluating the pain level by using the visual analogic scale. The consumption of analgesic during the postoperative period, the willingness for retreatment and the characteristic of the graft were also analyzed. Statistically significant differences in pain perception were found between test and control groups in each of the studied days (p < 0.01). Analgesic consumption was lower in the test group (p < 0.01). Graft width < 14 mm was found to be associated with lower discomfort (p < 0.01). Adding an additional layer of cyanoacrylate over a hemostatic collagen sponge on the palatal wound following EGG harvesting was found to be successful in minimizing the postoperative discomfort and the need for analgesics. Postoperative pain after palatal tissue harvesting can be successfully minimized if the donor site open wound is protected with an external layer of cyanoacrylate over a collagen sponge.


Effect of static and cyclic loading on ceramic laminate veneers adhered to teeth with and without aged composite restorations.
Existing composite restorations on teeth are often remade prior to the cementation of fixed dental prostheses. The aim of this study was to evaluate the effect of static and cyclic loading on ceramic laminate veneers adhered to aged resin composite restorations. Eighty sound maxillary incisors were collected and randomly divided into four groups: group 1: control group, no restorations; group 2: two Class III restorations; group 3: two Class IV restorations; group 4: complete composite substrate. Standard composite restorations were made using a microhybrid resin composite (Anterior Shine). Restored teeth were subjected to thermocycling (6000 cycles). Window preparations were made on the labial surface of the teeth for ceramic laminate fabrication (Empress II). Teeth were conditioned using an etch-and-rinse system. Existing composite restorations representing the aged composites were silica coated (CoJet) and silanized (ESPE-Sil). Ceramic laminates were cemented using a bis-GMA-based cement (Variolink Veneer). The specimens were randomly divided into two groups and were subjected to either static (groups 1a, 2a, 3a, 4a) or cyclic loading (groups 1b, 2b, 3b, 4b). Failure type and location after loading were classified. Data were analyzed using one-way ANOVA and Tukey's test. Significantly higher fracture strength was obtained in group 4 (330 ± 81 N) compared to the controls in group 1 (179 ± 120 N) (one-way ANOVA, p < 0.05). Group 1b survived a lower mean number of cyclic loads (672,820 cycles) than teeth of groups 2b to 4b (846x103 to 873x103 cycles). Failure type evaluation after the fracture test showed predominantly adhesive failures between dentin and cement, but after cyclic loading, more cohesive fractures in the ceramic were seen. Ceramic laminate veneers bonded to conditioned aged composite restorations provided favorable results. Surface conditioning of existing restorations may eliminate the necessity of removing aged composite restorations.


Phase I/II study of subcutaneous homoharringtonine in patients with chronic myeloid leukemia who have failed prior therapy.
Homoharringtonine (HHT) is a cephalotaxus alkaloid that inhibits the synthesis of proteins leading to apoptosis. Intravenous HHT has demonstrated activity in patients with chronic myeloid leukemia (CML) after failure with interferon. A Phase I study was completed of subcutaneous (s.c.) HHT in patients with CML in accelerated or blast phases and demonstrated efficacy and good tolerance at the same doses used by intravenous (i.v.) administration. The maximal tolerated dose (MTD) was 1.25 mg/m(2) s.c. twice daily. The cohort was then expanded to treated at the MTD to include patients in late chronic phase CML after imatinib failure. Therapy consisted of an i.v. loading dose of HHT 2.5 mg/m(2) over 24 hours, followed by 1.25 mg/m(2) s.c. twice daily for 14 days every 28 days until remission, then for 7 days every 28 days. Six patients (median age, 53 years) who had failed imatinib were treated and 5 were evaluable. Patients received a median of 4.5 courses of s.c. HHT. Complete hematologic remission was obtained in all 5 evaluable patients and 3 had cytogenetic (CG) responses: 1 complete and 2 minor. The 2 patients with BCR-ABL kinase domain mutations at the start of therapy with HHT had a CG response and in both instances the mutations became undetectable. All patients developed myelosuppression and 3 had their HHT dose reduced due to prolonged neutropenia. Nonhematologic toxicity was mild and manageable. Subcutaneous HHT is well tolerated and may have clinical activity in patients with CML after imatinib failure.


DiSCIoser: unlocking recovery potential of arm sensorimotor functions after spinal cord injury by promoting activity-dependent brain plasticity by means of brain-computer interface technology: a randomized controlled trial to test efficacy.
Traumatic cervical spinal cord injury (SCI) results in reduced sensorimotor abilities that strongly impact on the achievement of daily living activities involving hand/arm function. Among several technology-based rehabilitative approaches, Brain-Computer Interfaces (BCIs) which enable the modulation of electroencephalographic sensorimotor rhythms, are promising tools to promote the recovery of hand function after SCI. The "DiSCIoser" study proposes a BCI-supported motor imagery (MI) training to engage the sensorimotor system and thus facilitate the neuroplasticity to eventually optimize upper limb sensorimotor functional recovery in patients with SCI during the subacute phase, at the peak of brain and spinal plasticity. To this purpose, we have designed a BCI system fully compatible with a clinical setting whose efficacy in improving hand sensorimotor function outcomes in patients with traumatic cervical SCI will be assessed and compared to the hand MI training not supported by BCI. This randomized controlled trial will include 30 participants with traumatic cervical SCI in the subacute phase randomly assigned to 2 intervention groups: the BCI-assisted hand MI training and the hand MI training not supported by BCI. Both interventions are delivered (3 weekly sessions; 12 weeks) as add-on to standard rehabilitation care. A multidimensional assessment will be performed at: randomization/pre-intervention and post-intervention. Primary outcome measure is the Graded Redefined Assessment of Strength, Sensibility and Prehension (GRASSP) somatosensory sub-score. Secondary outcome measures include the motor and functional scores of the GRASSP and other clinical, neuropsychological, neurophysiological and neuroimaging measures. We expect the BCI-based intervention to promote meaningful cortical sensorimotor plasticity and eventually maximize recovery of arm functions in traumatic cervical subacute SCI. This study will generate a body of knowledge that is fundamental to drive optimization of BCI application in SCI as a top-down therapeutic intervention, thus beyond the canonical use of BCI as assistive tool. Name of registry: DiSCIoser: improving arm sensorimotor functions after spinal cord injury via brain-computer interface training (DiSCIoser). NCT05637775; registration date on the ClinicalTrial.gov platform: 05-12-2022.


Labeling of epirubicin with technetium-99m: Optimization, biodistribution and scintigraphic imaging in tumor bearing mice.
Epirubicin is an antineoplastic agent of anthracycline antibiotic, used for treating a variety of tumor types such as lymphoma, cancer of the breast, lung, ovary and stomach. The objective of this work was to demonstrate direct radiolabeling of epirubicin with 99mTc, quality control, biological characterization and scientigraphic evaluation in tumor bearing mice. The 99mTc-epirubicin labeling was optimized by varying the amounts of ligand 100-350μg, stannous chloride dihydride 20-50μg and pH range 2-10 by using NaOH or HCl. The radiochemical purity of 99mTc-epirubicin was evaluated by chromatographic techniques (Whatman No. 3 paper and ITLC-SG). HPLC analyses were performed to check purity of epirubicin and radiochemical purity of labeled 99mTc- epirubicin. Biodistribution and scintigraphic imaging of 99mTc-epirubicin was performed in normal and tumor bearing mice at various time intervals. The optimum conditions ensuring 99mTc-epirubicin labeling yield as high as 99% by adding 35μg SnCl2.2H2O, 200μg of ligand at pH 6 for 30 min at room temperature (25°C±2°C). HPLC of 99mTc-epirubicin shows about 99% binding of the compound with technetium-99m. Electrophoresis study indicated the neutral nature of 99mTc-epirubicin. Biodistribution data and scintigraphic results showed that 99mTc-epirubicin accumulated in the liver as well as in tumor with significant uptake and excellent retention. 99mTc-epirubicin shows good stability in human serum. In vitro and in vivo studies revealed the significantly uptake of 99mTc-epirubicin in the tumor, and also indicating the efficiency of 99mTc-epirubicin as a tumor diagnostic agent.


The impact of mass transfer limitations on size distributions of particle associated SVOCs in outdoor and indoor environments.
Semi-volatile organic compounds (SVOCs) partition between the gas phase and airborne particles. The size distribution of particle-associated SVOCs impacts their fate in outdoor and indoor environments, as well as human exposure to these compounds and subsequent health risks. Allen et al. (1996) previously proposed that the rate of mass transfer can impact polycyclic aromatic hydrocarbon (PAH) partitioning among different sized particles, especially for time scales relevant to urban aerosols. The present study quantitatively builds on this idea, presenting a model that incorporates dynamic SVOC/particle interaction and applying this model to typical outdoor and indoor scenarios. The model indicates that the impact of mass transfer limitations on the size distribution of a particle-associated SVOC can be evaluated by the ratio of the time to achieve gas-particle equilibrium relative to the residence time of particles. The higher this ratio, the greater the influence of mass transfer limitations on the size distribution of particle-associated SVOCs. The influence of such constraints is largest on the fraction of particle-associated SVOCs in the coarse mode (>2 μm). Predictions from the model have been found to be in reasonable agreement with size distributions measured for PAHs at roadside and suburban locations in Japan. The model also quantitatively explains shifts in the size distributions of particle associated SVOCs compared to those for particle mass, and the manner in which these shifts vary with temperature and an SVOC's molecular weight.


Spike-frequency adapting neural ensembles: beyond mean adaptation and renewal theories.
We propose a Markov process model for spike-frequency adapting neural ensembles that synthesizes existing mean-adaptation approaches, population density methods, and inhomogeneous renewal theory, resulting in a unified and tractable framework that goes beyond renewal and mean-adaptation theories by accounting for correlations between subsequent interspike intervals. A method for efficiently generating inhomogeneous realizations of the proposed Markov process is given, numerical methods for solving the population equation are presented, and an expression for the first-order interspike interval correlation is derived. Further, we show that the full five-dimensional master equation for a conductance-based integrate-and-fire neuron with spike-frequency adaptation and a relative refractory mechanism driven by Poisson spike trains can be reduced to a two-dimensional generalization of the proposed Markov process by an adiabatic elimination of fast variables. For static and dynamic stimulation, negative serial interspike interval correlations and transient population responses, respectively, of Monte Carlo simulations of the full five-dimensional system can be accurately described by the proposed two-dimensional Markov process.


Reverse transcription, amplification and sequencing of poliovirus RNA by Taq DNA polymerase.
A model for virion RNA of the poliomyelitis virus, which does not pass the stage of DNA copies during biogenesis, demonstrates that Taq DNA polymerase is capable of synthesizing 960-bp cDNA with the specific primer. When comparing the nucleotide sequence of the starting virion RNA and recombinant DNAs, isolated from several independent clones, copying and amplification of virion RNA appear accurate (one substitution per 960 bp). A comparison of Taq and Tth DNA polymerases in RT/PCR indicates that the sensitivity of Taq polymerase seems to be two orders of magnitude higher than that of Tth polymerase. The RNA detection level under the chosen conditions approached 10(4) RNA copies per test. The present investigation indicates the great versatility of Taq polymerase, which promoted the reverse transcription reaction of RNA, cDNA amplification, screening of recombinant clones as well as sequencing of recombinant DNA. Thus application of Taq polymerase is rather promising not only to detect nucleic acids in biological samples, but also for isolating and cloning individual genes, encoded on DNA and/or on RNA templates.


Intellectual Property Rights in China-A Literature Review on the Public's Perspective.
Despite significant advances in terms of the adoption of formal Intellectual Property Rights (IPR) protection, enforcement of and compliance with IPR regulations remains a contested issue in one of the world's major contemporary economies-China. The present review seeks to offer insights into possible reasons for this discrepancy as well as possible paths of future development by reviewing prior literature on IPR in China. Specifically, it focuses on the public's perspective, which is a crucial determinant of the effectiveness of any IPR regime. It uncovers possible differences with public perspectives in other countries and points to mechanisms (e.g., political, economic, cultural, and institutional) that may foster transitions over time in both formal IPR regulation and in the public perception of and compliance with IPR in China. On this basis, the review advances suggestions for future research in order to improve scholars' understanding of the public's perspective of IPR in China, its antecedents and implications.


Possible interaction sites of mRNA, tRNA, translation factors and the nascent peptide in 5S, 5.8S and 28S rRNA in in vivo assembled eukaryotic ribosomal complexes.
We have investigated possible interaction sites for mRNA, tRNA, translation factors and the nascent peptide on 5S, 5.8S and 28S rRNA in in vivo assembled translational active mouse ribosomes by comparing the chemical footprinting patterns derived from native polysomes, salt-washed polysomes (mainly lacking translational factors) and salt-washed runoff ribosomes (lacking mRNA, tRNA and translational factors). Several ligand-induced footprints were observed in 28S rRNA while no reactivity changes were seen in 5S and 5.8S rRNA. Footprints derived from mRNA, tRNA and/or the nascent peptide chain were observed in domain I of 28S rRNA (hairpin 23), in domain II (helix 37/38 and helices 42 and 43 and in the eukaryotic expansion segment 15), in domain IV (helices 67 and 74) and in domain V (helices 94 and 96 and in the peptidyl transferase ring). Some of the protected sites were homologous to sites previously suggested to be involved in mRNA, tRNA and/or peptide binding in in vitro assembled prokaryotic complexes. Additional footprints were located in regions that have not previously been found involved in ligand binding. Part of these sites could derive from the nascent peptide in the exit channel of the ribosome.


Water quality transformations during soil aquifer treatment at the Mesa Northwest Water Reclamation Plant, USA.
Water quality transformations during soil aquifer treatment at the Mesa Northwest Water Reclamation Plant (NWWRP) were evaluated by sampling a network of groundwater monitoring wells located within the reclaimed water plume. The Mesa Northwest Water Reclamation Plant has used soil aquifer treatment (SAT) since it began operation in 1990 and the recovery of reclaimed water from the impacted groundwater has been minimal. Groundwater samples obtained represent travel times from several days to greater than five years. Samples were analyzed for a wide range of organic and inorganic constituents. Sulfate was used as a tracer to estimate travel times and define reclaimed water plume movement. Dissolved organic carbon concentrations were reduced to approximately 1 mg/L after 12 to 24 months of soil aquifer treatment with an applied DOC concentration from the NWWRP of 5 to 7 mg/L. The specific ultraviolet absorbance (SUVA) increased during initial soil aquifer treatment on a time-scale of days and then decreased as longer term soil aquifer treatment removed UV absorbing compounds. The trihalomethane formation potential (THMFP) was a function of the dissolved organic carbon concentration and ranged from 50 to 65 micrograms THMFP/mg DOC. Analysis of trace organics revealed that the majority of trace organics were removed as DOC was removed with the exception of organic iodine. The majority of nitrogen was applied as nitrate-nitrogen and the reclaimed water plume had lower nitrate-nitrogen concentrations as compared to the background groundwater. The average dissolved organic carbon concentrations in the reclaimed water plume were less than 50% of the drinking water dissolved organic concentrations from which the reclaimed water originated.


Kinetic proofreading at single molecular level: aminoacylation of tRNA(Ile) and the role of water as an editor.
Proofreading/editing in protein synthesis is essential for accurate translation of information from the genetic code. In this article we present a theoretical investigation of efficiency of a kinetic proofreading mechanism that employs hydrolysis of the wrong substrate as the discriminatory step in enzyme catalytic reactions. We consider aminoacylation of tRNA(Ile) which is a crucial step in protein synthesis and for which experimental results are now available. We present an augmented kinetic scheme and then employ methods of stochastic simulation algorithm to obtain time dependent concentrations of different substances involved in the reaction and their rates of formation. We obtain the rates of product formation and ATP hydrolysis for both correct and wrong substrates (isoleucine and valine in our case, respectively), in single molecular enzyme as well as ensemble enzyme kinetics. The present theoretical scheme correctly reproduces (i) the amplitude of the discrimination factor in the overall rates between isoleucine and valine which is obtained as (1.8×10(2)).(4.33×10(2)) = 7.8×10(4), (ii) the rates of ATP hydrolysis for both Ile and Val at different substrate concentrations in the aminoacylation of tRNA(Ile). The present study shows a non-michaelis type dependence of rate of reaction on tRNA(Ile) concentration in case of valine. The overall editing in steady state is found to be independent of amino acid concentration. Interestingly, the computed ATP hydrolysis rate for valine at high substrate concentration is same as the rate of formation of Ile-tRNA(Ile) whereas at intermediate substrate concentration the ATP hydrolysis rate is relatively low. We find that the presence of additional editing domain in class I editing enzyme makes the kinetic proofreading more efficient through enhanced hydrolysis of wrong product at the editing CP1 domain.


Gene promoter methylation in prostate tumor-associated stromal cells.
Gene expression can be silenced through the methylation of specific sites in the promoter region. This mechanism of gene silencing has an important role in the carcinogenesis of prostate and other cancers. Although tumor-associated stromal cells also exhibit changes in gene expression, promoter methylation has not been described in these cells. Tumor epithelia, tumor-associated stroma and normal epithelia, and stroma adjacent to tumor tissues were isolated from whole-mount prostatectomy specimens (two per patient) of patients (n = 5) with localized prostate cancer and from normal epithelia and stroma from benign prostate hyperplasia specimens (two per patient) from men (n = 5) without prostate cancer by using laser capture microdissection or expression microdissection. The methylation status of three genes important in prostate carcinogenesis, GSTP1, RARbeta2, and CD44, were evaluated using quantitative methylation-sensitive polymerase chain reaction. GSTP1 and RARbeta2 were methylated in the tumor epithelium of all five prostate cancer patients and in the tumor-associated stroma in four of the five patients. CD44 was methylated in the tumor epithelium from four of the five patients but not in the tumor stroma. GSTP1 and RARbeta2 were methylated in normal epithelium of two and four patients, respectively, and in normal stroma of one and two patients, respectively, that were isolated from regions adjacent to the tumors and may have resulted from a tumor-field effect; CD44 methylation was not observed in normal epithelium or stroma. In contrast, normal epithelia and stroma from benign prostate hyperplasia specimens showed no promoter methylation in GSTP1, RARbeta2, or CD44. The observation of promoter methylation in the non-neoplastic cells of the prostate tumor microenvironment may advance our understanding of prostate cancer development and progression and lead to new diagnostic and prognostic markers and therapeutic targets.


Evidence that neuropeptide Y and norepinephrine mediate electrical field-stimulated vasoconstriction of rabbit middle cerebral artery.
We investigated the contractile response of isolated rabbit middle cerebral artery (MCA) segments to electrical field stimulation (EFS). The dynamics of the EFS contraction were compared with a similar-sized branch of rabbit ear artery. In comparison with the ear artery, the EFS contractions of the MCA displayed a longer latency and a higher stimulus frequency threshold. Greater stimulation train lengths were required to attain equilibrium, and the time course of EFS response--including force development, plateau, and return to rest tension--was significantly slower than in the ear artery. Morphological and pharmacological studies of the MCA showed that it receives sympathetic adrenergic innervation: whole-mount preparations displayed catecholamine histofluorescence; electron micrographs of MCA sections revealed a population of varicosities containing chromaffin positive large and small vesicles; and EFS contractions were blocked by tetrodotoxin (30 nM) and guanethidine (5 microM) and by chronic surgical sympathectomy. Exposure to prazosin (10 microM) or phenoxybenzamine (1 microM) blocked norepinephrine contractions but did not significantly influence the EFS contraction. Procedures and drugs that antagonized the responses to neuropeptide Y, serotonin, or histamine were also ineffective in blocking the EFS contraction. The involvement of ATP could not be assessed, since the purinergic P2 agonist alpha,beta-methylene ATP was ineffective in blocking ATP-mediated contractions. The EFS contraction, however, could be blocked by a combination of neuropeptide Y desensitization and phenoxybenzamine (30 nM) or prazosin (0.1 microM). These results suggest that norepinephrine and neuropeptide Y are released from sympathetic nerves and mediate EFS contraction by occupation of postjunctional alpha-adrenoceptor and neuropeptide Y receptors. Since the blockade of only one of these components does not diminish the response to EFS, the adrenergic neuroeffector system in this artery may involve complex prejunctional regulatory mechanisms.


The pharmacokinetic profile of a novel fixed-dose combination tablet of ibuprofen and paracetamol.
Ibuprofen and paracetamol differ in their mode of action and related therapeutic effects, suggesting that combined administration may offer improved analgesia. Reported here are the results of two studies on the pharmacokinetic properties of a novel ibuprofen (200 mg) and paracetamol (500 mg) fixed-dose combination tablet. Both studies were open-label, randomised studies in healthy volunteers: Study 1 was a four-way crossover, single-dose study; Study 2 was a two-way cross-over, repeat-dose study. Pharmacokinetic parameters for ibuprofen and paracetamol were similar for the combination and monotherapy tablets (values falling within the 80% to 125% acceptable bioequivalence range) except for the rate of absorption of paracetamol from the combination (tmax), which was significantly faster compared with monotherapy (median difference 10 minutes; p < 0.05). Mean plasma concentrations of both drugs were higher, earlier, following administration of the combination tablet compared with monotherapy. Mean plasma levels at 10 and 20 minutes were 6.64 microg x mL(-1) and 16.81 microg x mL(-1), respectively, for ibuprofen from the combination, compared with 0.58 microg x mL(-1) and 9.00 microg x mL-1, respectively, for monotherapy. For paracetamol, mean plasma levels at 10 and 20 minutes were 5.43 microg x mL(-1) and 14.54 microg x mL(-, respectively, for the combination compared with 0.33 microg x mL(-1) and 9.19 microg x mL(-1), respectively, for monotherapy. The rate of absorption of both ibuprofen and paracetamol was significantly delayed when the combination tablet was administered in the fed versus fasted state; median delay was 25 minutes for ibuprofen (p > 0.05) and 55 minutes for paracetamol (p < 0.001). The pharmacokinetic parameters were comparable irrespective of whether the combination tablet was given twice or three times daily; systemic exposure was, however, approximately 1.4 times greater for both drugs when given three times daily. Administration of ibuprofen and paracetamol in a fixed-dose combination tablet does not significantly alter the pharmacokinetic profiles of either drug, except for enhancing the rate of paracetamol absorption, offering potential therapeutic benefits in relation to the onset of analgesia. Concentrations of both drugs reached previously reported therapeutic levels when the combination tablet was administrated in the fed or fasted state. Three times daily dosing may offer enhanced therapeutic effect for longer than twice daily dosing.


Comparison of Ray Tracing and Monte Carlo Calculation Algorithms for Thoracic Spine Lesions Treated With CyberKnife-Based Stereotactic Body Radiation Therapy.
Stereotactic body radiation therapy (SBRT) is an emerging technology for the treatment of spinal metastases, although the dosimetric impact of the calculation method on spinal dose distribution is unknown. This study attempts to determine whether CyberKnife (CK)-based SBRT using a Ray Tracing (RyTc) algorithm is comparable dosimetrically to that of Monte Carlo (MC) for thoracic spinal lesions. Our institutional CK-based SBRT database for thoracic spinal lesions was queried and a cohort was generated. Patients were planned using RyTc and MC algorithms using the same beam angles and monitor units. Dose-volume histograms of the planning target volume (PTV), spinal cord, esophagus, and skin were generated, and dosimetric parameters were compared. There were 37 patients in the cohort. The average percentage volume of PTV covered by the prescribed dose with RyTc and MC algorithms was 91.1% and 80.4%, respectively (P < .001). The difference in average maximum spinal cord dose between RyTc and MC plans was significant (1126 vs 1084 cGy, P = .004), with the MC dose ranging from 18.7% below to 13.8% above the corresponding RyTc dose. A small reduction in maximum skin dose was also noted (P = .017), although no difference was seen in maximum esophageal dose (P = .15). Only PTVs smaller than 27 cm(3) were found to correlate with large (>10%) changes in dose to 90% of the volume (P = .014), while no correlates with the average percentage volume of PTV covered by the prescribed dose were demonstrated. For thoracic spinal CK-based SBRT, RyTc computation may overestimate the MC calculated average percentage volume of PTV covered by the prescribed dose and have unpredictable effects on doses to organs at risk, particularly the spinal cord. In this setting, use of RyTc optimization should be limited and always verified with MC.


Identification of a biomarker panel using a multiplex proximity ligation assay improves accuracy of pancreatic cancer diagnosis.
Pancreatic cancer continues to prove difficult to clinically diagnose. Multiple simultaneous measurements of plasma biomarkers can increase sensitivity and selectivity of diagnosis. Proximity ligation assay (PLA) is a highly sensitive technique for multiplex detection of biomarkers in plasma with little or no interfering background signal. We examined the plasma levels of 21 biomarkers in a clinically defined cohort of 52 locally advanced (Stage II/III) pancreatic ductal adenocarcinoma cases and 43 age-matched controls using a multiplex proximity ligation assay. The optimal biomarker panel for diagnosis was computed using a combination of the PAM algorithm and logistic regression modeling. Biomarkers that were significantly prognostic for survival in combination were determined using univariate and multivariate Cox survival models. Three markers, CA19-9, OPN and CHI3L1, measured in multiplex were found to have superior sensitivity for pancreatic cancer vs. CA19-9 alone (93% vs. 80%). In addition, we identified two markers, CEA and CA125, that when measured simultaneously have prognostic significance for survival for this clinical stage of pancreatic cancer (p < 0.003). A multiplex panel assaying CA19-9, OPN and CHI3L1 in plasma improves accuracy of pancreatic cancer diagnosis. A panel assaying CEA and CA125 in plasma can predict survival for this clinical cohort of pancreatic cancer patients.


The 'jaws' model of tau-microtubule interaction examined in CHO cells.
Tau is a neuronal microtubule-associated protein which promotes microtubule assembly. The C-terminal half of the protein contains three or four tandem repeats that are often considered to be the microtubule binding domain. This view is in conflict with in vitro data showing that the repeat domain binds only weakly to microtubules while the domains flanking the repeats bind strongly, even in the absence of the repeats. This has lead us to propose a 'jaws' model of tau whereby the regions flanking the repeats are considered as targetting domains, responsible for positioning tau on the microtubule surface, and the repeats which act as catalytic domains for microtubule assembly. To examine whether this model is appropriate in vivo we generated recombinant tau isoforms and microinjected them into CHO cells. Immunofluorescence microscopy of microtubules and tau shows that binding to microtubules, stabilization of microtubules and formation of bundles is not achieved by tau constructs comprising individual domains, but requires the combination of the flanking regions and the repeat domain. The results show that the jaws model describes the interactions between tau and microtubules in living cells. Since the targetting and catalytic domains are affected differently by phosphorylation the model provides a basis for studying the regulation of the interaction between microtubules and tau or other microtubule-associated proteins.


Effect of ximelagatran and warfarin on stroke subtypes in atrial fibrillation.
The most common stroke subtype among atrial fibrillation (AF) patients not receiving anticoagulants is cardioembolic. In the SPORTIF III and V trials, the oral direct thrombin inhibitor ximelagatran was as effective as warfarin in reducing the risk of stroke in patients with nonvalvular AF. We assessed any differential effect of warfarin versus ximelagatran on the risk and outcome of cardioembolic and noncardioembolic stroke. 7329 patients with AF and > or = 1 risk factors for stroke were randomized to treatment with warfarin (target international normalized ratio 2.0--3.0) or fixed-dose ximelagatran. Strokes were classified into specific subtypes. Therapeutic effect of warfarin and ximelagatran, adverse events, and stroke outcomes were assessed according to stroke subtype. The annual stroke rate was low for both cardioembolic (ximelagatran, 0.39%; warfarin, 0.47%) and noncardioembolic stroke (ximelagatran, 0.57%; warfarin, 0.37%). In ischemic strokes, 33.9% (ximelagatran) and 34.3% (warfarin) had strokes of presumed cardioembolic origin. When fatal stroke, disabling stroke, myocardial infarction, and death from any cause were combined as poor outcome, patients with cardioembolic strokes had the highest rate of poor outcome (40%) but this was non- significant. In SPORTIF III and V the efficacy of warfarin and ximelagatran were similar for prevention of cardioembolic and noncardioembolic strokes. Overall outcome tended to be worse following cardioembolic stroke. Ximelagatran has been withdrawn from the market due to hepatic side effects, but similar compounds are presently being studied.


Post-ecological discourse in the making.
This article analyses the discourse of 15- to16-year-old Swiss junior high school students in order to understand public discourse on the environment and environmental protection. Discourse analysis reveals four interpretive repertoires as the building blocks for the so-called post-ecological discourse, which can be used to describe important aspects of current ways of talking about ecological issues in Europe. We show that 10 theoretically identifiable dimensions of this discourse can be understood in terms of a mutual interplay between the four interpretive repertoires. Post-ecological discourse in today's (Swiss) society appears to be at its core a loss-of-control-discourse, which leads (in our students) to a latent eco-depression. Thus, the public understanding of science can be affected by unintended consequences of the talk itself (in this case an unintended environmental depression), that is, by the inherent characteristics of the involved repertoires, here especially the so-called folk science repertoire. Fostering public understanding of science is thus not merely a question of providing the public with scientific 'facts'. It is also an issue of paying attention to the available discursive repertoires. If necessary, viable alternative repertoires may have to be offered. In school, for example, conversations about the nature of science, and about complexity and applied ethics might help students learn new interpretive repertoires and how to mobilize these in talking about the environment and environmental protection.


Why are we fat? Discussions on the socioeconomic dimensions and responses to obesity.
This paper draws together contributions to a scientific table discussion on obesity at the European Science Open Forum 2008 which took place in Barcelona, Spain. Socioeconomic dimensions of global obesity, including those factors promoting it, those surrounding the social perceptions of obesity and those related to integral public health solutions, are discussed. It argues that although scientific accounts of obesity point to large-scale changes in dietary and physical environments, media representations of obesity, which context public policy, pre-eminently follow individualistic models of explanation. While the debate at the forum brought together a diversity of views, all the contributors agreed that this was a global issue requiring an equally global response. Furthermore, an integrated ecological model of obesity proposes that to be effective, policy will need to address not only human health but also planetary health, and that therefore, public health and environmental policies coincide.