Auxin signaling and transport promote susceptibility to the root-infecting fungal pathogen Fusarium oxysporum in Arabidopsis.
Fusarium oxysporum is a root-infecting fungal pathogen that causes wilt disease on a broad range of plant species, including the model plant Arabidopsis thaliana. Currently, very little is known about the molecular or physiological processes that are activated in the host during infection and the roles these processes play in resistance and susceptibility to F. oxysporum. In this study, we analyzed global gene expression profiles of F. oxysporum-infected Arabidopsis plants. Genes involved in jasmonate biosynthesis as well as jasmonate-dependent defense were coordinately induced by F. oxysporum. Similarly, tryptophan pathway genes, including those involved in both indole-glucosinolate and auxin biosynthesis, were upregulated in both the leaves and the roots of inoculated plants. Analysis of plants expressing the DR5:GUS construct suggested that root auxin homeostasis was altered during F. oxysporum infection. However, Arabidopsis mutants with altered auxin and tryptophan-derived metabolites such as indole-glucosinolates and camalexin did not show an altered resistance to this pathogen. In contrast, several auxin-signaling mutants were more resistant to F. oxysporum. Chemical or genetic alteration of polar auxin transport also conferred increased pathogen resistance. Our results suggest that, similarly to many other pathogenic and nonpathogenic or beneficial soil organisms, F. oxysporum requires components of auxin signaling and transport to colonize the plant more effectively. Potential mechanisms of auxin signaling and transport-mediated F. oxysporum susceptibility are discussed.


European Society of Gynecological Oncology Task Force for Fertility Preservation: Clinical Recommendations for Fertility-Sparing Management in Young Endometrial Cancer Patients.
Endometrial cancer (EC) in young women of reproductive age is a relatively rare diagnosis. However, since in the modern era women delay their childbearing for a variety of social reasons, more and more women in the near future will be nulliparous and have a diagnosis of EC at the same time. Hence, a more conservative approach of EC is desirable to preserve fertility of these women, without compromising their survival. Recently, the number of studies reporting encouraging results on fertility-sparing management of EC with high dose of progestins is increasing. It seems that preserving the uterus and the ovaries in a carefully selected patient with EC confers only a very small risk combined with an enormous benefit. Selection of women suitable for such a conservative approach, as well as method of treatment, follow-up, recurrence, obstetric outcomes, and survival rates are very important parameters when consulting women with EC wishing to preserve their fertility. In this article, we try to elucidate all the previously mentioned aspects and formulate clinical recommendations, based on published data, about the most proper approach and consultation of these patients.


Towards optimisation of surface enhanced photodynamic therapy of breast cancer cells using gold nanoparticle-photosensitiser conjugates.
Gold nanoparticles (AuNPs; ca. 4 nm) were synthesised and functionalised with a mixed monolayer of polyethylene glycol (PEG) and one of two zinc phthalocyanines (ZnPcs), the difference between the two molecules was the length of the carbon chain that connects the Pc to the gold core. The chain was composed of either three (C3Pc) or eleven (C11Pc) carbon atoms. The C11Pc photosensitiser displayed higher fluorescence emission intensity than the C3Pc in solution. By contrast, the C3Pc photosensitiser exhibited higher fluorescence when bound to the surface of the AuNPs than the C11Pc, despite the shorter carbon chain which was expected to quench the fluorescence. In addition, the C3Pc nanoparticle conjugates exhibited an enhancement in the production of singlet oxygen (1O2). The metal-enhanced 1O2 production led to a remarkable photodynamic efficacy for the treatment of human breast cancer cells.


Role of type IV pili in virulence of Pseudomonas syringae pv. tabaci 6605: correlation of motility, multidrug resistance, and HR-inducing activity on a nonhost plant.
To investigate the role of type IV pili in the virulence of phytopathogenic bacteria, four mutant strains for pilus biogenesis-related genes were generated in Pseudomonas syringae pv. tabaci 6605. PilA encodes the pilin protein as a major subunit of type IV pili, and the pilO product is reported to be required for pilus assembly. The fimU and fimT genes are predicted to produce minor pilins. Western blot analysis revealed that pilA, pilO, and fimU mutants but not the fimT mutant failed to construct type IV pili. Although the swimming motility of all mutant strains was not impaired in liquid medium, they showed remarkably reduced motilities on semisolid agar medium, suggesting that type IV pili are required for surface motilities. Virulence toward host tobacco plants and hypersensitive response-inducing ability in nonhost Arabidopsis leaves of pilA, pilO, and fimU mutant strains were reduced. These results might be a consequence of reduced expression of type III secretion system-related genes in the mutant strains. Further, all mutant strains showed enhanced expression of resistance-nodulation-division family members mexA, mexB, and oprM, and higher tolerance to antimicrobial compounds. These results indicate that type IV pili are an important virulence factor of this pathogen.


Pruritus. What to do when the itching won't stop.
Pruritus is a common problem that can result from many conditions. Some, such as fungal or parasitic infection, may be fairly obvious. However, others, such as iron deficiency and psychogenic disorder, are more difficult to diagnose. Evaluation must include a thorough inspection of the skin, history taking for drug intake and chemical exposure, and appropriate laboratory testing. The location on the body and characteristics of the itching may point to a cause. In some cases, attention to exacerbating factors (eg, dry skin, coarse fabrics against the skin, dry environmental conditions) and application of topical preparations may be sufficient. Antihistamines are the foundation of oral treatment, and with the advent of second-generation agents, they can be taken with fewer concerns about their sedative effects. Specific conditions of which pruritus is one feature may require specific treatment. For example, in patients undergoing dialysis, activated charcoal, UV light treatment, or heparin therapy may be useful.


The role of indigenous phlebotomine sandflies and mammals in the spreading of leishmaniasis agents in the Mediterranean region.
An updated view of the establishment and spread of the leishmaniases in Europe is presented, mostly with respect to newly emerging and re-emerging foci and the incrimination of neglected as well as new reservoir hosts. At the same time, a concept of specific versus permissive vectors reassesses the potential role of various sandfly species in Leishmania transmission and considers the risk of introduction of exotic Leishmania species in Europe. The leishmaniases are dynamic diseases and the circumstances of transmission are continually changing in relation to environmental, demographic and human behavioural factors. Changes in the habitat of the natural hosts and vectors, immunosuppressive conditions (like infection with human immunodeficiency virus (HIV) or organ transplantation-associated therapies in humans) and the consequences of war, all contribute to the transformation of the epidemiology of leishmaniasis. Such changes should be considered when studying the spread of the disease throughout Europe for targeted control measures to safeguard public health.


Environmental, social, and economic implications of global reuse and recycling of personal computers.
Reverse supply chains for the reuse, recycling, and disposal of goods are globalizing. This article critically reviews the environmental, economic, and social issues associated with international reuse and recycling of personal computers. Computers and other e-waste are often exported for reuse and recycling abroad. On the environmental side, our analysis suggests that the risk of leaching of toxic materials in computers from well-managed sanitary landfills is very small. On the other hand, there is an increasing body of scientific evidence that the environmental impacts of informal recycling in developing countries are serious. On the basis of existing evidence informal recycling is the most pressing environmental issue associated with e-waste. Socially, used markets abroad improve access to information technology by making low-priced computers available. Economically, the reuse and recycling sector provides employment. Existing policies efforts to manage e-waste focus on mandating domestic recycling systems and reducing toxic content of processes. We argue that existing policy directions will mitigate but not solve the problem of the environmental impacts of informal recycling. There are many opportunities yet to be explored to develop policies and technologies for reuse/recycling systems which are environmentally safe, encourage reuse of computers, and provide jobs.


Early oral feeds in laryngectomized patients.
It is a common practice to start oral feeding after 7 to 10 days in patients who have undergone laryngeal surgeries. It was our observation that when oral feeds were initiated earlier than this period, there was no increase in the incidence of pharyngocutaneous fistulas. This prospective study is about our experience in initiating early oral feeds in the postoperative period (on the 2nd day) in laryngectomized patients. Seventy-eight patients underwent laryngectomy with or without partial pharyngectomy over a period of 38 months between October 2001 and December 2004. The oral feeds were initiated on the 2nd postoperative day in 40 patients. Thirty-eight patients served as controls in whom feeds were initiated after the 10th postoperative day. Only 1 patient in the study group and 2 patients in the control group developed pharyngocutaneous fistulas. Most patients in the control group wished to avoid nasogastric intubation in the recovery period because of discomfort, gastric symptoms, and the need to taste food. With this study we can assume that in a select group of patients, it is possible to initiate oral feeding much earlier in the postoperative period than was formerly thought.


The disposition and metabolism of [14C]piritrexim in dogs after intravenous and oral administration.
The disposition of [14C]piritrexim ([14C]PTX) in male dogs after iv and po doses of 1.8 mg/kg was examined. After either route of administration, greater than 90% of the dose was recovered in the exreta within 72 hr; approximately 20% was recovered in urine and 70% in feces. [14C]PTX was extensively metabolized by dogs; unchanged drug accounted for less than 15% of the dose in the excreta. The O-demethylated metabolites, 2'- and 5'-demethyl PTX, the glucuronide conjugate of 2'-demethyl PTX, and the sulfate conjugate of 5'-demethyl PTX were the major metabolites. Unchanged drug accounted for a large proportion of the drug-related radiocarbon in plasma. The average plasma half-life of PTX after iv administration was 2.6 +/- 0.3 hr, and the average total body clearance was 0.33 +/- 0.13 liter/hr/kg. After po administration, peak plasma concentrations of 0.9 +/- 0.3 micrograms/ml occurred about 1.1 hr after the dose; the absolute oral bioavailability of PTX was 0.63 +/- 0.14. Because the O-demethyl metabolites were active dihydrofolate reductase inhibitors, 2'- and 5'-demethyl PTX were synthesized, and the pharmacokinetics and bioavailability of these compounds in dogs after iv and po administration (5 mg/kg) were examined. The plasma concentration-time data for both compounds after iv doses were described by a two-compartment model, with t1/2 beta = 1.3 and 0.8 hr for the 2'- and 5'- demethyl compounds, respectively. Neither compound showed significant advantages over PTX in terms of pharmacokinetics or bioavailability.


Sharing concerns: Interpersonal worry regulation in romantic couples.
Two dyadic studies investigated interpersonal worry regulation in heterosexual relationships. In Study 1, we video-recorded 40 romantic couples discussing shared concerns. Male partners' worry positively predicted female partners' interpersonal calming attempts, and negatively predicted female partners' interpersonal alerting attempts (i.e., attempts to make their partners appreciate the seriousness of concerns). Video-cued recall data also indicated that changes in partner A's worry over time positively predicted partner B's motivation to reduce partner A's worry, and that this effect was stronger when B was the female partner. Study 2 was a dyadic survey of 100 couples. Individual differences in partner A's negative affect were positive predictors of partner B's interpersonal calming, and individual differences in partner A's expressive suppression were negative predictors of partner B's interpersonal calming. Further, individual differences in male partners' expressivity were significant positive predictors of female partners' interpersonal calming, and individual differences in male partners' reappraisal were significant positive predictors of female partners' interpersonal alerting. These findings suggest that interpersonal worry regulation relates to partners' expression and intrapersonal regulation of worry, but not equally for men and women. (PsycINFO Database Record


Determination of reference intervals of glycated albumin and hemoglobin A1c in healthy pregnant Japanese women and analysis of their time courses and influencing factors during pregnancy.
Glycemic control is an important issue in gestational diabetes mellitus (GDM) and in diabetic pregnant women. We determined the reference intervals of glycated albumin (GA) and hemoglobin A1c (HbA1c) as glycemic control markers in healthy Japanese pregnant women and analyzed their time courses and factors that influence these variables during pregnancy. 676 women were screened for the present study. After the exclusion of non-pregnant and puerperal women, 574 women were studied to determine the reference intervals. HbA1c, GA, casual plasma glucose, urinary glucose, urinary protein, and body mass index (BMI) (non-pregnancy) were measured. HbA1c levels significantly decreased in the second trimester of pregnancy and increased in the third trimester, while GA levels significantly decreased towards the third trimester. Casual plasma glucose levels decreased in the first trimester and subsequently remained constant. The reference intervals of GA and HbA1c in the healthy pregnant women were 11.5-15.7% and 4.5-5.7%, respectively. GA levels were lower (p<0.01) and HbA1c levels were higher (p<0.05) in pregnant women with proteinuria. In the obese group, GA levels were lower (p<0.01) than those of the control group (18.5≤ BMI <25kg/m²), and HbA1c levels were higher (p<0.01) than those of the control group. On the basis of the results of this multicenter study, the reference intervals of GA and HbA1c in healthy Japanese pregnant women were determined. Strict glycemic control is essential to reduce perinatal complications. GA appears to be a useful marker for pregnant women, since it can be measured easily and changes rapidly and markedly.


A randomized, controlled trial of immersive virtual reality analgesia, during physical therapy for pediatric burns.
This randomized, controlled, within-subjects (crossover design) study examined the effects of immersive virtual reality as an adjunctive analgesic technique for hospitalized pediatric burn inpatients undergoing painful physical therapy. Fifty-four subjects (6-19 years old) performed range-of-motion exercises under a therapist's direction for 1-5 days. During each session, subjects spent equivalent time in both the virtual reality and the control conditions (treatment order randomized and counterbalanced). Graphic rating scale scores assessing the sensory, affective, and cognitive components of pain were obtained for each treatment condition. Secondary outcomes assessed subjects' perception of the virtual reality experience and maximum range-of-motion. Results showed that on study day one, subjects reported significant decreases (27-44%) in pain ratings during virtual reality. They also reported improved affect ("fun") during virtual reality. The analgesia and affect improvements were maintained with repeated virtual reality use over multiple therapy sessions. Maximum range-of-motion was not different between treatment conditions, but was significantly greater after the second treatment condition (regardless of treatment order). These results suggest that immersive virtual reality is an effective nonpharmacologic, adjunctive pain reduction technique in the pediatric burn population undergoing painful rehabilitation therapy. The magnitude of the analgesic effect is clinically meaningful and is maintained with repeated use.


Low resolution scans can provide a sufficiently accurate, cost- and time-effective alternative to high resolution scans for 3D shape analyses.
Advances in 3D shape capture technology have made powerful shape analyses, such as geometric morphometrics, more feasible. While the highly accurate micro-computed tomography (µCT) scanners have been the "gold standard," recent improvements in 3D surface scanners may make this technology a faster, portable, and cost-effective alternative. Several studies have already compared the two devices but all use relatively large specimens such as human crania. Here we perform shape analyses on Australia's smallest rodent to test whether a 3D scanner produces similar results to a µCT scanner. We captured 19 delicate mouse (Pseudomys delicatulus) crania with a µCT scanner and a 3D scanner for geometric morphometrics. We ran multiple Procrustes ANOVAs to test how variation due to scan device compared to other sources such as biologically relevant variation and operator error. We quantified operator error as levels of variation and repeatability. Further, we tested if the two devices performed differently at classifying individuals based on sexual dimorphism. Finally, we inspected scatterplots of principal component analysis (PCA) scores for non-random patterns. In all Procrustes ANOVAs, regardless of factors included, differences between individuals contributed the most to total variation. The PCA plots reflect this in how the individuals are dispersed. Including only the symmetric component of shape increased the biological signal relative to variation due to device and due to error. 3D scans showed a higher level of operator error as evidenced by a greater spread of their replicates on the PCA, a higher level of multivariate variation, and a lower repeatability score. However, the 3D scan and µCT scan datasets performed identically in classifying individuals based on intra-specific patterns of sexual dimorphism. Compared to µCT scans, we find that even low resolution 3D scans of very small specimens are sufficiently accurate to classify intra-specific differences. We also make three recommendations for best use of low resolution data. First, we recommend that extreme caution should be taken when analyzing the asymmetric component of shape variation. Second, using 3D scans generates more random error due to increased landmarking difficulty, therefore users should be conservative in landmark choice and avoid multiple operators. Third, using 3D scans introduces a source of systematic error relative to µCT scans, therefore we recommend not combining them when possible, especially in studies expecting little biological variation. Our findings support increased use of low resolution 3D scans for most morphological studies; they are likely also applicable to low resolution scans of large specimens made in a medical CT scanner. As most vertebrates are relatively small, we anticipate our results will bolster more researchers in designing affordable large scale studies on small specimens with 3D surface scanners.


Transcriptome profiling of whole blood cells identifies PLEK2 and C1QB in human melanoma.
Developing analytical methodologies to identify biomarkers in easily accessible body fluids is highly valuable for the early diagnosis and management of cancer patients. Peripheral whole blood is a "nucleic acid-rich" and "inflammatory cell-rich" information reservoir and represents systemic processes altered by the presence of cancer cells. We conducted transcriptome profiling of whole blood cells from melanoma patients. To overcome challenges associated with blood-based transcriptome analysis, we used a PAXgene™ tube and NuGEN Ovation™ globin reduction system. The combined use of these systems in microarray resulted in the identification of 78 unique genes differentially expressed in the blood of melanoma patients. Of these, 68 genes were further analyzed by quantitative reverse transcriptase PCR using blood samples from 45 newly diagnosed melanoma patients (stage I to IV) and 50 healthy control individuals. Thirty-nine genes were verified to be differentially expressed in blood samples from melanoma patients. A stepwise logit analysis selected eighteen 2-gene signatures that distinguish melanoma from healthy controls. Of these, a 2-gene signature consisting of PLEK2 and C1QB led to the best result that correctly classified 93.3% melanoma patients and 90% healthy controls. Both genes were upregulated in blood samples of melanoma patients from all stages. Further analysis using blood fractionation showed that CD45(-) and CD45(+) populations were responsible for the altered expression levels of PLEK2 and C1QB, respectively. The current study provides the first analysis of whole blood-based transcriptome biomarkers for malignant melanoma. The expression of PLEK2, the strongest gene to classify melanoma patients, in CD45(-) subsets illustrates the importance of analyzing whole blood cells for biomarker studies. The study suggests that transcriptome profiling of blood cells could be used for both early detection of melanoma and monitoring of patients for residual disease.


Predictors of response to 17-alpha hydroxyprogesterone caproate for prevention of recurrent spontaneous preterm birth.
Prematurity is the leading cause of neonatal morbidity and death among nonanomalous neonates in the United States. Intramuscular 17-alpha hydroxyprogesterone caproate injections reduce the risk of recurrent prematurity by approximately one third. Unfortunately, prophylactic 17-alpha hydroxyprogesterone caproate is not always effective, and one-third of high-risk women will have a recurrent preterm birth, despite 17-alpha hydroxyprogesterone caproate therapy. The reasons for this variability in response are unknown. Previous investigators have examined the influence of a variety of factors on 17-alpha hydroxyprogesterone caproate response but have analyzed data that used a fixed outcome of term delivery to define progesterone response. We hypothesized that the demographics, history, and pregnancy course among women who deliver at a similar gestational age with 17-alpha hydroxyprogesterone caproate for recurrent spontaneous preterm birth prevention differs when compared with those women who deliver later with 17-alpha hydroxyprogesterone caproate and that these associations could be refined by the use of a contemporary definition of 17-alpha hydroxyprogesterone caproate "responder." This was a planned secondary analysis of a prospective, multicenter, longitudinal study of women with ≥1 previous documented singleton spontaneous preterm birth at <37 weeks gestation. Data were collected at 3 prespecified gestational age epochs during pregnancy. All women who were included in this analysis received 17-alpha hydroxyprogesterone caproate during the studied pregnancy. We classified women as a 17-alpha hydroxyprogesterone caproate responder or nonresponder by calculating the difference in delivery gestational age between the 17-alpha hydroxyprogesterone caproate-treated pregnancy and her earliest spontaneous preterm birth. Responders were defined as those with pregnancy that extended ≥3 weeks later with 17-alpha hydroxyprogesterone caproate, compared with the delivery gestational age of their earliest previous spontaneous preterm birth. Data were analyzed with the use of chi-square test, t-test, and logistic regression. One hundred fifty-five women met the inclusion criteria. The 118 responders delivered later on average (37.7 weeks gestation) than the 37 nonresponders (33.5 weeks gestation; P < .001). Among responders, 32% (38/118 women) had a recurrent spontaneous preterm birth. Demographics (age, race/ethnicity, education, and parity) were similar between groups. In the regression model, the gestational age of the previous spontaneous preterm birth (odds ratio, 0.68; 95% confidence interval, 0.56-0.82; P < .001), vaginal bleeding/abruption in the current pregnancy (odds ratio, 0.24; 95% confidence interval, 0.06-0.88; P = .031), and first-degree family history of spontaneous preterm birth (odds ratio, 0.37; 95% confidence interval, 0.15-0.88; P = .024) were associated with response to 17-alpha hydroxyprogesterone caproate. Because women with a penultimate preterm pregnancy were more likely to be 17-alpha hydroxyprogesterone caproate nonresponders, we performed an additional limited analysis examining only the 130 women whose penultimate pregnancy was preterm. In regression models, the results were similar to those in the main cohort. Several historic and current pregnancy characteristics define women who are at risk for recurrent preterm birth at a similar gestational age, despite 17-alpha hydroxyprogesterone caproate therapy. These data should be studied prospectively in larger cohorts and combined with genetic and environmental data to identify women who are most likely to benefit from this intervention.


Incidence of heart failure or cardiomyopathy after adjuvant trastuzumab therapy for breast cancer.
The purpose of this study was to estimate heart failure (HF) and cardiomyopathy (CM) rates after adjuvant trastuzumab therapy and chemotherapy in a population of older women with early-stage breast cancer. Newer biologic therapies for breast cancer such as trastuzumab have been reported to increase HF and CM in clinical trials, especially in combination with anthracycline chemotherapy. Elderly patients, however, typically have a higher prevalence of cardiovascular risk factors and have been underrepresented in trastuzumab clinical trials. Using Surveillance, Epidemiology, and End Results-Medicare data from 2000 through 2007, we identified women 67 to 94 years of age with early-stage breast cancer. We calculated 3-year incidence rates of HF or CM for the following mutually exclusive treatment groups: trastuzumab (with or without nonanthracycline chemotherapy), anthracycline plus trastuzumab, anthracycline (without trastuzumab and with or without nonanthracycline chemotherapy), other nonanthracycline chemotherapy, or no adjuvant chemotherapy or trastuzumab therapy. HF or CM events were ascertained from administrative Medicare claims. Poisson regression was used to quantify risk of HF or CM, adjusting for sociodemographic factors, cancer characteristics, and cardiovascular conditions. We identified 45,537 older women (mean age: 76.2 years, standard deviation: 6.2 years) with early-stage breast cancer. Adjusted 3-year HF or CM incidence rates were higher for patients receiving trastuzumab (32.1 per 100 patients) and anthracycline plus trastuzumab (41.9 per 100 patients) compared with no adjuvant therapy (18.1 per 100 patients, p < 0.001). Adding trastuzumab to anthracycline therapy added 12.1, 17.9, and 21.7 HF or CM events per 100 patients over 1, 2, and 3 years of follow-up, respectively. HF or CM are common complications after trastuzumab therapy for older women, with higher rates than those reported from clinical trials.


Functional and phylogenetic characterization of proteins detected in various nematode intestinal compartments.
The parasitic nematode intestine is responsible for nutrient digestion and absorption, and many other processes essential for reproduction and survival, making it a valuable target for anthelmintic drug treatment. However, nematodes display extreme biological diversity (including occupying distinct trophic habitats), resulting in limited knowledge of intestinal cell/protein functions of fundamental or adaptive significance. We developed a perfusion model for isolating intestinal proteins in Ascaris suum (a parasite of humans and swine), allowing for the identification of over 1000 intestinal A. suum proteins (using mass spectrometry), which were assigned to several different intestinal cell compartments (intestinal tissue, the integral and peripheral intestinal membranes, and the intestinal lumen). A multi-omics analysis approach identified a large diversity of biological functions across intestinal compartments, based on both functional enrichment analysis (identifying terms related to detoxification, proteolysis, and host-parasite interactions) and regulatory binding sequence analysis to identify putatively active compartment-specific transcription factors (identifying many related to intestinal sex differentiation or lifespan regulation). Orthologs of A. suum proteins in 15 other nematodes species, five host species, and two outgroups were identified and analyzed. Different cellular compartments demonstrated markedly different levels of protein conservation; e.g. integral intestinal membrane proteins were the most conserved among nematodes (up to 96% conservation), whereas intestinal lumen proteins were the most diverse (only 6% conservation across all nematodes, and 71% with no host orthologs). Finally, this integrated multi-omics analysis identified conserved nematode-specific intestinal proteins likely performing essential functions (including V-type ATPases and ABC transporters), which may serve as promising anthelmintic drug or vaccine targets in future research. Collectively, the findings provide valuable new insights on conserved and adaptive features of nematode intestinal cells, membranes and the intestinal lumen, and potential targets for parasite treatment and control.


Phase I study of the novel cyclic AMP (cAMP) analogue 8-chloro-cAMP in patients with cancer: toxicity, hormonal, and immunological effects.
The cyclic AMP (cAMP)-dependent protein kinase regulatory subunit RI is overexpressed in cancer cells. 8-Chloro-cAMP (8-Cl-cAMP) is an RII site-specific analogue that down-regulates RI and inhibits the growth of a wide range of cancer cells in vitro and in vivo. We performed a Phase I trial of 8-Cl-cAMP in 32 patients with malignancies that were refractory to standard treatments. 8-Cl-cAMP was initially given in a 1-month cycle by constant infusion at 0.005 mg/kg/h for 21 days, followed by 1 week of rest. The dose was escalated to 0.045 mg/kg/h, but hypercalcemia became the dose-limiting toxicity. The length of drug administration was, therefore, reduced to 5 days per week for the first 3 weeks of the cycle, but it was not possible to increase the drug dose without producing hypercalcemia. Hence, the length of drug administration was reduced to 3 days per week for the first 3 weeks of the cycle. The maximum tolerated dose for this regimen was 0.15 mg/kg/h, and the dose-limiting toxicities were reversible hypercalcemia and hepatotoxicity. Stable disease for > or =4 months was observed in two patients treated at > or =0.045 mg/kg. cAMP-dependent protein kinase is involved in hormone- and cytokine-mediated signaling, and so representative hormone, cytokine, and peripheral lymphocyte subsets were measured. The drug had a parathyroid hormone-like effect on calcium homeostasis and significantly increased circulating luteinizing hormone and 17-hydoxyprogesterone levels (P < 0.02 and P < 0.0006, respectively). We conclude that 8-Cl-cAMP is well tolerated without attendant myelotoxicity, and in this study, it was associated with biological effects. In Phase II studies, a dose of 0.11 mg/kg/h for 3 days per week would be appropriate.


Guiding-Strand-Controlled DNA Nucleases with Enhanced Specificity and Tunable Kinetics for DNA Mutation Detection.
Nucleases are powerful tools in various biomedical applications, such as genetic engineering, biosensing, and molecular diagnosis. However, the commonly used nucleases (endonuclease IV, apurinic/apyrimidinic endonuclease-1, and λ exonuclease) are prone to the nonspecific cleavage of single-stranded DNA, making the desired reactions extremely low-yield and unpredictable. Herein, we have developed guiding-strand-controlled nuclease systems and constructed theoretical kinetic models to explain their mechanisms of action. The models displayed excellent agreement with the experimental results, making the kinetics highly predictable and tunable. Our method inhibited the nonspecific cleavage of single-stranded probes while maintaining highly efficient cleavage of double-stranded DNA. We also demonstrated the clinical practicability of the method by detecting a low-frequency mutation in a genomic DNA sample extracted from the blood of a patient with cancer. The limit of detection could be 0.01% for PTEN rs121909219. We believe that our findings provide a powerful tool for the field and the established model provides us a deeper understanding of the enzymatic activities of DNA nucleases.


Rural to Urban Population Density Scaling of Crime and Property Transactions in English and Welsh Parliamentary Constituencies.
Urban population scaling of resource use, creativity metrics, and human behaviors has been widely studied. These studies have not looked in detail at the full range of human environments which represent a continuum from the most rural to heavily urban. We examined monthly police crime reports and property transaction values across all 573 Parliamentary Constituencies in England and Wales, finding that scaling models based on population density provided a far superior framework to traditional population scaling. We found four types of scaling: i) non-urban scaling in which a single power law explained the relationship between the metrics and population density from the most rural to heavily urban environments, ii) accelerated scaling in which high population density was associated with an increase in the power-law exponent, iii) inhibited scaling where the urban environment resulted in a reduction in the power-law exponent but remained positive, and iv) collapsed scaling where transition to the high density environment resulted in a negative scaling exponent. Urban scaling transitions, when observed, took place universally between 10 and 70 people per hectare. This study significantly refines our understanding of urban scaling, making clear that some of what has been previously ascribed to urban environments may simply be the high density portion of non-urban scaling. It also makes clear that some metrics undergo specific transitions in urban environments and these transitions can include negative scaling exponents indicative of collapse. This study gives promise of far more sophisticated scale adjusted metrics and indicates that studies of urban scaling represent a high density subsection of overall scaling relationships which continue into rural environments.


Soy proteins as environmentally friendly sizing agents to replace poly(vinyl alcohol).
An environmentally friendly and inexpensive substitute to the widely used poly(vinyl alcohol) (PVA) has been developed from soy proteins for textile warp sizing. Textile processing is the major source of industrial water pollution across the world, and sizing and desizing operations account for nearly 30 % of the water consumed in a textile plant. PVA is one of the most common sizing agents used for synthetic fibers and their blends due to PVA's easy water solubility and ability to provide desired sizing performance. However, PVA does not degrade and is a major contributor to pollution in textile effluent treatment plants. Although considerable efforts have been made to replace PVA with biodegradable sizing materials, the performance properties provided by PVA on synthetic fibers and their blends have been unmatched so far. Soy proteins are inexpensive, biodegradable, and have been widely studied for potential use in food packaging, as resins and adhesives. In this research, the potential of using soy proteins as textile sizing agents to replace PVA was studied. Polyester and polyester/cotton rovings, yarns, and fabrics sized with soy protein showed a considerably better improvement in strength and abrasion resistance compared to commercially available PVA-based size. Soy protein size had a 5-day biochemical oxygen demand /chemical oxygen demand ratio of 0.57 compared to 0.01 for PVA indicating that soy protein sizes were easily biodegradable in activated sludge. The total and ammonia nitrogen released from the proteins also did not adversely impact the biodegradability. Good sizing performance and easy biodegradability demonstrate that soy protein-based sizes have potential to replace PVA-based sizes leading to substantial benefits to the textile industry and the environment.


Isolation of pathogenic Leptospira strains from naturally infected cattle in Uruguay reveals high serovar diversity, and uncovers a relevant risk for human leptospirosis.
Leptospirosis is a neglected zoonosis with worldwide distribution. The causative agents are spirochete bacteria of the Leptospira genus, displaying huge diversity of serovars, the identity of which is critical for effective diagnosis and vaccination purposes. Among many other mammalian species, Leptospira infects cattle, eliciting acute signs in calves, and chronic disease in adult animals often leading to abortions. In South America, and including in Uruguay, beef and dairy export are leading sources of national income. Despite the importance of bovine health, food safety, and bovine-related dissemination of leptospirosis to humans, extremely limited information is available as to the identity of Leptospira species and serovars infecting cattle in Uruguay and the South American subcontinent. Here we report a multicentric 3-year study resulting in the isolation and detailed characterization of 40 strains of Leptospira spp. obtained from infected cattle. Combined serologic and molecular typing identified these isolates as L. interrogans serogroup Pomona serovar Kennewicki (20 strains), L. interrogans serogroup Canicola serovar Canicola (1 strain), L. borgpetersenii serogroup Sejroe serovar Hardjo (10 strains) and L. noguchii (9 strains). The latter showed remarkable phenotypic and genetic variability, belonging to 6 distinct serogroups, including 3 that did not react with a large panel of reference serogrouping antisera. Approximately 20% of cattle sampled in the field were found to be shedding pathogenic Leptospira in their urine, uncovering a threat for public health that is being largely neglected. The two L. interrogans serovars that we isolated from cattle displayed identical genetic signatures to those of human isolates that had previously been obtained from leptospirosis patients. This report of local Leptospira strains shall improve diagnostic tools and the understanding of leptospirosis epidemiology in South America. These strains could also be used as new components within bacterin vaccines to protect against the pathogenic Leptospira strains that are actually circulating, a direct measure to reduce the risk of human leptospirosis.


Effect of host species on the distribution of mutational fitness effects for an RNA virus.
Knowledge about the distribution of mutational fitness effects (DMFE) is essential for many evolutionary models. In recent years, the properties of the DMFE have been carefully described for some microorganisms. In most cases, however, this information has been obtained only for a single environment, and very few studies have explored the effect that environmental variation may have on the DMFE. Environmental effects are particularly relevant for the evolution of multi-host parasites and thus for the emergence of new pathogens. Here we characterize the DMFE for a collection of twenty single-nucleotide substitution mutants of Tobacco etch potyvirus (TEV) across a set of eight host environments. Five of these host species were naturally infected by TEV, all belonging to family Solanaceae, whereas the other three were partially susceptible hosts belonging to three other plant families. First, we found a significant virus genotype-by-host species interaction, which was sustained by differences in genetic variance for fitness and the pleiotropic effect of mutations among hosts. Second, we found that the DMFEs were markedly different between Solanaceae and non-Solanaceae hosts. Exposure of TEV genotypes to non-Solanaceae hosts led to a large reduction of mean viral fitness, while the variance remained constant and skewness increased towards the right tail. Within the Solanaceae hosts, the distribution contained an excess of deleterious mutations, whereas for the non-Solanaceae the fraction of beneficial mutations was significantly larger. All together, this result suggests that TEV may easily broaden its host range and improve fitness in new hosts, and that knowledge about the DMFE in the natural host does not allow for making predictions about its properties in an alternative host.


Comparative studies of thought disorders. II. Schizoaffective disorder.
We examined thought disorder in 22 patients with schizoaffective disorder (12 schizoaffective-manic and ten schizoaffective-depressed) using Research Diagnostic Criteria. The Thought Disorder Index was used to tag 22 categories of thought disorder that ranged from mild to severe. Qualitative patterns in the thought disorder of schizoaffective patients were compared with those of 20 manic and 43 schizophrenic patients. Manic and schizoaffective-manic patients produced a high number of combinatory responses, but those produced by the schizoaffective-manic patients lacked the humor and playfulness of those of the manics. The schizoaffective-manic patients, like the schizophrenic patients, produced a high number of responses in the categories of idiosyncratic verbalizations, autistic thinking, and confusion. Unlike the manic patients, schizoaffective-depressed patients generally produced a few absurd and idiosyncratic responses in a setting of constricted output. The data strongly suggest that the thinking disorders of schizoaffective patients are like those of the schizophrenic patients.


Transcranial magnetic stimulation: A potential new treatment for depression associated with traumatic brain injury.
Each year, more than 1.7 million Americans suffer a traumatic brain injury (TBI) and the lifetime prevalence of major depressive disorder following TBI is between 25-50%. There are no validated established strategies to treat TBI depression. Repetitive transcranial magnetic stimulation (rTMS) is a novel putative treatment option for post-TBI depression, which, compared with standard pharmacological agents, may provide a more targeted treatment with fewer side-effects. However, TBI is associated with an increased risk of both early and late spontaneous seizures, a significant consideration in evaluating rTMS as a potential treatment for TBI depression. Whilst the risk of seizure from rTMS is low, underlying neuropathology may somewhat increase that risk. This review focuses on the safety aspects of rTMS in TBI patients. The authors review why low frequency rTMS might be less likely to trigger a seizure than high frequency rTMS and propose low frequency rTMS as a safer option in TBI patients. Because there is little data on the safety of rTMS in TBI, the authors also review the safety of rTMS in patients with other brain pathology. It is concluded that pilot safety and tolerability studies should be first conducted in persons with TBI and neuropsychiatric comorbidities. These results could be used to help design larger randomized controlled trials.


The adult with congenital heart disease: cardiac catheterization as a therapeutic intervention.
The adult with congenital heart disease who undergoes cardiac catheterization at the present time is most likely to have complex heart disease and is left with clinically important sequelae or residual defects, ventricular dysfunction or arrhythmias. Residual defects such as paravalvular leaks, coronary fistulas and pulmonary artery narrowings may be corrected with transcatheter techniques. Patients with simple forms of congenital heart disease (for example, atrial septal defect, patent ductus arteriosus, aortic valve stenosis, pulmonary valve stenosis) will go to the catheterization laboratory for treatment, not diagnosis. Certain lesions previously considered benign (for example, patent foramen ovale) may require definitive interventional therapy to reduce the risk of stroke from paradoxic embolism.


Adenosine, lidocaine, and Mg2+ (ALM): From cardiac surgery to combat casualty care--Teaching old drugs new tricks.
New frontline drugs and therapies are urgently required to protect the body from primary and secondary injuries. We review more than 10 years of work on adenosine, lidocaine, and magnesium (ALM) and its possible significance to civilian and military medicine. Adenosine is an endogenous nucleoside involved in nucleotide production, adenosine triphosphate turnover, and restoration of supply and demand imbalances. Lidocaine is a local anesthetic and Class 1B antiarrhythmic, and magnesium is essential for ionic regulation and cellular bioenergetics. Individually, each plays important roles in metabolism, immunomodulation, inflammation, and coagulation. The original idea to combine all three was as a "polarizing" cardioplegia, an idea borrowed from natural hibernators. Two recent prospective, randomized human trials have demonstrated its safety and superiority in myocardial protection over high-potassium "depolarizing" solutions. The next idea came from witnessing how the human heart spontaneously reanimated after complex operations with little inotropic support. At high doses, ALM arrests the heart, and at lower doses, it resuscitates the heart. In rat and pig models, we have shown that ALM intravenous bolus and infusion "drip" protects against acute regional myocardial ischemia, lethal arrhythmias, cardiac arrest, compressible and noncompressible blood loss and shock, endotoxemia, and sepsis. Individually, adenosine, lidocaine, or magnesium fails to protect. Protection is afforded in part by reducing inflammation, correcting coagulopathy, and lowering energy demand. We propose a unifying hypothesis involving improved central, cardiovascular and endothelium coupling to maintain sufficient tissue oxygenation and reduce primary and secondary "hit" complications. As with any new drug innovation, translation into humans is challenging.


Low CD4/CD8 Ratio Is Associated with Non AIDS-Defining Cancers in Patients on Antiretroviral Therapy: ANRS CO8 (Aproco/Copilote) Prospective Cohort Study.
To study the association between CD4/CD8 ratio and morbidity in HIV-infected patients on antiretroviral therapy (ART). The APROCO/COPILOTE cohort enrolled patients initiating a protease inhibitor-containing ART in 1997-1999. The association between occurrence of first non AIDS-defining severe events (NADE) and time-dependent measures of immune restoration was assessed by 4 Cox models with different definitions of restoration, CD4+ cell counts (CD4), CD4/CD8 ratio, both CD4 and CD4/CD8 ratio, or a composite variable (CD4< 500/mm3, CD4 > 500/mm3 and CD4/CD8 ratio < 1, CD4 > 500/mm3 and CD4/CD8 ratio > 1). Models adjusted on baseline characteristics and time-dependent viral load were compared using Akaike Information Criterion. We included 1227 patients. Median duration of follow-up was 9.2 years (IQR: 4.2-11.4). Median CD4 was 530/mm3 at 9 years. Median CD4/CD8 ratio was 0.3 (IQR: 0.2-0.5) at baseline and 0.6 (IQR: 0.4-0.9) after 9 years. Incidence of first NADE was 7.4/100 person-years, the most common being bacterial infections (21%), cardiovascular events (14%) and cancers (10%). For both bacterial infections and cardiovascular events, the CD4/CD8 ratio did not add predictive information to the CD4 cell count. However, low CD4/CD8 ratio was the best predictor of non-AIDS cancers (adjusted HR = 2.13 for CD4/CD8 < 0.5; 95% CI = 1.32-3.44). CD4/CD8 ratio remains < 1 in most HIV-infected patients despite long-term CD4+ cell counts restoration on ART. A CD4/CD8 ratio < 0.5 could identify patients who require a more intensive strategy of cancer prevention or screening.


Separate motion-detecting mechanisms for first- and second-order patterns revealed by rapid forms of visual motion priming and motion aftereffect.
Fast adaptation biases the perceived motion direction of a subsequently presented ambiguous test pattern (R. Kanai & F. A. Verstraten, 2005). Depending on both the duration of the adapting stimulus (ranging from tens to hundreds of milliseconds) and the duration of the adaptation-test blank interval, the perceived direction of an ambiguous test pattern can be biased towards the same or the opposite direction of the adaptation pattern, resulting in rapid forms of motion priming or motion aftereffect respectively. These findings were obtained employing drifting luminance gratings. Many studies have shown that first-order motion (luminance-defined) and second-order motion (contrast-defined) stimuli are processed by separate mechanisms. We assessed whether these effects also exist within the second-order motion domain. Results show that fast adaptation to second-order motion biases the perceived direction of a subsequently presented second-order ambiguous test pattern with similar time courses to that obtained for first-order motion. To assess whether a single mechanism could account for these results, we ran a cross-order adaptation condition. Results showed little or no transfer between the two motion cues and probes, suggesting a degree of separation between the neural substrates subserving fast adaptation of first- and second-order motion.


The effect of diagnosis, age, and symptom severity on cortical surface area in the cingulate cortex and insula in autism spectrum disorders.
Functional activity in the anterior cingulate cortex and insula has been reported to be abnormal during social tasks in autism spectrum disorders. However, few studies have examined surface morphometry in these regions and how this may be related to autism spectrum disorder symptomatology. In this study, 27 individuals with autism spectrum disorders and 25 controls between the ages of 7 to 39 years underwent structural magnetic resonance imaging. Our primary analysis examined differences in surface area in the cingulate and insula, between individuals with and without autism spectrum disorders, as well as age-related changes and associations with social impairments. Surface area in the right cingulate was significantly different between groups and decreased more rapidly with age in autism spectrum disorder participants. In addition, greater surface area in the insula and isthmus was associated with poorer social behaviors. Results suggest atypical surface morphometry in brain regions involved in social function, which appeared to be related to poorer social ability scores.


Neuroprotective effects of an herbal medicine, Yi-Gan San on MPP+/MPTP-induced cytotoxicity in vitro and in vivo.
A traditional herb, Yi-Gan San, has been widely used for the management of neurodegenerative disorders in traditional East Asian Medicine. The present study investigated the neuroprotective effects of Yi-Gan San in 1-methyl-4-phenylpyridine/1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced cytotoxicity in vitro and in vivo and sought to clarify its underlying mechanisms. The effect of Yi-Gan San on 1-methyl-4-phenylpyridine was measured in terms of 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assays, caspase-3 activity, and western blot analysis of phosphorylated Akt, one of the survival-related signaling proteins in SH-SY5Y cells. The effects of Yi-Gan San were also confirmed in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinsonian mouse model using a rotarod test and tyrosine hydroxylase-immunohistochemistry. Pretreatment of Yi-Gan San with 1-methyl-4-phenylpyridine showed a significant protective effect on SH-SY5Y cells and significantly decreased the level of caspase-3 activity compared to the values for the 1-methyl-4-phenylpyridine-treated cells. This process increased the protein expressions of phosphorylated Akt, and an inhibitor of phosphatidylinositol 3-kinase (PI3K)/Akt, LY294002, significantly decreased this protective effect of Yi-Gan San. In the mouse Parkinson's disease model, treatment with Yi-Gan San also significantly improved motor functioning and prevented dopaminergic loss related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine challenge. Using both in vitro and in vivo methods, this study revealed that Yi-Gan San has neuroprotective effects and rescues dopaminergic neurons from 1-methyl-4-phenylpyridine/1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity, possibly via the PI3K/Akt pathway.


Climate controls over ecosystem metabolism: insights from a fifteen-year inductive artificial neural network synthesis for a subalpine forest.
Eddy covariance (EC) datasets have provided insight into climate determinants of net ecosystem productivity (NEP) and evapotranspiration (ET) in natural ecosystems for decades, but most EC studies were published in serial fashion such that one study's result became the following study's hypothesis. This approach reflects the hypothetico-deductive process by focusing on previously derived hypotheses. A synthesis of this type of sequential inference reiterates subjective biases and may amplify past assumptions about the role, and relative importance, of controls over ecosystem metabolism. Long-term EC datasets facilitate an alternative approach to synthesis: the use of inductive data-based analyses to re-examine past deductive studies of the same ecosystem. Here we examined the seasonal climate determinants of NEP and ET by analyzing a 15-year EC time-series from a subalpine forest using an ensemble of Artificial Neural Networks (ANNs) at the half-day (daytime/nighttime) time-step. We extracted relative rankings of climate drivers and driver-response relationships directly from the dataset with minimal a priori assumptions. The ANN analysis revealed temperature variables as primary climate drivers of NEP and daytime ET, when all seasons are considered, consistent with the assembly of past studies. New relations uncovered by the ANN approach include the role of soil moisture in driving daytime NEP during the snowmelt period, the nonlinear response of NEP to temperature across seasons, and the low relevance of summer rainfall for NEP or ET at the same daytime/nighttime time step. These new results offer a more complete perspective of climate-ecosystem interactions at this site than traditional deductive analyses alone.


Development of ramulosis disease of cotton under controlled environment and field conditions.
Colletotrichum gossypii var. cephalosporioides, the fungus that causes ramulosis disease of cotton, is widespread in Brazil and can cause severe yield loss. Because weather conditions greatly affect disease development, the objective of this work was to develop weather-based models to assess disease favorability. Latent period, incidence, and severity of ramulosis symptoms were evaluated in controlled environment experiments using factorial combinations of temperature (15, 20, 25, 30, and 35 degrees C) and leaf wetness duration (0, 4, 8, 16, 32, and 64 h after inoculation). Severity was modeled as an exponential function of leaf wetness duration and temperature. At the optimum temperature of disease development, 27 degrees C, average latent period was 10 days. Maximum ramulosis severity occurred from 20 to 30 degrees C, with sharp decreases at lower and higher temperatures. Ramulosis severity increased as wetness periods were increased from 4 to 32 h. In field experiments at Piracicaba, São Paulo State, Brazil, cotton plots were inoculated (10(5) conidia ml(-1)) and ramulosis severity was evaluated weekly. The model obtained from the controlled environment study was used to generate a disease favorability index for comparison with disease progress rate in the field. Hourly measurements of solar radiation, temperature, relative humidity, leaf wetness duration, rainfall, and wind speed were also evaluated as possible explanatory variables. Both the disease favorability model and a model based on rainfall explained ramulosis growth rate well, with R(2) of 0.89 and 0.91, respectively. They are proposed as models of ramulosis development rate on cotton in Brazil, and weather-disease relationships revealed by this work can form the basis of a warning system for ramulosis development.


Care for patients with severe chronic airflow obstruction and respiratory failure.
The successful care of patients with disorders causing chronic airflow obstruction (CAO) and potential chronic respiratory failure and pulmonary heart disease (cor pulmonale) requires the following:1. Recognize CAO as the cause of a patient's problem.2. Describe and measure airflow obstruction and the individual's response to it.3. Undertake therapeutic trials to maximize airflow.4. Teach patients monitoring skills and interventions in order to prevent acute respiratory failure and hospital admission.5. Maintain optimism and interest in the patient's chronic illness, appreciating its impact on the total person and his daily life.


Characterisation of the influence of anti-gastrin, anti-epidermal growth factor, anti-oestradiol, and anti-luteinising hormone releasing hormone antibodies on the proliferation of 27 cell lines from the gastrointestinal tract.
Numerous data from published reports prove that the proliferation of gastrointestinal tumour cell lines are under the control of many hormones or growth factors, or both. Most of these publications report the influence on a very small number of cell lines of one or two such factors only. This work deals with the in vitro characterisation of the influence of the anti-gastrin, the anti-epidermal growth factor (EGF), the anti-oestradiol (E2), and the anti-luteinising hormone releasing hormone (LHRH) antibodies on the proliferation of a large series of gastrointestinal cell lines. Cell proliferation was assessed by means of the colorimetric MTT assay on a series of 27 gastrointestinal cell lines obtained from the American Type Culture Collection (ATCC). Of the 27 cell lines, the anti-gastrin, the anti-EGF, the anti-E2, and the anti-LHRH neutralising antibodies considerably influenced the proliferation of 13, 25, 12, and 16. No gastrointestinal cell line was unresponsive to the four antibodies simultaneously. The anti-gastrin and anti-EGF antibody induced effects on the 27 gastrointestinal cell line proliferation were significantly correlated, as was also the case for the anti-E2 and anti-LHRH antibody induced effects. Of the anti-gastrin, the anti-EGF, the anti-E2, and the anti-LHRH antibodies, it was the anti-EGF one that had the greatest influence, both quantitatively and qualitatively, on gastrointestinal cell proliferation. The correlation of the effects of definite anti-hormone antibodies is suggestive of a common mechanism of action for the corresponding hormones and casts some doubt on the efficiency of anti-hormone monotherapy.


Advice for improving memory: exercising, strengthening, and cultivating natural memory, 1860-1910.
The idea that human memory can be improved appears to be as ancient as the concept of memory itself. For centuries, authors have promised that using artificial mnemonical systems can improve remembering. However, in the late nineteenth century many authors of memory improvement texts emphasized the importance of enhancing natural memory as opposed to developing artificial memory systems. In doing so, they portrayed natural memory as something analogous to other body functions and parts, such as muscles, and promoted a metaphorical view of memory that did not rely wholly on the more familiar root metaphors of storage and inscription. At the same time, they stressed that natural memory could be reconciled with moral purposes, especially through notions of exercise, training, and discipline. This article explores these ideas and how they chimed with Victorian concerns about free will, the education of the young, moral imperatives around self-improvement, and the increasing interest in science and especially a science of the mind.


Dichloroacetate therapy attenuates the blood lactate response to submaximal exercise in patients with defects in mitochondrial energy metabolism.
We determined acute and chronic effects of dichloroacetate (DCA) on maximal (MAX) and submaximal (SUB) exercise responses in patients with abnormal mitochondrial energetics. Subjects (n = 9) completed a MAX treadmill bout 1 h after ingesting 25 mg/kg DCA or placebo (PL). A 15-min SUB bout was completed the next day while receiving the same treatment. After a 1-d washout, MAX and SUB were repeated while receiving the alternate treatment (acute). Gas exchange and heart rate were measured throughout all tests. Blood lactate (Bla) was measured 0, 3, and 10 min after MAX, and 5, 10, and 15 min during SUB. MAX and SUB were repeated after 3 months of daily DCA or PL. After a 2-wk washout, a final MAX and SUB were completed after 3 months of alternate treatment (chronic). Average Bla during SUB was lower (P < 0.05) during both acute (1.99 +/- 1.10 vs. 2.49 +/- 1.52 mmol/liter) and chronic (1.71 +/- 1.37 vs. 2.39 +/- 1.32 mmol/liter) DCA vs. PL despite similar exercise intensities between conditions ( approximately 75 and 70% maximal exercise capacity during acute and chronic treatment). Thus, although DCA does not alter MAX responses, acute and chronic DCA attenuate the Bla response to moderate exercise in patients with abnormal mitochondrial energetics.


The anatomical basis of dystonia: current view using neuroimaging.
This review will consider the knowledge that neuroimaging studies have provided to the understanding of the anatomy of dystonia. Major advances have occurred in the use of neuroimaging for dystonia in the past 2 decades. At present, the most developed imaging approaches include whole-brain or region-specific studies of structural or diffusion changes, functional imaging using fMRI or positron emission tomography (PET), and metabolic imaging using fluorodeoxyglucose PET. These techniques have provided evidence that regions other than the basal ganglia are involved in dystonia. In particular, there is increasing evidence that primary dystonia can be viewed as a circuit disorder, involving the basal ganglia-thalamo-cortical and cerebello-thalamo-cortical pathways. This suggests that a better understanding of the dysfunction in each region in the network and their interactions are important topics to address. Current views of interpretation of imaging data as cause or consequence of dystonia, and the postmortem correlates of imaging data are presented. The application of imaging as a tool to monitor therapy and its use as an outcome measure will be discussed. © 2013 Movement Disorder Society.


Integrated care: a position paper of the WHO European Office for Integrated Health Care Services.
The WHO European Office for Integrated Health Care Services in Barcelona is an integral part of the World Health Organizations' Regional Office for Europe. The main purpose of the Barcelona office is within the integration of services to encourage and facilitate changes in health care services in order to promote health and improve management and patient satisfaction by working for quality, accessibility, cost-effectiveness and participation. This position paper outlines the need for Integrated Care from a European perspective, provides a theoretical framework for the meaning of Integrated Care and its strategies and summarizes the programmes of the office that will support countries in the WHO European Region to improve health services.


Post-Traumatic Stress Symptoms among Lithuanian Parents Raising Children with Cancer.
The study aims to evaluate post-traumatic stress symptom expression among Lithuanian parents raising children with cancer, including social, demographic, and medical factors, and to determine their significance for the risk of developing post-traumatic stress disorder. The study was carried out in two major Lithuanian hospitals treating children with oncologic diseases. The cross-sectional study included 195 parents, out of which 151 were mothers (77.4%) and 44 were fathers (22.6%). Post-traumatic stress symptoms were assessed using the Impact of Event Scale-Revised. To collect the sociodemographic, childhood cancer, and treatment data, we developed a questionnaire that was completed by the parents. Main study results were obtained using multiple linear regression. A total of 75.4% of parents caring for children with cancer had pronounced symptoms of post-traumatic stress disorder. The female gender (β = 0.83, p < 0.001) was associated with an increased manifestation of symptoms, whilst higher parental education (β = -0.21, p = 0.034) and the absence of relapse (β = -0.48, p < 0.001) of the child's disease reduced post-traumatic stress symptom expression. Obtained results confirmed that experiencing a child's cancer diagnosis and treatment is extremely stressful for many parents. This event may lead to impaired mental health and increased post-traumatic stress disorder (PTSD) risk; hence, it is necessary to provide better support and assistance to parents of children with cancer.


A longitudinal cohort study of HIV 'treatment as prevention' in gay, bisexual and other men who have sex with men: the Treatment with Antiretrovirals and their Impact on Positive And Negative men (TAIPAN) study protocol.
Australia has increased coverage of antiretroviral treatment (ART) over the past decade, reaching 73% uptake in 2014. While ART reduces AIDS-related deaths, accumulating evidence suggests that it could also bolster prevention efforts by reducing the risk of HIV transmission ('treatment as prevention'). While promising, evidence of community-level impact of treatment as prevention on reducing HIV incidence among gay and bisexual men is limited. We describe a study protocol that aims to determine if scale up of testing and treatment for HIV leads to a reduction in community viraemia and, in turn, if this reduction is temporally associated with a reduction in HIV incidence among gay and bisexual men in Australia's two most populous states. Over the period 2009 to 2017, we will establish two cohorts making use of clinical and laboratory data electronically extracted retrospectively and prospectively from 73 health services and laboratories in the states of New South Wales and Victoria. The 'positive cohort' will consist of approximately 13,000 gay and bisexual men (>90% of all people living with HIV). The 'negative cohort' will consist of at least 40,000 HIV-negative gay and bisexual men (approximately half of the total population). Within the negative cohort we will use standard repeat-testing methods to calculate annual HIV incidence. Community prevalence of viraemia will be defined as the proportion of men with a viral load ≥200RNA copies/mm3, which will combine viral load data from the positive cohort and viraemia estimates among those with an undiagnosed HIV infection. Using regression analyses and adjusting for behavioural and demographic factors associated with infection, we will assess the temporal association between the community prevalence of viraemia and the incidence of HIV infection. Further analyses will make use of these cohorts to assess incidence and predictors of treatment initiation, repeat HIV testing, and viral suppression. This study will provide important information on whether 'treatment as prevention' is associated with a reduction in HIV incidence at a community level among gay and bisexual men.


Inactivation of the amidotransferase activity of carbamoyl phosphate synthetase by the antibiotic acivicin.
Carbamoyl phosphate synthetase (CPS) from Escherichia coli catalyzes the formation of carbamoyl phosphate from 2 mol of ATP, bicarbonate, and glutamine. CPS was inactivated by the glutamine analog, acivicin. In the presence of ATP and bicarbonate the second-order rate constant for the inactivation of the glutamine-dependent activities was 4.0 x 10(4) m(-1) s(-1). In the absence of ATP and bicarbonate the second-order rate constant for inactivation of CPS was reduced by a factor of 200. The enzyme was protected against inactivation by the inclusion of glutamine in the reaction mixture. The ammonia-dependent activities were unaffected by the incubation of CPS with acivicin. These results are consistent with the covalent labeling of the glutamine-binding site located within the small amidotransferase subunit. The binding of ATP and bicarbonate to the large subunit of CPS must also induce a conformational change within the amidotransferase domain of the small subunit that enhances the nucleophilic character of the thiol group required for glutamine hydrolysis. The acivicin-inhibited enzyme was crystallized, and the three-dimensional structure was determined by x-ray diffraction techniques. The thiol group of Cys-269 was covalently attached to the dihydroisoxazole ring of acivicin with the displacement of a chloride ion.


Manipal Cervical Scoring System by Transvaginal Ultrasound in Predicting Successful Labour Induction.
Induction of labour (IOL) nowadays is a common procedure in obstetric practice. The success of IOL largely depends upon "favourability" or "readiness" cervix which is traditionally assessed by manual examination and Scored as Bishop Score. However, this method is limited by subjectivity and reproducibility and though done in all the patients prior to IOL, several studies have demonstrated poor correlation between Bishop Score and outcome of labour. To evaluate the role of preinduction transvaginal ultrasonographic (TVS) cervical assessment in predicting labour outcome and to compare its performance against Bishop Score in patients undergoing induction of labour (IOL). A tertiary medical college hospital in Southern India. Prospective observational and investigational study. Transvaginal ultrasound was performed in 131 patients who underwent labour induction at term with intact membranes and live fetus. Bishop Score was assessed by pervaginal examination and was compared with preinduction TVS cervical Score (parameters being cervical length, funneling, position of cervix and distance of presenting part from external os). Labour was induced within one hour of cervical assessment. The labour induction was considered successful if patient could get into active labour i.e., onset of regular uterine contractions (at interval of 2-3 minutes) and cervical dilatation of 4 cm or greater within 24 hours of induction. Labour induction was successful in 86.9% of patients. At cut off Scores of ≥ 4, TVS cervical Score performed better than Bishop Score (Sensitivity 77% vs. 65%, Specificity 93% vs. 86%). ROC analysis indicated that Area Under Curve (AUC) was more for TVS Score (0.90, 95% CI 0.84 - 0.95), compared to Bishop Score. It was found that an increase in cervical length and distance from the os by 1 mm from their means were associated with an increase in odds for failure of induction and there by caesarean delivery by 6.5% and 11% respectively. In women experiencing labour induction, transvaginal ultrasound score comprising of five different parameters indicated success of induction better than Bishop Score. Further, two of its components (longer cervical length and increased distance of presenting part from external os) demonstrated significant and independent prediction of the likelihood of failure of induction and risk of operative delivery.


A new mechanism for the low dielectric property of POSS nanocomposites: the key role of interfacial effect.
The low dielectric constant (ε) of polyhedral oligomeric silsesquioxanes (POSS) was generally attributed to its porous structure. In this work, we propose a new mechanism for the low ε of the POSS-based nanocomposites from the interfacial effect point of view. The investigation on a typical nanocomposite, polystyrene/POSS, found that POSS molecules take crystallization to form crystalline nanoplatelets (PCPs) in PS. Correspondingly, the dielectric constant can be reduced to around 2.30. A detailed investigation excluded the possible influence of the chain stacking and chain mobility of the polymers on ε. It was demonstrated, for the first time, that the ε shows a high correlation with interface area which is reflected by a rigid amorphous fraction (RAF), thus revealing the key role of the interfacial effect on reducing the low dielectric constant.


Melt extruded helical waxy matrices as a new sustained drug delivery system.
The aim of this research was to prepare helical and cylindrical extrudates by melt extrusion and to evaluate their potential as sustained release dosage form. The systems contained theophylline as water-soluble model drug and microcrystalline wax as thermoplastic binder. The temperature suitable to ensure a successful extrusion process of formulations containing the wax in three different percentages was found to be below the melting point of the excipient. After the production of the extrudates in three different helical shapes (having 2, 3 and 4 blades) and a classical cylindrical shape, the systems were studied by means of X-ray powder diffraction and differential scanning calorimetry to check possible variations of the solid state of the drug during the thermal process. The morphology and chemical composition of the surface of the extrudates were examined by Scanning Electron Microscopy/Energy Dispersive X-ray Microanalysis to evaluate the presence of the drug on the surface of the extrudates and to monitor changes on the aspect of the waxy matrix during dissolution. Then, the different systems were analysed from the in vitro dissolution point of view to study the influence of the shape and of the composition on the drug release. An in vivo pilot study on the best performing system (helix with 3 blades) was carried out on five healthy volunteers and monitoring the intestinal transit by X-ray images. The resulting plasma profiles were analysed by means of a suitable pharmacokinetic analysis. Finally, an ad hoc mathematical model was developed to perform an accurate description of the in vitro release and in vivo performance of the 3-blades helical system.


Estimating the incidence of coeliac disease with capture-recapture methods within four geographic areas in Italy.
To estimate the incidence rate of newly diagnosed cases of coeliac disease in Italy. This was a descriptive study of coeliac disease incidence in the period 1990-91. During 1990-91 newly diagnosed cases of coeliac disease were signalled by several sources including diagnostic records of departments of paediatrics, general medicine and gastroenterology, national health service records for the supply of gluten free diets and the archives of the Italian Coeliac Society. Altogether 1475 cases were flagged throughout Italy, 478 of whom were selected, corresponding to 270 individual patients from a target population resident in four areas: Provices of Turin and Cuneo (Piedmont Region, northern Italy); Province of Brescia (Lombardia Region, northern Italy); Umbria Region (central Italy) and Sardinia Region (insular Italy). Only for these areas were patients flagged from several sources and the reference population was identifiable. The overall crude incidence rates for all ages per 100,000 residents per year were 2.4, 2.7, 1.5, and 1.7 in the four areas, respectively. The childhood cumulative incidence rates (aged < or = 15 years) per 100,000 live births were 143, 141, 72, and 80 respectively. The mean ages at diagnosis were similar for both childhood and adult cases throughout the areas--these were around 4 and 34 years respectively. For each area, the incidence rate was constantly higher in the main city than elsewhere. Using the capture-recapture method, an estimated completeness of case archives of 0.84 was obtained, whereas this figure was only 0.47 for hospital sources. This population based study on the incidence of coeliac disease shows that several information sources should be used to avoid underestimation. The incidence rate of coeliac disease in Italy was among the highest in Europe, and was widely variable showing highest figures in Piedmont and Lombardia and the lowest in Umbria and Sardinia. This trend was not due to different age at diagnosis, which suggests variable diagnostic awareness of the disease rather than different environmental patterns affecting the clinical presentation.


In vivo and real-time measurement of magnetic nanoparticles distribution in animals by scanning SQUID biosusceptometry for biomedicine study.
Magnetic nanoparticles have been widely applied to biomagnetism, such as drug deliver, magnetic labeling, and contrast agent for in vivo image, etc. To localize the distribution of these magnetic particles in living organism is the first important issue to confirm the effects of magnetic nanoparticles and also evaluate the possible untoward effects. In this study, a scanning high T(c) rf-SQUID superconducting quantum interference devices (SQUIDs) biosusceptometry, composed of static SQUID unit and scanning coil sets, is developed for biomedicine study with the advantages of easy operation and unshielded environment. The characteristics tests showed that the system had the low noise of 8 pT/Hz at 400 Hz and the high sensitivity with the minimum detectable magnetization around 4.5 × 10(-3) EMU at distance of 13 mm. A magnetic nanoparticle detection test, performed by ex vivo scanning of the magnetic fluids filled capillary under swine skin for simulation of blood vessels in living bodies, confirmed that the system is feasible for dynamic tracking of magnetic nanoparticles. Based on this result, we performed further studies in rats to clarify the dynamic distribution of magnetic nanoparticle in living organism for the pharmacokinetics analysis like drug delivers, and propose the possible physiological metabolism of intravenous magnetic nanoparticles.


Role of Emergency Laparoscopic Colectomy for Colorectal Cancer: A Population-based Study in England.
To evaluate factors associated with the use of laparoscopic surgery and the associated postoperative outcomes for urgent or emergency resection of colorectal cancer in the English National Health Service. Laparoscopy is increasingly used for elective colorectal cancer surgery, but uptake has been limited in the emergency setting. Patients recorded in the National Bowel Cancer Audit who underwent urgent or emergency colorectal cancer resection between April 2010 and March 2016 were included. A multivariable multilevel logistic regression model was used to estimate odds ratios (ORs) of undergoing laparoscopic resection and postoperative outcome according to approach. There were 15,516 patients included. Laparoscopy use doubled from 15.1% in 2010 to 30.2% in 2016. Laparoscopy was less common in patients with poorer physical status [American Society of Anaesthesiologists (ASA) 4/5 vs 1, OR 0.29 (95% confidence interval, 95% CI 0.23-0.37), P < 0.001] and more advanced T-stage [T4 vs T0-T2, OR 0.28 (0.23-0.34), P < 0.001] and M-stage [M1 vs M0, OR 0.85 (0.75-0.96), P < 0.001]. Age, socioeconomic deprivation, nodal stage, hospital volume, and a dedicated colorectal emergency service were not associated with laparoscopy. Laparoscopic patients had a shorter length of stay [median 8 days (interquartile range (IQR) 5 to 15) vs 12 (IQR 8 to 21), adjusted mean difference -3.67 (-4.60 to 2.74), P < 0.001], and lower 90-day mortality [8.1% vs 13.0%; adjusted OR 0.78 (0.66-0.91), P = 0.004] than patients undergoing open resection. There was no significant difference in rates of readmission or reoperation by approach. The use of laparoscopic approach in the emergency resection of colorectal cancer is linked to a shorter length of hospital stay and reduced postoperative mortality.


Cyclic conductance switching in networks of redox-active molecular junctions.
Redox-active dithiolated tetrathiafulvalene derivatives (TTFdT) were inserted in two-dimensional nanoparticle arrays to build interlinked networks of molecular junctions. Upon oxidation of the TTFdT to the dication state, we observed a conductance increase of the networks by up to 1 order of magnitude. Successive oxidation and reduction cycles demonstrated a clear switching behavior of the molecular junction conductance. These results show the potential of interlinked nanoparticle arrays as chemical sensors.


Prescription opioid dependence is associated with poorer outcomes in disabling spinal disorders.
Prospective outcomes study involving patients with chronic disabling occupational spinal disorders (CDOSD) diagnosed with (n = 199) or without (n = 1124) postinjury opioid-dependence disorder (ODD), based on the Diagnostic and Statistical Manual of Mental Disorders-fourth edition cirteria. To determine whether prescription opioid dependence, assessed at the beginning of rehabilitation treatment, is associated with poorer treatment outcomes in patients with CDOSDs attending an interdisciplinary rehabilitation program. Controversy exists regarding the risk of iatrogenic ODD and treatment outcomes when long-term opioid therapy is used in the treatment of chronic nonmalignant pain conditions. A consecutive sample of patients with CDOSDs [n = 1323; mean (SD) length of disability = 18.8 (20.7) months] attending a tertiary referral center received intensive physical reactivation and pain/disability management interventions, based on a functional restoration model, including detoxification from opioids. One-year outcomes included return to work, work retention, healthcare utilization, new surgeries, recurrent injuries, and disability claim settlement. Prevalence of ODD in this CDOSD population on entering the rehabilitation program was 15%. Even after adjusting for relevant demographic factors and comorbid psychiatric disorders, opioid-dependent patients were 1.7 times [95% confidence interval (CI): 1.0, 2.7] less likely to return to work, 2 times (95% CI: 1.3, 3.0) less likely to retain work at the 1-year interview, and 1.7 times (95% CI: 1.2, 2.5) more likely to engage in healthcare utilization from new providers, compared with nonopioid-dependent patients. Iatrogenic prescription opioid dependence may be a risk factor for less successful long-term work and health outcomes, even after detoxification from opioids as part of an interdisciplinary functional rehabilitation program. Chronic prescription opioid dependence in this patient population is also associated with a significantly higher prevalence of comorbid psychiatric conditions, both axis I and II.


Polycystin 1 is required for the structural integrity of blood vessels.
Autosomal dominant polycystic kidney disease (ADPKD), often caused by mutations in the PKD1 gene, is associated with life-threatening vascular abnormalities that are commonly attributed to the frequent occurrence of hypertension. A previously reported targeted mutation of the mouse homologue of PKD1 was not associated with vascular fragility, leading to the suggestion that the vascular lesion may be of a secondary nature. Here we demonstrate a primary role of PKD1 mutations in vascular fragility. Mouse embryos homozygous for the mutant allele (Pkd1(L)) exhibit s.c. edema, vascular leaks, and rupture of blood vessels, culminating in embryonic lethality at embryonic day 15.5. Kidney and pancreatic ductal cysts are present. The Pkd1-encoded protein, mouse polycystin 1, was detected in normal endothelium and the surrounding vascular smooth muscle cells. These data reveal a requisite role for polycystin 1 in maintaining the structural integrity of the vasculature as well as epithelium and suggest that the nature of the PKD1 mutation contributes to the phenotypic variance in ADPKD.


Hybrid atomistic-coarse-grained treatment of multiscale processes in heterogeneous materials: a self-consistent-field approach.
A treatment of multiscale quasistatic processes that combines an atomistic description of microscopic heterogeneous ("near") regions of a material with a coarse-grained (quasicontinuum) description of macroscopic homogeneous ("far") regions is presented. The hybrid description yields a reduced system consisting of the original atoms of the near regions plus pseudoatoms (nodes of the coarse-graining mesh) of the far regions, which interact through an effective many-body potential energy V(eff) that depends on the thermodynamic state. The approximate nature of V(eff) gives rise to "ghost forces," which are reflected in spurious heterogeneities close to interfaces between near and far regions. The impact of ghost forces, which afflict all previous hybrid schemes, is greatly diminished by a self-consistent-field hybrid atomistic-coarse-grained (SCF-HACG) methodology. Tests of the SCF-HACG technique on a fully three-dimensional prototypal model [Lennard-Jones (12,6) crystal] yield thermomechanical properties (e.g., local stress) in good agreement with "exact" properties computed in the fully atomistic limit. The SCF-HACG method is also successfully used to characterize the grain boundary in a Lennard-Jones bicrystal.


The cellular distribution of extracellular superoxide dismutase in macrophages is altered by cellular activation but unaffected by the naturally occurring R213G substitution.
Extracellular superoxide dismutase (EC-SOD) is responsible for the dismutation of the superoxide radical produced in the extracellular space and known to be expressed by inflammatory cells, including macrophages and neutrophils. Here we show that EC-SOD is produced by resting macrophages and associated with the cell surface via the extracellular matrix (ECM)-binding region. Upon cellular activation induced by lipopolysaccharide, EC-SOD is relocated and detected both in the cell culture medium and in lipid raft structures. Although the secreted material presented a significantly reduced ligand-binding capacity, this could not be correlated to proteolytic removal of the ECM-binding region, because the integrity of the material recovered from the medium was comparable to that of the cell surface-associated protein. The naturally occurring R213G amino acid substitution located in the ECM-binding region of EC-SOD is known to affect the binding characteristics of the protein. However, the analysis of macrophages expressing R213G EC-SOD did not present evidence of an altered cellular distribution. Our results suggest that EC-SOD plays a dynamic role in the inflammatory response mounted by activated macrophages.


Bidirectional reaction steps in metabolic networks: III. Explicit solution and analysis of isotopomer labeling systems.
The last few years have brought tremendous progress in experimental methods for metabolic flux determination by carbon-labeling experiments. A significant enlargement of the available measurement data set has been achieved, especially when isotopomer fractions within intracellular metabolite pools are quantitated. This information can be used to improve the statistical quality of flux estimates. Furthermore, several assumptions on bidirectional intracellular reaction steps that were hitherto indispensable may now become obsolete. To make full use of the complete measurement information a general mathematical model for isotopomer systems is established in this contribution. Then, by introducing the important new concept of cumomers and cumomer fractions, it is shown that the arising nonlinear isotopomer balance equations can be solved analytically in all cases. In particular, the solution of the metabolite flux balances and the positional carbon-labeling balances presented in part I of this series turn out to be just the first two steps of the general solution procedure for isotopomer balances. A detailed analysis of the isotopomer network structure then opens up new insights into the intrinsic structure of isotopomer systems. In particular, it turns out that isotopomer systems are not as complex as they appear at first glance. This enables some far-reaching conclusions to be drawn on the information potential of isotopomer experiments with respect to flux identification. Finally, some illustrative examples are examined to show that an information increase is not guaranteed when isotopomer measurements are used in addition to positional enrichment data.


Alpha 4 integrin-dependent leukocyte recruitment does not require VCAM-1 in a chronic model of inflammation.
Rats immunized with Mycobacterium butyricum in Freund's adjuvant develop a chronic vasculitis, with large increases in leukocyte rolling and adhesion in mesenteric postcapillary venules that are significantly inhibited with an alpha 4 integrin Ab. Using intravital microscopy to visualize chronically inflamed microvessels, we demonstrated that alpha 4 integrin-dependent leukocyte rolling and adhesion was inhibited with a beta 1 integrin, but not a beta 7 integrin Ab. To date, VCAM-1 has been presumed to be the primary ligand for alpha 4 beta 1 integrin in the vasculature. However, alpha 4 beta 1 integrin-dependent interactions were not reduced by monoclonal or polyclonal VCAM-1 Abs or a VCAM-1 antisense oligonucleotide despite increased VCAM-1 expression in the mesenteric vasculature. To ensure that the VCAM-1 Abs were functional and used at saturating concentrations, blood from Ab-treated rats was perfused over monolayers of CHO cells transfected with rat VCAM-1. Sufficient alpha 4 integrin or VCAM-1 Ab was present to inhibit leukocyte interactions with rat VCAM-1 by 95-100%. Under in vitro flow conditions, only mononuclear leukocytes were recruited from blood of control rats onto purified VCAM-1. However, neutrophils were also recruited onto VCAM-1 from whole blood of adjuvant-immunized animals via alpha 4 integrin. Another ligand for alpha 4 beta 1 integrin is the connecting segment-1 (CS-1) region of fibronectin. An Ab to the CS-1 portion of fibronectin, which did not reduce rolling and adhesion in adjuvant arthritis animals, completely inhibited leukocyte adhesion to CS-1 under static conditions. These findings provide the first evidence that alpha 4 beta 1 integrin-dependent leukocyte rolling and adhesion can occur in vivo via a mechanism other than VCAM-1.


Sex-related differences in COPD in five Latin American cities: the PLATINO study.
There is evidence to suggest sex differences exists in chronic obstructive pulmonary disease (COPD) clinical expression. We investigated sex differences in health status perception, dyspnoea and physical activity, and factors that explain these differences using an epidemiological sample of subjects with and without COPD. PLATINO is a cross-sectional, population-based study. We defined COPD as post-bronchodilator forced expiratory volume in 1 s/forced vital capacity ratio <0.70, and evaluated health status perception (Short Form (SF)-12 questionnaire) and dyspnoea (Medical Research Council scale). Among 5,314 subjects, 759 (362 females) had COPD and 4,555 (2,850 females) did not. In general, females reported more dyspnoea and physical limitation than males. 54% of females without COPD reported a dyspnoea score ≥ 2 versus 35% of males. A similar trend was observed in females with COPD (63% versus 44%). In the entire study population, female sex was a factor explaining dyspnoea (OR 1.60, 95%CI 1.40-1.84) and SF-12 physical score (OR -1.13, 95%CI -1.56- -0.71). 40% of females versus 28% of males without COPD reported their general health status as fair-to-poor. Females with COPD showed a similar trend (41% versus 34%). Distribution of COPD severity was similar between sexes, but currently smoking females had more severe COPD than currently smoking males. There are important sex differences in the impact that COPD has on the perception of dyspnoea, health status and physical activity limitation.


Eastern Carolina Asthma Prevention Program (ECAPP): An Environmental Intervention Study Among Rural and Underserved Children with Asthma in Eastern North Carolina.
Asthma is the most common chronic childhood condition affecting 6.3 million (US) children aged less than 18 years. Home-based, multi-component, environmental intervention studies among children with asthma have demonstrated to be effective in reducing asthma symptoms. In this study, a local hospital and university developed an environmental intervention research pilot project, Eastern Carolina Asthma Prevention Program (ECAPP), to evaluate self-reported asthma symptoms, breathing measurements, and number of asthma-related emergency department (ED) visits among low-income, minority children with asthma living in rural, eastern North Carolina. Our goal was to develop a conceptual model and demonstrate any asthma respiratory improvements in children associated with our home-based, environmental intervention. This project used a single cohort, intervention design approach to compare self-reported asthma-related symptoms, breathing tests, and ED visits over a 6 month period between children with asthma in an intervention study group (n = 12) and children with asthma in a control study group (n = 7). The intervention study group received intense asthma education, three home visits, 2 week follow-up telephone calls, and environmental intervention products for reducing asthma triggers in the home. The control group received education at baseline and 2 week calls, but no intervention products. At the end of the study period, significant improvements were observed in the intervention group compared with the control group. Overall, the intervention group experienced a 58% (46 ± SD 26.9) reduction in self-reported asthma symptoms; 76% (34 ± SD 29.7) decrease in rescue medicine; 12% (145 ± SD 11.3) increase in controller medicine; 37% decrease in mean exhaled nitric oxide levels and 33% fewer ED asthma-related visits. As demonstrated, a combination of efforts appeared effective for improving asthma respiratory symptoms among children in the intervention group. ECAPP is a low cost pilot project that could readily be adapted and expanded into other communities throughout eastern North Carolina. Future efforts could include enhanced partnerships between environmental health professionals at local health departments and pediatric asthma programs at hospitals to carry out ECAPP.


Assessment of normal flow patterns in the pulmonary circulation by using 4D magnetic resonance velocity mapping.
The purpose of this study was to analyze flow patterns in the pulmonary circulation of healthy volunteers by using 4D flow magnetic resonance imaging. The study was approved by the local ethics committee and all subjects gave written informed consent. Eighteen volunteers underwent a 4D flow scan of the whole-heart. Two patients with congenital heart disease were also included to detect possible patterns of flow abnormalities (Patient 1: corrected transposition of great arteries (TGA); Patient 2: partial anomalous pulmonary venous return and atrial septal defect). To analyze flow patterns, 2D planes were placed on the main pulmonary artery (PA), left and right PA. Flow patterns were assessed manually by two independent viewers using vector fields, streamlines and particle traces, and semi-automatically by vorticity quantification. Two counter-rotating helices were found in the main PA of volunteers. Right-handed helical flow was detected in the right PA of 15 volunteers. Analysis of the helical flow by particles traces revealed that both helices contributed mainly to the flow in the right PA. In the patient with corrected TGA helical flow was not detected. Abnormal vortical flow was visualized in the main PA of patient 2, suggesting elevated mean PA pressure. Helical flow is normally present in the main PA and right PA. 4D flow is an excellent tool to evaluate noninvasively complex blood flow patterns in the pulmonary circulation. Knowledge of normal and abnormal flow patterns might help to evaluate patients with congenital heart disease adding functional information undetectable with other imaging modalities.


Using hypnosis to accelerate the healing of bone fractures: a randomized controlled pilot study.
Hypnosis has been used in numerous medical applications for functional and psychological improvement, but has been inadequately tested for anatomical healing. To determine whether a hypnotic intervention accelerates bodily tissue healing using bone fracture healing as a site-specific test. Randomized controlled pilot study. Massachusetts General Hospital, Boston, Mass, and McLean Hospital, Belmont, Mass. Twelve healthy adult subjects with the study fracture were recruited from an orthopedic emergency department and randomized to either a treatment (n = 6) or a control group (n = 6). One subject, randomized to the treatment group, withdrew prior to the intervention. All 11 subjects received standard orthopedic care including serial radiographs and clinical assessments through 12 weeks following injury. The treatment group received a hypnotic intervention (individual sessions, audiotapes) designed to augment fracture healing. Radiological and orthopedic assessments of fracture healing 12 weeks following injury and hypnotic subjects' final questionnaires and test scores on the Hypnotic Induction Scale. Results showed trends toward faster healing for the hypnosis group through week 9 following injury. Objective radiographic outcome data revealed a notable difference in fracture edge healing at 6 weeks. Orthopedic assessments showing trends toward better healing for hypnosis subjects through week 9 included improved ankle mobility; greater functional ability to descend stairs; lower use of analgesics in weeks 1, 3, and 9; and trends toward lower self-reported pain through 6 weeks. Despite a small sample size and limited statistical power, these data suggest that hypnosis may be capable of enhancing both anatomical and functional fracture healing, and that further investigation of hypnosis to accelerate healing is warranted.