The pathological changes caused by Eimeria falciformis var pragensis in mice.
Groups of Swiss white mice weighing 25-28 grams were infected orally with 500, 2,000, 5,000 or 20,000 oocysts of Eimeria falciformis var pragensis. Depression, anorexia, weight loss, diarrhea or dysentery, and dehydration were most pronounced at eight to ten days postinfection. The highest mortality, 31%, occurred in mice infected with 20,000 oocysts. None of the mice infected with 500 oocysts died. The pathological findings were equally severe in mice infected with 5,000 and 20,000 oocysts. The enteric lesions, most pronounced at eight to ten days postinfection, were restricted mainly to the large intestine and consisted initially of both cryptal and absorptive epithelial cell destruction and submucosal edema. These changes were followed in 12 to 24 hours by a transient influx of neutrophils into the lamina propria followed by mononuclear cell infiltration which lasted for five to ten days. As the infective dose decreased, the inflammatory response occurred later and was less extensive. When seen, hemorrhage occurred seven to 11 days postinfection. In 50% of the mice infected with 5,000 and 20,000 oocysts, varying degrees of a nonselective mucosal necrosis were seen at eight to 12 days postinfection. In mice infected with 500 oocysts, mucosal destruction was restricted to the epithelium. Neutrophils predominated when necrosis was extensive, otherwise, mononuclear cells were the main inflammatory cells. Two to three days following necrosis, crypt hyperplasia was marked and mucosal integrity was restored. Ulcers, some of which extended into the submucosa, healed by days 14 to 20. Localized granulomatous colitis, induced by trapped oocysts within the lamina propria, was seen until the experiment was terminated at 25 days postinfection. Infection was followed by lymphoid hyperplasia in the lymph nodes and the spleen.


Prevalence of major cardiovascular risk factors and adverse risk profiles among three ethnic groups in the Xinjiang Uygur Autonomous Region, China.
Prevalence of cardiovascular disease (CVD) risk factors have been scarcely studied in Xinjiang, a multi-ethnic region. Multi-ethnic, cross-sectional cardiovascular risk survey study in Xinjiang, including individuals of Uygur (n = 4695), Han (n = 3717) and Kazakh (n = 3196) ethnicities, aged 35-74 years. Analyses involved 11,608 participants with complete data enrolled between October 2007 and March 2010. There were differences in age-standardized prevalence of CVD risk factors between the three groups (all P < 0.001). Hypertension, obesity and smoking rates were higher among Kazakh (54.6%, 24.5%, and 35.8%, respectively). Dyslipidemia prevalence was higher among Uygur (54.3%), and diabetes prevalence was higher among Hans (7.1%). Age-standardized prevalence of adverse CVD risk profiles was different across different ethnicities. Compared with the Han participants, the Uygur and Kazakh had more CVD risk factors (P < 0.001). Compared with the Han participants, the adjusted odds ratios of 1, 2, and ≥3 risk factors profiles for Kazakh and Uygur participants were higher (all P < 0.001). The present study showed the pervasive burden of CVD risk factors in all participant groups in the Xinjiang region. Three major ethnic groups living in Xinjiang had striking differences in the prevalence of major CVD risk factors and adverse risk profiles. Ethnic-specific strategies should be developed to prevent CVD in different ethnic groups, as well as to develop strategies to prevent future development of adverse CVD risk factors at a younger age.


Probing the conformational dynamics of photosystem I in unconfined and confined spaces.
The fluorescence dynamics of Photosystem I (PSI) in bulk water and inside a confined environment like a liposome have been investigated using time resolved confocal microscopy. In bulk water, PSI exhibits a major emission peak at ∼680 nm, while in the liposome it exhibits a markedly blue shifted emission maximum at ∼485 nm. This is indicative of conformational changes due to entrapment and emergence of a stressed conformation of PSI inside the liposome. The observed time constants for the fluorescence lifetime of PSI inside the liposome are significantly high as opposed to PSI in bulk water. More interestingly, the fluorescence intensity of PSI in bulk water exhibits strong fluctuations with many high intensity jumps and these are anti-correlated with the fluorescence lifetime of PSI. In contrast, inside the liposome, no such anti-correlated behaviour is observed. We further demonstrated that PSI exhibits at least two conformational states in bulk water, whereas a single conformation is observed inside the liposome, indicating the conformational rigidity and locking of the PSI complex inside a liposome.


More far is more right: Manual and ocular line bisections, but not the Judd illusion, depend on radial space.
Line bisection studies generally find a left-to-right shift in bisection bias with increasing distance between the observer and the target line, which may be explained by hemispheric differences in the processing of proximo-distal information. In the present study, the segregation between near and far space was further characterized across the motor system and contextual cues. To this aim, 20 right-handed participants were required to perform a manual bisection task of simple lines presented at three different distances (60, 90, 120 cm). Importantly, the horizontal spatial location of the line was manipulated along with the viewing distance to investigate more deeply the hemispheric engagement in the transition from near to far space. As the motoric component of the manual task producing activations of left premotor and motor areas may be partially responsible for the observed transition, participants were also involved in an ocular bisection task. Further, participants were required to bisect Judd variants of the target lines, which are known to elicit a Müller-Lyer-type illusion. Since the Judd illusion depends on areas in the ventral visual stream, we predicted that line bisections of Judd-type lines would be unaffected by viewing distance. Results showed that manual bisection of simple lines was modulated separately by viewing distance and the hemispace of presentation, with this pattern being similar for ocular bisection. Critically, bisections in the Judd illusion task were not modulated by viewing distance, whether performed by hand or by eye. Overall, these findings support the hypothesis that the right hemisphere plays a dominant role in the processing of space close to the body. They also present novel evidence for a general reduction of this dominance at farther distances, whether hand motor actions are involved or not. Finally, our study documents a dissociation between the processing of pure visuospatial information and that of a visual illusion as a function of viewing distance, supporting more generally the dorsal/near space and the ventral/far space segregation.


The human noncoding genome defined by genetic diversity.
Understanding the significance of genetic variants in the noncoding genome is emerging as the next challenge in human genomics. We used the power of 11,257 whole-genome sequences and 16,384 heptamers (7-nt motifs) to build a map of sequence constraint for the human species. This build differed substantially from traditional maps of interspecies conservation and identified regulatory elements among the most constrained regions of the genome. Using new Hi-C experimental data, we describe a strong pattern of coordination over 2 Mb where the most constrained regulatory elements associate with the most essential genes. Constrained regions of the noncoding genome are up to 52-fold enriched for known pathogenic variants as compared to unconstrained regions (21-fold when compared to the genome average). This map of sequence constraint across thousands of individuals is an asset to help interpret noncoding elements in the human genome, prioritize variants and reconsider gene units at a larger scale.


Serologic markers of gluten sensitivity in a healthy population from the western region of Saudi Arabia.
To identify the prevalence of gluten sensitivity in a healthy adult Saudi population within a low endemic area of celiac disease using IgA tissue transglutaminase antibody. The study was conducted as a prospective pilot study for Saudi attendees of a blood donation centre at King Faisal Specialist Hospital & Research Centre in Jeddah, Saudi Arabia. Individuals were invited to participate in the study and screened for gluten sensitivity using immunoglobulin A tissue transglutaminase antibody (IgA TTG) along with serum IgA level. Descriptive data was presented and expressed as mean value; correlation between variables was estimated using Pearson correlation, and nonparametric data using Pearson rho correlation (level of P value <0.05 is considered to be statistically significant). Two hundred and four individuals (122 males and 82 females, mean age 35 years) attending the blood donation centre were screened. Three individuals tested positive for IgA TTG showing normal IgA level (1 female and 2 males) with a 1.5% prevalence in the cohort. Positive celiac screening is present at a low prevalence rate in our adult population, in which the individuals' age and their serum IgA levels are not associated with the positivity level. A study on a larger scale with the application of histologic confirmation of positive cases is needed.


Health supervision for children with Down syndrome.
These guidelines are designed to assist the pediatrician in caring for the child in whom a diagnosis of Down syndrome has been confirmed by chromosome analysis. Although a pediatrician's initial contact with the child is usually during infancy, occasionally the pregnant woman who has been given a prenatal diagnosis of Down syndrome will be referred for review of the condition and the genetic counseling provided. Therefore, this report offers guidance for this situation as well.


Atomic-level models of the bacterial carboxysome shell.
The carboxysome is a bacterial microcompartment that functions as a simple organelle by sequestering enzymes involved in carbon fixation. The carboxysome shell is roughly 800 to 1400 angstroms in diameter and is assembled from several thousand protein subunits. Previous studies have revealed the three-dimensional structures of hexameric carboxysome shell proteins, which self-assemble into molecular layers that most likely constitute the facets of the polyhedral shell. Here, we report the three-dimensional structures of two proteins of previously unknown function, CcmL and OrfA (or CsoS4A), from the two known classes of carboxysomes, at resolutions of 2.4 and 2.15 angstroms. Both proteins assemble to form pentameric structures whose size and shape are compatible with formation of vertices in an icosahedral shell. Combining these pentamers with the hexamers previously elucidated gives two plausible, preliminary atomic models for the carboxysome shell.


Influence of age, group size and the presence of porcine reproductive and respiratory syndrome virus on the collection of oral fluids.
Pen-based oral fluid (OF) samples have been approved for detecting porcine reproductive and respiratory syndrome virus (PRRSV) RNA and antibodies. The aim of the study was to investigate the influence of age, group size and the presence of PRRSV infection on sampling using pen-based OF collected by presenting pigs with a rope to chew. Samples were collected from pigs of 4/5 weeks of age, 7/8 weeks of age and 12/14 weeks of age. Subsequent PRRSV-PCR and ELISA analyses of OF and serum samples were performed. In this study, 76.5-81.9% of pigs chewed the rope. The group size had significant impact on the pig-rope-interaction (P=0.047). OF and serum had an almost perfect and significant agreement for the detection of antibodies (κ=0.829, P<0.001) and a fair and not significant agreement (κ=0.347, P=0.75) for the detection PRRSV-genome.


Tagasaste (Chamaecytisus palmensis) leaf supplementation to enhance nutrient intake and production performance of sheep in the Ethiopian highlands.
The objective of this study was to determine the effect of supplementing increasing levels of dried tagasaste (Chamaecytisus palmensis) leaf on the nutrition and performance of sheep fed a basal diet of barley straw. The study had four treatments, which involved supplementation of dried tagasaste leaf at 100, 200, 300, and 400 g/day. Twenty-four yearling Menz sheep (weight 17 ± 0.83 kg) were assigned to one of the four treatments in a randomized complete block design. The experiment comprised a feeding trial lasting for 90 days, a digestibility trial, and carcass evaluation using all animals. Samples of the feed consumed, refused, and feces were analyzed for nutrients. Intake and digestibility of dry matter (DM) and nutrients increased linearly (P < 0.001) as tagasaste supplementation increased from 100 to 400 g/day. Similarly, average daily body weight gain increased linearly (P < 0.001) from 20 to 73 g/day, feed conversion efficiency from 0.04 to 0.10, and dressing percentage from 40 to 48%, as the supplementation increased from 100 to 400 g/day. Proportion of tagasaste leaf in the diet increased from 20 to 50%, while the ratio of neutral detergent fiber (NDF) to crude protein (CP) decreased from 7.9 to 5.3, as the level of supplementation increased. It was thus concluded that supplementation of dried tagasaste leaf up to 50% of the diet DM, resulting in a NDF:CP ratio of 5.3, produces no deleterious effects on the performance of sheep, and inclusion to this level can be applied for superior growth performance and carcass yield in sheep fed crop residue-based diets.


A multicenter, randomized trial of a nurse-led, home-based intervention for optimal secondary cardiac prevention suggests some benefits for men but not for women: the Young at Heart study.
We examined the impact of a prolonged secondary prevention program on recurrent hospitalization in cardiac patients with private health insurance. The Young at Heart multicenter, randomized, controlled trial compared usual postdischarge care (UC) with nurse-led, home-based intervention (HBI). The primary end point was rate of all-cause hospital stay (31.5±7.5 months follow-up). In total, 602 patients (aged 70±10 years, 72% men) were randomized to UC (n=296) or HBI (n=306, 96% received ≥1 home visit). Overall, 42 patients (7.0%) died, and 492 patients (82%) accumulated 2397 all-cause hospitalizations associated with 10,258 hospital days costing >$17 million. There were minimal group differences (HBI versus UC) in the primary end point of all-cause hospital stay (5405 versus 4853 days; median [interquartile range], 0.08 [0.03-0.17] versus 0.07 [0.03-0.13]/patient per month). There were similar trends with respect to all hospitalizations (1197 versus 1200; P=0.802) and associated costs ($8.66 versus $8.58 million; P=0.375). At 2 years, however, more HBI versus UC (39% versus 27%; odds ratio, 1.67; 95% confidence interval, 1.15-2.41; P=0.007) patients were assessed as stable and optimally managed. For women, HBI outcomes were predominantly worse than UC outcomes. In men, HBI was associated with reduced risk of cardiovascular hospitalization (adjusted hazard ratio, 0.68; 95% confidence interval, 0.46-0.99; P=0.044) with less cardiovascular hospitalizations (192 versus 269; P=0.054) and costs ($2.49 versus $3.53 million; P=0.046). HBI did not reduce recurrent all-cause hospitalization compared with UC in privately insured cardiac patients overall. However, it did convey some benefits in cardiac outcomes for men. Australian New Zealand Clinical Trials Registry Unique Identifier: 12608000014358. URL: http://www.anzctr.org.au/trial_view.aspx?id=82509.


Facilitation of infantile spasms by partial seizures.
We report 16 patients with infantile spasms in whom onset of the clusters of spasms appeared to be triggered by close temporal association with partial seizures. Common features included the presence of focal cerebral lesions in 12 infants (3 were classifiable as cryptogenic); all had partial seizures with EEG localization, clusters of bilateral spasms always preceded by partial seizures, and response to adrenocorticotropic hormone (ACTH) and traditional antiepileptic drugs (AEDs) generally was poor. Three had complete agenesis of the corpus callosum, which argues against interhemispheric callosal spread of focal discharges resulting in the generalized spasms. Surgical cortical resections were performed in 6 of the infants, with good outcomes. This group of patients supports a model in which the spasms, although probably generated at a subcortical level, are facilitated or possibly induced by focal discharges from cortical pathology.


A genetic-based algorithm for personalized resistance training.
Association studies have identified dozens of genetic variants linked to training responses and sport-related traits. However, no intervention studies utilizing the idea of personalised training based on athlete's genetic profile have been conducted. Here we propose an algorithm that allows achieving greater results in response to high- or low-intensity resistance training programs by predicting athlete's potential for the development of power and endurance qualities with the panel of 15 performance-associated gene polymorphisms. To develop and validate such an algorithm we performed two studies in independent cohorts of male athletes (study 1: athletes from different sports (n = 28); study 2: soccer players (n = 39)). In both studies athletes completed an eight-week high- or low-intensity resistance training program, which either matched or mismatched their individual genotype. Two variables of explosive power and aerobic fitness, as measured by the countermovement jump (CMJ) and aerobic 3-min cycle test (Aero3) were assessed pre and post 8 weeks of resistance training. In study 1, the athletes from the matched groups (i.e. high-intensity trained with power genotype or low-intensity trained with endurance genotype) significantly increased results in CMJ (P = 0.0005) and Aero3 (P = 0.0004). Whereas, athletes from the mismatched group (i.e. high-intensity trained with endurance genotype or low-intensity trained with power genotype) demonstrated non-significant improvements in CMJ (P = 0.175) and less prominent results in Aero3 (P = 0.0134). In study 2, soccer players from the matched group also demonstrated significantly greater (P < 0.0001) performance changes in both tests compared to the mismatched group. Among non- or low responders of both studies, 82% of athletes (both for CMJ and Aero3) were from the mismatched group (P < 0.0001). Our results indicate that matching the individual's genotype with the appropriate training modality leads to more effective resistance training. The developed algorithm may be used to guide individualised resistance-training interventions.


Atopic dermatitis: a clinical review for the primary care physician.
Atopic dermatitis is a common disease, causing significant morbidity. The histology and cellular mechanisms suggest that atopic dermatitis is an atopic disease similar to asthma and allergic rhinitis, with helper T type 2 lymphocytes being at least a component of the pathogenesis of the disease. Specific allergies, including food allergies, should be explored and treated. Treatment should be directed at increasing the patient's quality of life. Antihistamines, topical steroids, and lubricants are the keystones of therapy. In severe cases, oral steroids may be necessary but should be used sparingly. Interferon, cyclosporine, phototherapy, and immunosuppressive agents may be necessary in refractory cases. It appears that leukotriene inhibitors may have a future role in therapy. Clinical assessment and follow-up are important, as other atopic diseases such as asthma and allergic nasosinus disease may eventually develop in many of these patients.


Genistein reverses diminished T-cell signal transduction, induced by post-menopausal estrogen levels.
This study addressed the ability of genistein to reverse the loss of T-cell signaling components, induced by estrogen deficiency associated with aging. Using Jurkat 6.1 T cells, genistein regulation of CD3zeta, JAK3, and NFkappaB was analysed by Western immunoblotting at 4 or 40 pg/mL (post- and pre-menopausal levels, respectively) estradiol (E(2)). Corresponding gene expressions were quantified by real-time polymerase chain reaction (RT-PCR). For functionality, levels of IL-2 were correlated with its transcription by RT-PCR. At 4 pg/mL E(2), signaling proteins were decreased compared with 40 pg/mL: CD3zeta, 1.58-fold; JAK3, 1.75-fold; and NFkappaB, 1.73-fold (P < 0.001). Genistein, at 0.5 and 5.0 microm, added to 4 pg/mL E(2) induced their expression to 40 pg/mL levels. While significantly diminished IL-2 mRNA levels were observed at 4 pg/mL E(2), genistein induced IL-2 mRNA to 40 pg/mL levels. Genistein restores CD3zeta, NFkappaB and JAK3 proteins and mRNAs at post-meonopausal estrogen levels, in vitro, with no significant effect at pre-menopausal estrogen levels.


Frontotemporal dementia (Pick's disease): clinical features and assessment.
The clinical presentation in frontotemporal dementia (FTD) reflects the distribution of the pathologic changes rather than the exact histologic subtype of the disease. Three major clinical syndromes can be identified: 1) frontal variant FTD (dementia of frontal type) in which changes in social behavior and personality predominate, reflecting the orbitobasal frontal lobe focus of the pathology. Traditional cognitive tests are insensitive, but more specific measures are under development; 2) semantic dementia (progressive fluent aphasia) in which there is a breakdown in the conceptual database which underlies language production and comprehension, although deficits in nonverbal semantic knowledge can also be shown on neuropsychologic testing. Patients with semantic dementia have asymmetric anterolateral temporal atrophy with relative sparing of the hippocampal formation, which is typically worse on the left side. A variant of this syndrome affecting the right temporal lobe presents with progressive prosopagnosia; 3) progressive nonfluent aphasia in which the phonologic and syntactic components of language are affected in association with left peri-Sylvian atrophy. The assessment of patients with potential FTD involves a multidisciplinary approach. The development of comprehensive caregiver-based neuropsychiatric instruments, neuropsychologic tasks sensitive to semantic memory and other key cognitive impairments, and functional (hexamethyly-propyleneamine-SPECT) and structural (MRI) brain imaging represent significant advances in the field.


Spontaneous Remission in a Patient With Acute Myeloid Leukemia Leading to Undetectable Minimal Residual Disease.
Although rare, spontaneous remission (SR) of acute myeloid leukemia (AML) has been reported in the literature, the underlying mechanisms driving remission remain unknown. However, it is most commonly associated with a preceding severe infection. We present a case of a 40-year-old man with no past medical history who presented to our hospital with severe left hip pain and fevers and was found to have AML. Chemotherapy was delayed because the patient required extensive debridement and fasciotomy of his left hip and a prolonged course of antibiotics. After his acute illness had stabilized, a repeat bone marrow biopsy was performed which showed no abnormal myeloid blasts and resolution of his original cytogenetic and molecular abnormalities. At the time of this writing, our patient remains in remission with undetectable minimal residual disease (MRD), now 14 months from his initial diagnosis of AML.


Estimating parameters of generalized integrate-and-fire neurons from the maximum likelihood of spike trains.
When a neuronal spike train is observed, what can we deduce from it about the properties of the neuron that generated it? A natural way to answer this question is to make an assumption about the type of neuron, select an appropriate model for this type, and then choose the model parameters as those that are most likely to generate the observed spike train. This is the maximum likelihood method. If the neuron obeys simple integrate-and-fire dynamics, Paninski, Pillow, and Simoncelli (2004) showed that its negative log-likelihood function is convex and that, at least in principle, its unique global minimum can thus be found by gradient descent techniques. Many biological neurons are, however, known to generate a richer repertoire of spiking behaviors than can be explained in a simple integrate-and-fire model. For instance, such a model retains only an implicit (through spike-induced currents), not an explicit, memory of its input; an example of a physiological situation that cannot be explained is the absence of firing if the input current is increased very slowly. Therefore, we use an expanded model (Mihalas & Niebur, 2009 ), which is capable of generating a large number of complex firing patterns while still being linear. Linearity is important because it maintains the distribution of the random variables and still allows maximum likelihood methods to be used. In this study, we show that although convexity of the negative log-likelihood function is not guaranteed for this model, the minimum of this function yields a good estimate for the model parameters, in particular if the noise level is treated as a free parameter. Furthermore, we show that a nonlinear function minimization method (r-algorithm with space dilation) usually reaches the global minimum.


Yersinia pestis and plague: an updated view on evolution, virulence determinants, immune subversion, vaccination, and diagnostics.
Plague is a vector-borne disease caused by Yersinia pestis. Transmitted by fleas from rodent reservoirs, Y. pestis emerged <6000 years ago from an enteric bacterial ancestor through events of gene gain and genome reduction. It is a highly remarkable model for the understanding of pathogenic bacteria evolution, and a major concern for public health as highlighted by recent human outbreaks. A complex set of virulence determinants, including the Yersinia outer-membrane proteins (Yops), the broad-range protease Pla, pathogen-associated molecular patterns (PAMPs), and iron capture systems play critical roles in the molecular strategies that Y. pestis employs to subvert the human immune system, allowing unrestricted bacterial replication in lymph nodes (bubonic plague) and in lungs (pneumonic plague). Some of these immunogenic proteins as well as the capsular antigen F1 are exploited for diagnostic purposes, which are critical in the context of the rapid onset of death in the absence of antibiotic treatment (less than a week for bubonic plague and <48 h for pneumonic plague). Here, we review recent research advances on Y. pestis evolution, virulence factor function, bacterial strategies to subvert mammalian innate immune responses, vaccination, and problems associated with pneumonic plague diagnosis.


A resource reallocation model for school dental screening: taking advantage of teledentistry in low-risk areas.
To estimate the scale of resource transfer that could be achieved by screening low-risk schoolchildren using teledentistry rather than using traditional visual dental examination. This study was based on a previous cost-minimisation study that compared the costs of two dental-screening approaches (visual and teledentistry). The data for the population of children 5-14 years of age was obtained from the Australian Bureau of Statistics and was divided across Australia according to statistical local area (SA2). The cost models (for teledentistry and visual screening) for each SA2 relative to the state, Remoteness Area (RA) and Socio-Economic Index for Area (SEIFA) indexes were estimated. The geographical information system was used to superimpose modelled cost data on the geographical map to provide a visual presentation of the data. Resource transfer scenarios, based on risk minimisation, were then developed and analysed. This study demonstrated a suboptimal allocation of dental-care resources, such that children living in high socio-economic areas (major cities) with low disease burdens consuming half of the estimated resources of a universal visual dental screening system. The findings suggest that utilising teledentistry screening for low-risk children has the potential to free up $40 million per annum. Such resources can be reallocated to increase care access and improve the quality of dental services for vulnerable children. To reduce inequalities in dental health within a community, scarce health-care resources should be targeted at the population at most risk. These findings can be used to inform policymakers, guide the appropriate distribution of scarce resources and target dental services to benefit high-need children.


First Report of a Cucumber mosaic virus-Associated Satellite RNA in Lobelia erinus.
Lobelia (Lobelia erinus L.) is a common herbaceous annual used in flower beds and hanging baskets. The plant blooms from early to late summer. In the summer of 2000, Lobelia plants expressing virus-like symptoms were collected from a greenhouse-based production site in Ohio. Affected plants expressed a mild leaf mosaic and stunting. Viral-associated dsRNA was isolated from 7 g of symptomatic leaf tissue (1). Four dsRNAs were observed at 3.9, 3.0, 2.25, and 1.05 kb indicating the presence of a Cucumovirus. A fifth dsRNA at 0.75 kb also was observed, consistent with the presence of a satellite RNA. Enzyme-linked immunosorbent assay (ELISA) analysis (Agdia, Inc., Elkhart, IN) of symptomatic Lobelia tissue confirmed the presence of Cucumber mosaic virus (CMV). A (S)CARNA-5 (-) cDNA clone (American Type Culture Collection #45124) was labeled with digoxygenin (DIG) as per the manufacturer's instructions (Genius II DIG-DNA Labeling Kit, Boehringer Mannheim) and used as a diagnostic probe to detect this satellite RNA. Northern hybridization confirmed the identity of the satellite RNA (2). This is the first report of any satellite RNA associated with a virus infection in Lobelia and the first report of CMV in this host in Ohio. References: (1) J. R. Fisher and S. G. P. Nameth. HortScience 35:230-234, 2000. (2) R. A. Valverde et.al. Plant Dis. 74:255-258, 1990.


Fatigue in early, intensively treated and tight-controlled rheumatoid arthritis patients is frequent and persistent: a prospective study.
Fatigue has a large impact on quality of life and is still unmanageable for many patients. Study aims were describe (1) the prevalence and pattern of fatigue over time in patients with early rheumatoid arthritis under a treat-to-target strategy and (2) identify predictive factors for worsening and recovering of fatigue over time. Data from the tREACH study were used, comparing different treatment strategies with fatigue as secondary objective. Patient outcomes on fatigue, quality of life, depression, and coping were obtained every 6 months and clinically assessed every 3 months. Prediction of fatigue at 12 months was investigated with an ROC curve. Analysis was stratified into non-fatigue and fatigue at baseline. Logistic regression was used for the evolution of fatigue in relation with the covariates over time. Almost half of all patients (n = 246) had high fatigue levels at baseline, decreasing slightly over time. At 12 months, 43% of patients were fatigued; while 23% of the initially fatigued patients showed lower levels of fatigue, the fatigue level had increased in 15% of the initially non-fatigued patients. The strongest predictor of fatigue was the previous fatigue levels (AUC 0.89). Higher score on the depression scale and coping with limitations was associated with developing fatigue over time in the initially non-fatigued group. Despite a strict treat-to-target strategy, fatigue remained an overall problem during the first year of treatment, and was mainly predicted by its baseline status. In subgroups, a small additional effect of depression was seen. Monitoring fatigue and depression may be important in managing fatigue.


Subcortical circuits mediate communication between primary sensory cortical areas in mice.
Integration of information across the senses is critical for perception and is a common property of neurons in the cerebral cortex, where it is thought to arise primarily from corticocortical connections. Much less is known about the role of subcortical circuits in shaping the multisensory properties of cortical neurons. We show that stimulation of the whiskers causes widespread suppression of sound-evoked activity in mouse primary auditory cortex (A1). This suppression depends on the primary somatosensory cortex (S1), and is implemented through a descending circuit that links S1, via the auditory midbrain, with thalamic neurons that project to A1. Furthermore, a direct pathway from S1 has a facilitatory effect on auditory responses in higher-order thalamic nuclei that project to other brain areas. Crossmodal corticofugal projections to the auditory midbrain and thalamus therefore play a pivotal role in integrating multisensory signals and in enabling communication between different sensory cortical areas.


Nortriptyline for neuropathic pain in adults.
Antidepressants are widely used to treat chronic neuropathic pain (pain due to nerve damage), usually in doses below those at which they exert antidepressant effects. An earlier review that included all antidepressants for neuropathic pain is being replaced by new reviews of individual drugs examining individual neuropathic pain conditions.Nortriptyline is a tricyclic antidepressant that is occasionally used for treating neuropathic pain, and is recommended in European, UK, and USA guidelines. To assess the analgesic efficacy and associated adverse events of nortriptyline for chronic neuropathic pain in adults. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and EMBASE from inception to 7 January 2015, and the reference lists of retrieved papers and other reviews. We also searched two clinical trials databases for ongoing or unpublished studies. We included randomised, double-blind studies of at least two weeks' duration comparing nortriptyline with placebo or another active treatment in chronic neuropathic pain. Participants were adults aged 18 years and over. We included only full journal publication articles and clinical trial summaries. Two review authors independently extracted efficacy and adverse event data, and examined issues of study quality. We considered the evidence using three tiers. First tier evidence derived from data meeting current best standards and subject to minimal risk of bias (outcome equivalent to substantial pain intensity reduction, intention-to-treat analysis without imputation for dropouts; at least 200 participants in the comparison, 8 to 12 weeks' duration, parallel design); second tier evidence from data that failed to meet one or more of these criteria and were considered at some risk of bias but with adequate numbers in the comparison; and third tier evidence from data involving small numbers of participants that was considered very likely to be biased or used outcomes of limited clinical utility, or both.We planned to calculate risk ratio (RR) and numbers needed to treat for an additional beneficial outcome (NNT) and harmful outcome (NNH) using standard methods expected by The Cochrane Collaboration. We included six studies treating 310 participants (mean or median age 49 to 64 years) with various neuropathic pain conditions. Five studies used a cross-over design, and one used a parallel-group design; 272 participants were randomised to treatment with nortriptyline, 145 to placebo, 94 to gabapentin, 56 to gabapentin plus nortriptyline, 55 to morphine, 55 to morphine plus nortriptyline, 39 to chlorimipramine, and 33 to amitriptyline. Treatment periods lasted from three to eight weeks. All studies had one or more sources of potential major bias.No study provided first or second tier evidence for any outcome. Only one study reported our primary outcome of people with at least 50% reduction in pain. There was no indication that either nortriptyline or gabapentin was more effective in postherpetic neuralgia (very low quality evidence). Two studies reported the number of people with at least moderate pain relief, and one reported the number who were satisfied with their pain relief and had tolerable adverse effects. We considered these outcomes to be equivalent to our other primary outcome of Patient Global Impression of Change (PGIC) much or very much improved.We could not pool data, but third tier evidence in individual studies indicated similar efficacy to other active interventions (gabapentin, morphine, chlorimipramine, and amitriptyline), and to placebo in the conditions studied (very low quality evidence). Adverse event reporting was inconsistent and fragmented. More participants reported adverse events with nortriptyline than with placebo, similar numbers with nortriptyline and other antidepressants (amitriptyline and chlorimipramine) and gabapentin, and slightly more with morphine (very low quality evidence). No study reported any serious adverse events or deaths. We found little evidence to support the use of nortriptyline to treat the neuropathic pain conditions included in this review. There were no studies in the treatment of trigeminal neuralgia. The studies were methodologically flawed, largely due to small size, and potentially subject to major bias. The results of this review do not support the use of nortriptyline as a first line treatment. Effective medicines with much greater supportive evidence are available, such as duloxetine and pregabalin.


Effect of a lysine depletion-repletion protocol on the compensatory growth of growing-finishing pigs.
The effect of Lys restriction followed by a repletion period on the performance of growing pigs was studied during 3 feeding phases, each lasting 28 d. A total of 47 castrated male pigs (G Performer 8.0 × Fertilis 25 pigs; Genetiporc Inc., Saint-Bernard, QC, Canada; initial BW of 26.7 ± 2.7 kg) were given each d 70% or 100% of their Lys requirements according to 1 of the following 5 sequences: 70-70-70, 70-70-100, 70-100-70, 70-100-100, or 100-100-100 (for each sequence, numbers indicate the Lys supply percentage in phase 1, 2, and 3, respectively). Individual Lys requirements were estimated daily on the basis of each pig's actual BW and feed intake and BW gain patterns obtained by regression using each pig's historical data. At the end of phase 1, the pigs given 100% of their Lys requirements had higher ADFI ( = 0.01), ADG ( < 0.01), and average daily protein deposition ( < 0.01) than did the pigs given 70% of their requirements. Similar results were observed during phases 2 and 3. At the end of phase 2, the pigs in the 70-100 sequence did not display any compensatory response, given that their ADFI, ADG, and average daily protein deposition did not differ from those of the pigs in the 100-100 sequence. Similar results were observed during phase 3. Although no compensatory growth was observed during the growing phases, the fact that the pigs in the 70-100-100 treatment were able to catch up in terms of BW and body protein mass to the pigs in the 100-100-100 sequence could indicate that a small degree of compensation did occur; these research results cannot ascertain that any compensatory growth occurred.


Insights into channel architecture and substrate specificity from crystal structures of two macrocycle-forming thioesterases of modular polyketide synthases.
Modular polyketide synthases (PKSs) synthesize the polyketide cores of pharmacologically important natural products such as erythromycin and picromycin. Understanding PKSs at high resolution could present new opportunities for chemoenzymatic synthesis of complex molecules. The crystal structures of macrocycle-forming thioesterase (TE) domains from the picromycin synthase (PICS) and 6-deoxyerythronolide B synthase (DEBS) were determined to 1.8-3.0 A with an R(crys) of 19.2-24.4%, including three structures of PICS TE (crystallized at pH 7.6, 8.0, and 8.4) and a second crystal form of DEBS TE. As predicted by the previous work on DEBS TE [Tsai, S. C., et al. (2001) Proc. Natl. Acad. Sci. U.S.A. 98, 14808-14813], PICS TE contains an open substrate channel and a hydrophobic dimer interface. Notwithstanding their similarity, the dimer interfaces and substrate channels of DEBS TE and PICS TE reveal key differences. The structural basis for the divergent substrate specificities of DEBS TE and PICS TE is analyzed. The size of the substrate channel increases with increasing pH, presumably due to electrostatic repulsion in the channel at elevated pH. Together, these structures support previous predictions that macrocycle-forming thioesterases from PKSs share the same protein fold, an open substrate channel, a similar catalytic mechanism, and a hydrophobic dimer interface. They also provide a basis for the design of enzymes capable of catalyzing regioselective macrocyclization of natural or synthetic substrates. A series of high-resolution snapshots of a protein channel at different pHs is presented alongside analysis of channel residues, which could help in the redesign of the protein channel architecture.


A set of NF-κB-regulated microRNAs induces acquired TRAIL resistance in lung cancer.
TRAIL (TNF-related apoptosis-inducing ligand) is a promising anticancer agent that can be potentially used as an alternative or complementary therapy because of its specific antitumor activity. However, TRAIL can also stimulate the proliferation of cancer cells through the activation of NF-κB, but the exact mechanism is still poorly understood. In this study, we show that chronic exposure to subtoxic concentrations of TRAIL results in acquired resistance. This resistance is associated with the increase in miR-21, miR-30c, and miR-100 expression, which target tumor-suppressor genes fundamental in the response to TRAIL. Importantly, down-regulation of caspase-8 by miR-21 blocks receptor interacting protein-1 cleavage and induces the activation of NF-κB, which regulates these miRNAs. Thus, TRAIL activates a positive feedback loop that sustains the acquired resistance and causes an aggressive phenotype. Finally, we prove that combinatory treatment of NF-κB inhibitors and TRAIL is able to revert resistance and reduce tumor growth, with important consequences for the clinical practice.


Trends in Use of Medical Imaging in US Health Care Systems and in Ontario, Canada, 2000-2016.
Medical imaging increased rapidly from 2000 to 2006, but trends in recent years have not been analyzed. To evaluate recent trends in medical imaging. Retrospective cohort study of patterns of medical imaging between 2000 and 2016 among 16 million to 21 million patients enrolled annually in 7 US integrated and mixed-model insurance health care systems and for individuals receiving care in Ontario, Canada. Calendar year and country (United States vs Canada). Use of computed tomography (CT), magnetic resonance imaging (MRI), ultrasound, and nuclear medicine imaging. Annual and relative imaging rates by imaging modality, country, and age (children [<18 years], adults [18-64 years], and older adults [≥65 years]). Overall, 135 774 532 imaging examinations were included; 5 439 874 (4%) in children, 89 635 312 (66%) in adults, and 40 699 346 (30%) in older adults. Among adults and older adults, imaging rates were significantly higher in 2016 vs 2000 for all imaging modalities other than nuclear medicine. For example, among older adults, CT imaging rates were 428 per 1000 person-years in 2016 vs 204 per 1000 in 2000 in US health care systems and 409 per 1000 vs 161 per 1000 in Ontario; for MRI, 139 per 1000 vs 62 per 1000 in the United States and 89 per 1000 vs 13 per 1000 in Ontario; and for ultrasound, 495 per 1000 vs 324 per 1000 in the United States and 580 per 1000 vs 332 per 1000 in Ontario. Annual growth in imaging rates among US adults and older adults slowed over time for CT (from an 11.6% annual percentage increase among adults and 9.5% among older adults in 2000-2006 to 3.7% among adults in 2013-2016 and 5.2% among older adults in 2014-2016) and for MRI (from 11.4% in 2000-2004 in adults and 11.3% in 2000-2005 in older adults to 1.3% in 2007-2016 in adults and 2.2% in 2005-2016 in older adults). Patterns in Ontario were similar. Among children, annual growth for CT stabilized or declined (United States: from 10.1% in 2000-2005 to 0.8% in 2013-2016; Ontario: from 3.3% in 2000-2006 to -5.3% in 2006-2016), but patterns for MRI were similar to adults. Changes in annual growth in ultrasound were smaller among adults and children in the United States and Ontario compared with CT and MRI. Nuclear medicine imaging declined in adults and children after 2006. From 2000 to 2016 in 7 US integrated and mixed-model health care systems and in Ontario, rates of CT and MRI use continued to increase among adults, but at a slower pace in more recent years. In children, imaging rates continued to increase except for CT, which stabilized or declined in more recent periods. Whether the observed imaging utilization was appropriate or was associated with improved patient outcomes is unknown.


[Representations on patient illness and cure at the Chemical Dependency Center of the Central Navy Hospital].
This article presents one of the segments of ethnographic research which was conducted over a two-year period, by means of participant observation, at the Chemical Dependency Center of the Brazilian Navy. Patients of 2 treatment groups were observed during 24 sessions of group therapy. Among the 22 existing patients of the two groups, 13 patients were randomly selected for individual interviews. Their illness and healing representations related to mental and behavioral disorders caused by drugs were examined, and also the influence of the work environment on patient involvement with drugs was investigated. Results show that patients believe that they are responsible for their illness and for their alcoholic sobriety and they also believe they will never be cured. Furthermore, they do not usually accept the on-going medical discourse or the Alcoholics Anonymous belief that they are recovering alcoholics; they build their own views about their diagnoses, prognoses, and treatments. There are cultural traits particular to the naval life that indicate that the categories analyzed are mainly social, and that certain work-related conditions lead to the emergence of alcoholism in many patients, despite the fact that drugs are commonly tackled from the administrative perspective.


The role of nurses in the human immunodeficiency virus/acquired immune deficiency syndrome policy process in Botswana.
In Botswana, there is dearth of literature on the role of nursing in health-care policy and resource allocation and yet nurses constitute the majority (85%) of health manpower. The health-care delivery system depends mostly on nurses for service provision. There were two main purposes of this study: first, to gather descriptive data from major key players (with particular emphasis on nurses) concerning knowledge of the policy process and resource allocation for management and care of clients with human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) in Botswana; and, second, to identify nurse characteristics (e.g. position, education, experience, job category) associated with motivation to influence health-care policy in HIV/AIDS management and care in Botswana. A policy process conceptual framework was used to guide data collection and analysis. A case-study research method was used to conduct in-depth interviews from a purposive sample of 19 policy makers, and a survey questionnaire was used to collect data from a purposive sample of 95 registered nurses from six study sites in Botswana. The study findings indicate minimal participation of nurses in health-care policy process and resource allocation. The demographic variable of position was a predictor of the involvement of nurses in policy and in budgetary decisions. Both survey and interview data indicated that this minimal participation of nurses in the policy process resulted in implementation problems, thus compromising service provision. Implications of the findings for the nursing profession, nursing practice and policy, which address the importance of nurses' involvement, are discussed.


Cervical cancer.
Cervical cancer is the second most common type of cancer in women worldwide, after breast cancer. A preponderance of evidence supports a causal link between human papillomavirus infection and cervical neoplasia. The presence of high-risk human papillomavirus genital subtypes increases the risk of malignant transformation. Widespread use of the Papanicolaou smear has dramatically reduced the incidence of cervical cancer in developed countries. Accurate and early recognition of abnormal cytologic changes prevents progression of the disease from preinvasive to invasive. Research is under way to determine if efforts to reduce the false-negative rate of the Papanicolaou smear should include rescreening programs and fluid-based technology. Once cervical cancer is diagnosed, clinical staging takes place. Early-stage tumors can be managed with cone biopsy or simple hysterectomy. Higher stage tumors can be treated surgically or with radiotherapy. Advanced metastatic disease may respond to radiation therapy and concurrent chemotherapy. Protein markers for detection of recurrence and vaccines for prevention of cervical cancer are under investigation.


Mass Casualty Decontamination in the United States: An Online Survey of Current Practice.
Mass casualty decontamination is a public health intervention that would be employed by emergency responders following a chemical, biological, or radiological incident. The decontamination of large numbers of casualties is currently most often performed with water to remove contaminants from the skin surface. An online survey was conducted to explore US fire departments' decontamination practices and their preparedness for responding to incidents involving mass casualty decontamination. Survey respondents were asked to provide details of various aspects of their decontamination procedures, including expected response times to reach casualties, disrobing procedures, approaches to decontamination, characteristics of the decontamination showering process, provision for special populations, and any actions taken following decontamination. The aim of the survey was to identify any differences in the way in which decontamination guidance is implemented across US states. Results revealed that, in line with current guidance, many US fire departments routinely use the "ladder-pipe system" for conducting rapid, gross decontamination of casualties. The survey revealed significant variability in ladder-pipe construction, such as the position and number of fire hoses used. There was also variability in decontamination characteristics, such as water temperature and water pressure, detergent use, and shower duration. The results presented here provide important insights into the ways in which implementation of decontamination guidance can vary between US states. These inconsistencies are thought to reflect established perceived best practices and local adaptation of response plans to address practical and logistical constraints. These outcomes highlight the need for evidence-based national guidelines for conducting mass casualty decontamination.


Predictive analytics of environmental adaptability in multi-omic network models.
Bacterial phenotypic traits and lifestyles in response to diverse environmental conditions depend on changes in the internal molecular environment. However, predicting bacterial adaptability is still difficult outside of laboratory controlled conditions. Many molecular levels can contribute to the adaptation to a changing environment: pathway structure, codon usage, metabolism. To measure adaptability to changing environmental conditions and over time, we develop a multi-omic model of Escherichia coli that accounts for metabolism, gene expression and codon usage at both transcription and translation levels. After the integration of multiple omics into the model, we propose a multiobjective optimization algorithm to find the allowable and optimal metabolic phenotypes through concurrent maximization or minimization of multiple metabolic markers. In the condition space, we propose Pareto hypervolume and spectral analysis as estimators of short term multi-omic (transcriptomic and metabolic) evolution, thus enabling comparative analysis of metabolic conditions. We therefore compare, evaluate and cluster different experimental conditions, models and bacterial strains according to their metabolic response in a multidimensional objective space, rather than in the original space of microarray data. We finally validate our methods on a phenomics dataset of growth conditions. Our framework, named METRADE, is freely available as a MATLAB toolbox.


Postoperative changes of liver enzymes can distinguish between biliary stricture and graft rejection after living donor liver transplantation: A longitudinal study.
There is no known useful clinical parameter that can specifically predict a biliary stricture and differentiate it from other related complications after living donor liver transplantations (LDLT). The aims of this study were to determine whether the changes of liver enzymes can predict postoperative biliary stricture apart from other complications. We reviewed the medical records of 203 patients who underwent LDLT with duct to duct anastomosis from 2008 to 2010. The longitudinal changes of liver enzyme over time and the occurrence of complication were evaluated. A total of 124 patients had no complication up to 2 years after LDLT, and 74 patients had complications including biliary stricture and graft rejection. Complications developed more frequently in patients who's alkaline phosphatase (ALP) and gamma-glutamyl transpeptidase (GGT) did not return to the baseline plateau at 30 days after LDLT (ALP; P = .045, GGT; P = .047). Aspartate transaminase (AST) and alanine transaminase (ALT) increased continuously until the diagnosis of complication in both stricture and rejection groups with more rapid increase in enzymes in the rejection versus stricture group (P < .05). In addition, AST and ALT were 2-fold higher in the rejection than the stricture group at the diagnosis of each complication (AST; P < .05, ALT; P < .05). The increasing slope and final levels of AST and ALT are potentially helpful parameters to differentiate rejection and stricture, the 2 most common posttransplantation complications.


Mesenchymal stem cell transplantation can restore lupus disease-associated miRNA expression and Th1/Th2 ratios in a murine model of SLE.
C3.MRL-Faslpr/J mice spontaneously develop high titers of anti-dsDNA, mild glomerular nephritis, and severe lymphoproliferation symptoms. This study aimed to compare the effects of long-term serial administration of human adipose tissue-derived mesenchymal stem cells (ASCs), and cyclophosphamide treatment in C3.MRL-Faslpr/J mice using a murine SLE model. C3.MRL-Faslpr/J mice were divided into saline (C), cyclophosphamide (Y), and ASC (H) treatment groups. Background-matched control C3H mice treated with saline (N) were also compared. The Y group showed the greatest improvement in disease parameters, but with damaged trabecular integrity. ASC transplantation reduced anti-dsDNA levels, glomerular C3 deposition and CD138 proportion significantly, without trabecular damage. Furthermore, both cyclophosphamide and ASC treatment significantly decreased the ratio of Th1/Th2 compared with the saline-treatment. The expression levels of miR-31-5p, miR-96-5p, miR-182-5p, miR-183-5p, and miR-379-5p were significantly higher, while those of miR150-5p were significantly lower in the C group than in the N group. The expression levels of miR-96-5p, miR-182-5p in the Y and H groups were significantly lower than in the C group. Thus, treatment with cyclophosphamide or ASC can change miRNAs and decrease miR-96-5p and miR-182-5p expression, as well as decreasing the CD138 proportion and the Th1/Th2 ratio, which might be involved in the therapeutic mechanism.


Bitwise efficiency in chaotic models.
Motivated by the increasing energy consumption of supercomputing for weather and climate simulations, we introduce a framework for investigating the bit-level information efficiency of chaotic models. In comparison with previous explorations of inexactness in climate modelling, the proposed and tested information metric has three specific advantages: (i) it requires only a single high-precision time series; (ii) information does not grow indefinitely for decreasing time step; and (iii) information is more sensitive to the dynamics and uncertainties of the model rather than to the implementation details. We demonstrate the notion of bit-level information efficiency in two of Edward Lorenz's prototypical chaotic models: Lorenz 1963 (L63) and Lorenz 1996 (L96). Although L63 is typically integrated in 64-bit 'double' floating point precision, we show that only 16 bits have significant information content, given an initial condition uncertainty of approximately 1% of the size of the attractor. This result is sensitive to the size of the uncertainty but not to the time step of the model. We then apply the metric to the L96 model and find that a 16-bit scaled integer model would suffice given the uncertainty of the unresolved sub-grid-scale dynamics. We then show that, by dedicating computational resources to spatial resolution rather than numeric precision in a field programmable gate array (FPGA), we see up to 28.6% improvement in forecast accuracy, an approximately fivefold reduction in the number of logical computing elements required and an approximately 10-fold reduction in energy consumed by the FPGA, for the L96 model.


Arbitrarily short coherence length in wave fields within finite lossless source regions.
We show that it is possible to construct stochastic source distributions that generate wave fields with any desired spatial coherence properties inside a prescribed finite region, regardless of the refractive-index distribution therein. In particular, we demonstrate that there is no universal sinc-function form for the field correlations produced by statistically homogeneous and isotropic source distributions within large lossless regions, contrary to what is suggested by previous work. The results also disprove the commonly held belief that in lossless source regions the coherence length of the light is bounded below by the blackbody coherence length-that is, by approximately half the wavelength of the field.


Characterisation and correction of a mammalian cell mutant defective in late step of base excision repair.
An Indian muntjac cell line, SVM, is unusually sensitive to cell killing induced by a range of alkylating agents. Cells transfected with the Escherichia coli ada gene or human genomic DNA have allowed the response of SVM to alkylating agents to be dissociated into two distinct components. Thus, in SVM, which expresses very low levels of alkyltransferase (AT), O6-alkylguanine appears to be the major cytotoxic, clastogenic, and recombinogenic lesion following exposure to agents such as methylnitrosourea (MNU). However, SVM is also very sensitive to agents such as dimethylsulfate (DMS), which produce only very low levels of O6-methylguanine damage. Sensitivity to DMS resides in an inability to complete base excision repair, with the appearance of persistent single-strand DNA breaks (SSBs), and does not appear to involve defects in glycosylase, apurinic/apyrimidinic endonuclease, or DNA ligase activities. Another, possibly related, phenotypic trait in SVM is its limited ability to ligate transfected linear plasmid DNA. Transfectants of SVM, harboring human DNA sequences, show a significant correction of DMS-induced cytotoxicity and clastogenicity and a reduction in the levels of DMS-induced DNA SSBs. The DMS-resistant transfectants have an increased ability to ligate linear plasmid DNA, and also express AT, making these lines resistant to alkylating agents such as MNU. These results suggest that cells possess a mechanism that regulates AT expression, plasmid break-joining ability, and certain aspects of base excision repair. Transfectants of SVM containing human DNA provide a means to isolate genes involved in a coordinate response to alkylation damage.


Pleasure as an Overlooked Target of Substance Use Disorder Research and Treatment.
People commonly use psychoactive substances to increase physical and psychological pleasure. Neuroadaptations in the brain's reward system coupled with changes in social functioning and networking resulting from chronic substance use impede the ability to derive pleasure from non-substance related activities. We elucidate and validate the hypothesis that treatments for substance use disorders would potentially have a stronger and broader impact by helping recipients to experience pleasure as part of an expansive focus of increasing adaptive functioning, well-being, and personal fulfillment and actualization. We have organized and integrated relatively sparse and disparate theory and research to describe a multi-stage model linking pleasure and substance use. We review research on pleasure in the context of treatment for substance use, and describe future research directions. Our model integrates several independent research programs with prominent theories and models of substance dependence that together provide evidence that pleasure, or lack thereof, is a risk or protective factor for initiating, escalating and maintaining substance use and substance use disorders. Pleasure is an overlooked but potentially high-yield target of existing evidence-based treatments. Research is needed to investigate the relation between pleasure and substance use, and existing and newly developed treatments that have the potential to increase pleasure. By increasing pleasure such treatments have the potential to help recipients to live fuller and richer lives. Integration of pleasure into existing treatments has compelling transdiagnostic implications for individuals at any point along a substance use severity continuum.


Fast and accurate database searches with MS-GF+Percolator.
One can interpret fragmentation spectra stemming from peptides in mass-spectrometry-based proteomics experiments using so-called database search engines. Frequently, one also runs post-processors such as Percolator to assess the confidence, infer unique peptides, and increase the number of identifications. A recent search engine, MS-GF+, has shown promising results, due to a new and efficient scoring algorithm. However, MS-GF+ provides few statistical estimates about the peptide-spectrum matches, hence limiting the biological interpretation. Here, we enabled Percolator processing for MS-GF+ output and observed an increased number of identified peptides for a wide variety of data sets. In addition, Percolator directly reports p values and false discovery rate estimates, such as q values and posterior error probabilities, for peptide-spectrum matches, peptides, and proteins, functions that are useful for the whole proteomics community.


The Full Blood Count Blood Test for Colorectal Cancer Detection: A Systematic Review, Meta-Analysis, and Critical Appraisal.
A full blood count (FBC) blood test includes 20 components. We systematically reviewed studies that assessed the association of the FBC and diagnosis of colorectal cancer to identify components as risk factors. We reviewed FBC-based prediction models for colorectal cancer risk. MEDLINE, EMBASE, CINAHL, and Web of Science were searched until 3 September 2019. We meta-analysed the mean difference in FBC components between those with and without a diagnosis and critically appraised the development and validation of FBC-based prediction models. We included 53 eligible articles. Three of four meta-analysed components showed an association with diagnosis. In the remaining 16 with insufficient data for meta-analysis, three were associated with colorectal cancer. Thirteen FBC-based models were developed. Model performance was commonly assessed using the c-statistic (range 0.72-0.91) and calibration plots. Some models appeared to work well for early detection but good performance may be driven by early events. Red blood cells, haemoglobin, mean corpuscular volume, red blood cell distribution width, white blood cell count, and platelets are associated with diagnosis and could be used for referral. Existing FBC-based prediction models might not perform as well as expected and need further critical testing.


Linear-to-circular polarization transformation upon optical tunneling through an embedded low-index film.
Quarter-wave retardation can be achieved in optical tunneling through a low-index thin film that is surrounded by a medium of higher refractive index, for any index ratio N>2.414, over a range of incidence angles that is determined by N. A novel frustrated-total-internal-reflection circular polarization beam splitter (CPBS) is proposed that uses an adjustable air gap between two Ge prisms. This tunable CPBS operates over a broad (2-12 microm) IR spectral range by controlling the air-gap thickness to match one-tenth of the wavelength of light by use of a piezoelectric transducer.


Approaches to passive mosquito surveillance in the EU.
The recent emergence in Europe of invasive mosquitoes and mosquito-borne disease associated with both invasive and native mosquito species has prompted intensified mosquito vector research in most European countries. Central to the efforts are mosquito monitoring and surveillance activities in order to assess the current species occurrence, distribution and, when possible, abundance, in order to permit the early detection of invasive species and the spread of competent vectors. As active mosquito collection, e.g. by trapping adults, dipping preimaginal developmental stages or ovitrapping, is usually cost-, time- and labour-intensive and can cover only small parts of a country, passive data collection approaches are gradually being integrated into monitoring programmes. Thus, scientists in several EU member states have recently initiated programmes for mosquito data collection and analysis that make use of sources other than targeted mosquito collection. While some of them extract mosquito distribution data from zoological databases established in other contexts, community-based approaches built upon the recognition, reporting, collection and submission of mosquito specimens by citizens are becoming more and more popular and increasingly support scientific research. Based on such reports and submissions, new populations, extended or new distribution areas and temporal activity patterns of invasive and native mosquito species were found. In all cases, extensive media work and communication with the participating individuals or groups was fundamental for success. The presented projects demonstrate that passive approaches are powerful tools to survey the mosquito fauna in order to supplement active mosquito surveillance strategies and render them more focused. Their ability to continuously produce biological data permits the early recognition of changes in the mosquito fauna that may have an impact on biting nuisance and the risk of pathogen transmission associated with mosquitoes. International coordination to explore synergies and increase efficiency of passive surveillance programmes across borders needs to be established.


The prevalence and determinants of problem gambling in Australia: assessing the impact of interactive gambling and new technologies.
New technology is changing the nature of gambling with interactive modes of gambling becoming putatively associated with higher rates of problem gambling. This paper presents the first nationally representative data on the prevalence and correlates of problem gambling among Australian adults since 1999 and focuses on the impact of interactive gambling. A telephone survey of 15,006 adults was conducted. Of these, 2,010 gamblers (all interactive gamblers and a randomly selected subsample of those reporting land-based gambling in the past 12 months) also completed more detailed measures of problem gambling, substance use, psychological distress, and help-seeking. Problem gambling rates among interactive gamblers were 3 times higher than for noninteractive gamblers. However, problem and moderate risk gamblers were most likely to attribute problems to electronic gaming machines and land-based gambling, suggesting that although interactive forms of gambling are associated with substantial problems, interactive gamblers experience significant harms from land-based gambling. The findings demonstrate that problem gambling remains a significant public health issue that is changing in response to new technologies, and it is important to develop strategies that minimize harms among interactive gamblers.


Potential plant poisonings in dogs and cats in southern Africa.
Plant poisoning occurs less commonly in dogs and cats than in herbivorous livestock, but numerous cases have been documented worldwide, most of them caused by common and internationally widely cultivated ornamental garden and house plants. Few cases of poisoning of cats and dogs have been reported in southern Africa, but many of the plants that have caused poisoning in these species elsewhere are widely available in the subregion and are briefly reviewed in terms of toxic principles, toxicity, species affected, clinical signs, and prognosis. The list includes Melia azedarach (syringa), Brunfelsia spp. (yesterday, today and tomorrow), Datura stramonium (jimsonweed, stinkblaar), a wide variety of lilies and lily-like plants, cycads, plants that contain soluble oxalates, plants containing cardiac glycosides and other cardiotoxins and euphorbias (Euphorbia pulcherrima, E. tirucalli). Poisoning by plant products such as macadamia nuts, onions and garlic, grapes and raisins, cannabis (marijuana, dagga) or hashish and castor oil seed or seedcake is also discussed. Many of the poisonings are not usually fatal, but others frequently result in death unless rapid action is taken by the owner and the veterinarian, underlining the importance of awareness of the poisonous potential of a number of familiar plants.


Guinea pig tracheal epithelial cells in primary culture: morphological and metabolic characterization.
The tracheo-bronchial epithelial cells are the first cells of the respiratory tract to encounter inhaled pathogens or allergens. In order to study these interactions in vitro we developed a culture of epithelial cells from guinea pig trachea which were kept as a primary culture for 3-13 days. Electron microscopy showed that the specific ultrastructure of epithelial cells was maintained, particularly cytokeratin intermediate filaments detected by immunofluorescence. The cells in culture produced eicosanoid metabolites, mainly leukotriene B4 and prostaglandin E2 spontaneously and upon calcium ionophore A23187 stimulation.


Contribution of the frontal lobe to externally and internally specified verbal responses: fMRI evidence.
It has been suggested that within the frontal cortex there is a lateral to medial shift in the control of action, with the lateral premotor area (PMA) involved in externally specified actions and the medial supplementary motor areas (SMA) involved in internally specified actions. Recent brain imaging studies demonstrate, however, that the control of externally and internally specified actions may involve more complex and overlapping networks involving not only the PMA and the SMA, but also the pre-SMA and the lateral prefrontal cortex (PFC). The aim of the present study was to determine whether these frontal regions are differentially involved in the production of verbal responses, when they are externally specified and when they are internally specified. Participants engaged in three overt speaking tasks in which the degree of response specification differed. The tasks involved reading aloud words (externally specified), or generating words aloud from narrow or broad semantic categories (internally specified). Using fMRI, the location and magnitude of the BOLD activity for these tasks was measured in a group of ten participants. Compared with rest, all tasks activated the primary motor area and the SMA-proper, reflecting their common role in speech production. The magnitude of the activity in the PFC (Brodmann area 45), the left PMAv and the pre-SMA increased for word generation, suggesting that each of these three regions plays a role in internally specified action selection. This confirms previous reports concerning the participation of the pre-SMA in verbal response selection. The pattern of activity in PMAv suggests participation in both externally and internally specified verbal actions.


Development of layer I of the human cerebral cortex after midgestation: architectonic findings, immunocytochemical identification of neurons and glia, and in situ labeling of apoptotic cells.
The development of layer I was studied in the human frontal cortex from 21 weeks of gestation (GW) to 2.5 postnatal months in series of adjacent sections processed for thionin staining, Bodian silver staining, and immunocytochemical labeling of neurons and glia. In addition, the terminal dUTP nick-end labeling (TUNEL) method was used to label in situ DNA fragmentation. A progressive decrease of cell density and the disappearance of the subpial granular layer (SGL) appeared as distinctive developmental features of human layer I, consistently with previous investigations. The neuronal antigen microtubule-associated protein2 was found to label preferentially Cajal-Retzius cells and dendritic processes extending from the cortical plate. At midgestation, the calcium binding protein calretinin stained in the marginal zone numerous neurons, including the Cajal-Retzius cells and their processes. Calretinin-immunoreactive neurons decreased during the subsequent maturation: such decline was abrupt in the SGL, whereas bipolar calretinin-immunopositive cells accumulated in the inner marginal zone to be presumably incorporated into the cortical plate. Cajal-Retzius cells expressed calretinin throughout the examined developmental stages. The glial antigen vimentin was already expressed at midgestation, and vimentin immunopositivity decreased progressively in cell bodies and fibers of layer I during development. Glial fibrillary acidic protein-positive elements gradually matured, and the positive cell bodies displayed the features of mature astrocytes at the end of gestation. Moreover, a decrease of free glial cells was observed in layer I, suggesting their progressive incorporation into the cortical plate. TUNEL-positive cells were detected at midgestation in the marginal zone, and they were concentrated in the SGL until its disappearance; their number decreased dramatically throughout layer I after 30 gestational weeks. TUNEL-positive nuclei or regressive changes were not detected in Cajal-Retzius cells throughout the examined developmental stages. Thus, our data point out that naturally occurring cell death is an active mechanism contributing to the disappearance of the SGL but not to the subsequent developmental reshaping of human layer I, in which, instead, migratory phenomena should play a major role. In addition, our findings argue against a disappearance of Cajal-Retzius cells due to regressive processes.


Transseptal Catheterization with Transesophageal Guidance in High Risk Patients.
Atrial transseptal catheterization is usually performed with fluoroscopic guidance of the needle. We report our experience with both fluoroscopic and transesophageal guidance in patients who would otherwise have been at risk by using only fluoroscopy. A total of eleven procedures were performed during a 4 year period. The relative contraindications (some patients had several contraindications) included prior valve replacement (5 patients), prior myocardial revascularization (4 patients), severe dilatation of the left atrium (4 patients), severe dilatation of the ascending aorta (4 patients), and kyphoscoliosis (3 patients). All eleven patients had the transesophageal guided transseptal catheterization performed without complications and without significantly prolonging the procedure. The results of this preliminary, small, and retrospective study suggest that transesophageal echocardiography may enhance the safety of transseptal catheterization in high risk patients. Further prospective studies are needed.


Envelope Membranes from Spinach Chloroplasts Are a Site of Metabolism of Fatty Acid Hydroperoxides.
Enzymes in envelope membranes from spinach (Spinacia oleracea L.) chloroplasts were found to catalyze the rapid breakdown of fatty acid hydroperoxides. In contrast, no such activities were detected in the stroma or in thylakoids. In preparations of envelope membranes, 9S-hydroperoxy-10(E),12(Z)-octadecadienoic acid, 13S-hydroperoxy-9(Z),11(E)-octadecadienoic acid, or 13S-hydroperoxy-9(Z),11(E),15(Z)-octadecatrienoic acid were transformed at almost the same rates (1-2 [mu]mol min-1 mg-1 protein). The products formed were separated by reversed-phase high-pressure liquid chromatography and further characterized by gas chromatography-mass spectrometry. Fatty acid hydroperoxides were cleaved (a) into aldehydes and oxoacid fragments, corresponding to the functioning of a hydroperoxide lyase, (b) into ketols that were spontaneously formed from allene oxide synthesized by a hydroperoxide dehydratase, (c) into hydroxy compounds synthesized enzymatically by a system that has not yet been characterized, and (d) into oxoenes resulting from the hydroperoxidase activity of a lipoxygenase. Chloroplast envelope membranes therefore contain a whole set of enzymes that catalyze the synthesis of a variety of fatty acid derivatives, some of which may act as regulatory molecules. The results presented demonstrate a new role for the plastid envelope within the plant cell.


All numbers are not equal: an electrophysiological investigation of small and large number representations.
Behavioral and brain imaging research indicates that human infants, humans adults, and many nonhuman animals represent large nonsymbolic numbers approximately, discriminating between sets with a ratio limit on accuracy. Some behavioral evidence, especially with human infants, suggests that these representations differ from representations of small numbers of objects. To investigate neural signatures of this distinction, event-related potentials were recorded as adult humans passively viewed the sequential presentation of dot arrays in an adaptation paradigm. In two studies, subjects viewed successive arrays of a single number of dots interspersed with test arrays presenting the same or a different number; numerical range (small numerical quantities 1-3 vs. large numerical quantities 8-24) and ratio difference varied across blocks as continuous variables were controlled. An early-evoked component (N1), observed over widespread posterior scalp locations, was modulated by absolute number with small, but not large, number arrays. In contrast, a later component (P2p), observed over the same scalp locations, was modulated by the ratio difference between arrays for large, but not small, numbers. Despite many years of experience with symbolic systems that apply equally to all numbers, adults spontaneously process small and large numbers differently. They appear to treat small-number arrays as individual objects to be tracked through space and time, and large-number arrays as cardinal values to be compared and manipulated.


Effects of maternal undernutrition during early pregnancy on apoptosis regulators in the ovine fetal ovary.
This study aimed to determine whether reduced fetal ovary folliculogenesis in ewes undernourished during early/midpregnancy is associated with altered ovarian cell proliferation and/or the expression of apoptosis-regulating genes. Groups of ewes (n = 11-19) were fed either 100% (high; H) or 50% (low; L) of metabolisable energy requirements for live-weight maintenance during selected windows of gestation. All animals were killed at days 50, 65 or 110 of gestation. Between mating and slaughter, control animals were fed the H ration, while animals of other subgroups were fed the L ration from (a) mating to slaughter at 50, 65 or 110 days; (b) 0 to 30 days; (c) 31 to 50 or 65 days; or (d), in the day 110 slaughter group only, from 66 to 110 days. Bouin's-fixed fetal ovaries were examined for (a) Ki67 immunoexpression (proliferation) and (b) Bax and Mcl-1 (apoptosis-regulating genes) expression by in situ hybridisation (day 110) and immunohistochemistry (days 50, 65 and 110). At day 50, maternal nutrition had no effect on Ki67, predominant in germ cells, or Bax and Mcl-1, predominant in the oocytes. Restricted maternal food intake from 0 to 30 days significantly reduced staining for Ki67 in germ cells at day 65 (P < 0.05) but increased staining in granulosa cells at day 110 (P < 0.05). In animals fed the L ration for 110 days, primordial follicle Bax and Mcl-1 were significantly increased (Bax: P < 0.01; Mcl-1: P < 0.05). Granulosa cell Bax was also increased (P < 0.05). When the L ration was fed from 66 to 110 days, granulosa cell Bax (P < 0.05) and primordial follicle Mcl-1 (P < 0.01) were also significantly increased. In the fetal ovarian vasculature, animals underfed for 0-110 days had significantly elevated perivascular Mcl-1 (P < 0.001) and endothelial Bax expression (P < 0.05). Moreover, at day 110, endothelial Mcl-1 was increased by underfeeding from 0 to 30 days (P < 0.05). These data indicate that maternal undernutrition alters proliferation and the expression of apoptosis-regulating genes in the developing fetal ovary. The precise mechanism depends on the window of maternal food restriction.


Comparison of direct digital and conventional radiography for the detection of proximal surface caries in the mixed dentition.
The aim of this study was to compare the performance of direct digital radiography and traditional dental radiography for the detection of proximal surface dental caries in the mixed dentition. 15 quadrants of extracted teeth, arranged from the primary canine to permanent first molar, were imaged using direct digital (Schick Technologies, Long Island City, NY, USA) and conventional films (D-speed and E-speed Plus; Eastman Kodak Co., Rochester, NY, USA). Five pediatric dentists viewed the images and scored the 270 proximal surfaces for presence of caries on a 5 point scale and extent of caries on a 4 point scale. The teeth were sectioned and viewed microscopically to determine the gold standard. Receiver operating characteristic (ROC) analysis and analysis of variance (ANOVA) were used to evaluate the viewer's performance for detecting proximal caries using the 3 different image receptor types. Experienced examiners were significantly more accurate in diagnosis of proximal surface caries using either D-speed or E-speed Plus films than they were using the direct digital receptor. The mean areas under the ROC curve (Az) for the viewers were 0.7595 for D-speed film, 0.7557 for E-speed Plus film, and 0.5928 for the direct digital receptor. The results also indicated that selected viewers' accuracy increased when viewing the direct digital images a second time. CCD based direct digital radiography was not as accurate as conventional film images for the purpose of diagnosing proximal surface caries in the mixed dentition. However, the results imply that with increased experience, direct digital images may be as accurate as conventional film based images for diagnosis.


The NADPH oxidase subunit p22phox inhibits the function of the tumor suppressor protein tuberin.
Mutations in the von Hippel-Lindau (VHL) gene give rise to renal cell carcinoma. Reactive oxygen species, generated by Nox oxidases, are involved in tumorigenesis. We have previously demonstrated that in VHL-deficient cells, p22(phox)-dependent Nox1 and Nox4 oxidases maintain hypoxia inducible factor-2alpha (HIF-2alpha) protein expression through an Akt-dependent translational pathway. Phosphorylation of tuberin, by Akt, results in its inactivation. Here we show that diphenyleneiodonium chloride, an inhibitor of Nox oxidases, and small-interfering RNA-mediated down-regulation of p22(phox) inhibit Akt-dependent phosphorylation of tuberin and stabilizes tuberin protein levels in VHL-deficient renal carcinoma cells. p22(phox)-mediated inactivation of tuberin is associated with an increase in ribosomal protein S6 kinase 1 and eukaryotic initiation factor 4E-binding protein-1 (4E-BP1) phosphorylation as well as HIF-2alpha stabilization. Importantly, we find that marked up-regulation of p22(phox) in human renal cell carcinoma correlates with increased tuberin phosphorylation, decreased tuberin protein levels, and increased phosphorylation of 4E-BP1. Our data provide the first evidence that p22(phox)-based Nox oxidases maintain HIF-2alpha protein expression through inactivation of tuberin and downstream activation of ribosomal protein S6 kinase 1/4E-BP1 pathway.


Point mutations in acetylcholinesterase 1 associated with chlorpyrifos resistance in the brown planthopper, Nilaparvata lugens Stål.
Insecticide resistance frequently results from target-site insensitivity, such as point mutations in acetylcholinesterases (AChEs) for resistance to organophosphates and carbamates. From a field-originated population of Nilaparvata lugens, a major rice pest, a resistant population (R9) was obtained by nine-generation continuous selection with chlorpyrifos. From the same field population, a relatively susceptible population (S9) was also constructed through rearing without any insecticides. Compared to the susceptible strain, Sus [medium lethal dose (LC50 ) = 0.012 mg/l], R9 had a resistance ratio (RR) of 253.08-fold, whereas the RR of S9 was only 2.25-fold. Piperonyl butoxide and triphenyl phosphate synergized chlorpyrifos in R9 less than three-fold, indicating other important mechanisms for high resistance. The target-site insensitivity was supported by the key property differences of crude AChEs between R9 and S9. Compared to S9, three mutations (G119S, F331C and I332L) were detected in NlAChE1 from individuals of the R9 and field populations, but no mutation was detected in NlAChE2. G119S and F331C could decreased insecticide sensitivities in recombinant NlAChE1, whereas I332L took effect through increasing the influence of F331C on target insensitivity. F331C might be deleterious because of its influence on the catalytic efficiency of NlAChE1, whereas I332L would decrease these adverse effects and maintain the normal functions of AChEs.


Significance of platelet-derived endothelial cell growth factor in the angiogenesis of human gastric cancer.
We have previously shown that platelet-derived endothelial cell growth factor (PD-ECGF) is associated with angiogenesis of human colon cancer; this factor is expressed at high levels in vascular tumors that express low levels of vascular endothelial growth factor (VEGF). In these colon cancers, the major source of PD-ECGF is the infiltrating cells. In this study, we examined the role of PD-ECGF in the angiogenesis of human gastric cancer. Immunostaining for PD-ECGF was done on 93 gastric cancers previously stained for VEGF, basic fibroblast growth factor, and factor VIII-related antigen (specific for endothelial cells). To determine the cell type expressing PD-ECGF, double staining was done using antibodies to both PD-ECGF and CD68 (specific for macrophages). PD-ECGF was expressed more frequently in infiltrating cells (positive CD68 staining; 53.8%) than in tumor epithelium (9.7%; P < 0.0001). Infiltrating cells simultaneously stained positive for both PD-ECGF and CD68. An association between PD-ECGF expression in infiltrating cells, VEGF expression in tumor epithelium, and vessel count was observed in intestinal-type gastric cancer but not in diffuse-type gastric cancer. Vessel count was greater in tumors with high expression of both PD-ECGF and VEGF than in those with high expression of either factor alone (P = 0.002). Multiple angiogenic factors expressed by both tumor cells and infiltrating cells may play a role in the regulation of angiogenesis in intestinal-type gastric cancer.


Phytochemical profile and qualification of biological activity of an isolated fraction of Bellis perennis.
This study describes the isolation and identification of apigenin-7-O-ghicopyranoside, a flavonoid isolated from the flowers of Bellis perennis L., Asteraceae, an species with a broad spectrum of biological activities. The in vitro antioxidant activity and the inhibition of the enzyme acetylcholinesterase were evaluated. The flavonoid showed strong in vitro antioxidant potential, because of the capacity of removal of hydroxyl radicals and nitric oxide, and also prevented the formation of thiobarbituric acid-reactive substances. These parameters were inhibited at the highest concentration of ApG at rates of 77.7%, 72% and 73.4%, respectively, in addition to inhibiting acetylcholinesterase, suggesting potential use in the treatment of neurodegenerative diseases.


Differences in young adult psychopathology among drug abstainers, experimenters, and frequent users.
Shedler and Block offered the provocative proposal that individuals who experiment with drugs are psychologically healthier than either those who abstain completely or those who are frequent users. Not all studies have come to such conclusions, however. In an effort to specify under what conditions Shedler and Block's conclusions might hold, the present study examined three groups of drug users (abstainers, experimenters, frequent users) classified according to three different criteria: (a) marijuana use at age 20; (b) alcohol use during 10th grade; and (c) alcohol use at age 20. The three groups were compared at age 20 in terms of personality, deviant behavior, and psychopathology. The results revealed that abstainers were never more psychologically impaired, and were occasionally healthier, than experimenters. Frequent users of marijuana were consistently more imparied than both the abstainers and experimenters, in terms of both internalizing and externalizing disorders. Classification according to marijuana use appeared to be more related to psychopathology than did classification according to alcohol use.


A Bayesian Nonparametric Approach for Functional Data Classification with Application to Hepatic Tissue Characterization.
Computed tomography perfusion (CTp) is an emerging functional imaging technology that provides a quantitative assessment of the passage of fluid through blood vessels. Tissue perfusion plays a critical role in oncology due to the proliferation of networks of new blood vessels typical of cancer angiogenesis, which triggers modifications to the vasculature of the surrounding host tissue. In this article, we consider a Bayesian semiparametric model for the analysis of functional data. This method is applied to a study of four interdependent hepatic perfusion CT characteristics that were acquired under the administration of contrast using a sequence of repeated scans over a period of 590 seconds. More specifically, our modeling framework facilitates borrowing of information across patients and tissues. Additionally, the approach enables flexible estimation of temporal correlation structures exhibited by mappings of the correlated perfusion biomarkers and thus accounts for the heteroskedasticity typically observed in those measurements, by incorporating change-points in the covariance estimation. This method is applied to measurements obtained from regions of liver surrounding malignant and benign tissues, for each perfusion biomarker. We demonstrate how to cluster the liver regions on the basis of their CTp profiles, which can be used in a prediction context to classify regions of interest provided by future patients, and thereby assist in discriminating malignant from healthy tissue regions in diagnostic settings.


Immunomagnetic diffractometry for detection of diagnostic serum markers.
We describe an integrated approach for detection of diagnostic markers using in situ assembled optical diffraction gratings in combination with immunomagnetic capture. Folate receptor (FR), a serum protein indicative of various cancers, was chosen as a model system to demonstrate the potential of the method. Magnetic beads coupled to FR antibody were used to capture FR from serum. The FR-bound magnetic beads self-assembled onto microcontact-printed folate-coupled BSA (F-BSA) patterns to form diffraction gratings which served to detect FR by measuring the diffraction intensities caused by laser illumination. The FR-containing beads, upon binding to the F-BSA surface, served as intrinsic signal enhancement agents, circumventing the need for additional enzymatic signal amplification or fluorescent labeling steps. With this approach, a detection sensitivity of 700 fM (20 pg/mL) was achieved. The potential use of this approach in clinical diagnostics was demonstrated by measuring FR concentration in blood samples obtained from cancer patients.


Fisetin, a 3,7,3',4'-Tetrahydroxyflavone Inhibits the PI3K/Akt/mTOR and MAPK Pathways and Ameliorates Psoriasis Pathology in 2D and 3D Organotypic Human Inflammatory Skin Models.
Psoriasis is a chronic immune-mediated skin disease that involves the interaction of immune and skin cells, and is characterized by cytokine-driven epidermal hyperplasia, deviant differentiation, inflammation, and angiogenesis. Because the available treatments for psoriasis have significant limitations, dietary products are potential natural sources of therapeutic molecules, which can repair the molecular defects associated with psoriasis and could possibly be developed for its management. Fisetin (3,7,3',4'-tetrahydroxyflavone), a phytochemical naturally found in pigmented fruits and vegetables, has demonstrated proapoptotic and antioxidant effects in several malignancies. This study utilized biochemical, cellular, pharmacological, and tissue engineering tools to characterize the effects of fisetin on normal human epidermal keratinocytes (NHEKs), peripheral blood mononuclear cells (PBMC), and CD4+ T lymphocytes in 2D and 3D psoriasis-like disease models. Fisetin treatment of NHEKs dose- and time-dependently induced differentiation and inhibited interleukin-22-induced proliferation, as well as activation of the PI3K/Akt/mTOR pathway. Fisetin treatment of TNF-α stimulated NHEKs also significantly inhibited the activation of p38 and JNK, but had enhanced effect on ERK1/2 (MAPK). In addition, fisetin treatment significantly decreased the secretion of Th1/Th-17 pro-inflammatory cytokines, particularly IFN-γ and IL-17A by 12-O-tetradecanolylphorbol 13-acetate (TPA)-stimulated NHEKs and anti-CD3/CD28-activated human PBMCs. Furthermore, we established the in vivo relevance of fisetin functions, using a 3D full-thickness human skin model of psoriasis (FTRHSP) that closely mimics in vivo human psoriatic skin lesions. Herein, fisetin significantly ameliorated psoriasis-like disease features, and decreased the production of IL-17 by CD4+ T lymphocytes co-cultured with FTRHSP. Collectively, our data identify the prodifferentiative, antiproliferative, and anti-inflammatory effects of fisetin, via modulation of the PI3K-Akt-mTOR and p38/JNK pathways and the production of cytokines in 2D and 3D human skin models of psoriasis. These results suggest that fisetin has a great potential to be developed as an effective and inexpensive agent for the treatment of psoriasis and other related inflammatory skin disorders.


Systematic review on human resources for health interventions to improve maternal health outcomes: evidence from low- and middle-income countries.
There is a broad consensus and evidence that shows qualified, accessible, and responsive human resources for health (HRH) can make a major impact on the health of the populations. At the same time, there is widespread recognition that HRH crises particularly in low- and middle-income countries (LMICs) impede the achievement of better health outcomes/targets. In order to achieve the Sustainable Development Goals (SDGs), equitable access to a skilled and motivated health worker within a performing health system is need to be ensured. This review contributes to the vast pool of literature towards the assessment of HRH for maternal health and is focused on interventions delivered by skilled birth attendants (SBAs). Studies were included if (a) any HRH interventions in management system, policy, finance, education, partnership, and leadership were implemented; (b) these were related to SBA; (c) reported outcomes related to maternal health; (d) the studies were conducted in LMICs; and (e) studies were in English. Studies were excluded if traditional birth attendants and/or community health workers were trained. The review identified 25 studies which revealed reasons for poor maternal health outcomes in LMICs despite the efforts and policies implemented throughout these years. This review suggested an urgent and immediate need for formative evidence-based research on effective HRH interventions for improved maternal health outcomes. Other initiatives such as education and empowerment of women, alleviating poverty, establishing gender equality, and provision of infrastructure, equipment, drugs, and supplies are all integral components that are required to achieve SDGs by reducing maternal mortality and improving maternal health.


Nanostructured silicon ferromagnet collected by a permanent neodymium magnet.
Nanostructured silicon (N-Si) was prepared by anodic electroetching of p-type silicon wafers. The obtained magnetic particles were separated by a permanent neodymium magnet as a magnetic nanostructured silicon (mN-Si). The N-Si and mN-Si exhibited different magnetic properties: the N-Si exhibited ferromagnetic-like behaviour, whereas the mN-Si exhibited superparamagnetic-like behaviour.