Cortico-basal ganglia pathways are essential for the recall of well-established visuomotor associations.
Recent human neuroimaging studies, supported by lesion studies with nonhuman primates, have suggested that learning arbitrary associations between sensory cues and behavioural responses requires interactions between the infero-temporal, prefrontal and premotor cortices. We directly tested the hypothesis suggested from our neuroimaging experiments that functional links between the basal ganglia and premotor cortex are involved in the process via which task performance becomes automatic. We made unilateral excitotoxic lesions, centred on the internal pallidum, in four macaques previously given extensive experience on the associations between nonspatial visual cues and movements of a joystick. The basal ganglia lesion was later combined with a premotor cortical lesion in the opposite hemisphere so as to interrupt the connections between them. Three of the animals were subsequently found to be impaired in relearning pre-operatively acquired associations; they eventually succeeded but made three-times as many errors. A fourth animal was unimpaired but its premotor cortex lesion was later found to be incomplete. Response times were only marginally increased and the learning of novel associations appeared relatively unaffected by these lesions. As a control, the effects of a unilateral premotor cortex lesion were assessed with two additional animals but this lesion did not result in a relearning impairment. We therefore suggest that when visuomotor associations have become well established through over-training, performance depends on connections between the basal ganglia and premotor cortex.


The 2009 Nobel conference on the role of genetics in promoting suicide prevention and the mental health of the population.
A 3-day Nobel Conference entitled 'The role of genetics in promoting suicide prevention and the mental health of the population' was held at the Nobel Forum, Karolinska Institute (KI) in Stockholm, Sweden, during 8-10 June 2009. The conference was sponsored by the Nobel Assembly for Physiology or Medicine and organized by the National Prevention for Suicide and Mental Ill-Health and the Center for Molecular Medicine at KI. The program consisted of 19 invited presentations, covering the genetic basis of mood/psychotic disorders and substance abuse in relation to suicide, with topics ranging from cellular-molecular mechanisms to (endo)phenotypes of mental disorders at the level of the individual and populations. Here, we provide an overview based on the highlights of what was presented.


The effect of dose expectancies on caffeine withdrawal symptoms during tapered dose reduction.
Negative expectancies can exacerbate withdrawal symptoms via the nocebo effect. As such, information provided about dose reductions during attempts to taper a drug could contribute to withdrawal symptoms and increase the likelihood of relapse. The current study tested whether blinding participants to dose reductions during a supervised caffeine dose taper reduced these nocebo-induced withdrawal symptoms. Three groups of moderate to heavy coffee drinkers had their dose of caffeine reduced (tapered) from 300 mg per day to 0 mg over the course of five days and reported withdrawal symptoms twice daily. Groups were given differing information about how much caffeine they were receiving. An Open Reduction group was given accurate information about dose reductions. A Blind Reduction group was given no dose information whatsoever. A Deceptive Reduction group was misinformed about dose, with instructions suggesting that the dose remained on 300 mg for three days then dropped to 0 mg. The Open Reduction group reported more pronounced caffeine withdrawal symptoms than the Deceptive Reduction group on the days with the greatest discrepancy between actual dose and informed dose, indicating a nocebo effect of open versus deceptive reductions. In addition, the rate of increase in reported withdrawal symptoms in the Blind Reduction and Deceptive Reduction groups was less than that of the Open Reduction group. These results suggest that awareness of dose reductions during a dose taper can result in a nocebo withdrawal effect, and that removing this awareness can reduce withdrawal. This has important implications for standard supervised dose-tapering practice, where patients are aware of the timing and magnitude of dose reductions.


Rotation-invariant texture retrieval via signature alignment based on steerable sub-Gaussian modeling.
This paper addresses the construction of a novel efficient rotation-invariant texture retrieval method that is based on the alignment in angle of signatures obtained via a steerable sub-Gaussian model. In our proposed scheme, we first construct a steerable multivariate sub-Gaussian model, where the fractional lower-order moments of a given image are associated with those of its rotated versions. The feature extraction step consists of estimating the so-called covariations between the orientation subbands of the corresponding steerable pyramid at the same or at adjacent decomposition levels and building an appropriate signature that can be rotated directly without the need of rotating the image and recalculating the signature. The similarity measurement between two images is performed using a matrix-based norm that includes a signature alignment in angle between the images being compared, achieving in this way the desired rotation-invariance property. Our experimental results show how this retrieval scheme achieves a lower average retrieval error, as compared to previously proposed methods having a similar computational complexity, while at the same time being competitive with the best currently known state-of-the-art retrieval system. In conclusion, our retrieval method provides the best compromise between complexity and average retrieval performance.


Validity and Usability of Physical Activity Monitoring in Patients with Chronic Obstructive Pulmonary Disease (COPD).
A large proportion of COPD patients do not achieve the recommended level of physical activity. It is suggested that feedback on the level of activity by using an activity monitoring device (PAM) increases awareness and may stimulate patients to increase their physical activity in daily life. Our objective was to assess the validity and usability of a simple and low-cost physical activity monitor (Polar A300™) when compared with the validated and established Bodymedia-SenseWear™ (SWA) device. To assess the diagnostic equivalent, two different PAM devices were used in parallel in 20 COPD patients GOLD I to IV during 3 consecutive days of daily life. Both systems were compared in terms of steps, calories burned, daily activity time and metabolic equivalents using linear regression analysis and Bland-Altman plots. Practical usability was examined by a 16-item-questionnaire. High correlations of both devices were observed with regard to the sensed step count (r = 0.96; p < 0.01) and calories burned (r = 0.74; p < 0.01), and a lower correlation of daily activity (r = 0.25; p < 0.01) was found. Data analysis over 3 days showed that 90% of the steps (95% CI -4223 to 1887), 100% of the calories (95% CI -2798 to 1887), 90% of the daily activity data (95% CI -12.32, 4065) and 95% of the MET (95% CI -3.11 to 2.75) were within the limits of agreement. A favorable usability (system-, information- and interface quality) of the A300™ device was shown (p < 0.01). The A300™ device with easy practical usability was shown not to be inferior for assessment of physical activity time, step count and calorie consumption in COPD patients when compared with the SWA. It is suggested to consider widespread available devices as commonly used for monitoring recreational sporting activities also in patients for assessment of physical activity in daily life.


Systematic reviews of surgical interventions.
All physicians are familiar with the type of general review articles found in many medical journals. Systematic reviews are different. They apply a strict, scientific methodology to the reviewing process to produce a review that is comprehensive, reliable, and as free from bias as possible. As a result, systematic reviews occupy the highest position in the "levels of evidence" tables associated with the practice of evidence-based health care. Systematic reviews relevant to surgery are no less relevant than systematic reviews in other areas of health care. They should be a prerequisite of any new research, a key component in decision making, and an opportunity for all surgical practitioners to get involved in the conduct and interpretation of research.


Structure determination of the 1918 H1N1 neuraminidase from a crystal with lattice-translocation defects.
Few examples of macromolecular crystals containing lattice-translocation defects have been published in the literature. Lattice translocation and twinning are believed to be two common but different crystal-growth anomalies. While the successful use of twinned data for structure determination has become relatively routine in recent years, structure determination of crystals with lattice-translocation defects has not often been reported. To date, only four protein crystal structures containing such a crystal defect have been determined, using corrected, but not uncorrected, intensity data. In this report, the crystallization, structure determination and refinement of N1 neuraminidase derived from the 1918 H1N1 influenza virus (18NA) at 1.65 A resolution are described. The crystal was indexed in space group C222(1), with unit-cell parameters a = 117.7, b = 138.5, c = 117.9 A, and the structure was solved by molecular replacement. The lattice-translocation vector in the 18NA crystal was (0, 1/2, 1/2) or its equivalent vector (1/2, 0, 1/2) owing to the C lattice symmetry. Owing to this special lattice-translocation vector in space group C222(1), structure refinement could be achieved in two different ways: using corrected or uncorrected diffraction data. In the refinement with uncorrected data, a composite model was built to represent the molecules in the translated and untranslated layers, respectively. This composite structure model provided a unique example to examine how the molecules were arranged in the two lattice domains resulting from lattice-translocation defects.


Plumage Genes and Little Else Distinguish the Genomes of Hybridizing Warblers.
When related taxa hybridize extensively, their genomes may become increasingly homogenized over time. This mixing via hybridization creates conservation challenges when it reduces genetic or phenotypic diversity and when it endangers previously distinct species via genetic swamping [1]. However, hybridization also facilitates admixture mapping of traits that distinguish each species and the associated genes that maintain distinctiveness despite ongoing gene flow [2]. We address these dual aspects of hybridization in the golden-winged/blue-winged warbler complex, two phenotypically divergent warblers that are indistinguishable using traditional molecular markers and that draw substantial conservation attention [3-5]. Whole-genome comparisons show that differentiation is extremely low: only six small genomic regions exhibit strong differences. Four of these divergence peaks occur in proximity to genes known to be involved in feather development or pigmentation: agouti signaling protein (ASIP), follistatin (FST), ecodysplasin (EDA), wingless-related integration site (Wnt), and beta-carotene oxygenase 2 (BCO2). Throat coloration-the most striking plumage difference between these warblers-is perfectly associated with the promoter region of agouti, and genotypes at this locus obey simple Mendelian recessive inheritance of the black-throated phenotype characteristic of golden-winged warblers. The more general pattern of genomic similarity between these warblers likely results from a protracted period of hybridization, contradicting the broadly accepted hypothesis that admixture results from solely anthropogenic habitat change in the past two centuries [4]. Considered in concert, these results are relevant to both the genetic architecture of avian feather pigmentation and the evolutionary history and conservation challenges associated with these declining songbirds.


Videokeratoscope-line-of-sight misalignment and its effect on measurements of corneal and internal ocular aberrations.
A growing number of research laboratories are using the new technologies of videokeratoscopy and Shack-Hartmann aberrometry, in combination, to study the optical structure of the human eye. A potential source of error arises, however, because the two instruments are designed to measure the human eye along different reference axes. The Shack-Hartmann aberrometer is usually aligned coaxially with the line of sight, but videokeratoscopes usually are not. Thus far, corneal optics research has not adequately addressed the problem of videokeratoscope-line-of-sight misalignment and its effect on the computation of corneal and internal ocular aberrations. We measured corneal, ocular, and internal aberrations for three normal human eyes, developed a method to compensate for videokeratoscope-line-of-sight misalignment, and analyzed the importance of compensating for the misalignment. Our results show that when the value of angle lambda (the angle between the line of sight and the pupillary axis) is larger than 2 degrees-3 degrees, the misalignment, if ignored, can lead to incorrect estimates of corneal and internal aberrations as well as the corneal/internal aberration balance.


Group treatment of fibromyalgia: a 6 month outpatient program.
To evaluate the impact of a 6 month group therapy program on the treatment of patients with fibromyalgia (FM). Since FM is a common problem in rheumatology practice, a program was designed to treat patients in a group setting using allied health professionals. The FM group (15 to 25 patients) met once a week for 6 months. The average session lasted 90 min and consisted of formal lectures, group sessions emphasizing behavior modification, stress reduction techniques, strategies to improve fitness and flexibility and support sessions for spouses/significant others. The 2 major outcome measures were the fibromyalgia impact questionnaire (FIQ) and the total tender point score. Secondary outcome measures were the quality of life scale, questionnaires to assess coping strategies and attitudes to illness, an index of aerobic conditioning, flexibility, distance walked in 6 min., Beck depression and Beck anxiety questionnaires. Patients were followed 2 years and compared to a group of patients outside the program. Between 1989 and 1993 170 patients were evaluated and 104 patients completed the program. At the end of the 6 months 73 (70%) of patients had <11 tender points and FIQ improved 25%. Having a pain profile on MMPI or having major depression, did not predict poorer outcome. Thirty-three patients followed for 2 years after the program continue to show improvement. A control group of 29 patients who never entered the program showed no significant improvement. The group treatment of patients with FM in an outpatient setting shows promise; a more formal controlled study is needed to confirm this impression.


Overexpression of DNA polymerase beta: a genomic instability enhancer process.
DNA polymerase beta (Pol beta) is the most inaccurate of the six DNA polymerases found in mammalian cells. In a normal situation, it is expressed at a constant low level and its role is believed to be restricted to repair synthesis in the base excision repair pathway participating to the genome stability. However, excess of Pol beta, found in some human tumors, could confer an increase in spontaneous mutagenesis and result in a highly mutagenic tolerance phenotype toward bifunctional DNA cross-linking anticancer drugs. Here, we present a hypothesis on the mechanisms used by Pol beta to be a genetic instability enhancer through its overexpression. We hypothesize that an excess of Pol beta perturbs the well-defined specific functions of DNA polymerases developed by the cell and propose Pol beta-mediated gap fillings during DNA transactions like repair, replication, or recombination pathways as key processes to introduce illegitimate deoxyribonucleotides or mutagenic base analogs like those produced by intracellular oxidative processes. These mechanisms may predominate during cellular nonproliferative phases in the absence of DNA replication.


Emerging multipotent aspects of hepatocyte growth factor.
Specific tissue interactions between epithelia and mesenchyme (or stroma), e.g., epithelial-mesenchymal (or -stromal) interactions mediate crucial aspects of normal development and tissue regeneration. These events affect tissue induction, organogenesis, cell movement, and morphogenesis of multicellular structures. Extensive and diverse studies have established that hepatocyte growth factor (HGF), a ligand for the c-met protooncogene product of receptor tyrosine kinase, is a mesenchymal- or stromal-derived multipotent polypeptide which mediates epithelial-mesenchymal interactions. During embryogenesis, HGF supports organogenesis and morphogenesis of various tissues and organs, including the liver, kidney, lung, gut, mammary gland, tooth, skeletal system, etc. In adult tissues, HGF elicits a potent organotrophic function which supports regeneration of organs including the liver, kidney, and lung. In the brain, HGF is a new member of the family of neurotrophic factors. In neoplastic tissue, HGF is involved in tumor invasion and metastasis, through tumor-stromal interactions. While HGF was originally identified as a potent mitogen for mature hepatocytes, the biological functions of this factor reach far beyond the original identifications. Such being the case, use of HGF for purposes of therapeutics is being given increasing attention.


Gene expression variation in duplicate lactate dehydrogenase genes: do ecological species show distinct responses?
Lactate dehydrogenase (LDH) has been shown to play an important role in adaptation of several aquatic species to different habitats. The genomes of Daphnia pulex, a pond species, and Daphnia pulicaria, a lake inhabitant, encode two L-LDH enzymes, LDHA and LDHB. We estimated relative levels of Ldh gene expression in these two closely related species and their hybrids in four environmental settings, each characterized by one of two temperatures (10°C or 20°C), and one of two concentrations of dissolved oxygen (DO; 6.5-7 mg/l or 2-3 mg/l). We found that levels of LdhA expression were 4 to 48 times higher than LdhB expression (p<0.005) in all three groups (the two parental species and hybrids). Moreover, levels of LdhB expression differed significantly (p<0.05) between D. pulex and D. pulicaria, but neither species differed from the hybrid. Consistently higher expression of LdhA relative to LdhB in both species and the hybrid suggests that the two isozymes could be performing different functions. No significant differences in levels of gene expression were observed among the four combinations of temperature and dissolved oxygen (p>0.1). Given that Daphnia dwell in environments characterized by fluctuating conditions with long periods of low dissolved oxygen concentration, we suggest that these species could employ regulated metabolic depression to survive in such environments.


Femtosecond parabolic pulse shaping in normally dispersive optical fibers.
Formation of parabolic pulses at femtosecond time scale by means of passive nonlinear reshaping in normally dispersive optical fibers is analyzed. Two approaches are examined and compared: the parabolic waveform formation in transient propagation regime and parabolic waveform formation in the steady-state propagation regime. It is found that both approaches could produce parabolic pulses as short as few hundred femtoseconds applying commercially available fibers, specially designed all-normal dispersion photonic crystal fiber and modern femtosecond lasers for pumping. The ranges of parameters providing parabolic pulse formation at the femtosecond time scale are found depending on the initial pulse duration, chirp and energy. Applicability of different fibers for femtosecond pulse shaping is analyzed. Recommendation for shortest parabolic pulse formation is made based on the analysis presented.


The networks of human gut microbe-metabolite associations are different between health and irritable bowel syndrome.
The goal of this study was to determine if fecal metabolite and microbiota profiles can serve as biomarkers of human intestinal diseases, and to uncover possible gut microbe-metabolite associations. We employed proton nuclear magnetic resonance to measure fecal metabolites of healthy children and those diagnosed with diarrhea-predominant irritable bowel syndrome (IBS-D). Metabolite levels were associated with fecal microbial abundances. Using several ordination techniques, healthy and irritable bowel syndrome (IBS) samples could be distinguished based on the metabolite profiles of fecal samples, and such partitioning was congruent with the microbiota-based sample separation. Measurements of individual metabolites indicated that the intestinal environment in IBS-D was characterized by increased proteolysis, incomplete anaerobic fermentation and possible change in methane production. By correlating metabolite levels with abundances of microbial genera, a number of statistically significant metabolite-genus associations were detected in stools of healthy children. No such associations were evident for IBS children. This finding complemented the previously observed reduction in the number of microbe-microbe associations in the distal gut of the same cohort of IBS-D children.


The Brain and Propranolol Pharmacokinetics in the Elderly.
Propranolol, a non-selective β-blocker, has been found to have a tremendous array of indications. Recent evidence has suggested that propranolol may be effective in patients suffering from post-traumatic stress disorder by suppressing activity in the amygdala and thereby inhibiting emotional memory formation. Dosage requirements have been well established in the pediatric and adult population, however, there has been no definitive geriatric dose recommended in the package inserts made available to the public. The aim of this paper is to use pharmacokinetic simulations in order to establish a pharmacokinetic profile dosage equivalent for the elderly as has been found in young patients. After completing the Monte-Carlo simulations for the elderly and young patients, a single 10mg dose in the elderly has shown comparable pharmacokinetic profiles as found in young patients administered a 40mg single dose.


Optogenetically induced behavioral and functional network changes in primates.
Optogenetics is currently the state-of-the-art method for causal-oriented brain research. Despite an increasingly large number of invertebrate and rodent studies showing profound electrophysiological and behavioral effects induced by optogenetics, only two primate studies have reported modulation of local single-cell activity but with no behavioral effects. Here, we show that optogenetic stimulation of cortical neurons within rhesus monkey arcuate sulcus, during the execution of a visually guided saccade task, evoked significant and reproducible changes in saccade latencies as a function of target position. Moreover, using concurrent optogenetic stimulation and opto-fMRI), we observed optogenetically induced changes in fMRI activity in specific functional cortical networks throughout the monkey brain. This is critical information for the advancement of optogenetic primate research models and for initiating the development of optogenetically based cell-specific therapies with which to treat neurological diseases in humans.


Genes for de novo biosynthesis of omega-3 polyunsaturated fatty acids are widespread in animals.
Marine ecosystems are responsible for virtually all production of omega-3 (ω3) long-chain polyunsaturated fatty acids (PUFA), which are essential nutrients for vertebrates. Current consensus is that marine microbes account for this production, given their possession of key enzymes including methyl-end (or "ωx") desaturases. ωx desaturases have also been described in a small number of invertebrate animals, but their precise distribution has not been systematically explored. This study identifies 121 ωx desaturase sequences from 80 species within the Cnidaria, Rotifera, Mollusca, Annelida, and Arthropoda. Horizontal gene transfer has contributed to this hitherto unknown widespread distribution. Functional characterization of animal ωx desaturases provides evidence that multiple invertebrates have the ability to produce ω3 PUFA de novo and further biosynthesize ω3 long-chain PUFA. This finding represents a fundamental revision in our understanding of ω3 long-chain PUFA production in global food webs, by revealing that numerous widespread and abundant invertebrates have the endogenous capacity to make significant contributions beyond that coming from marine microbes.


Teenage mothers.
Australia's teenage birth rate has fallen to historic lows, but teenage motherhood still occurs and can be challenging for mother and baby. The aim of this article is to review current evidence on the epidemiology and clinical care of teenage pregnancy and parenting, and provide recommendations around management of these young people in Australia. Teenage mothers may have experienced family, sexual, and partner violence, family disruption, and socioeconomic disadvantage. Outcomes on a range of peripartum measures are worse for teenage mothers and their babies. Longer term risks for the mother include depression and rapid repeat pregnancy; for the child, intergenerational teenage parenthood; and for both, socioeconomic disadvantage. Teenage motherhood occurs more often within communities where poverty, Aboriginal and Torres Strait Islander status and rural/remote location intersect. General practitioners play a critical role in identification of at-risk teens, preventing unintended teenage pregnancy, clinical care of pregnant teens, and promoting the health and wellbeing of teenage mothers and their children.


Attracting junior doctors to rural centres: A national study of work-life conditions and satisfaction.
Junior doctors, in their first four years of medical work, are an important part of the health care team. Attracting and retaining these doctors to rural areas underpins the development of the future rural workforce. This is the first national-scale study about satisfaction of junior doctors, based on their work location, to inform recruitment and retention. Repeat cross-sectional data 2008 and 2015, pooled for analysis. Medicine in Australia: Balancing Employment and Life survey. First responses of 4581 pre-vocational doctors working as interns up to their fourth postgraduate year. Differences between metropolitan and rural respondents in satisfaction and positivity on two inventories. Overall work satisfaction was approximately 85% amongst rural and metropolitan junior doctors, but controlling for other factors rural junior doctors had significantly higher overall satisfaction. Rural junior doctors were significantly more satisfied with their work-life balance, ability to obtain desired leave and leave at short notice, personal study time and access to leisure interests compared with metropolitan junior doctors. Metropolitan junior doctors were more satisfied with the network of doctors supporting them and the opportunities for family. While both metropolitan and rural junior doctors are generally satisfied, many professional and personal aspects of satisfaction differ considerably by work location. In order to attract early career doctors, the benefits of rural work should be emphasised and perceived weaknesses mitigated.


Weight gain of Kenyan school children infected with hookworm, Trichuris trichiura and Ascaris lumbricoides is improved following once- or twice-yearly treatment with albendazole.
We studied growth in infected children given one dose (600 mg) or two doses of albendazole per school year. Children were examined and allocated at random within sex by descending hookworm egg count to one of three groups: placebo (n = 93), one dose (1x, n = 96) or two doses (2x, n = 95). Each child was treated and then re-examined and treated 3.6 and 8.2 mo later (Exams 2 and 3). The 1x and 2x groups gained significantly more by Exam 3 than the placebo group in weight (1.1 and 0.9 kg more, respectively), percent weight-for-age (3.3 and 2.7 percentage points more), percent weight-for-height (3.1 and 2.9 percentage points more), percent arm circumference-for-age (2.3 and 2.0 percentage points more) and triceps and subscapular skinfolds but did not differ significantly from each other. The placebo group showed significant decreases between exams (P < 0.0002) in percent weight-for-age and percent arm circumference-for-age and no change in percent weight-for-height, whereas the 1x and 2x groups exhibited significant increases (P < 0.005). At Exam 3, arithmetic mean egg reduction rates for the 1x and 2x groups were 84 and 95% for hookworm, 42 and 32% for Trichuris and 55 and 87% for Ascaris, respectively. We conclude that one or two doses of albendazole per year resulted in similar growth improvements, despite reinfection, in school-age children in an area where these helminths and poor growth are prevalent.


Responsiveness of patient reported outcome measures in multiple sclerosis relapses: the REMS study.
To assess the responsiveness of the three most used patient reported multiple sclerosis (MS) specific questionnaires: the Functional Assessment of MS (FAMS), the MS Impact Scale (MSIS-29) and the 54 item MS Quality of Life (MSQOL-54). Prospective multicentre longitudinal study on 104 MS patients treated with intravenous steroids for clinical exacerbation. Patient reported data, Expanded Disability Status Scale (EDSS) score and clinical information were collected at admission and 8 weeks later. "Internal" (distribution based) responsiveness was assessed by standardised response means (SRM). "External" (anchor based) responsiveness was assessed by receiver operating characteristic (ROC) curves in relation to corresponding changes in a pre-specified reference measure (anchor). The pre-specified anchor was patients' self-reported recovery assessed on a 5 point Likert scale. SRM was 0.39 for FAMS, 0.58 for MSIS-29 physical scale, 0.45 for MSIS-29 psychological scale, 0.71 for MSQOL-54 physical health composite and 0.57 for MSQOL-54 mental health composite. Seventy-three patients (70%) reported they had improved; physicians agreed substantially with patient assessments (kappa statistic 0.70, 95% CI 0.54 to 0.85). Areas under ROC curves differed significantly from 0.50 only for the MSIS-29 and MSQOL-54 scales where areas ranged from 0.65 (95% CI 0.53 to 0.76) for the MSIS-29 psychological scale to 0.70 (95% CI 0.58 to 0.81) for the MSQOL-54 mental health composite. Areas under ROC curves assessed using a physician based anchor were similar to the patient based areas. The responsiveness of the MS specific instruments was less than ideal. The MSIS-29 and MSQOL-54 were significantly more responsive, using both distribution based and anchor based approaches, than FAMS, and should be preferred in longitudinal studies.


Melatonin and oxidative stress in melasma - an unexplored territory; a prospective study.
Melasma, an acquired disorder of hyperpigmentation, is the most common pigmentary disorder in India. Many factors are implicated in the pathogenesis, and recently the role of oxidative damage including melatonin has been postulated. This study was undertaken to evaluate the role of oxidative stress and serum melatonin in pathogenesis of melasma. Seventy-five patients with melasma and an equal number of age and sex-matched controls were included in the study. Clinical characteristics were noted, and baseline severity assessment using modified Melasma Area and Severity Index (MASI) was done in all patients. Serum melatonin, catalase, protein carbonyl, and nitric oxide levels were measured and compared between cases and controls. The serum levels of melatonin and catalase were significantly lower among the cases as compared to controls, while the serum levels of protein carbonyl and nitric oxide were significantly higher in cases compared to controls. There was no statistically significant correlation between these markers of oxidative stress and severity of the disease. Oxidative stress is increased in patients with melasma compared to the control group in this study. A state of melatonin deficit also exists in patients with melasma. No correlation between the oxidative stress and severity of the disease was found. Further and larger studies including therapeutic trials with powerful antioxidants are warranted.


A prospective study of the impact of child maltreatment and friend support on psychological distress trajectory: From adolescence to emerging adulthood.
Transition into adulthood is a critical developmental period that may be influenced by adverse life events as well as by protective factors. This study aimed at investigating the effect of different forms of child maltreatment experienced prior to age 14 (i.e., sexual abuse, physical abuse and exposure to intimate partner violence), and of friend support at age 14 on the psychological distress trajectory from age 14 to 24. Participants were 605 adolescents from the general population involved in a 10-year longitudinal study. Psychological distress was evaluated at ages 14, 16, 18 and 24. Child maltreatment prior to 14 years was retrospectively assessed at 14 and 24 years while perception of support from friends was evaluated at age 14. Multilevel growth modeling indicated that psychological distress followed a significant decreasing curvilinear trajectory, with participants reporting fewer distressing psychological symptoms after 18 years. All three forms of child maltreatment, as well as their cumulative effect, predicted more psychological distress over 10 years above and beyond the protective effect of support from friends. Higher support from friends at age 14 was related to lower distress at baseline andover 10 years, beyond the effect of child maltreatment. Self-report nature of all measures, attrition, and measures of child maltreatment forms. Psychological distress decreased during the transition from adolescence to emerging adulthood. Results also revealed the detrimental impact of child maltreatment and the promotive role of friend support, which underscore the importance of early intervention.


Evaluation of the Toxicity of Sugammadex in Zebrafish Larvae.
Sugammadex is a new neuromuscular blockade reversal agent. Recently, it has been used in patients under general anesthesia. However, sugammadex could be toxic to fetuses and pediatric patients under 3 years of age. In this study, we demonstrated the safety of sugammadex in fetuses, using zebrafish larvae. Furthermore, its neurotoxicity was evaluated using neuronal cell lines. We used SH-SY5Y cells to determine the viability of neuronal cells treated with sugammadex. Zebrafish larvae were used to determine the teratogenic effects of sugammadex. Sugammadex showed no adverse effects on neuronal cells and zebrafish larvae. The survival rates of neuronal cells were not different in all concentrations. In addition, the heart formation of zebrafish embryos, which were exposed to various concentrations of sugammadex, were not different. This study demonstrated the feasibility of using sugammadex during pregnancy. However, further clinical studies will be required to extrapolate these results to humans.


When Do Socioeconomic Resources Matter Most in Early Childhood?
Research has established the importance of early socioeconomic advantage and disadvantage for understanding later life outcomes, but less is known about change in the relationship between socioeconomic status (SES) and child development within the period of early childhood. Competing hypotheses drawn from the literature posited: (1) a stable SES-development relationship, (2) a stronger relationship in infancy than at older ages, and (3) a stronger relationship at school entry than at younger ages. Using the nationally representative Early Childhood Longitudinal Study-Birth Cohort (2001-2007), we followed 8600 children from infancy through kindergarten entry to model change over time in the relationship between socioeconomic status and cognitive and behavioral development. The unexpected main finding was that the relationships between three socioeconomic measures (household income, assets, and maternal educational attainment) strengthened from infancy through age 4 or 4½, then weakened slightly until the start of kindergarten. Indirect evidence suggested preschool education as one possible explanation. We argue for researchers to expand the school transition concept to include the now widespread prekindergarten year, as well as for attention to psychological and physiological developmental factors that may shape the relationship between SES and cognitive and behavioral development throughout early childhood.


Transomics analysis reveals allosteric and gene regulation axes for altered hepatic glucose-responsive metabolism in obesity.
Impaired glucose tolerance associated with obesity causes postprandial hyperglycemia and can lead to type 2 diabetes. To study the differences in liver metabolism in healthy and obese states, we constructed and analyzed transomics glucose-responsive metabolic networks with layers for metabolites, expression data for metabolic enzyme genes, transcription factors, and insulin signaling proteins from the livers of healthy and obese mice. We integrated multiomics time course data from wild-type and leptin-deficient obese (ob/ob) mice after orally administered glucose. In wild-type mice, metabolic reactions were rapidly regulated within 10 min of oral glucose administration by glucose-responsive metabolites, which functioned as allosteric regulators and substrates of metabolic enzymes, and by Akt-induced changes in the expression of glucose-responsive genes encoding metabolic enzymes. In ob/ob mice, the majority of rapid regulation by glucose-responsive metabolites was absent. Instead, glucose administration produced slow changes in the expression of carbohydrate, lipid, and amino acid metabolic enzyme-encoding genes to alter metabolic reactions on a time scale of hours. Few regulatory events occurred in both healthy and obese mice. Thus, our transomics network analysis revealed that regulation of glucose-responsive liver metabolism is mediated through different mechanisms in healthy and obese states. Rapid changes in allosteric regulators and substrates and in gene expression dominate the healthy state, whereas slow changes in gene expression dominate the obese state.


25th anniversary article: polymer-particle composites: phase stability and applications in electrochemical energy storage.
Polymer-particle composites are used in virtually every field of technology. When the particles approach nanometer dimensions, large interfacial regions are created. In favorable situations, the spatial distribution of these interfaces can be controlled to create new hybrid materials with physical and transport properties inaccessible in their constituents or poorly prepared mixtures. This review surveys progress in the last decade in understanding phase behavior, structure, and properties of nanoparticle-polymer composites. The review takes a decidedly polymers perspective and explores how physical and chemical approaches may be employed to create hybrids with controlled distribution of particles. Applications are studied in two contexts of contemporary interest: battery electrolytes and electrodes. In the former, the role of dispersed and aggregated particles on ion-transport is considered. In the latter, the polymer is employed in such small quantities that it has been historically given titles such as binder and carbon precursor that underscore its perceived secondary role. Considering the myriad functions the binder plays in an electrode, it is surprising that highly filled composites have not received more attention. Opportunities in this and related areas are highlighted where recent advances in synthesis and polymer science are inspiring new approaches, and where newcomers to the field could make important contributions.


Whole-genome sequencing demonstrates that fidaxomicin is superior to vancomycin for preventing reinfection and relapse of infection with Clostridium difficile.
Whole-genome sequencing was used to determine whether the reductions in recurrence of Clostridium difficile infection observed with fidaxomicin in pivotal phase 3 trials occurred by preventing relapse of the same infection, by preventing reinfection with a new strain, or by preventing both outcomes. Paired isolates of C. difficile were available from 93 of 199 participants with recurrences (28 were treated with fidaxomicin, and 65 were treated with vancomycin). Given C. difficile evolutionary rates, paired samples ≤2 single-nucleotide variants (SNVs) apart were considered relapses, paired samples >10 SNVs apart were considered reinfection, and those 3-10 SNVs apart (or without whole-genome sequences) were considered indeterminate in a competing risks survival analysis. Fidaxomicin reduced the risk of both relapse (competing risks hazard ratio [HR], 0.40 [95% confidence interval {CI}, .25-.66]; P = .0003) and reinfection (competing risks HR, 0.33 [95% CI, 0.11-1.01]; P = .05).


Poroelasticity-driven lubrication in hydrogel interfaces.
It is widely accepted that hydrogel surfaces are slippery, and have low friction, but dynamic applied stresses alter the hydrogel composition at the interface as water is displaced. The induced osmotic imbalance of compressed hydrogel which cannot swell to equilibrium should drive the resistance to slip against it. This paper demonstrates the driving role of poroelasticity in the friction of hydrogel-glass interfaces, specifically how poroelastic relaxation of hydrogels increases adhesion. We translate the work of adhesion into an effective surface energy density that increases with the duration of applied pressure from 10 to 50 mJ m-2, as measured by micro-indentation. A model of static friction coefficient is derived from an area-based rules of mixture for the surface energies, and predicts the friction coefficient changes upon initiation of slip. For kinetic friction, the competition between duration of contact and relaxation time is quantified by a contacting Péclet number, PeC. A single length parameter on the scale of micrometers fits these two models to experimental micro-friction data. These models predict how short durations of applied pressure and faster sliding speeds, do not disrupt interfacial hydration; this prevailing water maintains low friction. At low speeds where interface drainage dominates, the osmotic suction works against slip for higher friction. The prediction of friction coefficients after adhesion characterization by micro-indentation makes use of the interplay between poroelasticity, adhesion, and friction. This approach provides a starting point for prediction of, and design for, hydrogel interfacial friction.


Developmental control of allelic methylation in the imprinted mouse Igf2 and H19 genes.
The Insulin-like growth factor 2 (Igf2) and H19 genes are reciprocally imprinted and closely linked. Igf2 encodes a fetal growth-factor and is predominantly expressed from the paternal allele, while H19 is expressed from the maternal allele and encodes a transcript which may downregulate cellular proliferation. One of the epigenetic modifications thought to be involved in parental imprinting is DNA methylation. Here we analyse methylation in two regions of the Igf2 gene, one approx. 3 kb upstream of the gene and one in the 3' part of the gene. Both regions are more methylated on the expressed paternal chromosome. Genomic sequencing of individual chromosomes in the first region shows this parent-specific methylation to be highly mosaic; interestingly, individual sperm chromosomes carry different methylation patterns into the egg. In the more 3' region, which is fully methylated in sperm, the level of methylation on the paternal allele is highly tissue-specific and is correlated with expression of the gene in fetal tissues. Hence, the paternal allele is highly methylated in fetal liver (high expression) but is undermethylated in fetal brain (virtually no expression). Adult choroid plexus, a brain tissue in which Igf2 is expressed from both alleles and H19 is not expressed, represents an apparent loss of imprinting. Here, both Igf2 and H19 adopt a paternal type methylation pattern on both parental chromosomes. Analysis of early-passage androgenetic and parthenogenetic embryonic stem (ES) cells shows that the methylation patterns of Igf2 and H19 on maternal and paternal chromosomes are very similar. Androgenetic and parthenogenetic teratomas derived from these ES cells show the appropriate paternal and maternal patterns, respectively, of allelic methylation in both genes. Our results suggest that allelic methylation patterns in Igf2 and H19 arise early in embryogenesis and change progressively during development. Some of these developmental changes are apparently under tissue-specific control.


A three-year dataset supporting research on building energy management and occupancy analytics.
This paper presents the curation of a monitored dataset from an office building constructed in 2015 in Berkeley, California. The dataset includes whole-building and end-use energy consumption, HVAC system operating conditions, indoor and outdoor environmental parameters, as well as occupant counts. The data were collected during a period of three years from more than 300 sensors and meters on two office floors (each 2,325 m2) of the building. A three-step data curation strategy is applied to transform the raw data into research-grade data: (1) cleaning the raw data to detect and adjust the outlier values and fill the data gaps; (2) creating the metadata model of the building systems and data points using the Brick schema; and (3) representing the metadata of the dataset using a semantic JSON schema. This dataset can be used in various applications-building energy benchmarking, load shape analysis, energy prediction, occupancy prediction and analytics, and HVAC controls-to improve the understanding and efficiency of building operations for reducing energy use, energy costs, and carbon emissions.


Combining biomarkers to detect disease with application to prostate cancer.
In early detection of disease, combinations of biomarkers promise improved discrimination over diagnostic tests based on single markers. An example of this is in prostate cancer screening, where additional markers have been sought to improve the specificity of the conventional Prostate-Specific Antigen (PSA) test. A marker of particular interest is the percent free PSA. Studies evaluating the benefits of percent free PSA reflect the need for a methodological approach that is statistically valid and useful in the clinical setting. This article presents methods that address this need. We focus on and-or combinations of biomarker results that we call logic rules and present novel definitions for the ROC curve and the area under the curve (AUC) that are applicable to this class of combination tests. Our estimates of the ROC and AUC are amenable to statistical inference including comparisons of tests and regression analysis. The methods are applied to data on free and total PSA levels among prostate cancer cases and matched controls enrolled in the Physicians' Health Study.


Strategies of a Bornean tropical rainforest water use as a function of rainfall regime: isohydric or anisohydric?
Although Bornean tropical rainforests are among the moistest biomes in the world, they sporadically experience periods of water stress. The observations indicate that these ecosystems tend to have little regulation of water use, despite episodes of relatively severe drought. This water-use behaviour is often referred to as anisohydric behaviour, as opposed to isohydric plants that regulate stomatal movement to prevent hydraulic failure. Although it is generally thought that anisohydric behaviour is an adaptation to more drought-prone habitats, we show that anisohydric plants may also be more favoured than isohydric plants under very moist environments where there is little risk of hydraulic failure. To explore this subject, we examined the advantages of isohydric and anisohydric species as a function of the hydroclimatic environment using a stochastic model of soil moisture and carbon assimilation dynamics parameterized by field observations. The results showed that under very moist conditions, anisohydric species tend to have higher productivity than isohydric plants, despite the fact that the two plant types show almost the same drought-induced mortality. As precipitation decreases, the mortality of anisohydric plants drastically increases whereas that of isohydric plants remains relatively constant and low; in these conditions, isohydric plants surpass anisohydric plants in their productivity.


Immunologic injury of renal homografts.
Rejection of renal allografts in man and animals is most frequently induced by cell-mediated immunity, the morphologic hallmark of which is the infiltration of the graft by mononuclear cells. In some presensitized recipients rejection may be mediated by humoral transplantation antibodies, and this is characterized clinically by a rapid tempo of rejection and morphologically by accumulation of polymorphonuclear neutrophils and renal cortical necrosis. In recipients treated with immunosuppressive drugs, most renal allografts function well for over 1 yr. However, late deterioration is observed in many grafts. This may take the form of proliferative glomerulonephritis with accumulation of immunoglobulin and complement along glomerular basement membranes. This glomerular lesion of the graft may be of immunologic nature without being rejection. In many instances the glomerular lesion may be due to recurrence of the original disease of the recipient. In other instances it may represent a de novo immunologic process induced by the response to antigens shared by the graft and recipient as evidenced by animal experiments. The glomerular lesion in the graft may also be caused by humoral transplantation antibodies. Therefore, the final outcome of the renal transplantation may to a great extent depend on the strength of transplantation antibody response, being more favorable for low than high responders.


In Vitro Studies on Zinc Binding and Buffering by Intestinal Mucins.
The investigation of luminal factors influencing zinc availability and accessibility in the intestine is of great interest when analyzing parameters regulating intestinal zinc resorption. Of note, intestinal mucins were suggested to play a beneficial role in the luminal availability of zinc. Their exact zinc binding properties, however, remain unknown and the impact of these glycoproteins on human intestinal zinc resorption has not been investigated in detail. Thus, the aim of this study is to elucidate the impact of intestinal mucins on luminal uptake of zinc into enterocytes and its transfer into the blood. In the present study, in vitro zinc binding properties of mucins were analyzed using commercially available porcine mucins and secreted mucins of the goblet cell line HT-29-MTX. The molecular zinc binding capacity and average zinc binding affinity of these glycoproteins demonstrates that mucins contain multiple zinc-binding sites with biologically relevant affinity within one mucin molecule. Zinc uptake into the enterocyte cell line Caco-2 was impaired by zinc-depleted mucins. Yet this does not represent their form in the intestinal lumen in vivo under zinc adequate conditions. In fact, zinc-uptake studies into enterocytes in the presence of mucins with differing degree of zinc saturation revealed zinc buffering by these glycoproteins, indicating that mucin-bound zinc is still available for the cells. Finally, the impact of mucins on zinc resorption using three-dimensional cultures was studied comparing the zinc transfer of a Caco-2/HT-29-MTX co-culture and conventional Caco-2 monoculture. Here, the mucin secreting co-cultures yielded higher fractional zinc resorption and elevated zinc transport rates, suggesting that intestinal mucins facilitate the zinc uptake into enterocytes and act as a zinc delivery system for the intestinal epithelium.


Salt stress affects cortical microtubule organization and helical growth in Arabidopsis.
Cortical microtubule arrays are critical in determining the growth axis of diffusely growing plant cells, and various environmental and physiological factors are known to affect the array organization. Microtubule organization is partly disrupted in the spiral1 mutant of Arabidopsis thaliana, which displays a right-handed helical growth phenotype in rapidly elongating epidermal cells. We show here that mutations in the plasma membrane Na(+)/H(+) antiporter SOS1 and its regulatory kinase SOS2 efficiently suppressed both microtubule disruption and helical growth phenotypes of spiral1, and that sos1 and sos2 roots in the absence of salt stress exhibited altered helical growth response to microtubule-interacting drugs at low doses. Salt stress also altered root growth response to the drugs in wild-type roots. Suppression of helical growth appeared to be specific to spiral1 since other helical growth mutants were not rescued. The effects of sos1 in suppressing spiral1 defects and in causing abnormal drug responses were nullified in the presence of the hkt1 Na(+) influx carrier mutation in roots but not in hypocotyls. These results suggest that cytoplasmic salt imbalance caused by insufficient SOS1 activity compromises cortical microtubule functions in which microtubule-localized SPIRAL1 is specifically involved.


Circumstances in which parsimony but not compatibility will be provably misleading.
Phylogenetic methods typically rely on an appropriate model of how data evolved in order to infer an accurate phylogenetic tree. For molecular data, standard statistical methods have provided an effective strategy for extracting phylogenetic information from aligned sequence data when each site (character) is subject to a common process. However, for other types of data (e.g., morphological data), characters can be too ambiguous, homoplastic, or saturated to develop models that are effective at capturing the underlying process of change. To address this, we examine the properties of a classic but neglected method for inferring splits in an underlying tree, namely, maximum compatibility. By adopting a simple and extreme model in which each character either fits perfectly on some tree, or is entirely random (but it is not known which class any character belongs to) we are able to derive exact and explicit formulae regarding the performance of maximum compatibility. We show that this method is able to identify a set of non-trivial homoplasy-free characters, when the number [Formula: see text] of taxa is large, even when the number of random characters is large. In contrast, we show that a method that makes more uniform use of all the data-maximum parsimony-can provably estimate trees in which none of the original homoplasy-free characters support splits.


Enhancement of the Auditory Late Response (N1-P2) by Presentation of Stimuli From an Unexpected Location.
Passive electrophysiological protocols, such as the middle latency response and speech auditory brainstem response, are often advocated in the objective assessment of central auditory processing disorder (CAPD). However, few established electrophysiological protocols exist for CAPD assessment that have patients participate in active tasks which more closely approximate real-world listening. To this end, the present study used a discrimination task (i.e., oddball paradigm) to measure an enhancement of the auditory late response (N1-P2) that occurs when participants direct their auditory attention toward speech arising from an unexpected spatial location. To establish whether N1-P2 is enhanced when auditory attention is directed toward an unexpected location during a two-word discrimination task. In addition, it was also investigated whether any enhancements in this response were contingent on the stimulus being counted as part of the oddball paradigm. Prospective study with a repeated measures design. Ten normal hearing adults, with an age range of 18-24 years. The N1 and P2 latencies and peak-to-peak amplitudes were recorded during a P300 paradigm. A series of repeated measures of analysis of variance and a correlation analysis was performed. There was a significant effect of stimulus location, in which words arising from the unexpected location showed a larger N1-P2 peak-to-peak amplitude and an earlier N1 latency. This effect was seen regardless of whether or not participants had to count the word total in memory. These findings suggest that spatial enhancement of the N1-P2 is a fairly robust phenomenon in normal hearing adult listeners. Additional studies are needed to determine whether this enhancement is absent or reduced in patients with CAPD.


Congenital adrenal hyperplasia due to 21-hydroxylase deficiency.
More than 90% of cases of congenital adrenal hyperplasia (CAH, the inherited inability to synthesize cortisol) are caused by 21-hydroxylase deficiency. Females with severe, classic 21-hydroxylase deficiency are exposed to excess androgens prenatally and are born with virilized external genitalia. Most patients cannot synthesize sufficient aldosterone to maintain sodium balance and may develop potentially fatal "salt wasting" crises if not treated. The disease is caused by mutations in the CYP21 gene encoding the steroid 21-hydroxylase enzyme. More than 90% of these mutations result from intergenic recombinations between CYP21 and the closely linked CYP21P pseudogene. Approximately 20% are gene deletions due to unequal crossing over during meiosis, whereas the remainder are gene conversions--transfers to CYP21 of deleterious mutations normally present in CYP21P. The degree to which each mutation compromises enzymatic activity is strongly correlated with the clinical severity of the disease in patients carrying it. Prenatal diagnosis by direct mutation detection permits prenatal treatment of affected females to minimize genital virilization. Neonatal screening by hormonal methods identifies affected children before salt wasting crises develop, reducing mortality from this condition. Glucocorticoid and mineralocorticoid replacement are the mainstays of treatment, but more rational dosing and additional therapies are being developed.


Schizophrenia: a disorder of neurodevelopment?
For the first time, there is a pathogenic hypothesis of schizophrenia based upon reasonable empirical data. The hypothesis is that schizophrenia is a disorder arising from aberrant brain development. The neurodevelopmental view of schizophrenia is supported by neuropathological, epidemiological and clinical findings. Here, the evidence in favour of the model is summarized, together with a consideration of its weaknesses.


The effect of transmitted HIV-1 drug resistance on pre-therapy viral load.
Reduced replication capacity of viruses expressing drug resistant mutations implies that patients with transmitted drug resistance (TDR) could have lower HIV RNA viral load than those infected with wild-type virus. We performed analysis using data from the UK HIV Drug Resistance Database and the UK CHIC study. Eligible patients had a resistance test performed between 1997 and 2007 while naive to antiretroviral therapy, were 16 years or older, and had a viral load and CD4 cell count measurement within 6 months of this test. Models were adjusted for CD4 cell count, viral subtype, ethnicity, risk group, sex, age, calendar year, clinical centre, and viral load assay. Of a total of 7994 patients included, 709 (9%) had TDR: 604 (85%) had resistance to one drug class only [350 nucleos(t)ide reverse transcriptase inhibitors (NRTIs), 164 non-nucleos(t)ide reverse transcriptase inhibitors (NNRTIs), 90 protease inhibitors (PIs)], 77 (11%) to two classes (42 NRTIs/NNRTIs, 31 NRTIs/PIs, 4 NNRTIs/PIs), and 28 (4%) had resistance to all three classes. The overall mean (SD) viral load at the time of resistance testing was 4.60 (0.82) log(10) copies/ml, and did not differ by class of TDR. However, patients harbouring M184V/I (n = 61) had a significantly lower viral load [adjusted mean difference -0.33 log10 copies/ml (95% CI -0.54 to -0.11), 53% lower (95% CI 22 to 71%), P = 0.002] compared to wild-type virus. Our study provides clear evidence of an in-vivo fitness cost associated with the M184V/I mutation independent of drug effects which select for this mutation. This was not observed for any other mutation, but true effects may have been obscured by reversion of initially resistant viruses to wild-type.


Validation of the Edinburgh Cognitive and Behavioural Amyotrophic Lateral Sclerosis Screen (ECAS): A cognitive tool for motor disorders.
Our objective was to assess the validity of the Edinburgh Cognitive and Behaviour ALS Screen (ECAS), a multi-domain screen designed to detect cognitive deficits in patients with motor disorders. Forty ALS patients (without pre-diagnosed dementia) and 40, age-, gender- and education-matched healthy controls were recruited. All participants underwent extensive neuropsychological assessment and the ECAS. Performance at neuropsychological assessment across five domains (fluency, executive function, language, memory and visuospatial function) was compared to the ECAS ALS-Specific (fluency, executive functions and social cognition, language), ALS Non-specific (memory, visuospatial functions), and Total scores. Data from the healthy controls produced population-based abnormality cut-offs: composite score performance ≤ 2 SD in any domain classified impairment at neuropsychological assessment. Thirty-three percent of patients were impaired, most commonly in a single domain (executive or language dysfunction). Receiver Operator Curve (ROC) analyses using ECAS Total scores and ALS-Specific scores revealed 85% sensitivity and 85% specificity in the detection of cognitive impairment characteristic of ALS (fluency, executive function, language). A five-point borderline range produced optimal values (ALS-Specific Score 77-82, and ECAS-Total Score 105-110). In conclusion, validation against gold standard extensive neuropsychology demonstrated that the ECAS is a screening tool with high sensitivity and specificity to impairment characteristic of ALS.


Helix induction in antimicrobial peptides by alginate in biofilms.
Bacterial exopolysaccharides provide protection against phagocytosis, opsonization, and dehydration and act as a major structural component of the extracellular matrix in biofilms. They contribute to biofilm-related resistance by acting as a diffusion barrier to positively charged antimicrobial agents including cationic antimicrobial peptides (CAPs). We previously created novel CAPs consisting of a nonamphipathic hydrophobic core flanked by Lys residues and containing a Trp residue in the hydrophobic segment as a fluorescent probe. Peptides of this type above a specific hydrophobicity threshold insert spontaneously into membranes and have antimicrobial activity against Gram-positive and Gram-negative bacteria at micromolar concentrations. Here we show that alginate, a polymer of beta-d-mannuronate and alpha-l-guluronate secreted by the cystic fibrosis pathogen Pseudomonas aeruginosa, induces an alpha-helical conformation detected by circular dichroism spectroscopy and blue shifts in Trp fluorescence maxima in peptides above the hydrophobicity threshold, changes typically observed upon association of such peptides with nonpolar (membrane) environments. Parallel effects were observed in the archetypical CAPs magainin II amide and cecropin P1. Fluorescence resonance energy transfer studies indicated that alginate induces peptide-peptide association only in peptides above the hydrophobicity threshold, suggesting that the hydrophilic alginate polymer behaves as an "auxiliary membrane" for the bacteria, demonstrating a unique protective role for biofilm matrices against CAPs.


Control by H-2 genes of the Th1 response induced against a foreign antigen expressed by attenuated Salmonella typhimurium.
Attenuated salmonellae represent an attractive vehicle for the delivery of heterologous protective antigens to the immune system. Here, we have investigated the influence of the genetic background of the host which regulates the growth and elimination of Salmonella cells on the cellular response induced against a foreign antigen delivered by an aroA Salmonella strain. We have tested CD4+ T-cell responses (cell proliferation and cytokine production) in various mouse strains following immunization with Salmonella typhimurium SL3261 expressing a high level of the recombinant Escherichia coli MalE protein. We were able to detect a CD4+ T-cell response against the recombinant MalE protein only in a restricted number of mouse strains, whereas all mice produced good levels of anti-MalE immunoglobulin G antibodies. The Ity gene did not play a major role in these differences in T-cell responses, since both Ity-resistant and -susceptible strains of mice were found to be unresponsive to MalE delivered by recombinant salmonellae. In contrast, when B10 congenic mice were used, a correlation was established between MalE-specific T-cell unresponsiveness and H-2 genes. The discrepancies described in this paper in the ability of various strains of mice to develop an efficient Th1 response against a recombinant antigen displayed by a live Salmonella vaccine underscore the difficulties that can be encountered in the vaccination of human populations by such a strategy.


Partitioning an object-oriented terminology schema.
Controlled medical terminologies are increasingly becoming strategic components of various healthcare enterprises. However, the typical medical terminology can be difficult to exploit due to its extensive size and high density. The schema of a medical terminology offered by an object-oriented representation is a valuable tool in providing an abstract view of the terminology, enhancing comprehensibility and making it more usable. However, schemas themselves can be large and unwieldy. We present a methodology for partitioning a medical terminology schema into manageably sized fragments that promote increased comprehension. Our methodology has a refinement process for the subclass hierarchy of the terminology schema. The methodology is carried out by a medical domain expert in conjunction with a computer. The expert is guided by a set of three modeling rules, which guarantee that the resulting partitioned schema consists of a forest of trees. This makes it easier to understand and consequently use the medical terminology. The application of our methodology to the schema of the Medical Entities Dictionary (MED) is presented.


Recombinant polypeptide from the endonuclease region of the acquired immune deficiency syndrome retrovirus polymerase (pol) gene detects serum antibodies in most infected individuals.
Sera from the majority of individuals that were positive in an enzyme-linked immunosorbent assay (ELISA) retrovirus (ARV), an isolate of the for antibodies to acquired immune deficiency syndrome (AIDS)-associated retrovirus (ARV), an isolate of the retrovirus identified as the etiologic agent of AIDS, were found to react with a 31,000-dalton protein (p31) in virus Western blot assays. To determine if this 31,000-dalton immunoreactive species originated from the putative endonuclease region of the polymerase (pol) gene of ARV, we cloned this portion of pol into bacterial expression vectors for direct expression and for expression as a fusion protein with human superoxide dismutase. Transformants from both constructions expressed immunoreactive protein detected in immunoblots with an AIDS patient's serum. Extracts from transformants expressing these sequences competed with the binding of antibodies from AIDS patients' sera to the 31,000-dalton protein in virus immunoblots, confirming that viral p31 originated from the endonuclease domain of the ARV polymerase gene. The superoxide dismutase-p31 fusion protein was purified, and an ELISA for detecting antibodies to p31 was developed. The majority (95%) of serum samples obtained from individuals seropositive in the virus ELISA were also positive in the p31 antibody ELISA.


CD14++ monocytes, CD14+/CD16+ subset and soluble CD14 as biological markers of inflammatory systemic diseases and monitoring immunosuppressive therapy.
The majority of peripheral blood monocytes strongly positive for the lipopolysaccharides (LPS)-receptor CD14 are negative for Fcgamma receptor type III (CD16). However, a subset of monocytes coexpressing CD14 and CD16 accounts for about 8% of all monocytes. This population exhibits features of tissue macrophages, and is largely expanded (> 20%) during acute and chronic inflammatory diseases including cases with pararheumatic systemic vasculitis. In addition, compared to normal controls, soluble CD14 (sCD14) is elevated (> 3 microg/ml) in serum specimens of these patients. CD14+/CD16+ monocytes show a higher phagocytosis rate than CD14+/CD16 negative cells, and express higher levels of interleukin-1 and major histocompatibility complex, such as histocompatibility antigens HLA-DR, -DP and -DQ antigens. Glucocorticoids downregulate expression of CD14 and rapidly deplete CD14+/CD16+ monocytes from peripheral blood. Patients under chronic immunosuppressive therapy exhibit low CD14/+/CD16+ rates, which may rise during infectious and non-infectious inflammatory complications, however. Thus, serial analyses for sCD14 and the proinflammatory CD14+/CD16+ subset of monocytes suggest a valuable tool monitoring patients under immunosuppressive and/or antiinflammatory therapy.


Setting standards of prescribing performance in primary care: use of a consensus group of general practitioners and application of standards to practices in the north of England.
There is considerable variation in prescribing, and existing standards against which primary care prescribing is routinely judged consist largely of local or national averages. There is thus a need for more sophisticated standards, which must be widely applicable and have credibility among the general practice profession. A study aimed to develop a range of criteria of prescribing quality, to set standards of performance for these criteria, and apply these standards to practices. A consensus group consisting of eight general practitioners and a resource team was convened to develop and define criteria and set standards of prescribing performance using prescribing analyses and cost (PACT) data. The standards were applied to 1992-93 prescribing data from all 518 practices in the former Northern Regional Health Authority. The group developed criteria and set numeric standards for 13 aspects of prescribing performance in four areas: generic prescribing, prescribing within specific therapeutic groups, drugs of limited clinical value and standards based on prescribing volume. Except for generic prescribing, standards for individual criteria were achieved by between 9% and 34% of practices. For each criterion, a score was allocated based on whether the standard was achieved or not. Total scores showed considerable variation between practices. The distribution of scores was similar between fundholding and non-fundholding practices, and also between dispensing and non-dispensing practices. Using a consensus group of general practitioners it is possible to agree criteria and standards of prescribing performance. This novel approach offers a professionally driven method for assessing the quality of prescribing in primary care.


Analysis of HIV-1 protease gene reveals frequent multiple infections followed by recombination among drug treated individuals living in São Paulo and Santos, Brazil.
The present study investigated the prevalence of HIV-1 multiple infections in a population composed by 47 patients under HAART failure and enrolled at the National DST/AIDS, Program, Ministry of Health, Brazil.Detection of multiple infections was done using a previously published RFLP assay for the HIV-1 protease gene, which is able of distinguishing between infections caused by a single or multiple HIV-1 subtypes. Samples with multiple infections were cloned, and sequence data submitted to phylogenetic analysis. We were able to identify 17 HIV-1 multiple infections out of 47 samples. Multiple infections were mostly composed by a mixture of recombinant viruses (94%), with only one case in which protease gene pure subtypes B and F were recovered. This is the first study that reports the prevalence of multiple infections and intersubtype recombinants in a population undergoing HAART in Brazil. Based on the data there was a steep increase of multiple infections after the introduction of the combined antiretroviral therapy in Brazil. Cases of multiple infections may be associated with HIV-1 genetic diversity through recombination allowing for the generation of viruses showing a combination of resistance mutations.


The Stealthy Superbug: the Role of Asymptomatic Enteric Carriage in Maintaining a Long-Term Hospital Outbreak of ST228 Methicillin-Resistant Staphylococcus aureus.
Whole-genome sequencing (WGS) of 228 isolates was used to elucidate the origin and dynamics of a long-term outbreak of methicillin-resistant Staphylococcus aureus (MRSA) sequence type 228 (ST228) SCCmec I that involved 1,600 patients in a tertiary care hospital between 2008 and 2012. Combining of the sequence data with detailed metadata on patient admission and movement confirmed that the outbreak was due to the transmission of a single clonal variant of ST228, rather than repeated introductions of this clone into the hospital. We note that this clone is significantly more frequently recovered from groin and rectal swabs than other clones (P < 0.0001) and is also significantly more transmissible between roommates (P < 0.01). Unrecognized MRSA carriers, together with movements of patients within the hospital, also seem to have played a major role. These atypical colonization and transmission dynamics can help explain how the outbreak was maintained over the long term. This "stealthy" asymptomatic colonization of the gut, combined with heightened transmissibility (potentially reflecting a role for environmental reservoirs), means the dynamics of this outbreak share some properties with enteric pathogens such as vancomycin-resistant enterococci or Clostridium difficile. Using whole-genome sequencing, we showed that a large and prolonged outbreak of methicillin-resistant Staphylococcus aureus was due to the clonal spread of a specific strain with genetic elements adapted to the hospital environment. Unrecognized MRSA carriers, the movement of patients within the hospital, and the low detection with clinical specimens were also factors that played a role in this occurrence. The atypical colonization of the gut means the dynamics of this outbreak may share some properties with enteric pathogens.


Tumor hypoxia induces nuclear paraspeckle formation through HIF-2α dependent transcriptional activation of NEAT1 leading to cancer cell survival.
Activation of cellular transcriptional responses, mediated by hypoxia-inducible factor (HIF), is common in many types of cancer, and generally confers a poor prognosis. Known to induce many hundreds of protein-coding genes, HIF has also recently been shown to be a key regulator of the non-coding transcriptional response. Here, we show that NEAT1 long non-coding RNA (lncRNA) is a direct transcriptional target of HIF in many breast cancer cell lines and in solid tumors. Unlike previously described lncRNAs, NEAT1 is regulated principally by HIF-2 rather than by HIF-1. NEAT1 is a nuclear lncRNA that is an essential structural component of paraspeckles and the hypoxic induction of NEAT1 induces paraspeckle formation in a manner that is dependent upon both NEAT1 and on HIF-2. Paraspeckles are multifunction nuclear structures that sequester transcriptionally active proteins as well as RNA transcripts that have been subjected to adenosine-to-inosine (A-to-I) editing. We show that the nuclear retention of one such transcript, F11R (also known as junctional adhesion molecule 1, JAM1), in hypoxia is dependent upon the hypoxic increase in NEAT1, thereby conferring a novel mechanism of HIF-dependent gene regulation. Induction of NEAT1 in hypoxia also leads to accelerated cellular proliferation, improved clonogenic survival and reduced apoptosis, all of which are hallmarks of increased tumorigenesis. Furthermore, in patients with breast cancer, high tumor NEAT1 expression correlates with poor survival. Taken together, these results indicate a new role for HIF transcriptional pathways in the regulation of nuclear structure and that this contributes to the pro-tumorigenic hypoxia-phenotype in breast cancer.


Psychosocial correlates of safe sex communication between Latina women and their stable male partners: an integrative review.
Latina women in stable relationships have risks for human immunodeficiency virus and other sexually transmitted infections. Improving safe sexual communication (SSC) could enable women to accurately assess and mitigate their risk of infection within their relationship. Literature to identify psychosocial correlates that facilitate or inhibit SSC between Latina women and their partners has not yet been synthesized. The purpose of this study was to conduct an integrative review and synthesis of empirical and theoretical research that examines psychosocial correlates of SSC among adult Latina women from the United States, Latina America, and the Caribbean with stable male partners. A systematic search of LILACS, EBSCO, and PsychInfo databases was conducted to identify qualitative and quantitative studies that investigated psychosocial correlates of SSC among adult Latina women with a stable male partner. Pertinent data were abstracted and quality of individual studies was appraised. A qualitative synthesis was conducted following Miles and Huberman's method. Five qualitative and three quantitative studies meet eligibility criteria. Factors related to SSC related to three main themes: (1) relationship factors such as length, quality, and power/control, (2) individual factors including attitudes, beliefs, background, behaviors, and intrapersonal characteristics, and (3) partner factors related to partner beliefs and behaviors. The interplay of relationship, individual, and partner factors should be considered in the assessment of SSC for Latina women with their stable partners. To inform future interventions and clinical guidelines, additional research is needed to identify which factors are most related to SSC for this population, and how comparable experiences are for Latina women of different subcultures and living in different countries.


B-cell depletion with rituximab: a promising treatment for diffuse cutaneous systemic sclerosis.
Recent preclinical and clinical studies lend support to the notion that B-cell depletion is a promising therapeutic target in patients with diffuse cutaneous systemic sclerosis. A recent open-label trial provides further evidence showing marked effects of rituximab treatment on skin thickening, functional ability, and disease activity in conjunction with effects on lesional and circulating B cells and on interleukin-6 and BAFF (B-cell activating factor of tumor necrosis factor family). The excellent safety profile of rituximab in this and other trials warrants further well-designed clinical trials in larger patient groups combined with comprehensive biomarker studies.


Amplified spontaneous emission from an Ag-backed red-fluorescent-dye-doped polymer film.
We demonstrate that the amplified spontaneous emission (ASE) in an Ag-backed red-fluorescent-dye-doped polymer film can be controlled by the effect of the film thickness. Optical losses associated with the metallic contacts necessary for charge injection, an obstacle to the development of an electrically pumped organic solid-state laser, may be possible to be reduced by increasing the gain medium layer thickness. The study of ASE characteristics of Ag-backed 4-(Dicyanomethylene)-2-t-butyl-6-(1,1,7,7-tetramethyljulolidyl-9-enyl)-4H-pyran (DCJTB)-doped polystyrene (PS) films with different thicknesses shows that increasing the film thickness can reduce the influence of the Ag layer. The threshold, gain, and loss of the device with a thickness of 800 nm are comparable to those of a metal-free device. Our findings demonstrate that the Ag-backed DCJTB:PS film can still be a good organic gain medium material for the fabrication of solid-state lasers, when the thickness of the DCJTB:PS layer increases to an appropriate value.


Functional characterization of a ClC transporter by solid-supported membrane electrophysiology.
EcClC, a prokaryotic member of the ClC family of chloride channels and transporters, works as coupled H(+)/Cl(-) exchanger. With a known structure and the possibility of investigating its behavior with different biochemical and biophysical techniques, the protein has become an important model system for the family. Although many aspects of its function have been previously characterized, it was difficult to measure transport on the same sample under different environmental conditions. To overcome this experimental limitation, we have studied EcClC by solid-supported membrane electrophysiology. The large transport-related transient currents and a simple way of relating transport rates to the measured signal have allowed a thorough investigation of ion selectivity, inhibition, and the dependence of transport on changes in ion concentration and pH. Our results confirm that the protein transports larger anions with about similar rates, whereas the smaller fluoride is not a substrate. We also show that 4,4'-diisothiocyano-2,2'-stilbenedisulfonic acid (DIDS), a known inhibitor of other anion transport protein, irreversibly inhibits EcClC from the intracellular side. The chloride dependence shows an apparent saturation at millimolar concentrations that resembles a similar behavior in eukaryotic ClC channels. Our experiments have also allowed us to quantify the pH dependence of transport. EcClC shows a strong activation at low pH with an apparent pKa of 4.6. The pronounced pH dependence is lost by the mutation of a conserved glutamate facing the extracellular solution that was previously shown to be an acceptor for transported protons, whereas it is largely retained by the mutation of an equivalent residue at the intracellular side. Our results have provided a quantitative basis for the transport behavior of EcClC, and they will serve as a reference for future investigations of novel electrogenic transporters with still-uncharacterized properties.


Biophysical properties and metabolic regulation of a TASK-like potassium channel in rat carotid body type 1 cells.
The single channel properties of TASK-like oxygen-sensitive potassium channels were studied in rat carotid body type 1 cells. We observed channels with rapid bursting kinetics, active at resting membrane potentials. These channels were highly potassium selective with a slope conductance of 14-16 pS, values similar to those reported for TASK-1. In the absence of extracellular divalent cations, however, single channel conductance increased to 28 pS in a manner similar to that reported for TASK-3. After patch excision, channel activity ran down rapidly. Channel activity in inside-out patches was markedly increased by 2 and 5 mM ATP and by 2 mM ADP but not by 100 microM ADP or 1 mM AMP. In cell-attached patches, both cyanide and 2,4-dinitrophenol strongly inhibited channel activity. We conclude that 1) whilst the properties of this channel are consistent with it being a TASK-like potassium channel they do not precisely conform to those of either TASK-1 or TASK-3, 2) channel activity is highly dependent on cytosolic factors including ATP, and 3) changes in energy metabolism may play a role in regulating the activity of these background K+ channels.


Importance of the organ-independent elimination of cisatracurium.
Cisatracurium, one of 10 isomers of atracurium, undergoes pH and temperature-dependent Hofmann elimination in plasma and tissues. The clearance of cisatracurium due to Hofmann elimination and organ elimination was estimated by applying a nontraditional two-compartment pharmacokinetic model with elimination occurring from both compartments to plasma cisatracurium concentration-time data from 31 healthy adult surgical patients with normal renal and hepatic function. The elimination rate constant from the central compartment, intercompartmental rate constants, and the volume of the central compartment were obtained from the model fit. The elimination rate constant from the peripheral compartment could not be independently estimated in vivo and was therefore fixed to the rate of degradation of cisatracurium in human plasma (pH 7.4 and 37 degrees C) and held constant in the model. Total body clearance, Hofmann clearance, organ clearance, and the volume of distribution at steady-state were derived from the model parameter estimates. Renal clearance was calculated from cisatracurium urinary excretion data from 12 of the 31 patients. Clearance values (mean +/- SD) were 5.20 +/- 0.86, 4.00 +/- 1.04, 1.20 +/- 0.71, and 0.85 +/- 0.32 mL.min-1.kg-1 for total body clearance, Hofmann clearance, organ clearance, and renal clearance, respectively. Hofmann clearance accounted for 77% of total body clearance. Organ clearance was 23% of total body clearance. Renal clearance, a component of organ clearance, was 16% of total body clearance. The organ-independent nature of the elimination of cisatracurium was characterized by a relationship between steady-state volume of distribution and total body clearance. The half-life is an independent variable and is not dependent on the total body clearance nor the steady-state volume of distribution. Hofmann elimination is the predominant pathway for cisatracurium elimination in humans.


Scale-up of HIV treatment through PEPFAR: a historic public health achievement.
Since its inception in 2003, the US President's Emergency Plan for AIDS Relief (PEPFAR) has been an important driving force behind the global scale-up of HIV care and treatment services, particularly in expansion of access to antiretroviral therapy. Despite initial concerns about cost and feasibility, PEPFAR overcame challenges by leveraging and coordinating with other funders, by working in partnership with the most affected countries, by supporting local ownership, by using a public health approach, by supporting task-shifting strategies, and by paying attention to health systems strengthening. As of September 2011, PEPFAR directly supported initiation of antiretroviral therapy for 3.9 million people and provided care and support for nearly 13 million people. Benefits in terms of prevention of morbidity and mortality have been reaped by those receiving the services, with evidence of societal benefits beyond the anticipated clinical benefits. However, much remains to be accomplished to achieve universal access, to enhance the quality of programs, to ensure retention of patients in care, and to continue to strengthen health systems.


Multiwavelength time-stretch imaging system.
A high-speed microscopic imaging system based on a multiwavelength source and time-stretch technique is proposed and demonstrated. We realize an imaging system at 1D scan rate of 80 MHz with 20 resolvable points. This scheme breaks the bottleneck of large bandwidth and high repetition rate in mode-lock lasers and has great potential for imaging system integration.


Changes in sexual desires and behaviours of people living with HIV after initiation of ART: implications for HIV prevention and health promotion.
As immune compromised HIV sero-positive people regain health after initiating antiretroviral treatment (ART), they may seek a return to an active 'normal' life, including sexual activity. The aim of the paper is to explore the changing sexual desires and behaviour of people on ART in Uganda over a 30 month period. This study employed longitudinal qualitative interviews with forty people starting ART. The participants received their ART, adherence education and counselling support from The AIDS Support Organisation (TASO). The participants were selected sequentially as they started ART, stratified by sex, ART delivery mode (clinic or home-based) and HIV progression stage (early or advanced) and interviewed at enrolment, 3, 6, 18 and 30 months of their ART use. Sexual desire changed over time with many reporting diminished desire at 3 and 6 months on ART compared to 18 and 30 months of use. The reasons for remaining abstinent included fear of superinfection or infecting others, fear that engaging in sex would awaken the virus and weaken them and a desire to adhere to the counsellors' health advice to remain abstinent. The motivations for resumption of sexual activity were: for companionship, to obtain material support, social norms around marriage, desire to bear children as well as to satisfy sexual desires. The challenges for most of the participants were using condoms consistently and finding a suitable sexual partner (preferably someone with a similar HIV serostatus) who could agree to have a sexual relationship with them and provide for their material needs. These findings point to the importance of tailoring counselling messages to the changing realities of the ART users' cultural expectations around child bearing, marriage and sexual desire. People taking ART require support so they feel comfortable to disclose their HIV status to sexual partners.


Evaluation of B7-H3 expression as a biomarker of biochemical recurrence after salvage radiation therapy for recurrent prostate cancer.
The ability to predict which men will experience biochemical recurrence (BCR) after salvage radiation therapy (SRT) for recurrent prostate cancer (PCa) remains less than optimal. Related to this, novel targets for adjuvant therapies are also lacking. Here, we evaluate the association of B7-H3 expression in primary PCa tumors and BCR after SRT. We identified 148 patients who received SRT between July 1987 and July 2003. Expression of B7-H3 in primary PCa tumors was detected using a monoclonal antibody. The staining levels were quantified via visual assessment and categorized as weak, moderate, or marked. Relative risks (RRs) and 95% confidence intervals (CIs) from Cox proportional hazards models were used to examine the association between B7-H3 staining and BCR. With a median follow-up of 6.2 years (minimum, 0.6; maximum, 14.7), 78 patients (53%) experienced BCR. In single-variable analysis, there was evidence of an increased risk of BCR for patients with moderate (RR, 2.25; 95% CI, 1.24-4.09, p = 0.008) and marked (RR, 4.40, 95% CI, 2.29-8.43, p < 0.001) B7-H3 staining compared with weak staining. This evidence remained, albeit weaker, after adjustment for additional clinicopathologic covariates (RR, 1.82, p = 0.068 [moderate vs. weak]; RR, 2.87, p = 0.003 [marked vs. weak]). This is the first report that higher tumor B7-H3 staining in primary PCa tumors is associated with increased risk of BCR after SRT. Future studies involving larger numbers of patients are required to validate these results and also to explore possible means of targeting B7-H3 in an adjuvant setting.


Determining histology-MRI slice correspondences for defining MRI-based disease signatures of prostate cancer.
Mapping the spatial disease extent in a certain anatomical organ/tissue from histology images to radiological images is important in defining the disease signature in the radiological images. One such scenario is in the context of men with prostate cancer who have had pre-operative magnetic resonance imaging (MRI) before radical prostatectomy. For these cases, the prostate cancer extent from ex vivo whole-mount histology is to be mapped to in vivo MRI. The need for determining radiology-image-based disease signatures is important for (a) training radiologist residents and (b) for constructing an MRI-based computer aided diagnosis (CAD) system for disease detection in vivo. However, a prerequisite for this data mapping is the determination of slice correspondences (i.e. indices of each pair of corresponding image slices) between histological and magnetic resonance images. The explicit determination of such slice correspondences is especially indispensable when an accurate 3D reconstruction of the histological volume cannot be achieved because of (a) the limited tissue slices with unknown inter-slice spacing, and (b) obvious histological image artifacts (tissue loss or distortion). In the clinic practice, the histology-MRI slice correspondences are often determined visually by experienced radiologists and pathologists working in unison, but this procedure is laborious and time-consuming. We present an iterative method to automatically determine slice correspondence between images from histology and MRI via a group-wise comparison scheme, followed by 2D and 3D registration. The image slice correspondences obtained using our method were compared with the ground truth correspondences determined via consensus of multiple experts over a total of 23 patient studies. In most instances, the results of our method were very close to the results obtained via visual inspection by these experts.


VAET: A Visual Analytics Approach for E-Transactions Time-Series.
Previous studies on E-transaction time-series have mainly focused on finding temporal trends of transaction behavior. Interesting transactions that are time-stamped and situation-relevant may easily be obscured in a large amount of information. This paper proposes a visual analytics system, Visual Analysis of E-transaction Time-Series (VAET), that allows the analysts to interactively explore large transaction datasets for insights about time-varying transactions. With a set of analyst-determined training samples, VAET automatically estimates the saliency of each transaction in a large time-series using a probabilistic decision tree learner. It provides an effective time-of-saliency (TOS) map where the analysts can explore a large number of transactions at different time granularities. Interesting transactions are further encoded with KnotLines, a compact visual representation that captures both the temporal variations and the contextual connection of transactions. The analysts can thus explore, select, and investigate knotlines of interest. A case study and user study with a real E-transactions dataset (26 million records) demonstrate the effectiveness of VAET.


The Association of Cardiorespiratory Fitness and Ideal Cardiovascular Health in the Aerobics Center Longitudinal Study.
This study examined the cross-sectional and longitudinal associations of cardiorespiratory fitness (CRF) and ideal cardiovascular health (CVH). CRF and the 7 CVH components were measured in 11,590 (8865 males; 2725 females) adults at baseline and in 2532 (2160 males; 372 females) adults with at least one follow-up examination from the Aerobics Center Longitudinal Study. Ideal CVH score was calculated as a composite of 7 measures, each scored 0 to 2. CVH groups were based on participant point score: ≤7 (poor), 8 to 11 (intermediate), and 12 to 14 (ideal). Analyses included general linear, logistic regression, and linear mixed models. At baseline, participants in the high CRF category had 21% and 45% higher mean CVH scores than those in the moderate and poor CRF categories (P < .001). The adjusted odds (95% confidence interval) of being in the poor CVH group at baseline were 4.9 (4.4-5.4) and 16.9 (14.3-19.9) times greater for individuals with moderate and low CRF, respectively, compared with those with high CRF (P < .001). Longitudinal analysis found that for every 1-minute increase in treadmill time, CVH score increased by 0.23 units (P < .001) independent of age, sex, exam number, and exam year. Higher CRF is associated with better CVH profiles, and improving CRF over time is independently associated with greater improvements in CVH.


Inhibitory Effect of Crocin on Metastasis of Triple-Negative Breast Cancer by Interfering with Wnt/β-Catenin Pathway in Murine Model.
Triple-negative breast cancer (TNBC) is the most metastatic subtype of breast cancer and cannot be controlled with any standard-of-care therapy. However, various studies have recommended medicinal plants as complementary treatments for cancer. In particular, crocin, the main bioactive carotenoid of saffron, has exhibited anticancer effects on primary tumors. This research, for the first time, investigated the antimetastatic potency of crocin on murine model of metastatic TNBC and its effect on the Wnt/β-catenin pathway. To induce tumors, 4T1 cells were injected to female BALB/c mice. Measurement of biochemical markers showed nontoxicity of crocin. The crocin-treated mice possessed more weight, higher survival rates, and smaller tumors. Histological examination detected no metastatic deposits in their livers and lungs. Also, downregulation of the expression of Wnt/β-catenin target genes in tumors and lungs was observed compared to the untreated group. Our findings suggest crocin as a promising complementary antimetastatic herbal medicine for treatment of TNBC.