Investigation of host factors possibly enhancing the emergence of the chondroitin sulfate A-binding phenotype in Plasmodium falciparum.
In malaria endemic areas, regardless of immunity acquired during lifelong exposure to malaria, pregnant women become susceptible to Plasmodium falciparum infections. Malaria during pregnancy is associated with a massive sequestration of infected erythrocytes in the placenta and the emergence of a unique parasite-derived adhesive molecule (encoded by var2CSA) that binds to chondroitin sulfate A (CSA). How P. falciparum achieves the timely expression of the CSA ligand in pregnant women remains puzzling. We investigated whether host serum-specific factors present only during pregnancy may induce var2CSA expression. Our panel of experiments did not reveal significant changes in var2CSA levels and CSA-binding capacity.


Carbapenems versus alternative antibiotics for the treatment of bacteraemia due to Enterobacteriaceae producing extended-spectrum β-lactamases: a systematic review and meta-analysis.
To study the comparative mortality associated with carbapenems and alternative antibiotics for the treatment of patients with extended-spectrum β-lactamase (ESBL)-positive Enterobacteriaceae bacteraemia. We searched systematically PubMed and Scopus databases for studies providing data for mortality among patients treated with carbapenems, β-lactam/β-lactamase inhibitor combinations (BL/BLIs) or non-BL/BLIs (mainly cephalosporins and fluoroquinolones), preferably as monotherapy. Studies focusing on patients of all ages with community- and healthcare-associated bacteraemia were eligible. Data were pooled using the technique of meta-analysis. Twenty-one articles, studying 1584 patients, were included. Escherichia coli and Klebsiella pneumoniae were the most commonly studied bacteria. Delay in appropriate treatment up to 6 days was reported. Carbapenems were used mainly as definitive therapy. Carbapenems were associated with lower mortality than non- BL/BLIs for definitive [risk ratio (RR) 0.65, 95% CI 0.47-0.91] and empirical (RR 0.50, 95% CI 0.33-0.77) treatment. No statistically significant differences in mortality were found between carbapenems and BL/BLIs administered as definitive (RR 0.52, 95% 0.23-1.13) or empirical (RR 0.91, 95% CI 0.66-1.25) treatment. BL/BLIs were not associated with lower mortality than non-BL/BLIs administered either definitively (RR 1.59, 95% 0.83-3.06) or empirically (RR 0.82, 95% 0.48-1.41). Data regarding subgroups according to the setting, comorbidity and bacterial species could not be extracted. Based on data from non-randomized studies, carbapenems may be considered the treatment of choice for empirical treatment of patients with ESBL-producing Enterobacteriaceae bacteraemia. The role of BL/BLIs should be further evaluated for definitive treatment. Further research should focus on faster identification of ESBL-positive pathogens and potential differences in the treatment of each bacterial species.


Natural history and prognostic factors for chronic hepatitis type B.
One hundred and five hepatitis B surface antigen (HBsAg) positive patients presenting with chronic persistent hepatitis (n = 46) or chronic active hepatitis without cirrhosis (n = 59) were followed longitudinally for one to 16 years (mean 5.5 years) and underwent follow up biopsy. During a mean histological follow up of 3.7 years, active cirrhosis developed in 21 (20%) patients one to 13 years after entry to the study with a calculated annual incidence of 5.9%. The probability of evolution to cirrhosis was significantly higher in patients with chronic active hepatitis and bridging hepatic necrosis than in those with moderate chronic active hepatitis or chronic persistent hepatitis (p less than 0.0001). Cox multiple regression analysis showed that the following three variables independently implied poor prognosis: older age, presence of bridging hepatic necrosis, and persistence of hepatitis B virus DNA in serum (p less than 0.0001). These findings indicate that patients with severe chronic active hepatitis and persistent hepatitis B virus replication are at very high risk of rapid progression to cirrhosis.


Are local health department expenditures related to racial disparities in mortality?
This study estimated whether 1990-1997 changes in expenditures per capita of local health departments (LHDs) and percentage share of local public revenue allocated to LHDs were associated inversely with 1990-1997 changes in mortality rates for Black and White racial/ethnic groups in the US. Population was 883 local jurisdictions with 1990 and 1997 mortality rates for Black and White racial populations from the Centers for Disease Control and Prevention Wonder Compressed Mortality File and LHD expenditures from the National Association of County and City Health Officials. Using a time-trend ecologic design, changes in LHD expenditures per capita and percentage share of public revenue were not related to reductions in Black/White disparities in total, all-cause mortality rates. Increased LHD expenditures or percentage share were associated with reduced Black/White disparities for adults aged 15-44 and males. LHD expenditures or percentage share were related to absolute reductions in mortality for infants, Blacks, and White females but did not close Black-White mortality differences for these groups. Therefore, disparities in Black and White mortality rates for subgroups with the greatest mortality gaps may be more likely to be reduced by public investment in local health departments than disparities in Black and White total, all-cause mortality rates.


Detection Technologies. Ambient mass spectrometry.
A recent innovation in mass spectrometry is the ability to record mass spectra on ordinary samples, in their native environment, without sample preparation or preseparation by creating ions outside the instrument. In desorption electrospray ionization (DESI), the principal method described here, electrically charged droplets are directed at the ambient object of interest; they release ions from the surface, which are then vacuumed through the air into a conventional mass spectrometer. Extremely rapid analysis is coupled with high sensitivity and high chemical specificity. These characteristics are advantageously applied to high-throughput metabolomics, explosives detection, natural products discovery, and biological tissue imaging, among other applications. Future possible uses of DESI for in vivo clinical analysis and its adaptation to portable mass spectrometers are described.


A Minimally Invasive Exosome Spray Repairs Heart after Myocardial Infarction.
Myocardial infarction (MI) remains the most common cause of death worldwide. Many MI survivors will suffer from recurrent heart failure (HF), which has been recognized as a determinant of adverse prognosis. Despite the success of improved early survival after MI by primary percutaneous coronary intervention, HF after MI is becoming the major driver of late morbidity, mortality, and healthcare costs. The development of regenerative medicine has brought hope to MI treatment in the past decade. Mesenchymal stem cell (MSC)-derived exosomes have been established as an essential part of stem cell paracrine factors for heart regeneration. However, its regenerative power is hampered by low delivery efficiency to the heart. We designed, fabricated, and tested a minimally invasive exosome spray (EXOS) based on MSC exosomes and biomaterials. In a mouse model of acute myocardial infarction, EXOS improved cardiac function and reduced fibrosis, and promoted endogenous angiomyogenesis in the post-injury heart. We further tested the feasibility and safety of EXOS in a pig model. Our results indicate that EXOS is a promising strategy to deliver therapeutic exosomes for heart repair.


Clinical evaluation of Nigella sativa seeds for the treatment of hyperlipidemia: a randomized, placebo controlled clinical trial.
Natural products are proved to play a good role as an alternative to synthetic chemicals in many clinical conditions. Hypercholesterolemia is the most important risk factor for atherosclerosis. Previous studies showed that Nigella sativa L. has both antioxidant and lipid lowering potentials. To evaluate the efficacy of the seeds of Nigella sativa on the treatment of hyperlipidemia. In this randomized, placebo controlled clinical trial which was conducted in Isfahan city (Iran), 88 subjects aged > or =18 years with a total cholesterol concentration >200 mg/dl were included. According to the patients" profiles number, they were randomized to receive either N. sativa capsules or the matching placebo. Each N sativa capsule contained 500 +/- 10 mg N. sativa crushed seeds, and patients had to take 2 g N. sativa per day for 4 weeks. Fasting baseline laboratory values (fasting blood sugar, total cholesterol, low density lipoprotein, high density lipoprotein and triglyceride) were obtained for all parameters on each subject prior to the start of the study and at the end of 4 weeks. In our study a significant decrease was observed in the concentration of total cholesterol (4.78%), Low density lipoprotein (7.6%) and Triglyceride (16.65%), and this decrease was more significant for TG concentration. N. sativa had not any beneficial effects on Fasting blood sugar and High density lipoprotein. According to the results of our present study it seems that N. sativa may have some beneficial therapeutic effects in the treatment of hyperlipidemia. However, further investigations with a larger sample size are necessary.


Plasma levels of growth differentiation factor 15 are associated with future risk of venous thromboembolism.
Growth differentiation factor 15 (GDF-15), a marker of inflammation and oxidative stress, has emerged as a biomarker for arterial cardiovascular disease. However, the association between GDF-15 and venous thromboembolism (VTE) remains uncertain. We therefore investigated the association between plasma GDF-15 levels and future risk of incident VTE and explored the potential of a causal association using Mendelian randomization (MR). We conducted a population-based nested case-control study comprising 416 VTE patients and 848 age- and sex-matched controls derived from the Tromsø Study. Logistic regression was used to calculate odds ratios (ORs) for VTE across GDF-15 quartiles. For the MR, we used data from the International Network on Venous Thrombosis (INVENT) consortium to examine whether single nucleotide polymorphisms (SNPs) associated with GDF-15 levels with genome-wide significance were related to VTE. We found that the ORs for VTE increased across GDF-15 quartiles (Ptrend = .002). Participants with GDF-15 values in the highest quartile (≥358 pg/mL) had an OR for VTE of 2.05 (95% confidence interval, 1.37-3.08) compared with those with GDF-15 in the lowest quartile (<200 pg/mL) in the age- and sex-adjusted model. ORs remained essentially the same after further adjustment for body mass index, smoking, hormone therapy, physical activity, and C-reactive protein. Similar results were obtained for provoked/unprovoked events, deep vein thrombosis, and pulmonary embolism. GDF-15 levels, as predicted by the SNPs, were not associated with VTE in MR. Our results indicate that high GDF-15 levels are associated with increased risk of VTE, but MR suggests that this association is not causal.


Perceptions and experiences of access to public healthcare by people with disabilities and older people in Uganda.
In the year 2000, a set of eight Millennium Development Goals (MDGs) were presented as a way to channel global efforts into the reduction of poverty and the promotion of social development. A global discussion regarding how to renew these goals is underway and it is in this context that the Goals and Governance for Global Health (Go4Health) research consortium conducted consultations with marginalized communities in Asia, Latin America, the Pacific and Africa as a way to include their voices in world's new development agenda. The goal of this paper is to present the findings of the consultations carried out in Uganda with two groups within low-resource settings: older people and people living with disabilities. This qualitative study used focus group discussions and key informant interviews with older people in Uganda's Kamwenge district, and with persons with disabilities from the Gulu region. Thematic analysis was performed and emerging categories and themes identified and presented in the findings. Our findings show that a sense of community marginalization is present within both older persons and persons living with disabilities. These groups report experiencing political sidelining, discrimination and inequitable access to health services. This is seen as the key reason for their poor health. Clinical services were found to be of low quality with little or no access to facilities, trained personnel, and drugs and there are no rehabilitative or mental health services available. Uganda must fulfil its international obligations and take progressive measures to meet the right to health for all its peoples, but especially allocate its limited resources to proactively support its most marginalized citizens. The growing impetus within post-2015 development negotiations to redress in-country health and other inequalities through a comprehensive systems approach is of importance in the Ugandan development context. This approach reflects the participant's perspectives, which also calls for a more equitable approach to health and development as opposed to a narrow, vertical focus on specific population groups, as was the case with the MDGs.


Effects of allopurinol treatment on the progression of chronic nephritis in Canine leishmaniosis (Leishmania infantum).
Forty dogs with canine leishmaniosis (CL) participated in this study, which was designed to investigate the effect of allopurinol on the progression of the renal lesions associated with this disease. The animals were allocated into 5 groups. Group A dogs (n = 12) had neither proteinuria nor renal insufficiency, group B dogs (n= 10) had asymptomatic proteinuria, and group C dogs (n = 8) were proteinuric and azotemic. Two more groups, CA and CB, comprising 5 dogs each, served as controls for groups A and B, respectively. Group A, B, and C dogs received allopurinol PO (10 mg/kg q12h) for 6 months, whereas group CA and CB dogs were placebo-treated. Serum biochemistry profile, urinalysis, urine protein/creatinine ratio, and glomerular filtration rate (GFR) measurements were carried out at the beginning of the study, the 3rd month, and the 6th month, whereas renal biopsies were carried out only at the beginning and the end of the trial. Membranoproliferative glomerulonephritis was the most common cause of chronic renal failure. Mesangioproliferative and tubulointerstitial nephritis were detected even in group A and CA dogs. Allopurinol not only lowered proteinuria in group B dogs but also prevented the deterioration of GFR and improved the tubulointerstitial, but not the glomerular, lesions in both group A and group B dogs. Further, it resolved the azotemia in 5 of the 8 dogs admitted with 2nd stage chronic renal failure (group C). Consequently, treatment with allopurinol is advisable in CL cases with asymptomatic proteinuria or 1st-2nd stage chronic renal failure.


An oral alpha-galactosylceramide adjuvanted Helicobacter pylori vaccine induces protective IL-1R- and IL-17R-dependent Th1 responses.
Helicobacter pylori causes chronic gastric infection that can lead to peptic ulcers and is an identified risk factor for gastric cancer development. Although much effort has been put into the development of a Helicobacter pylori vaccine over the last three decades, none has yet reached clinical application. Specific challenges pertaining to effective H. pylori vaccine development include the lack of proven vaccine-effective antigens and safe mucosal adjuvants to enhance local immune responses as well as the lack of accepted correlates of protection. Herein, we demonstrate that prophylactic intragastric immunisation with a whole-cell killed H. pylori antigen administered together with the non-toxic oral adjuvant α-galactosylceramide (α-GalCer) induced effective immune protection against H. pylori infection in mice, which was of similar magnitude as when using the "gold standard" cholera toxin as adjuvant. We further describe that this α-GalCer-adjuvanted vaccine formulation elicited strong intestinal and systemic Th1 responses as well as significant antigen-specific mucosal and systemic antibody responses. Finally, we report that the protective intestinal Th1 responses induced by α-GalCer are dependent on CD1d, IL-1R as well as IL-17R signalling. In summary, our results show that α-GalCer is a promising adjuvant for inclusion in an oral vaccine against H. pylori infection.


Ultracold atoms in a disordered crystal of light: towards a bose glass.
We use a bichromatic optical lattice to experimentally realize a disordered system of ultracold strongly interacting 87Rb bosons. In the absence of disorder, the atoms are pinned by repulsive interactions in the sites of an ideal optical crystal, forming one-dimensional Mott-insulator states. We measure the excitation spectrum of the system as a function of disorder strength and characterize its phase-coherence properties with a time-of-flight technique. Increasing disorder, we observe a broadening of the Mott-insulator resonances and the transition to a state with vanishing long-range phase coherence and a flat density of excitations, which suggest the formation of a Bose-glass phase.


Diabetes in the Old Order Amish: characterization and heritability analysis of the Amish Family Diabetes Study.
The Old Order Amish (OOA) are a genetically well-defined closed Caucasian founder population. The Amish Family Diabetes Study was initiated to identify susceptibility genes for type 2 diabetes. This article describes the genetic epidemiology of type 2 diabetes and related traits in this unique population. The study cohort comprised Amish probands with diabetes who were diagnosed between 35 and 65 years of age and their extended adult family members. We recruited 953 adults who represented 45 multigenerational families. Phenotypic characterization included anthropometry, blood pressure, diabetes status, lipid profile, and leptin levels. The mean age of study participants was 46 years, and the mean BMI was 26.9 kg/m2. Subjects with type 2 diabetes were older, more obese, and had higher insulin levels. The prevalence of diabetes in the OOA was approximately half that of the Caucasian individuals who participated in the Third National Health and Nutrition Examination Survey (95% CI 0.23-0.84). The prevalence of diabetes in the siblings of the diabetic probands was 26.5% compared with a prevalence of 7.0% in spouses (lambdaS = 3.28, 95% CI 1.58-6.80). The heritability of diabetes-related quantitative traits was substantial (13-70% for obesity-related traits, 10-42% for glucose levels, and 11-24% for insulin levels during the oral glucose tolerance test; P = 0.01 to <0.0001). Type 2 diabetes in the Amish has similar phenotypic features to that of the overall Caucasian population, although the prevalence in the Amish community is lower than that of the Caucasian population. There is significant familial clustering of type 2 diabetes and related traits. This unique family collection will be an excellent resource for investigating the genetic underpinnings of type 2 diabetes.


Stimulation of NF-kappa B-mediated transcription by mutant derivatives of the latent membrane protein of Epstein-Barr virus.
The latent membrane protein (LMP) of Epstein-Barr virus contributes to the immortalizing activity of the virus in primary, human B lymphocytes, but its mechanism of function is unknown. LMP is expressed at the plasma membrane and may act by influencing the signalling pathways of infected cells. LMP increases transcription of reporter plasmids that are responsive to members of the NF-kappa B/Rel family of transcription factors (M.-L. Hammarskjold and M. C. Simurda, J. Virol. 66:6496-6501, 1992, and A. Krikos, C. D. Laherty, and V. M. Dixit, J. Biol. Chem. 267:17971-17976, 1992). We measured the stimulation of the activity of a reporter plasmid by LMP in Jurkat and 293 cells in transfection experiments. Expression of LMP stimulated plasmids that contained kappa B enhancer elements but not plasmids that lacked the elements. In 293 cells, expression of the NF-kappa B inhibitor, I kappa B-alpha, reduced the stimulatory activity of LMP. We used deletional analysis to map the domains of LMP that are required for its activity in 293 cells. Wild-type LMP stimulated NF-kappa B by a factor of 20 to 30, while mutant derivatives of LMP that lack oncogenic activity stimulated NF-kappa B by a factor of 3. The multiple membrane-spanning segments together with the carboxy-terminal 55 amino acid residues of LMP were required for its maximal stimulatory function. Residues within its cytoplasmic amino terminus were not required for LMP's stimulation of NF-kappa B. We tested also for stimulation of NF-kappa B activity in cell lines known to support phenotypic changes mediated by expression of LMP. LMP stimulated little NF-kappa B activity in HEp2 cells and no detectable NF-kappa B activity in BALB/3T3 cells. The LMP stimulation of NF-kappa B factors that occurs in some cell lines provides a useful and biochemically tractable assay for determining the function of LMP.


Impact of droplets on immiscible liquid films.
The impact of droplets on liquid films is a ubiquitous phenomenon not only in nature but also in many industrial applications. Compared to the widely-studied impact of droplets on films of identical fluids, the impact of droplets on immiscible films has received far less attention. In the present work, we show using high-speed imaging that immiscibility has a profound effect on the impact dynamics. The impact of a water droplet on an oil film leads to the formation of a compound crown followed by a central jet, whereas that of an oil droplet on a water film results in rapid spreading on the film surface driven by a large, positive spreading factor. In the former scenario, the central jet occurs due to the severe stretching of the droplet during the formation of the crown and then the retraction of the droplet by capillarity, which leads to the collision of fluid at the impact point. A model for the elongation dynamics of the central jet is proposed based on energy conservation. The effects of key parameters controlling the impact process are analysed, including the droplet Ohnesorge and Weber numbers, the viscosity ratio, and the dimensionless film thickness. Different impact outcomes are discussed, such as bouncing, deposition, and oscillation of the impact droplet, the formation and collapse of the compound crown, and the formation and tip-pinching of the central jet. This study not only provides physical insights into the impact dynamics, but could also facilitate the control and optimisation of the droplet impact process in a number of applications as highlighted herein.


Model of polarization and bistability of cell fragments.
Directed cell motility is preceded by cell polarization-development of a front-rear asymmetry of the cytoskeleton and the cell shape. Extensive studies implicated complex spatial-temporal feedbacks between multiple signaling pathways in establishing cell polarity, yet physical mechanisms of this phenomenon remain elusive. Based on observations of lamellipodial fragments of fish keratocyte cells, we suggest a purely thermodynamic (not involving signaling) quantitative model of the cell polarization and bistability. The model is based on the interplay between pushing force exerted by F-actin polymerization on the cell edges, contractile force powered by myosin II across the cell, and elastic tension in the cell membrane. We calculate the thermodynamic work produced by these intracellular forces, and show that on the short timescale, the cell mechanics can be characterized by an effective energy profile with two minima that describe two stable states separated by an energy barrier and corresponding to the nonpolarized and polarized cells. Cell dynamics implied by this energy profile is bistable-the cell is either disk-shaped and stationary, or crescent-shaped and motile-with a possible transition between them upon a finite external stimulus able to drive the system over the macroscopic energy barrier. The model accounts for the observations of the keratocyte fragments' behavior and generates quantitative predictions about relations between the intracellular forces' magnitudes and the cell geometry and motility.


"Five-year changes in population newborn health associated with new preventive services in targeted risk-group pregnancies".
In 2009, the prevention service "Familieambulatoriet" (FA) was established in three pilot hospital areas offering psychosocial support and health monitoring to parents in high risk regarding mental health and substance use, for the purpose of preventing child mental health and developmental problems through preschool years. This study selected new-born health as a preliminary endpoint for evaluation of population effects in three pilot areas, utilizing national statistics for birth cohorts from 2005 to 2013. The aim of the study is to evaluate changes in population new born health incidences associated with the establishment of new supportive and preventive FA-services at three pilot sites from 2009 in contrast to previous years and the remaining country. This quasi-experimental design evaluated changes in populations with new services available not those receiving the services, and controlled for national historical changes, variation between hospital districts, and random variation across the years before or years after the pilot services were introduced. Our hypothesis was to expect reduced frequencies of preterm births, SGA births, low APGAR scores, pediatric transfer, and new born abstinence symptoms in the pilot areas. The baseline was established through 4 years preceding 2009, contrasting changes at pilot sites the following 4 years 2009-2013 using the remaining hospital area populations in Norway 2005-2008 and 2009-2013 as contrasts. Related to the introduction of FA services, we found three significant improvements in new born health using mixed effects logistic regression. 1) In the population rate of babies born prematurely with small for gestational age (SGA), using the 10th percentile criteria as the definition; odds ratio (OR) = 0.73 (95% Cl: 0.60 to 0.88). 2) A similar reduction using the 2.5th percentile criteria, although with wider confidence limits; OR = 0.73 (95% Cl: 0.54 to 0.99). 3) A decrease in the frequency of low APGAR scores (0-6) 5 min. after birth; OR = 0.80 (95% Cl: 0.68 to 0.95). Thus, the FA-areas remained significantly lowered on SGA rates or Low APGAR rates across the years after FA establishment, despite considerable variation, in contrast to the baseline years and to the remaining country. No significant effect was found for the outcomes frequency of premature births (unrelated to SGA), SGA among full-term babies, child abstinence symptoms or pediatric transfer of the baby. False negative findings may result from low-rate outcomes or studying the population rather than users. Population rates suggest that introducing FA services offering support and monitoring in high-risk families may contribute to improving aspects of new born infant health. Intervention components and strategies should be studied more closely using individual data.


Changing eating behaviour vs. losing weight: the role of goal focus for weight loss in overweight women.
A 6-week longitudinal study with N = 126 overweight women participating in a weight-loss programme investigated the hypothesis that focusing on the process (dietary behaviours) rather than on the outcome of dieting (weight loss) is associated with more successful goal pursuit and achievement. As expected, process focus was related positively to subjective daily success in dieting as well as to actual weight loss, and negatively to deviations from the diet. In contrast, outcome focus had a negative impact on successful dieting: focusing on weight loss was marginally negatively related to actual weight loss and was associated with more disinhibition after lapses. Confirming hypotheses, self-regulation failure (i.e. deviations from the diet, disinhibition) was negatively related to daily affective well-being. Contrary to hypotheses, however, goal focus was not directly associated with affective well-being but only indirectly through self-regulation. Focusing on the process rather than on the outcome of dieting, then, might help achieving difficult health-related goals and support self-regulation but does not contribute directly to affective well-being.


Tc-99m macro aggregated albumin scintigraphy - indications other than pulmonary embolism: A pictorial essay.
Tc-99m macro aggregated albumin (MAA) is synonymous for lung perfusion scintigraphy and is part of the study in the evaluation of pulmonary thromboembolism. We wanted to highlight the utilities of Tc-99m MAA other than pulmonary embolism as a pictorial assay. Patients referred for Tc-99m MAA scintigraphy under various indications were included in this pictorial essay. Commercially available TechneScan LyoMAA cold kit from Mallinckrodt Medical B.V., Holland was used. Acquisition protocols for different indications are described in this article. Different clinical indications (e.g., pulmonary artery stenosis, hepatopulmonary syndrome, FEV1 calculation in lung surgery planning, selective internal radiation therapy planning, venography for deep venous thrombosis, left to right cardiac shunts, etc.) where Tc-99m MAA scintigraphy was asked for; how it helped in different clinical scenarios and how it can be used clinically is explained with unique and interesting case examples and images. We also reviewed the literature to look for certain remote indications of MAA imaging for the sake of completion like - (shunt scintigraphy, peritoneopleural communication, etc.). Tc-99m MAA is a very useful radiopharmaceutical, which can be used for many other indications apart from the commonly used indication of lung perfusion scan in pulmonary embolism. It can provide useful clinical information in other indications, which we try to highlight in this article.


Laser-patterned paper-based sensors for rapid point-of-care detection and antibiotic-resistance testing of bacterial infections.
Antimicrobial resistance (AMR) has been identified by the World Health Organisation as a global threat that currently claims at least 25,000 deaths each year in Europe and 700,000 globally; the number is projected to reach 10 million per year between 2015 and 2050. Therefore, there is an urgent need for low-cost but reliable point-of-care diagnostics for early screening of infections especially in developing countries lacking in basic infrastructure and trained personnel. This work is aimed at developing such a device, a paper-based microfluidic device for infection testing by an unskilled user in a low resource setting. Here, we present our work relating to the use of our laser-patterned paper-based devices for detection and susceptibility testing of Escherichia coli, via a simple visually observable colour change. The results indicate the suitability of our integrated paper devices for timely identification of bacterial infections at the point-of-care and their usefulness in providing a hugely beneficial pathway for accurate antibiotic prescribing and thus a novel route to tackling the global challenge of AMR.


Extended "Timed Up and Go" assessment as a clinical indicator of cognitive state in Parkinson's disease.
To evaluate a modified extended Timed Up and Go (extended-TUG) assessment against a panel of validated clinical assessments, as an indicator of Parkinson's disease (PD) severity and cognitive impairment. Eighty-seven participants with idiopathic PD were sequentially recruited from a Movement Disorders Clinic. An extended-TUG assessment was employed which required participants to stand from a seated position, walk in a straight line for 7m, turn 180° and then return to the start, in a seated position. The extended-TUG assessment duration was correlated to a panel of clinical assessments, including the Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Quality of Life (PDQ-39), Scales for Outcomes in Parkinson's Disease (SCOPA-Cog), revised Addenbrooke's Cognitive Index (ACE-R) and Barratt's Impulsivity Scale 11 (BIS-11). Extended-TUG time was significantly correlated to MDS-UPDRS III score and to SCOPA-Cog, ACE-R (p<0.001) and PDQ-39 scores (p<0.01). Generalized linear models determined the extended-TUG to be a sole variable in predicting ACE-R or SCOPA-Cog scores. Patients in the fastest extended-TUG tertile were predicted to perform 8.3 and 13.4 points better in the SCOPA-Cog and ACE-R assessments, respectively, than the slowest group. Patients who exceeded the dementia cut-off scores with these instruments exhibited significantly longer extended-TUG times. Extended-TUG performance appears to be a useful indicator of cognition as well as motor function and quality of life in PD, and warrants further evaluation as a first line assessment tool to monitor disease severity and response to treatment. Poor extended-TUG performance may identify patients without overt cognitive impairment form whom cognitive assessment is needed.


Mechanical compression modulates matrix biosynthesis in chondrocyte/agarose culture.
This study focuses on the effect of static and dynamic mechanical compression on the biosynthetic activity of chondrocytes cultured within agarose gel. Chondrocyte/agarose disks (3 mm diameter) were placed between impermeable platens and subjected to uniaxial unconfined compression at various times in culture (2-43 days). [35S]sulfate and [3H]proline radiolabel incorporation were used as measures of proteoglycan and protein synthesis, respectively. Graded levels of static compression (up to 50%) produced little or no change in biosynthesis at very early times, but resulted in significant decreases in synthesis with increasing compression amplitude at later times in culture; the latter observation was qualitatively similar to that seen in intact cartilage explants. Dynamic compression of approximately 3% dynamic strain amplitude (approximately equal to 30 microns displacement amplitude) at 0.01-1.0 Hz, superimposed on a static offset compression, stimulated radiolabel incorporation by an amount that increased with time in culture prior to loading as more matrix was deposited around and near the cells. This stimulation was also similar to that observed in cartilage explants. The presence of greater matrix content at later times in culture also created differences in biosynthetic response at the center versus near the periphery of the 3 mm chondrocyte/agarose disks. The fact that chondrocyte response to static compression was significantly affected by the presence or absence of matrix, as were the physical properties of the disks, suggested that cell-matrix interactions (e.g. mechanical and/or receptor mediated) and extracellular physicochemical effects (increased [Na+], reduced pH) may be more important than matrix-independent cell deformation and transport limitations in determining the biosynthetic response to static compression. For dynamic compression, fluid flow, streaming potentials, and cell-matrix interactions appeared to be more significant as stimuli than the small increase in fluid pressure, altered molecular transport, and matrix-independent cell deformation. The qualitative similarity in the biosynthetic response to mechanical compression of chondrocytes cultured in agarose gel and chondrocytes in intact cartilage further indicates that gel culture preserves certain physiological features of chondrocyte behavior and can be used to investigate chondrocyte response to physical and chemical stimuli in a controlled manner.


Severe hypodontia: identifying patterns of human tooth agenesis.
Tooth agenesis is the most common dental anomaly. The aim of this retrospective study was to identify common patterns of tooth agenesis in a sample of 92 patients (55 females and 37 males; mean age 27.7 years) with non-syndromic severe hypodontia. The Tooth Agenesis Code (TAC) procedure was used for that purpose. The patients in this study were missing between 6 and 22 permanent teeth (mean 11.6; median 10.0; SD 4.35). In the maxilla, 47.9 (left side) and 50.0 (right side) per cent can be described using only five different patterns. The most common patterns involved agenesis of the maxillary lateral incisor and both premolars. In the mandible, 35.8 (lower left) or 43.5 (lower right) per cent can be described by five patterns, the most common of which was agenesis of all mandibular premolars. When comparing patients with and without symmetric agenesis patterns (symmetry in the upper or lower arch versus no symmetry), a Student's t-test revealed no difference in the total number of missing teeth. Common patterns of tooth agenesis were successfully identified in patients with non-syndromic severe hypodontia. The present findings may be used to develop interdisciplinary treatment protocols for the most common patterns to increase the quality of interdisciplinary treatment for patients with severe hypodontia.


Pretend play.
Pretend play is a form of playful behavior that involves nonliteral action. Although on the surface this activity appears to be merely for fun, recent research has discovered that children's pretend play has connections to important cognitive and social skills, such as symbolic thinking, theory of mind, and counterfactual reasoning. The current article first defines pretend play and then reviews the arguments and evidence for these three connections. Pretend play has a nonliteral correspondence to reality, hence pretending may provide children with practice with navigating symbolic relationships, which may strengthen their language skills. Pretend play and theory of mind reasoning share a focus on others' mental states in order to correctly interpret their behavior, hence pretending and theory of mind may be mutually supportive in development. Pretend play and counterfactual reasoning both involve representing nonreal states of affairs, hence pretending may facilitate children's counterfactual abilities. These connections make pretend play an important phenomenon in cognitive science: Studying children's pretend play can provide insight into these other abilities and their developmental trajectories, and thereby into human cognitive architecture and its development.


Epidemic O'Nyong-Nyong fever in southcentral Uganda, 1996-1997: entomologic studies in Bbaale village, Rakai District.
Entomologic studies were conducted between January 27 and February 2, 1997, in Bbaale village in southcentral Uganda during an o'nyong-nyong (ONN) virus epidemic, which began in mid 1996 and continued into 1997. The objectives were to confirm the role of anophelines in ONN virus transmission and to examine other mosquito species as epidemic vectors of ONN virus. Of 10,050 mosquitoes collected using light traps and pyrethrum knockdown sprays, Anopheles (Cellia) funestus Giles was presumed to be the principal vector because it was the most abundant mosquito species from which a strain of ONN virus was isolated. This virus was isolated for the first time from a culicine species, Mansonia (Mansonioides) uniformis Theobald. Bwamba virus and Nyando virus were also isolated from An. funestus.


Does awareness of being video recorded affect doctors' consultation behaviour?
Four general practitioners, two of whom had no previous experience of video recording in the consultation, took part in a study to assess the effect of awareness of video recording on their consultation behaviour. A video camera was sited unobtrusively in each consulting room for a month during which five randomly selected surgeries were recorded with the doctors being informed at the time, and five without their being informed. The video recorded consultations were analysed using TIMER, a tool designed to measure objectively behaviour in terms of physical, verbal and secondary activities in consultations. The proportions of time spent on the 27 consultation parameters were compared when doctors were aware and unaware of the recording, using analysis of variance. This demonstrated only one significant difference, in the low frequency parameter of the doctor's exploration of the patients' concepts (P less than 0.05). In a secondary analysis of the first four consultations in each surgery, where any effect of the presence of the video camera would be expected to be most marked, there was again only one significant difference in the 27 parameters (in patient preparation; P = 0.01). No significant difference owing to awareness of video recording was found in consultation length, the number of problems dealt with, or previous inexperience of video recording. When surgeries at the start of the month were compared with those at the end, four significant differences (P less than 0.05) out of 108 areas were demonstrated both when the doctor was aware and unaware of video recording, and there was no consistency in the direction of the differences.(ABSTRACT TRUNCATED AT 250 WORDS)


The effectiveness and efficiency of diabetes screening in Ontario, Canada: a population-based cohort study.
Little is known about the efficiency and effectiveness of the current level of diabetes screening activity in Ontario where there is universal access to health services. Our study aims were to: (i) determine how often Ontarians are screened for diabetes; (ii) estimate screening efficiency based on the number needed to screen (NNS) to diagnosis one diabetes case; (iii) examine the population effectiveness of screening as estimated by the number of undiagnosed diabetes cases. Ontario respondents of the Canadian Community Health Survey who agreed to have their responses linked to health care data (n = 37,400) provided the cohort. The five-year probabilities of glucose testing and diabetes diagnoses were estimated using a Cox Proportional Hazards Model. We defined NNS as the ratio of diabetes tests to number of diabetes diagnoses over the study period. We estimated the number of undiagnosed diabetes by dividing the number not tested at the end of study period by the NNS. 80% of women and 66% of men had a blood glucose test within 5 years. The efficiency of screening was estimated by a NNS of 14 among men and 22 among women. 127,100 cases of undiagnosed diabetes were estimated, representing 1.4% of the Ontario adult population. Increasing age, hypertension, immigrant and non-white ethnicity, and number of general practitioner visits were associated with an increased likelihood of having a glucose test (LR chi2 p < 0.001). Low income men were less likely to be tested. Diabetes screening was high in this population-based cohort of Ontarians. Screening efficiency varied considerably in the population. Undiagnosed diabetes continues to be prevalent and remains concentrated in the highest risk groups for diabetes, especially among men.


Superficially located enlarged lymphoid follicles characterise nodular gastritis.
Nodular gastritis is a form of chronic Helicobacter pylori gastritis affecting the gastric antrum and characterised endoscopically by the presence of small nodular lesions resembling gooseflesh. It is generally accepted that hyperplasia of lymphoid follicles histologically characterises nodular gastritis; however, quantitative analysis in support of this hypothesis has not been reported. Our goal was to determine whether nodular gastritis is characterised by lymphoid follicle hyperplasia.The number, size, and location of lymphoid follicles in nodular gastritis were determined and those properties compared to samples of atrophic gastritis. The percentages of high endothelial venule (HEV)-like vessels were also evaluated.The number of lymphoid follicles was comparable between nodular and atrophic gastritis; however, follicle size in nodular gastritis was significantly greater than that seen in atrophic gastritis. Moreover, lymphoid follicles in nodular gastritis were positioned more superficially than were those in atrophic gastritis. The percentage of MECA-79 HEV-like vessels was greater in areas with gooseflesh-like lesions in nodular versus atrophic gastritis.Superficially located hyperplastic lymphoid follicles characterise nodular gastritis, and these follicles correspond to gooseflesh-like nodular lesions observed endoscopically. These observations suggest that MECA-79 HEV-like vessels could play at least a partial role in the pathogenesis of nodular gastritis.


Mechanical sensitivity reveals evolutionary dynamics of mechanical systems.
A classic question in evolutionary biology is how form-function relationships promote or limit diversification. Mechanical metrics, such as kinematic transmission (KT) in linkage systems, are useful tools for examining the evolution of form and function in a comparative context. The convergence of disparate systems on equivalent metric values (mechanical equivalence) has been highlighted as a source of potential morphological diversity under the assumption that morphology can evolve with minimal impact on function. However, this assumption does not account for mechanical sensitivity-the sensitivity of the metric to morphological changes in individual components of a structure. We examined the diversification of a four-bar linkage system in mantis shrimp (Stomatopoda), and found evidence for both mechanical equivalence and differential mechanical sensitivity. KT exhibited variable correlations with individual linkage components, highlighting the components that influence KT evolution, and the components that are free to evolve independently from KT and thereby contribute to the observed pattern of mechanical equivalence. Determining the mechanical sensitivity in a system leads to a deeper understanding of both functional convergence and morphological diversification. This study illustrates the importance of multi-level analyses in delineating the factors that limit and promote diversification in form-function systems.


How well do principal diagnosis classifications predict disability 12 months postinjury?
The application of disability weights by nature of injury is central to the calculation of disability-adjusted life years (DALYs). Such weights should represent injury diagnosis groups that demonstrate homogeneity in disability outcomes. Existing classifications have not used empirical data in their development to inform groups that are homogeneous for disability outcomes, limiting the capacity to make informed recommendations for best practice in measuring injury burden. The Validating and Improving injury Burden Estimates (Injury-VIBES) Study includes pooled data from over 30 000 injured participants recruited to six cohort studies. The International Classification of Disease 10th Revision (ICD-10) diagnosis codes were mapped to existing injury burden study groupings and prediction models were developed to measure the capacity of the injury groupings and ICD-10 diagnoses to predict disability outcomes at 12 months. Models were adjusted for age, gender and data source and investigated for discrimination using area under the receiver operating characteristic curve (AUC) and calibration using Hosmer-Lemeshow statistics and calibration curves. Discrimination and calibration of models varied depending on the outcome measured. Models using full four-character ICD-10 diagnosis codes, rather than groupings of codes, demonstrated the highest discrimination ranging from an AUC (95% CI) of 0.627 (0.618 to 0.635) for the pain or discomfort item of the EQ-5D to 0.847 (0.841 to 0.853) for the extended Glasgow Outcome Scale independent living outcome. However, gain over other groupings was marginal. Prediction performance was best for measures of function such as independent living, mobility and self-care. The classifications were poorer predictors of anxiety/depression and pain/discomfort. There was no clearly superior classification.


[Co-occurrence of Carpenter syndrome and double outlet right ventricle].
Carpenter syndrome (Acrocephalopolysyndactyly type 2, OMIM 201000) is a rarely seen autosomal recessive disorder. In addition to abnormalities such as acrocephaly, craniosynostosis, facial asymmetry, polydactyly and syndactyly, obesity, hypogonadism, mental retardation, and corneal opacity, it may frequently be accompanied by congenital heart diseases such as ventricular septal defect, patent ductus arteriosus and pulmonary stenosis. Double outlet right ventricle is a defect in which both major arteries originate in the morphological right ventricle. To the best of our knowledge, this is the first report in the literature of double outlet right ventricle disease in combination with Carpenter syndrome.


Differential Aging Signals in Abdominal CT Scans.
Changes in the composition of body tissues are major aging phenotypes, but they have been difficult to study in depth. Here we describe age-related change in abdominal tissues observable in computed tomography (CT) scans. We used pattern recognition and machine learning to detect and quantify these changes in a model-agnostic fashion. CT scans of abdominal L4 sections were obtained from Baltimore Longitudinal Study of Aging (BLSA) participants. Age-related change in the constituent tissues were determined by training machine classifiers to differentiate age groups within male and female strata ("Younger" at 50-70 years old vs "Older" at 80-99 years old). The accuracy achieved by the classifiers in differentiating the age cohorts was used as a surrogate measure of the aging signal in the different tissues. The highest accuracy for discriminating age differences was 0.76 and 0.72 for males and females, respectively. The classification accuracy was 0.79 and 0.71 for adipose tissue, 0.70 and 0.68 for soft tissue, and 0.65 and 0.64 for bone. Using image data from a large sample of well-characterized pool of participants dispersed over a wide age range, we explored age-related differences in gross morphology and texture of abdominal tissues. This technology is advantageous for tracking effects of biological aging and predicting adverse outcomes when compared to the traditional use of specific molecular biomarkers. Application of pattern recognition and machine learning as a tool for analyzing medical images may provide much needed insight into tissue changes occurring with aging and, further, connect these changes with their metabolic and functional consequences.


Application of the Nordtest method for "real-time" uncertainty estimation of on-line field measurement.
Field sensor measurements are becoming more common for environmental monitoring. Solutions for enhancing reliability, i.e. knowledge of the measurement uncertainty of field measurements, are urgently needed. Real-time estimations of measurement uncertainty for field measurement have not previously been published, and in this paper, a novel approach to the automated turbidity measuring system with an application for "real-time" uncertainty estimation is outlined based on the Nordtest handbook's measurement uncertainty estimation principles. The term real-time is written in quotation marks, since the calculation of the uncertainty is carried out using a set of past measurement results. There are two main requirements for the estimation of real-time measurement uncertainty of online field measurement described in this paper: (1) setting up an automated measuring system that can be (preferably remotely) controlled which measures the samples (water to be investigated as well as synthetic control samples) the way the user has programmed it and stores the results in a database, (2) setting up automated data processing (software) where the measurement uncertainty is calculated from the data produced by the automated measuring system. When control samples with a known value or concentration are measured regularly, any instrumental drift can be detected. An additional benefit is that small drift can be taken into account (in real-time) as a bias value in the measurement uncertainty calculation, and if the drift is high, the measurement results of the control samples can be used for real-time recalibration of the measuring device. The procedure described in this paper is not restricted to turbidity measurements, but it will enable measurement uncertainty estimation for any kind of automated measuring system that performs sequential measurements of routine samples and control samples/reference materials in a similar way as described in this paper.


Personal exposure to radio-frequency electromagnetic fields in Europe: Is there a generation gap?
Exposure to radiofrequency electromagnetic fields (RF-EMF) from mobile communication technologies is changing rapidly. To characterize sources and associated variability, we studied the differences and correlations in exposure patterns between children aged 8 to 18 and their parents, over the course of the day, by age, by activity pattern, and for different metrics of exposure. Using portable RF-EMF measurement devices, we collected simultaneous real-time personal measurements of RF-EMF over 24 to 72 h in 294 parent-child pairs from Denmark, the Netherlands, Slovenia, Switzerland, and Spain. The devices measured the power flux density (mW/m2) in 16 different frequency bands every 4 s, and activity diary Apps kept by the participants were used to collect time-activity information in real-time. We analyzed their exposures by activity, for the different source constituents of exposure: downlink (radiation emitted from mobile phone base stations), uplink (transmission from phone to base station), broadcast, DECT (digital enhanced cordless telecommunications) and Wi-Fi. We looked at the correlations between parents and children overall, during day (06:00-22.00) and night (22:00-06:00) and while spending time at home. The mean of time-weighted average personal exposures was 0.16 mW/m2 for children and 0.15 mW/m2 for parents, on average predominantly originating from downlink sources (47% for children and 45% for parents), followed by uplink (18% and 27% respectively) and broadcast (25% and 19%). On average, exposure for downlink and uplink were highest during the day, and for Wi-Fi and DECT during the evening. Exposure during activities where most of the time is spent (home, school and work) was relatively low whereas exposure during travel and outside activities was higher. Exposure to uplink increased with age among young people, while DECT decreased slightly. Exposure to downlink, broadcast, and Wi-Fi showed no obvious trend with age. We found that exposure to total RF-EMF is correlated among children and their parents (Rspearman = 0.45), especially while at home (0.62) and during the night (0.60). Correlations were higher for environmental sources such as downlink (0.57) and broadcast (0.62) than for usage-related exposures such as uplink (0.29). The generation gap between children and their parents is mostly evident in uplink exposure, due to more and longer uplink and cordless phone calls among parents, and their tendency to spend slightly more time in activities with higher environmental RF-EMF exposure, such as travel. Despite these differences in personal behavior, exposure to RF-EMF is moderately correlated between children and their parents, especially exposures resulting from environmental RF-EMF sources.


Efficient plant male fertility depends on vegetative nuclear movement mediated by two families of plant outer nuclear membrane proteins.
Increasing evidence suggests that nuclear migration is important for eukaryotic development. Although nuclear migration is conserved in plants, its importance for plant development has not yet been established. The most extraordinary plant nuclear migration events involve plant fertilization, which is starkly different from that of animals. Instead of evolving self-propelled sperm cells (SCs), plants use pollen tubes to deliver SCs, in which the pollen vegetative nucleus (VN) and the SCs migrate as a unit toward the ovules, a fundamental but barely understood process. Here, we report that WPP domain-interacting proteins (WIPs) and their binding partners the WPP domain-interacting tail-anchored proteins (WITs) are essential for pollen nuclear migration. Loss-of-function mutations in WIT and/or WIP gene families resulted in impaired VN movement, inefficient SC delivery, and defects in pollen tube reception. WIPs are Klarsicht/ANC-1/Syne-1 Homology (KASH) analogs in plants. KASH proteins are key players in animal nuclear migration. Thus, this study not only reveals an important nuclear migration mechanism in plant fertilization but also, suggests that similar nuclear migration machinery is conserved between plants and animals.


Vasoactive intestinal polypeptide requires parallel changes in adenylate cyclase and phospholipase C to entrain circadian rhythms to a predictable phase.
Circadian oscillations in the suprachiasmatic nucleus (SCN) depend on transcriptional repression by Period (PER)1 and PER2 proteins within single cells and on vasoactive intestinal polypeptide (VIP) signaling between cells. Because VIP is released by SCN neurons in a circadian pattern, and, after photic stimulation, it has been suggested to play a role in the synchronization to environmental light cycles. It is not known, however, if or how VIP entrains circadian gene expression or behavior. Here, we tested candidate signaling pathways required for VIP-mediated entrainment of SCN rhythms. We found that single applications of VIP reset PER2 rhythms in a time- and dose-dependent manner that differed from light. Unlike VIP-mediated signaling in other cell types, simultaneous antagonism of adenylate cyclase and phospholipase C activities was required to block the VIP-induced phase shifts of SCN rhythms. Consistent with this, VIP rapidly increased intracellular cAMP in most SCN neurons. Critically, daily VIP treatment entrained PER2 rhythms to a predicted phase angle within several days, depending on the concentration of VIP and the interval between VIP applications. We conclude that VIP entrains circadian timing among SCN neurons through rapid and parallel changes in adenylate cyclase and phospholipase C activities.


Single-Pixel MEMS Imaging Systems.
Single-pixel imaging technology is an attractive technology considering the increasing demand of imagers that can operate in wavelengths where traditional cameras have limited efficiency. Meanwhile, the miniaturization of imaging systems is also desired to build affordable and portable devices for field applications. Therefore, single-pixel imaging systems based on microelectromechanical systems (MEMS) is an effective solution to develop truly miniaturized imagers, owing to their ability to integrate multiple functionalities within a small device. MEMS-based single-pixel imaging systems have mainly been explored in two research directions, namely the encoding-based approach and the scanning-based approach. The scanning method utilizes a variety of MEMS scanners to scan the target scenery and has potential applications in the biological imaging field. The encoding-based system typically employs MEMS modulators and a single-pixel detector to encode the light intensities of the scenery, and the images are constructed by harvesting the power of computational technology. This has the capability to capture non-visible images and 3D images. Thus, this review discusses the two approaches in detail, and their applications are also reviewed to evaluate the efficiency and advantages in various fields.


Contributions of adenosine receptor activation to the ocular actions of epinephrine.
Epinephrine is an effective drug for glaucoma treatment. However, the mechanisms responsible for the ocular hypotensive action of this compound are not completely understood. Adenosine is an autacoid released by all cells. This study evaluated the role of adenosine receptor activation in epinephrine-induced changes in ocular function. Rabbits were pretreated topically with the moderately selective adenosine A1 antagonist 8-(p-sulfophenyl)theophylline (8-SPT) or the adenosine A2 antagonist 3,7-dimethyl-l-propargylxanthine (DMPX). Epinephrine (500 microg) was then administered, and intraocular pressures (IOPs), pupil diameters (PDs), or total outflow facility was evaluated. In a separate group of animals, epinephrine or vehicle was administered, and aqueous humor samples obtained to evaluate changes in aqueous humor purine levels by means of high-performance liquid chromatography. In control animals, epinephrine produced a biphasic change in IOP: an initial rise in IOP of approximately 1 mm Hg from 1/2 to 1 hour followed by significant reduction in IOP of 8 to 9 mm Hg from 3 to 5 hours postadministration. These animals also exhibited a significant increase in PD of 2 to 3 mm from 1/2 to 2 hours postadministration. Pretreatment with 8-SPT (1000 microg) enhanced the initial rise in IOP, while significantly inhibiting the ocular hypotensive response. Pretreatment with 8-SPT also significantly enhanced the epinephrine-induced increase in PD. Inhibition of the epinephrine-induced reduction in IOP by 8-SPT was dose-related with an IC50 of 446 microg. Administration of 8-SPT alone did not significantly alter IOP or PD. The A2 antagonist DMPX did not alter the epinephrine-induced change in IOP or PD. In rabbits pretreated with 8-SPT, the epinephrine-induced increase in outflow facility was significantly reduced by 60% when compared with those in rabbits treated with epinephrine alone. In vehicle-treated rabbits, aqueous humor adenosine and inosine levels were 2.7 +/- 0.38 and 29 +/- 4.2 ng/100 microl, respectively. Three hours after epinephrine administration, adenosine and inosine levels had significantly increased to 11 +/- 1.6 and 66 +/- 4.4 ng/100 microl, respectively. These results support the idea that in rabbits epinephrine administration stimulates adenosine release in the anterior segment. This rise in endogenous levels of adenosine then leads to the activation of ocular adenosine receptors and is in part responsible for the ocular hypotensive action of epinephrine.


Small rural maternity units without caesarean delivery capabilities: is it safe and sustainable in the eyes of health professionals in Tasmania?
In Australia, over 50% of small rural maternity units have been closed in the past two decades. Workforce shortages, safety and quality concerns and cost considerations are the three interrelated reasons that have led to these closures. Women and families face many challenges when these critical services are absent from their local communities. In an effort to continue to provide maternity services in rural areas, small maternity units without caesarean delivery capabilities have been established in a few rural communities in Tasmania. However, they have divided the opinions of Tasmanian health professionals. This article is part of a larger study which focused on maternity services for rural women and reports the views of the health professionals on this model of care. A qualitative study using semi-structured interviews was conducted with 20 maternity health providers across Tasmania to explore their experiences and views on the model of offering small rural maternity units without obstetric services. The data were analysed in NVivo v9 (<a href='http://www.qsrinternational.com' target='_blank'>www.qsrinternational.com) using grounded theory. Three main themes are grounded from interview data: (1) women's difficulties in rural areas; (2) women's expectations; and (3) maternity units without caesarean delivery capabilities. The results reveal that low-intervention style birthing services in rural areas could reduce women's difficulties that include access issues, disruption, anxiety and travel related issues, and address women's expectations in term of access to local services. However, this model is less likely to meet women's safety expectations, especially in emergency situations. The findings of this study offer insights for policy-makers and state government with regard to the future planning of this model of care. It is recommended that safety and sustainability issues should be considered when this model of care is to be implemented in other rural communities.


Validity and reliability of submaximal fitness tests based on perceptual variables.
Few studies examined the validity of fitness tests based on perception scales. The field-based fitness tests batteries are composed by maximal tests and currently, a battery of submaximal tests does not exist. Seventeen physically active male participants (age 40.5±10.7 years) performed the Multistage Fitness Test, the Crunch Test, the Push-Up Test and a Trunk Flexion Test with a submaximal protocol based on perceptual variables that were defined as non-validated submaximal. The mentioned tests were repeated three times to assess their reliability. The participants also performed four validated maximal tests comprising a velocity dependent ramp test on the treadmill, the Crunch Test, the Push-Up Test, and Sit-and-Reach Test. The submaximal tests were correlated to the maximal ones to assess their criterion validity. All the submaximal tests showed an ICC superior to 0.8 apart from the submaximal Crunch Test. The correlation between Maximal Treadmill Test and submaximal Multistage Fitness Test was 0.77. The correlation between Sit-and-Reach Test and submaximal Trunk Flexion Test was 0.71. Correlations equal to 0.66 and 0.60 were found between the maximal and submaximal Crunch Test and Push-Up Test respectively. The use of submaximal tests based on a fixed value of perception can represent a suitable tool to assess cardiorespiratory fitness and flexibility because of their correlation with the corresponding maximal evaluation tests and because of their reliability. On the contrary, muscular endurance capacity seems not to be assessable in the same manner.


Structural and mutagenic analysis of the RM controller protein C.Esp1396I.
Bacterial restriction-modification (RM) systems are comprised of two complementary enzymatic activities that prevent the establishment of foreign DNA in a bacterial cell: DNA methylation and DNA restriction. These two activities are tightly regulated to prevent over-methylation or auto-restriction. Many Type II RM systems employ a controller (C) protein as a transcriptional regulator for the endonuclease gene (and in some cases, the methyltransferase gene also). All high-resolution structures of C-protein/DNA-protein complexes solved to date relate to C.Esp1396I, from which the interactions of specific amino acid residues with DNA bases and/or the phosphate backbone could be observed. Here we present both structural and DNA binding data for a series of mutations to the key DNA binding residues of C.Esp1396I. Our results indicate that mutations to the backbone binding residues (Y37, S52) had a lesser affect on DNA binding affinity than mutations to those residues that bind directly to the bases (T36, R46), and the contributions of each side chain to the binding energies are compared. High-resolution X-ray crystal structures of the mutant and native proteins showed that the fold of the proteins was unaffected by the mutations, but also revealed variation in the flexible loop conformations associated with DNA sequence recognition. Since the tyrosine residue Y37 contributes to DNA bending in the native complex, we have solved the structure of the Y37F mutant protein/DNA complex by X-ray crystallography to allow us to directly compare the structure of the DNA in the mutant and native complexes.


Ancestry and pharmacogenomics of relapse in acute lymphoblastic leukemia.
Although five-year survival rates for childhood acute lymphoblastic leukemia (ALL) are now over 80% in most industrialized countries, not all children have benefited equally from this progress. Ethnic differences in survival after childhood ALL have been reported in many clinical studies, with poorer survival observed among African Americans or those with Hispanic ethnicity when compared with European Americans or Asians. The causes of ethnic differences remain uncertain, although both genetic and non-genetic factors are likely important. Interrogating genome-wide germline SNP genotypes in an unselected large cohort of children with ALL, we observed that the component of genomic variation that co-segregated with Native American ancestry was associated with risk of relapse (P = 0.0029) even after adjusting for known prognostic factors (P = 0.017). Ancestry-related differences in relapse risk were abrogated by the addition of a single extra phase of chemotherapy, indicating that modifications to therapy can mitigate the ancestry-related risk of relapse.


Enhancement of optical absorption in thin-film solar cells through the excitation of higher-order nanoparticle plasmon modes.
Recent research in the rapidly emerging field of plasmonics has shown the potential to significantly enhance light trapping inside thin-film solar cells by using metallic nanoparticles. In this article it is demonstrated the plasmon enhancement of optical absorption in amorphous silicon solar cells by using silver nanoparticles. Based on the analysis of the higher-order surface plasmon modes, it is shown how spectral positions of the surface plasmons affect the plasmonic enhancement of thin-film solar cells. By using the predictive 3D modeling, we investigate the effect of the higher-order modes on that enhancement. Finally, we suggest how to maximize the light trapping and optical absorption in the thin-film cell by optimizing the nanoparticle array parameters, which in turn can be used to fine tune the corresponding surface plasmon modes.


Do amnesic patients with Korsakoff's syndrome use feedback when making decisions under risky conditions? An experimental investigation with the Game of Dice Task with and without feedback.
We investigated the role of feedback processing in decision making under risk conditions in 50 patients with amnesia in the course of alcoholic Korsakoff's syndrome (KS). Half of the patients were administered the Game of Dice Task (GDT) and the remaining 25 patients were examined with a modified version of the GDT in which no feedback was provided. Patients' results in the GDT and in the modified version were compared with that of 50 healthy subjects of whom 25 subjects performed the original GDT and 25 performed the modified version. While performance on the original GDT was superior to performance on the modified GDT in healthy subjects, KS patients performed similarly on both the GDT with and GDT without feedback. Performance on both task versions was correlated with categorization and set-shifting. The findings indicate that amnesic patients do not profit from receiving feedback for their decisions in explicit risk conditions.


Flow cytometric features of angioimmunoblastic T-cell lymphoma.
The immunophenotypic features of angioimmunoblastic T-cell lymphoma (AILT) have not been well described. We retrospectively reviewed our institutional experience with the flow cytometric features of 16 cases of AILT. Multiparameter flow cytometry was able to identify a distinct population of immunophenotypically aberrant T cells in 15 of 16 cases. In 13 lymph node specimens, the neoplastic cells ranged from 1.9 to 87% (median 23%) of cells. The ratio of reactive to neoplastic T cells ranged from 0.01 to 20 (median 1.5); reactive T cells outnumbered neoplastic in 9/13 (69%) cases. The neoplastic populations expressed CD2, CD4, CD5, and CD45RO in all cases, lacked expression of CD8 and CD56 in all cases, and showed negative or dim surface CD3 in most cases. CD10 was expressed by the neoplastic populations in 11 of 14 cases at diagnosis; in 3 of these 11 only a subpopulation of the neoplastic cells was CD10(+). CD10 tended to be absent on neoplastic cells in staging bone marrows. The neoplastic population in all but one of the 15 positive cases possessed multiple immunophenotypic abnormalities and these were generally retained during the follow-up analyses of several cases. These results indicate the potential utility of flow cytometry in the diagnosis and follow-up of AILT.


Severe chronic constipation of young women: 'idiopathic slow transit constipation'.
A series of 64 women complaining of severe constipation is described, in each of whom delayed elimination of markers from the colon was demonstrated but a barium enema was normal. All completed a detailed questionnaire and the responses are compared with those obtained in an age-matched series of healthy women with no bowel complaint. In each group 40 women also recorded in a manner suitable for analysis all food eaten over a period of seven days. The patients passed about one stool weekly with the aid of laxatives, and were greatly troubled by abdominal pain, bloating, malaise and nausea, to the extent that the symptoms were a major social disability and many lost time from work. Decreased bowel frequency and other symptoms were often first noticed around the age of puberty and slowly became worse until they were severe by the third decade. In a few, the symptoms began suddenly after an abdominal operation c-accident. Comparison with the control group showed no evidence that the patients had been underweight at any time or that they took less fibre; treatment with a bran supplement did not usually help them. The patients experienced rectal sensation before defaecation less often than the control subjects and they used digital pressure to assist defaecation more frequently. The women with constipation tended to have more painful and irregular menstrual periods, and there was an increased incidence of ovarian cystectomy and hysterectomy. Hesitancy in starting to pass urine was more common, as were some somatic symptoms such as cold hands or blackouts. Attention is drawn to this distinctive combination in young women of slow total gut transit time and a colon of normal width on barium enema, associated with abdominal, anorectal, gynaecological and somatic symptoms, as a disorder which can be disabling and particularly difficult to treat.


Transition metal compounds as cancer radiosensitizers.
The concomitant administration of ionising radiation (IR) in the form of external beam radiotherapy or targeted radionuclide therapy (TRT) alongside radiosensitizing small molecules is a highly successful strategy for the treatment of cancer. The major clinical impact of the radiosensitizing platinum(ii) drug cisplatin has encouraged the design of many transition metal coordination or organometallic complexes and their assessment as anticancer candidates. The growing recognition that metallodrugs halt cancer cell proliferation through mechanisms other than DNA damage and the recent expansion of the range of their potential biological targets has further stimulated the field. A central aim is to generate new therapeutic candidates with improved anticancer activity, distinct mechanisms of action(s) and reduced cross-resistance compared to existing drugs. The question arises of how lead candidates should be combined with other treatment modalities, particularly radiotherapy. In this review, work is highlighted that specifically examines transition metal complexes in combination with IR with an emphasis on complexes that function as radiosensitizers. The chemical design principles and cellular mechanisms of action to achieve synergistic or additive effects in cancer cell killing are outlined. Finally, we discuss emerging applications in this area of research, such as the combination of metallo-compound radiosensitizers with radionuclides and within drug delivery approaches.


Web-based computer-tailoring for practice nurses aimed to improve smoking cessation guideline adherence: A study protocol for a randomized controlled effectiveness trial.
Dutch practice nurses sub-optimally adhere to evidence-based smoking cessation guidelines. Web-based computer-tailoring could be effective in improving their guideline adherence. Therefore, this paper aims to describe the development of a web-based computer-tailored program and the design of a randomized controlled trial testing its (cost-)effectiveness. Theoretically grounded in the I-Change Model and Self-Determination Theory, and based on the results of a qualitative needs assessment among practice nurses, a web-based computer-tailored program was developed including three modules with tailored advice, an online forum, modules with up-to-date information about smoking cessation, Frequently Asked Questions (FAQs) and project information, and a counseling checklist. The program's effects are assessed by comparing an intervention group (access to all modules) with a control group (access to FAQs, project information and counseling checklist only). Smoking cessation guideline adherence and behavioral predictors (i.e. intention, knowledge, attitude, self-efficacy, social influence, action and coping planning) are measured at baseline and at 6- and 12-month follow-up. Additionally, the program's indirect effects on smokers' quit rates and the number of quit attempts are assessed after 6 and 12months. This paper describes the development of a web-based computer-tailored adherence support program for practice nurses and the study design of a randomized controlled trial testing its (cost-)effectiveness. This program potentially contributes to improving the quality of smoking cessation care in Dutch general practices. If proven effective, the program could be adapted for use by other healthcare professionals, increasing the public health benefits of improved smoking cessation counseling for smokers.


Efficiency and temporal response of crystalline Kerr media in collinear optical Kerr gating.
Optical Kerr gating is widely used in ultrafast measurements ranging from pulse characterization to spectroscopy and microscopy. We examined the efficiency and the temporal response of three cubic lattice Kerr media, YAG, GGG and BGO, and compared them with the well studied fused silica (fast response, low efficiency) and STO (high efficiency, slow response). YAG and GGG emerged as superior materials for ultrafast spectroscopy and microscopy applications thanks to their fast Kerr response and considerably higher gating efficiency than silica at low gating energies. Importantly, it was found that in collinear geometry all tested materials except STO are capable of reaching nearly 100% transmission.


An integrative view of the regulatory and transcriptional landscapes in mouse hematopoiesis.
Thousands of epigenomic data sets have been generated in the past decade, but it is difficult for researchers to effectively use all the data relevant to their projects. Systematic integrative analysis can help meet this need, and the VISION project was established for validated systematic integration of epigenomic data in hematopoiesis. Here, we systematically integrated extensive data recording epigenetic features and transcriptomes from many sources, including individual laboratories and consortia, to produce a comprehensive view of the regulatory landscape of differentiating hematopoietic cell types in mouse. By using IDEAS as our integrative and discriminative epigenome annotation system, we identified and assigned epigenetic states simultaneously along chromosomes and across cell types, precisely and comprehensively. Combining nuclease accessibility and epigenetic states produced a set of more than 200,000 candidate cis-regulatory elements (cCREs) that efficiently capture enhancers and promoters. The transitions in epigenetic states of these cCREs across cell types provided insights into mechanisms of regulation, including decreases in numbers of active cCREs during differentiation of most lineages, transitions from poised to active or inactive states, and shifts in nuclease accessibility of CTCF-bound elements. Regression modeling of epigenetic states at cCREs and gene expression produced a versatile resource to improve selection of cCREs potentially regulating target genes. These resources are available from our VISION website to aid research in genomics and hematopoiesis.


Recovery of flow-mediated vasodilatation after repetitive measurements is involved in early vascular impairment: comparison with indices of vascular tone.
In repetitive measurements of flow-mediated dilatation (FMD), the duration of the interval between measurements remains controversial. In this pilot study, we conducted three sequential measurements of low-flow-mediated constriction (L-FMC), FMD and flow-mediated total dilation (FMTD; L-FMC+ FMD) at baseline and intervals of 15 and 60 min in 30 healthy males. FMD15, L-FMC15, and FMTD15 were significantly lower than the respective first measurements, but all indices showed full recovery at 60 min in all subjects. The baseline diameter was slightly increased at 15 min and restored at 60 min, but the maximum diameter, and the baseline and reactive flow velocity unchanged. We examined the relationship between recovery rate of FMTD at 15 min (FMTD-R) and cardio-ankle vascular index (CAVI). Univariate analysis showed moderate correlation between FMTD-R, and CAVI and L-FMC0. Patients were divided according to FMTD-R value; the low-FMTD-R group [below the median value (-26.2%)] included a significantly higher proportion of smokers and higher CAVI values than the high-FMTD-R group. The reproducibility of FMTD and FMTD-R was evaluated in another group of 25 healthy subjects. The range of variation across measurements was 1.1% for FMTD and 4.6% for FMTD-R; with intraclass correlation coefficients of 0.93 and 0.95, respectively. The present study demonstrated blunted recovery of FMD within 15 min, suggesting the need for selection of a more adequate interval between measurements to avoid underestimation of FMD in subsequent measurements. The findings demonstrated the reproducibility of FMTD-R and FMTD measurements, and that FMTD-R might be involved in arterial stiffness and early vascular impairment in the healthy subjects.


Traumatic injuries in pregnant women: a case of motor vehicle accident for "Ground Round" discussion.
The main objective for introducing this case study is to create a platform from which the importance of road traffic related injuries and traumas can be emphasized and discussed within and across various fields of investigation. The long term goal is to entice public campaign around unmet needs for higher road safety measures to reduce primary, secondary, and tertiary risks of injuries and traumas. a 28-year-old pregnant woman with a 16-week gestational age fetus was involved in a road car crash resulting in multiple traumas. Evaluation and treatment was initiated in the local Urgent Care Unit and continued in the emergency department and operation room. Patient underwent the following procedures: laparotomy, diverting colostomy, terminating pregnancy, right calcaneal traction and long leg splint, as well as multiple irrigation-debridements. Finally, the wound was left open and the patient was admitted to Intensive Care Unit. We hope that the introduction of this case for a "Ground Round" discussion will stir up a comprehensive discussion regarding the injury and trauma related preventive measures as well as treatment approaches in cases involving pregnant women in car accidents, and will bring about a holistic overview of this issue by the experts in various fields.


Stimulant-related reductions of growth rates in the PATS.
To investigate growth of children with attention-deficit/hyperactivity disorder (ADHD) in the Preschool ADHD Treatment Study (PATS) before and after initiation of treatment with methylphenidate at titrated doses (average, 14.2 mg/day) administered three times daily, 7 days/week for asymptotically equal to1 year. The heights and weights of 140 children with ADHD were measured up to 29 times in the PATS protocol, starting at an average age of 4.4 years. The relationship between standard (z) scores and time on medication was examined using mixed-effect regression to estimate change in relative size (slope). Average relative size at baseline was significantly (p<.0001) greater than zero for z height (+0.45) and z weight (+0.78), indicating greater than expected height (by 2.04 cm) and weight (by 1.78 kg). During treatment, slopes were significantly (p<.0001) less than zero for z height (-0.304/yr) and z weight (-0.530/yr), indicating reduction of growth rates. For 95 children who remained on medication, annual growth rates were 20.3% less than expected for height (5.41 cm/yr-6.79 cm/yr=-1.38 cm/yr) and 55.2% for weight (1.07 kg/yr-2.39 kg/yr=-1.32 kg/yr). Risks of reduced growth rates should be balanced against expected benefits when preschool-age children are treated with stimulant medication.


The 9-homocubyl cation rearrangement revisited.
Complexity of the potential energy surface of the 9-homocubyl cation is revealed by Born-Oppenheimer molecular dynamics simulations and high ab initio levels. The stereospecific automerizations observed experimentally involve bridged ions, which have either an aromatic or an anti-aromatic character. New pathways leading to more stable isomers are unveiled.


Human cytomegalovirus and transplantation: drug development and regulatory issues.
Cytomegalovirus (CMV) infection is highly prevalent worldwide and can cause serious disease among immunocompromised individuals, including persons with HIV and transplant recipients on immunosuppressive therapies. It can also result in congenital cytomegalovirus when women are infected during pregnancy. Treatment and prevention of CMV in solid organ and haematopoietic stem cell transplant recipients is accomplished in one of three ways: (1) prophylactic therapy to prevent CMV viraemia; (2) pre-emptive therapy for those with low levels of replicating virus; and (3) treatment for established disease. Despite the high prevalence of CMV, there are few available approved drug therapies, and those that are available are hampered by toxicity and less-than-optimal efficacy. New therapies are being developed and tested; however, inconsistency in standardisation of virus levels and questions about potential endpoints in clinical trials present regulatory hurdles that must be addressed. This review covers the current state of CMV therapy, drugs currently under investigation, and clinical trial issues and questions that are in need of resolution.


Assessment of required nodal yield in a high risk cohort undergoing extended pelvic lymphadenectomy in robotic-assisted radical prostatectomy and its impact on functional outcomes.
To establish a minimal lymph node yield (LNY) necessary for accurate staging in a high risk cohort, since no consensus exists as to the optimal extent of pelvic lymph node dissection (PLND) needed during radical prostatectomy in high risk patients. To investigate the impact of an extended PLND on urinary and sexual function. In all, 760 men underwent robotic-assisted radical prostatectomy from January 2010 to May 2011 by a single surgeon (AKT). Low and intermediate risk groups (as defined by the D'Amico classification) underwent a minimum of a limited PLND (obturator/external iliac packets) and high risk patients underwent an extended PLND (as limited plus hypogastric, triangle of Marcille and common iliac packets up to the level of the ureteric crossing). In order to analyse LNY for staging purposes, the high risk group (n = 82) was subdivided into patients with ≥13 LNY vs <13 LNY and the incidence of lymph node (LN) invasion was compared between these groups. To study the impact of extended PLND on functional outcomes, we evaluated patients from our total cohort who were preoperatively potent (Sexual Health Inventory for Men ≥17), continent and who received bilateral nerve-sparing surgery. Return to potency at 26 weeks postoperatively was defined as a score of ≥3 on questions 2 and 3 of the Sexual Health Inventory for Men questionnaire, and continence was defined as zero pads per day or one pad for security per day. Median LNYs in the low, intermediate and high risk groups were (interquartile range [IQR]) 5 (2-10), 7 (3-12) and 13 (6-20) (P < 0.001); LN positivity was 0% (0 of 309), 0.8% (3 of 369) and 13.4% (11 of 82) in the three respective groups (P < 0.001). Median LNYs (IQR) among the high risk LN positive and negative patients were 20 (13-22) and 11 (5-18) (P = 0.05); 5% of the patients had positive LNs in the <13 LNY group vs 21% of patients in the >13 LNY group (P = 0.036). Median (IQR) console time was significantly different, at 120 min (95-137) for the ≥13 LNY group vs 100 min (85-120) for the <13 LNY group (P = 0.04). Among patients who fitted the inclusion criteria for functional outcomes (n = 561), 55.2% (16 of 29) with ≥20 LNs removed recovered potency at a median follow-up of 6 months postoperatively vs 70% of patients with <20 LNs (301 of 430) (P = 0.020). There was no significant difference in continence recovery between the groups. High risk patients should undergo an extended dissection with at least 13 LNs removed for accurate staging. Extended PLND with LNYs of ≥20 is associated with worse potency outcomes. With LN positivity occurring rarely in low risk patients, extended PLND may be of little oncological benefit but with significant functional compromise in this cohort.


Polyembryony in non-apomictic citrus genotypes.
Adventitious embryony from nucellar cells is the mechanism leading to apomixis in Citrus sp. However, singular cases of polyembryony have been reported in non-apomictic genotypes as a consequence of 2x × 4x hybridizations and in vitro culture of isolated nucelli. The origin of the plants arising from the aforementioned processes remains unclear. The genetic structure (ploidy and allelic constitution with microsatellite markers) of plants obtained from polyembryonic seeds arising from 2x × 4x sexual hybridizations and those regenerated from nucellus culture in vitro was systematically analysed in different non-apomictic citrus genotypes. Histological studies were also conducted to try to identify the initiation process underlying polyembryony. All plants obtained from the same undeveloped seed in 2x × 4x hybridizations resulted from cleavage of the original zygotic embryo. Also, the plants obtained from in vitro nucellus culture were recovered by somatic embryogenesis from cells that shared the same genotype as the zygotic embryos of the same seed. It appears that in non-apomictic citrus genotypes, proembryos or embryogenic cells are formed by cleavage of the zygotic embryos and that the development of these adventitious embryos, normally hampered, can take place in vivo or in vitro as a result of two different mechanisms that prevent the dominance of the initial zygotic embryo.


Transcorneal electrical stimulation for patients with retinitis pigmentosa: a prospective, randomized, sham-controlled exploratory study.
To assess the safety of transcorneal electrical stimulation (TES) and explore its efficacy in various subjective and objective parameters of visual function in patients with retinitis pigmentosa (RP). Twenty-four patients in this prospective, randomized, partially blinded, good-clinical-practice study underwent TES (5-ms biphasic pulses; 20 Hz; DTL electrodes) 30 minutes per week for 6 consecutive weeks. The patients were randomly assigned to one of three groups: sham, 66%, or 150% of individual electrical phosphene threshold (EPT). Visual acuity (VA), visual field (VF; kinetic, static), electroretinography (Ganzfeld, multifocal), dark-adaptation (DA), color discrimination, and EPTs were assessed at all visits or four times, according to the study plan. TES using DTL electrodes was tolerated well; all patients finished the study. Two adverse (foreign body sensation), but no serious adverse events were encountered. There was a tendency for most functional parameters to improve (8/18) or to remain constant (8/18) in the 150% group. VF area and scotopic b-wave amplitude reached statistical significance (P < 0.027 and P < 0.001, respectively). Only desaturated color discrimination and VF mean sensitivity decreased. There was no obvious trend in the 66% group. TES was found to be safe in RP patients. Positive trends were discovered, but due to the small sample size of this exploratory study, statistical significance was reached only for VF area and scotopic b-wave amplitude. Further studies with larger sample sizes and longer duration are needed to confirm the findings and to define optimal stimulation parameters. (ClinicalTrials.gov number, NCT00804102.).


Tracking the evolution of alternatively spliced exons within the Dscam family.
The Dscam gene in the fruit fly, Drosophila melanogaster, contains twenty-four exons, four of which are composed of tandem arrays that each undergo mutually exclusive alternative splicing (4, 6, 9 and 17), potentially generating 38,016 protein isoforms. This degree of transcript diversity has not been found in mammalian homologs of Dscam. We examined the molecular evolution of exons within this gene family to locate the point of divergence for this alternative splicing pattern. Using the fruit fly Dscam exons 4, 6, 9 and 17 as seed sequences, we iteratively searched sixteen genomes for homologs, and then performed phylogenetic analyses of the resulting sequences to examine their evolutionary history. We found homologs in the nematode, arthropod and vertebrate genomes, including homologs in several vertebrates where Dscam had not been previously annotated. Among these, only the arthropods contain homologs arranged in tandem arrays indicative of mutually exclusive splicing. We found no homologs to these exons within the Arabidopsis, yeast, tunicate or sea urchin genomes but homologs to several constitutive exons from fly Dscam were present within tunicate and sea urchin. Comparing the rate of turnover within the tandem arrays of the insect taxa (fruit fly, mosquito and honeybee), we found the variants within exons 4 and 17 are well conserved in number and spatial arrangement despite 248-283 million years of divergence. In contrast, the variants within exons 6 and 9 have undergone considerable turnover since these taxa diverged, as indicated by deeply branching taxon-specific lineages. Our results suggest that at least one Dscam exon array may be an ancient duplication that predates the divergence of deuterostomes from protostomes but that there is no evidence for the presence of arrays in the common ancestor of vertebrates. The different patterns of conservation and turnover among the Dscam exon arrays provide a striking example of how a gene can evolve in a modular fashion rather than as a single unit.


How to not get stuck-negative feedback due to crowding maintains flexibility in ant foraging.
Ant foraging is an important model system in the study of adaptive complex systems. Many ants use trail pheromones to recruit nestmates to resources. Differential recruitment depending on resource quality coupled with positive feedback allows ant colonies to make rapid and accurate collective decisions about how best to allocate their work-force. However, ant colonies can become trapped in sub-optimal foraging decisions if recruitment to a poor resource becomes too strong before a better resource is discovered. Genetic algorithms and Ant Colony Optimisation heuristics can also suffer from being trapped in such local optima. Recently, two negative feedback effects were described, in which an increase in crowding (crowding negative feedback-CNF) or trail pheromones (pheromone negative feedback-PNF) caused a decrease in subsequent pheromone deposition. Using agent based simulations with realistic parameters I test whether these negative feedback effects can prevent simulated ant colonies from becoming trapped in sub-optimal foraging decisions. Colonies are presented with two food sources of different qualities, and these qualities switch part way through the experiment. When either no negative feedback effects are implemented or only PNF is implemented colonies are completely unable to refocus their foraging effort to the high quality feeder. However, when CNF alone is implemented at a realistic level 97% of colonies successfully refocus their foraging effort. This ability to refocus colony foraging efforts is due to the strong reduction of pheromone deposition caused by CNF. This suggests that CNF is an important behaviour enabling ant colonies to maintain foraging flexibility. However, CNF comes at a slight cost to colonies when making their initial foraging decision.


Third head of biceps brachii in an Indian population.
The biceps brachii is one of the muscles of the anterior compartment of the upper arm. It is characteristically described as a two-headed muscle that originates proximally by a long head and a short head. The present study was carried out to find the occurrence of a third head of biceps brachii among a sample Indian population from the southern coastal part. The arms of 42 cadavers were dissected and observed for variations in the origin and insertion of biceps brachii muscle bilaterally. The cadavers were embalmed and preserved in ten percent formalin. Among 42 arms studied, three had biceps brachii with three heads on the right side. The third head was of humeral origin, which inserted into the radial tuberosity by a common tendon with the long and short heads. The results of the present study compared with that of previous studies from medical literature shows that the occurrence of a third head of the biceps brachii muscle is relatively rare in Indians. Knowledge of the existence of the third head of biceps brachii may become significant in preoperative diagnosis and during surgery of the upper limb.