Antibacterial potential of Croatian honey against antibiotic resistant pathogenic bacteria.
Aim To determine antimicrobial activity of honey against clinical bacterial strains and their respective reference strains. Methods Twelve samples of Croatian honey from various botanical origin were evaluated for their antimicrobial activity against four clinical antibiotic resistant pathogens and their respective reference strains: Staphylococcus aureus, Acinetobacter baumannii, Pseudomonas aeruginosa and Escherichia coli. Antibacterial susceptibility was checked out by using broth microdilution method and interpreted according to the European Committee for Antimicrobial Susceptibility Testing (EUCAST) recommendations. Results Significant differences in the antibacterial activity of tested honey samples were noticed. Fir honeydew honey and Mint honey showed the best antibacterial potential, while the Locust tree honey, Rapeseed honey and Spring pasture honey expressed the weakest antimicrobial activity. Conclusion Croatian honey, prominently honeydew honey, has the potential to become an important additive to therapeutic techniques available to a medical practitioner against resistant pathogens, but the exact mechanisms of its activity should be investigated further.


Intranasal delivery of caspase-9 inhibitor reduces caspase-6-dependent axon/neuron loss and improves neurological function after stroke.
Despite extensive research to develop an effective neuroprotective strategy for the treatment of ischemic stroke, therapeutic options remain limited. Although caspase-dependent death is thought to play a prominent role in neuronal injury, direct evidence of active initiator caspases in stroke and the functional relevance of this activity have not previously been shown. Using an unbiased caspase-trapping technique in vivo, we isolated active caspase-9 from ischemic rat brain within 1 h of reperfusion. Pathogenic relevance of active caspase-9 was shown by intranasal delivery of a novel cell membrane-penetrating highly specific inhibitor for active caspase-9 at 4 h postreperfusion (hpr). Caspase-9 inhibition provided neurofunctional protection and established caspase-6 as its downstream target. The temporal and spatial pattern of expression demonstrates that neuronal caspase-9 activity induces caspase-6 activation, mediating axonal loss by 12 hpr followed by neuronal death within 24 hpr. Collectively, these results support selective inhibition of these specific caspases as an effective therapeutic strategy for stroke.


The Evolution of Neurofilament Light Chain in Multiple Sclerosis.
Multiple sclerosis (MS) is an autoimmune, inflammatory neurodegenerative disease of the central nervous system characterized by demyelination and axonal damage. Diagnosis and prognosis are mainly assessed through clinical examination and neuroimaging. However, more sensitive biomarkers are needed to measure disease activity and guide treatment decisions in MS. Prompt and individualized management can reduce inflammatory activity and delay disease progression. Neurofilament Light chain (NfL), a neuron-specific cytoskeletal protein that is released into the extracellular fluid following axonal injury, has been identified as a biomarker of disease activity in MS. Measurement of NfL levels can capture the extent of neuroaxonal damage, especially in early stages of the disease. A growing body of evidence has shown that NfL in cerebrospinal fluid (CSF) and serum can be used as reliable indicators of prognosis and treatment response. More recently, NfL has been shown to facilitate individualized treatment decisions for individuals with MS. In this review, we discuss the characteristics that make NfL a highly informative biomarker and depict the available technologies used for its measurement. We further discuss the growing role of serum and CSF NfL in MS research and clinical settings. Finally, we address some of the current topics of debate regarding the use of NfL in clinical practice and examine the possible directions that this biomarker may take in the future.


Management of febrile convulsion: scene in a regional hospital.
To determine whether practice parameters are applied to the management of children with febrile convulsion. Retrospective study. Paediatric department of a public hospital, Hong Kong. Practice parameters of the American Academy of Pediatrics and audit measures recommended by the Joint Working Group of the Research Unit of the Royal College of Physicians and the British Paediatric Association were employed as standards. Records between January and April 2000 with the diagnostic coding of febrile convulsion, convulsion, status epilepticus, or meningitis/encephalitis/encephalopathy were reviewed. Areas assessed were appropriate documentation of hospital records and unit statistics (adverse outcomes, inappropriate investigations and treatment). Ninety-four consecutive records were evaluated. In the documentation of hospital notes, accurate description of seizure was observed in 92%, incorrect diagnosis or coding in 12%, and presence/absence of signs of meningitis and parental counselling documented in 64% and 85%, respectively. Regarding unit statistics, investigations performed included a complete blood count, blood glucose, serum calcium, serum electrolytes, renal function tests, liver function tests, chest X-ray, and urinalysis. The mean number of routine investigations was seven. The average length of stay was 2 days. There were no cases of delay in the diagnosis of central nervous system infection. Inappropriate investigations and treatment were as follows: electroencephalography 11%, computed tomography brain scan 2%, and maintenance anticonvulsants 2%. All patients were discharged home with panadol regardless of clinical state. The present study showed that the use of unnecessary investigations was common. Investigations, though resulting in significant expense, proved to be of little diagnostic value. Diagnostic procedures should be performed only when specifically called for by the patient's condition or medical history.


Intrapartum anaphylaxis to penicillin in a woman with rheumatoid arthritis who had no prior penicillin allergy.
Little is known about the development of drug allergy during pregnancy or in patients with altered immune status. To report a case of new-onset penicillin allergy during pregnancy in a woman with rheumatoid arthritis. A 39-year-old woman with rheumatoid arthritis developed intrapartum anaphylaxis that led to fetal demise. She had previously received penicillin-based antibiotics without any allergic reactions. Because of group B streptococcus colonization, an intravenous infusion of penicillin G was started during labor. Within minutes, she developed severe anaphylaxis. A fluorescent enzyme immunoassay revealed a moderate level of specific IgE to penicilloyl G and penicilloyl V (3.15 kU/L and 2.77 kU/L, respectively). Given the patient's history, these positive results were considered confirmatory of penicillin allergy. This case raises a number of salient points. First, patients can develop severe allergy to penicillin despite having safely received penicillins in the past. Possible factors that influenced the development of severe penicillin sensitivity in this patient are discussed. Second, unexpected intrapartum anaphylaxis can occur, which can be life threatening to the mother or fetus. Third, safe and reliable methods for diagnosis of drug allergy must be available. This case illustrates that during the current unavailability of skin testing reagents in the United States, a positive result on in vitro testing can be helpful in confirming penicillin allergy in cases in which drug challenge is deemed unsafe.


Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity.
BACKGROUND. NAFLD ranges from simple steatosis (SS) to non-alcoholic steatohepatitis (NASH). The natural history of NAFLD and the optimal strategy to identify subjects with progressive liver disease are unclear. Objectives. To assess the evidence in: (1) natural history of NAFLD; and (2) non-invasive methods to differentiate NAFLD histological subtypes. DESIGN AND SETTING. Among 4185 articles published on MEDLINE, Cochrane Library, EMBASE, Pubmed, national and International meeting abstracts through July 2010, 40 articles assessing the natural history of NAFLD and 32 articles evaluating the diagnostic accuracy of non-invasive tests against liver biopsy (LB) were included. MEASUREMENTS. Two reviewers retrieved articles and evaluated study quality by appropriate scores. Main outcomes were pooled using random- or fixed-effects models. RESULTS. NAFLD has an increased overall mortality (OR: 1.57, 95% CI: 1.18-2.10), deriving from liver-related and cardiovascular disease, and a 2-fold risk of diabetes. Compared to SS, NASH has a higher liver-related (OR for NASH: 5.71, 2.31-14.13; OR for NASH with advanced fibrosis: 10.06, 4.35-23.25), but not cardiovascular mortality (OR: 0.91, 0.42-1.98). Three non-invasive methods received independent validation: pooled AUROC, sensitivity and specificity of cytokeratin-18 for NASH are 0.82 (0.78-0.88), 0.78 (0.64-0.92), 0.87 (0.77-0.98). For NASH with advanced fibrosis, pooled AUROC, sensitivity and specificity of NAFLD fibrosis score and Fibroscan are 0.85 (0.80-0.93), 0.90 (0.82-0.99), 0.97 (0.94-0.99) and 0.94 (0.90-0.99), 0.94 (0.88-0.99) and 0.95 (0.89-0.99). CONCLUSIONS. NAFLD warrants screening for cardio-metabolic risk and for progressive liver disease. The combination of three noninvasive tests with LB may optimally individuate patients with NASH, with or without advanced fibrosis.


Elucidation of primary metabolic pathways in Aspergillus species: orphaned research in characterizing orphan genes.
Primary metabolism affects all phenotypical traits of filamentous fungi. Particular examples include reacting to extracellular stimuli, producing precursor molecules required for cell division and morphological changes as well as providing monomer building blocks for production of secondary metabolites and extracellular enzymes. In this review, all annotated genes from four Aspergillus species have been examined. In this process, it becomes evident that 80-96% of the genes (depending on the species) are still without verified function. A significant proportion of the genes with verified metabolic functions are assigned to secondary or extracellular metabolism, leaving only 2-4% of the annotated genes within primary metabolism. It is clear that primary metabolism has not received the same attention in the post-genomic area as many other research areas--despite its role at the very centre of cellular function. However, several methods can be employed to use the metabolic networks in tandem with comparative genomics to accelerate functional assignment of genes in primary metabolism. In particular, gaps in metabolic pathways can be used to assign functions to orphan genes. In this review, applications of this from the Aspergillus genes will be examined, and it is proposed that, where feasible, this should be a standard part of functional annotation of fungal genomes.


XV-2c/KM19 haplotypes analysis of cystic fibrosis patients from western Mexico.
The analysis of polymorphic markers within or closely linked to the cystic fibrosis transmembrane regulator (CFTR) gene is useful as a molecular tool for carrier detection of known and unknown mutations. To establish the association between mutations in the CFTR gene in western Mexican cystic fibrosis (CF) patients, the distribution of XV2c/KM19 haplotypes was analyzed by PCR and restriction enzyme digestion in 384 chromosomes from 74 CF patients, their unaffected parents, and normal subjects. The haplotype analysis revealed that haplotype B was present in 71.9% of CF chromosomes compared to 0% of non-CF chromosomes. The F508del and G542X mutations were strongly associated with haplotype B (96.7% and 100% of chromosomes, respectively). The haplotype distribution of the CF chromosomes carrying other CFTR mutations had a more heterogeneous background. Our results show that haplotype B is associated with CFTR mutations. Therefore, haplotype analysis is a suitable alternate strategy for screening CF patients with a heterogeneous clinical picture from populations with a high molecular heterogeneity where carrier detection programs are not available. In addition, it may be a helpful diagnostic tool for genetic counseling and carrier detection in the relatives of CF patients and in couples who are planning to have children.


Psychotic traits in comedians.
The popular belief that creativity is associated with madness has increasingly become the focus of research for many psychologists and psychiatrists. However, despite being prime examples of creative thinking, comedy and humour have been largely neglected. To test the hypothesis that comedians would resemble other creative individuals in showing a higher level of psychotic characteristics related to both schizophrenia and manic depression. A group of comedians (n = 500+) and a control sample of actors (n = 350+) completed an online questionnaire containing the short version of the Oxford-Liverpool Inventory of Feelings and Experiences (O-LIFE), with scales measuring four dimensions of psychotic traits. Scores were compared with general population norms. Comedians scored significantly above O-LIFE norms on all four scales. Actors also differed from the norms but on only three of the scales. Most striking was the comedians' high score on both introverted anhedonia and extraverted impulsiveness. This unusual personality structure may help to explain the facility for comedic performance.


Reassessment of inflammation of airways in chronic bronchitis.
The term chronic bronchitis has been criticised because it is associated with hypersecretion of mucus rather than bronchial inflammation. This study was designed to establish the presence or absence of clinical chronic bronchitis and measure pulmonary function in 45 patients about to undergo resection of the lung. The condition in the cartilaginous and small airways and the severity of the emphysema were then measured in the resected specimen. The results from 20 patients who had clinical chronic bronchitis were compared with those in 25 patients who did not. The data show that patients with chronic bronchitis had greater inflammation (a) on mucosal surfaces (p less than 0.05) of all bronchi larger than 2 mm luminal diameter and (b) around glands (p less than 0.005) and gland ducts (p less than 0.05) in bronchi larger than 4 mm diameter. A variable degree of inflammation was present in the submucosa of smaller bronchi. The groups had equivalent proportions of mucous glands and Reid's indices in central airways, and no differences were noted in measurements of pulmonary function, condition of small airways, or emphysema. These data show that the term chronic bronchitis is justified by inflammation of cartilaginous airways and suggest that this abnormality may be the cause of the chronic productive cough.


The archaeology of coding RNA.
Different theories concerning the origin of RNA (and, in particular, mRNA) point to the concatenation and expansion of proto-tRNA-like structures. Different biochemical and biophysical tools have been used to search for ancient-like RNA elements with a specific structure in genomic viral RNAs, including that of the hepatitis C virus, as well as in cellular mRNA populations, in particular those of human hepatocytes. We define this method as "archaeological," and it has been designed to discover evolutionary patterns through a nonphylogenetic and nonrepresentational strategy. tRNA-like elements were found in structurally or functionally relevant positions both in viral RNA and in one of the liver mRNAs examined, the antagonist interferon-alpha subtype 5 (IFNA5) mRNA. Additionally, tRNA-like elements are highly represented within the hepatic mRNA population, which suggests that they could have participated in the formation of coding RNAs in the distant past. Expanding on this finding, we have observed a recurring dsRNA-like motif next to the tRNA-like elements in both viral RNAs and IFNA5 mRNA. This suggested that the concatenation of these RNA motifs was an activity present in the RNA pools that might have been relevant in the RNA world. The extensive alteration of sequences that likely triggered the transition from the predecessors of coding RNAs to the first fully functional mRNAs (which was not the case in the stepwise construction of noncoding rRNAs) hinders the phylogeny-based identification of RNA elements (both sequences and structures) that might have been active before the advent of protein synthesis. Therefore, our RNA archaeological method is presented as a way to better understand the structural/functional versatility of a variety of RNA elements, which might represent "the losers" in the process of RNA evolution as they had to adapt to the selective pressures favoring the coding capacity of the progressively longer mRNAs.


[Risk factors for class II dental restoration survival:a practice-based study].
The aim of this practice-based cohort study was to determine the performance and influence of possible variables in class II restorations related to practice, patient, tooth, and restoration. To do this, electronic patient files from 11 general practices in the Netherlands were collected, and 31,472 restorations placed between January 2015 and October 2017 were analysed. The observation time of restorations varied from 0 to 2.7 years, resulting in a mean annual failure rate (AFR) of 7.8% at 2 years. However, wide variation in AFRs existed among the operators, varying between 3.6% and 11.4%. An excess of patient-related variables, such as age, general health, periodontal status, caries risk and the presence of parafunctional habits and tooth or restoration-related factors, increases the risk of reintervention. Restorations placed due to fracture were more prone to fail than restorations placed due to caries. This study demonstrated that a wide variety of risk factors on the practice, patient, and tooth levels influences the survival of class II restorations.


Audiovestibular Handicap and Quality of Life in Patients With Vestibular Schwannoma and "Excellent" Hearing.
Studies examining patient-reported outcomes in subjects with vestibular schwannoma (VS) and "excellent" hearing are lacking. To assess patient-reported audiovestibular handicap and overall quality of life (QoL) in VS patients with class A hearing in both ears. Among 539 VS patients treated during 1998 to 2008, we identified 296 patients with either bilateral class A (AA) hearing or 1 good ear and 1 deaf ear (AD) according to the American Academy of Otolaryngology-Head and Neck Surgery classification. Patients responded to validated hearing, tinnitus, and dizziness handicap inventories and 2 QoL questionnaires, and the 2 groups were compared. A reference group of 103 adults filled out the same questionnaires. Forty-nine patients (16.6%) had class AA and 247 patients (83.4%) had class AD hearing. AA patients scored poorer than control subjects without tumor on all handicap questionnaires ( P < .001) and a VS-specific QoL instrument ( P = .006). Con-versely, AA patients scored significantly better than patients with AD on the hearing inventory and the disease-specific QoL instrument ( P < .001), but no difference was found between these groups with regard to tinnitus and dizziness. The hearing disability score was approximately 3 times poorer for AA patients compared with control subjects without tumor; a third of AA patients reported a hearing handicap. Patients with VS and bilateral class A hearing report significantly poorer hearing handicap than control subjects without tumor but better hearing than those with unilateral deafness. When patients with bilateral class A hearing are counseled, it should be noted that one-third of patients experience self-perceived hearing handicap.


SU-E-J-212: Real-Time Treatment Failure Detection for Moving Tumor with Image Guidance.
Respiratory motion can cause misalignment of the radiation beam and will greatly degrade the effectiveness of cancer radiation treatment. Failure of radiation treatment can be detected by real-time image. The efficiency of both internal tracking and external tracking has been assessed in this. Both 3D internal fiducial marker motion and 1D external abdominal surface motion data of 11 patients were collected simultaneously. Linear and quadratic functions have been applied to correlate the internal and external motion signal. To detect tracking failure of external imaging, three approaches have been proposed: (i) correlation only: which will compare directly between the tracked and the based curve. (2) fixed baseline shift: which interferes the treatment by adjusting the baseline of tracked signal to compensate target motion for each treatment fraction. (3) dynamic baseline shift: dynamically interfere with treatment for each breathing cycle. (4) dynamic baseline with base curve update, is the third approach with base curve for each fraction. Generally, the quadratic function produced better correlation results than the linear correlation. With more historical data available, the quadratic prediction gives better correlation outcomes. The tracking frequency of 30, 10, 5, 2, 1, and 0.2Hz has been evaluated. Although high imaging frequency usually results in better correlation, imaging rate of 1 Hz will results acceptable results. For the failure detection, the average Euclidean misalignment is 3.46, 2.42, 2.21, 1.80 for the above four approach. With treatment interference, the beam-on-time percentages are 54.03, 58.26, 63.94, and 60.48 respectively. High imaging frequency is not required. approaches with baseline shift and base curve update will improve the treatment efficiency and treatment accuracy. Guidance using hybrid imaging with high-frequency of external imaging and low internal imaging is needed to compensate tumor respiratory motion.


NetGirls: the Internet, Facebook, and body image concern in adolescent girls.
The primary aim of the study was to examine the relationship between Internet exposure and body image concern in adolescent girls, with a particular focus on the social networking site of Facebook. A sample of 1,087 girls in the first two years (Years 8 and 9) of high school (aged 13-15 years) completed questionnaire measures of Internet consumption and body image concerns. The overwhelming majority of girls (95.9%) had access to the Internet in their home. Time spent on the Internet was significantly related to internalization of the thin ideal, body surveillance, and drive for thinness. Further, 75% of the girls had a Facebook profile, and spent an average of 1.5 hours there daily. Facebook users scored significantly more highly on all body image concern measures than non-users. It was concluded that the Internet represents a potent socio-cultural medium of relevance to the body image of adolescent girls.


Potential role of Thermus thermophilus and T. oshimai in high rates of nitrous oxide (N2O) production in ∼80 °C hot springs in the US Great Basin.
Ambient nitrous oxide (N(2)O) emissions from Great Boiling Spring (GBS) in the US Great Basin depended on temperature, with the highest flux, 67.8 ± 2.6 μmol N(2)O-N m(-2) day(-1) , occurring in the large source pool at 82 °C. This rate of N(2)O production contrasted with negligible production from nearby soils and was similar to rates from soils and sediments impacted with agricultural fertilizers. To investigate the source of N(2)O, a variety of approaches were used to enrich and isolate heterotrophic micro-organisms, and isolates were screened for nitrate reduction ability. Nitrate-respiring isolates were identified by 16S rRNA gene sequencing as Thermus thermophilus (31 isolates) and T. oshimai (three isolates). All isolates reduced nitrate to N(2)O but not to dinitrogen and were unable to grow with N(2)O as a terminal electron acceptor. Representative T. thermophilus and T. oshimai strains contained genes with 96-98% and 93% DNA identity, respectively, to the nitrate reductase catalytic subunit gene (narG) of T. thermophilus HB8. These data implicate T. thermophilus and T. oshimai in high flux of N(2)O in GBS and raise questions about the genetic basis of the incomplete denitrification pathway in these organisms and on the fate of biogenic N(2)O in geothermal environments.


Analysis of Lyn/CD22 double-deficient B cells in vivo demonstrates Lyn- and CD22-independent pathways affecting BCR regulation and B cell survival.
B cell fate is determined by the strength of signals from the antigen receptor and from co-receptors that adjust the activation threshold and tune the B cell to its environment. These co-receptors have been broadly classified into inhibitory and enhancing groups, yet some, such as CD22, may have dual effects. CD22 recruits a variety of signal enhancers at the same time as Lyn-dependent phosphorylation leads to the binding of the inhibitory phosphatase SHP-1. To assess the relative importance of Lyn- and CD22-dependent and -independent pathways, we generated Lyn and CD22 single-deficient mice and Lyn/CD22 double-deficient mice expressing the MD4 immunoglobulin transgene against hen egg lysozyme (IgHEL). This genetic approach has enabled us to compare the contributions of Lyn and CD22 to B cell development in vivo, independent of BCR specificity and in the presence and absence of self-antigen. Our results show that although the effects of Lyn are dominant in negative regulation of B cell hyperactivity, Lyn and CD22 have independent and additive effects on B cell survival. These findings emphasize the subtle nature of regulation at the BCR and the usefulness of genetic complementation to dissect common and parallel pathways.


Enhanced antimicrobial activity of silver nanoparticles-Lonicera Japonica Thunb combo.
Silver metals have long been known to possess antimicrobial properties. Recently, even the nanoparticle version of silver (AgNPs) has also been established as antimicrobials. In this study AgNPs were combined with extracts of the medicinal plant Chinese honeysuckle, Lonicera japonica Thunb. The antimicrobial activity of the AgNPs-herb was tested against pathogenic Escherichia coli CMCC44113. Using different AgNPs or herb (honeysuckle water extract or HWE) ratios in the presence of a fixed concentration of E. coli CMCC44113, potencies were found to be proportional with concentrations. The antimicrobial activities of AgNPs-HWE combo were significant enhanced, when compared with solely AgNPs or HWE. Thus, atomic force microscopic and propidium monoazide-PCR were used to probe the damages caused by AgNPs-HWE combo on the cell morphology and cell membrane integrity of E. coli. The mechanism of AgNPs-HWE combo against E. coli may attribute to AgNPs leads to cell wall lysis and damages cell membrane integrity, and thus increases the penetration of HWE into the bacterium, which results in more serious damage to bacterial cells. These findings indicated that AgNPs-herb was more potent than the AgNPs alone and holds promise for the development of nanoparticle enhanced herbal pharmaceuticals.


Do DNA microarrays tell the story of gene expression?
Poor reproducibility of microarray measurements is a major obstacle to their application as an instrument for clinical diagnostics. In this paper, several aspects of poor reproducibility are analyzed. All of them belong to the category of interpretive weaknesses of DNA microarray technology. First, the attention is drawn to the fact that absence of the information regarding post-transcriptional mRNA stability makes it impossible to evaluate the level of gene activity from the relative mRNA abundances, the quantities available from microarray measurements. Second, irreducible intracellular variability with persistent patterns of stochasticity and burstiness put natural limits to reproducibility. Third, strong interactions within intracellular biomolecular networks make it highly problematic to build a bridge between transcription rates of individual genes and structural fidelity of their genetic codes. For these reasons, the microarray measurements of relative mRNA abundances are more appropriate in laboratory settings as a tool for scientific research, hypotheses generating and producing the leads for subsequent validation through more sophisticated technologies. As to clinical settings, where firm conclusive diagnoses, not the leads for further experimentation, are required, microarrays still have a long way to go until they become a reliable instrument in patient-related decision making.


Development and testing of the fibromyalgia diagnostic screen for primary care.
The Fibromyalgia Diagnostic Screen was developed for use by primary care clinicians to assist in the diagnostic evaluation of fibromyalgia, a disorder that predominantly affects women. The screen was designed to have a patient-completed questionnaire and a clinician-completed section, which included a brief physical examination pertinent to the differential diagnosis of fibromyalgia. The items in the questionnaire were based on patient focus groups and clinician and patient Delphi exercises, which resulted in a ranking of the most common and troublesome fibromyalgia symptoms. One hundred new chronic pain patients (pain > 30 days) and their primary care physicians completed the screen. The patients were grouped as fibromyalgia or nonfibromyalgia by an independent fibromyalgia specialist, who was blind to screen responses. Logistic regression was used to model the probability of fibromyalgia as a function of physician-reported and patient-reported variables. Best subset regression was used to identify a subset of symptoms that were summed to form a single measure. Receiver operating characteristic (ROC) analysis was then used to select thresholds for continuous variables. The symptom and clinical variables were combined to create candidate prediction rules that were compared in terms of sensitivity and specificity to select the best criterion. Two final models were selected based on overall accuracy in predicting fibromyalgia: one used the patient-reported questionnaire only, and the other added a subset of the physical examination items to this patient questionnaire. A patient-reported questionnaire with or without a brief physical examination may improve identification of fibromyalgia patients in primary care settings.


How the discovery of ISS-N1 led to the first medical therapy for spinal muscular atrophy.
Spinal muscular atrophy (SMA), a prominent genetic disease of infant mortality, is caused by low levels of survival motor neuron (SMN) protein owing to deletions or mutations of the SMN1 gene. SMN2, a nearly identical copy of SMN1 present in humans, cannot compensate for the loss of SMN1 because of predominant skipping of exon 7 during pre-mRNA splicing. With the recent US Food and Drug Administration approval of nusinersen (Spinraza), the potential for correction of SMN2 exon 7 splicing as an SMA therapy has been affirmed. Nusinersen is an antisense oligonucleotide that targets intronic splicing silencer N1 (ISS-N1) discovered in 2004 at the University of Massachusetts Medical School. ISS-N1 has emerged as the model target for testing the therapeutic efficacy of antisense oligonucleotides using different chemistries as well as different mouse models of SMA. Here, we provide a historical account of events that led to the discovery of ISS-N1 and describe the impact of independent validations that raised the profile of ISS-N1 as one of the most potent antisense targets for the treatment of a genetic disease. Recent approval of nusinersen provides a much-needed boost for antisense technology that is just beginning to realize its potential. Beyond treating SMA, the ISS-N1 target offers myriad potentials for perfecting various aspects of the nucleic-acid-based technology for the amelioration of the countless number of pathological conditions.


ACE gene polymorphism in cardiovascular disease: meta-analyses of small and large studies in whites.
The objective of this study was to assess the influence of the ACE gene insertion (I)/deletion (D) polymorphism on plasma ACE activity; blood pressure; and risk of myocardial infarction, ischemic heart disease, and ischemic cerebrovascular disease by comparing small and large studies. The meta-analyses are based on a literature search of MEDLINE up until April 1998 and assessment of bibliographies of published studies and reviews. Forty-six studies were selected, including a total of 32 715 white individuals. Plasma ACE activity was increased 40% and 71% for ID and DD versus II in small studies and 21% and 48% in large studies (small versus large: P<0.001 and P<0.001). Blood pressure was not influenced by genotype. Risk of myocardial infarction and ischemic heart disease was increased by 47% and 29%, respectively, for DD versus ID and II genotypes in small studies but not in large studies (small versus large: P<0.001 for risk of myocardial infarction and P=0.01 for risk of ischemic heart disease). Risk of ischemic cerebrovascular disease was not increased either in the small or in the largest study. In conclusion, the ACE gene polymorphism affects plasma ACE activity but not blood pressure and is not associated with increased risk of myocardial infarction, ischemic heart disease, or ischemic cerebrovascular disease in the largest studies.


Flows of research manuscripts among scientific journals reveal hidden submission patterns.
The study of science-making is a growing discipline that builds largely on online publication and citation databases, while prepublication processes remain hidden. Here, we report on results from a large-scale survey of the submission process, covering 923 scientific journals from the biological sciences in years 2006 to 2008. Manuscript flows among journals revealed a modular submission network, with high-impact journals preferentially attracting submissions. However, about 75% of published articles were submitted first to the journal that would publish them, and high-impact journals published proportionally more articles that had been resubmitted from another journal. Submission history affected post-publication impact: Resubmissions from other journals received significantly more citations than first-intent submissions, and resubmissions between different journal communities received significantly fewer citations.


A quantitative confidence signal detection model: 1. Fitting psychometric functions.
Perceptual thresholds are commonly assayed in the laboratory and clinic. When precision and accuracy are required, thresholds are quantified by fitting a psychometric function to forced-choice data. The primary shortcoming of this approach is that it typically requires 100 trials or more to yield accurate (i.e., small bias) and precise (i.e., small variance) psychometric parameter estimates. We show that confidence probability judgments combined with a model of confidence can yield psychometric parameter estimates that are markedly more precise and/or markedly more efficient than conventional methods. Specifically, both human data and simulations show that including confidence probability judgments for just 20 trials can yield psychometric parameter estimates that match the precision of those obtained from 100 trials using conventional analyses. Such an efficiency advantage would be especially beneficial for tasks (e.g., taste, smell, and vestibular assays) that require more than a few seconds for each trial, but this potential benefit could accrue for many other tasks.


DNA profiling of B chromosomes from the yellow-necked mouse Apodemus flavicollis (Rodentia, Mammalia).
Using AP-PCR-based DNA profiling we examined some structural features of B chromosomes from yellow-necked mice Apodemus flavicollis. Mice harboring one, two, or three or lacking B chromosomes were examined. Chromosomal structure was scanned for variant bands by using a series of arbitrary primers and from these, informative bands were selected. The selection criteria used were the ability to differentiate between individuals of the species, to detect markers common for both A and B chromosomes, and, importantly, to differentiate between A- and B-chromosome sets. In addition to primers, profiling conditions were found to be critical for meeting the selection criteria. Primers and analysis conditions that demonstrated structural characteristics unique to the B-chromosome set are described. These characteristics included variant bands as qualitative parameters and altered electrophoretic band intensities as quantitative distinctions estimated by integration of densitometric profiles of electrophoretograms. B chromosome-specific molecular markers are easy to detect by AP-PCR-based DNA profiling in the presence of a full set of A chromosomes. Models for the origin of yellow-necked mouse B chromosomes are discussed in the context of presented data.


Crisis management: some opportunities.
Modern crises present decision makers with many agonizing management choices. Very often a crisis manager is confronted with a plethora of conflicting information and given very little time to choose an appropriate course of action. Although contemporary methods of systems analysis have been used in attempts to organize data and clarify options, they have generally been of little use in presenting an accurate picture of an opponent's values and perceptions. Thus it is clear that we must now make use of the improved communications and technological devices at our disposal if crises are to be avoided or resolved with minimum damage. Our proposal to establish international model-oriented computer-assisted conferences is designed to promote greater cooperation and understanding among scientists and crisis managers of differing nations by enabling them to share images of themselves and one another. With better information and more rational options available, the chances of catastrophic misunderstanding or miscalculation can be meaningfully reduced. We have proposed a possible scenario for the initial implementation of such a system to combat famine, and hope that the same approach might be used in other areas over time. The ultimate goal is a system by which specialists of all persuasions cooperate so that international crises will be resolved on the bases of mutual benefits without resort to armed conflict.


Degrading habitats and the effect of topographic complexity on risk assessment.
Topographic complexity is a key component of habitats that influences communities by modulating the interactions among individuals that drive population processes such as recruitment, competition, and predation. A broad range of disturbance agents affect biological communities indirectly through their modifications to habitat complexity. Individuals that best judge the threat of predation within their environment and can trade-off vigilance against behaviors that promote growth will be rewarded with the highest fitness. This study experimentally examined whether topographic habitat complexity affected the way a damselfish assessed predation risk using olfactory, visual, or combined cues. Fish had higher feeding rates in the low complexity environment. In a low complexity environment, damage-released olfactory cues and visual cues of predators complemented each other in the prey's assessment of risk. However, where complexity was high and visual cues obscured, prey had lower feeding rates and relied more heavily on olfactory cues for risk assessment. Overall, fish appear to be more conservative in the high complexity treatment. Low complexity promoted extremes of behavior, with higher foraging activity but a greater response to predation threats compared with the high complexity treatment. The degree of flexibility that individuals and species have in their ability to adjust the balance of senses used in risk assessment will determine the extent to which organisms will tolerate modifications to their habitat through disturbance.


GABAergic signaling is linked to a hypermigratory phenotype in dendritic cells infected by Toxoplasma gondii.
During acute infection in human and animal hosts, the obligate intracellular protozoan Toxoplasma gondii infects a variety of cell types, including leukocytes. Poised to respond to invading pathogens, dendritic cells (DC) may also be exploited by T. gondii for spread in the infected host. Here, we report that human and mouse myeloid DC possess functional γ-aminobutyric acid (GABA) receptors and the machinery for GABA biosynthesis and secretion. Shortly after T. gondii infection (genotypes I, II and III), DC responded with enhanced GABA secretion in vitro. We demonstrate that GABA activates GABA(A) receptor-mediated currents in T. gondii-infected DC, which exhibit a hypermigratory phenotype. Inhibition of GABA synthesis, transportation or GABA(A) receptor blockade in T. gondii-infected DC resulted in impaired transmigration capacity, motility and chemotactic response to CCL19 in vitro. Moreover, exogenous GABA or supernatant from infected DC restored the migration of infected DC in vitro. In a mouse model of toxoplasmosis, adoptive transfer of infected DC pre-treated with GABAergic inhibitors reduced parasite dissemination and parasite loads in target organs, e.g. the central nervous system. Altogether, we provide evidence that GABAergic signaling modulates the migratory properties of DC and that T. gondii likely makes use of this pathway for dissemination. The findings unveil that GABA, the principal inhibitory neurotransmitter in the brain, has activation functions in the immune system that may be hijacked by intracellular pathogens.


Isolation and characterization of Mycoplasma genitalium strains from the human respiratory tract.
Mycoplasma genitalium, an organism first isolated from the urethras of two men with nongonococcal urethritis, has been found in throat specimens from military recruits participating in an inactivated Mycoplasma pneumoniae vaccine field trial in 1974-1975. Four of 16 preserved throat isolates, previously identified as strains of M. pneumoniae, have now been shown to be mixtures of M. pneumoniae and M. genitalium. Purification of these mixed mycoplasmas by selection of single colonies confirmed the presence of M. genitalium. Identification of M. genitalium was based upon the occurrence of a species-specific 140-kilodalton protein adhesin in these isolates and their serologic reactivity to an M. genitalium antiserum. The frequent occurrence of both M. pneumoniae and M. genitalium in a number of these throat specimens, in combination with their shared antigenic cross-reactivities, suggests the likelihood that M. genitalium strains are easily missed in the usual laboratory identification procedures. What role M. genitalium may play in human respiratory disease remains to be determined.


Reproducibility of cerebrospinal venous blood flow and vessel anatomy with the use of phase contrast-vastly undersampled isotropic projection reconstruction and contrast-enhanced MRA.
The chronic cerebrospinal venous insufficiency hypothesis raises interest in cerebrospinal venous blood flow imaging, which is more complex and less established than in arteries. For accurate assessment of venous flow in chronic cerebrospinal venous insufficiency diagnosis and research, we must account for physiologic changes in flow patterns. This study examines day-to-day flow variability in cerebrospinal veins by use of 4D MR flow and contrast-enhanced MRA under typical, uncontrolled conditions in healthy individuals. Ten healthy volunteers were scanned in a test-retest fashion by use of a 4D flow MR imaging technique and contrast-enhanced MRA. Flow parameters obtained from phase contrast-vastly undersampled isotropic projection reconstruction and contrast-enhanced MRA scoring measurements in the head, neck, and chest veins were analyzed for internal consistency and interscan reproducibility. Internal consistency was satisfied at the torcular herophili, with an input-output difference of 2.2%. Percentages of variations in flow were 20.3%, internal jugular vein; 20.4%, azygos vein; 6.8%, transverse sinus; and 5.1%, common carotid artery. Retrograde flow was found in the lower internal jugular vein (4.8%) and azygos vein (7.2%). Contrast-enhanced MRA interscan κ values for the internal jugular vein (left: 0.474, right: 0.366) and azygos vein (-0.053) showed poor interscan agreement. Phase contrast-vastly undersampled isotropic projection reconstruction blood flow measurements are reliable and highly reproducible in intracranial veins and in the common carotid artery but not in veins of the neck (internal jugular vein) and chest (azygos vein) because of normal physiologic variation. Retrograde flow normally may be observed in the lower internal jugular vein and azygos vein. Low interrater agreement in contrast-enhanced MRA scans was observed. These findings have important implications for imaging diagnosis and experimental research of chronic cerebrospinal venous insufficiency.


Examining autonomy's boundaries: a follow-up review of perinatal mortality cases in UK independent midwifery.
An earlier matched cohort study in the United Kingdom found a significantly higher perinatal mortality rate for births booked under an independent midwife compared with births in National Health Service units (1.7% [25/1,508] vs 0.6% [45/7,366]). This study examined independent midwives' management and decision making in the 15 instances of perinatal death that occurred at term. Thematic analysis of independent midwives' case notes was performed in instances of perinatal mortality. Semi-structured interviews were conducted with the midwives concerned. Home birth was attempted in 13 of the 15 cases. Significant (often multiple) antenatal risk factors were identified in 13 cases, including twin pregnancy, planned vaginal births after cesarean section, breech presentations, and maternal illness. Several women had declined some or all routine antenatal screening. Three deaths occurred before labor onset. Postmortem results were known in only four cases; many causes of death remained unexplained. Professional consensus was that seven deaths were unpreventable; elective cesarean section may have changed the outcome in eight cases. However, the pregnant women had declined this option; some were reported to be avoiding National Health Service care because of previous bad experiences. Transfer to hospital care, when it occurred, was often problematic. Care management was judged to be clinically acceptable within the parameters set by the mothers' choices. Information about clinical processes (and outcomes) is essential if informed decisions are to be made. The women in this review had reportedly accepted the potential consequences of their high-risk situations. If reality is to match rhetoric about "patient" autonomy, such decision making in high-risk situations must be accepted.


Wettability conversion from superoleophobic to superhydrophilic on titania/single-walled carbon nanotube composite coatings.
Superoleophobic surfaces were demonstrated on perfluorosilane-rendered titania (TiO(2))/single-walled carbon nanotube (SWNT) composite coatings. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) observations revealed that SWNTs play a key role in the formation of overhanging structures and the nanoscale roughness on the coating surface, which compose the two critical morphologic factors for a superoleophobic surface. The wettability conversion from superoleophobic to superhydrophilic of the composite coatings was realized by the gradual decomposition of 1H,1H,2H,2H-perfluorodecyltrichlorosilane (FDTS) on the coating surface using UV irradiation. Contact angle measurement on both smooth TiO(2) surface and rough composite coating surface under different UV irradiation time revealed that the wetting behavior of the liquids on the composite coating surface passes from the Cassie to the Wenzel and finally to the inversed-Cassie regime. Different liquids show different irradiation time for the wetting state change. By controlling the UV irradiation dose, liquids with surface tension difference smaller than 5 mN/m can exist in completely converse wetting states on the same coating surface, that is, superphobic for one liquid while superphilic for another with lower surface tension. Mixed organic liquids with different surface tension can be completely separated through a coated grid using this wettability tuning technique.


Correlation transfer equation for multiply scattered light modulated by an ultrasonic pulse.
We develop a temporal correlation transfer equation (CTE) and a Monte Carlo algorithm (MC) for multiply scattered light modulated by an ultrasonic pulse propagating in an optically scattering medium, where the ultrasound field can be nonuniform and the medium can have spatially heterogeneous distribution of optical parameters. The CTE and MC can be used to obtain the time-varying specific intensity and the spatial distribution of the time-dependent power spectral density, respectively, of ultrasound-modulated light. We expect the CTE and MC to be applicable for estimation of contrast and resolution in a wide spectrum of conditions in ultrasound-modulated optical tomography of soft biological tissues.


Antiarrhythmic effects of ethmozin in cardiac Purkinje fibers: suppression of automaticity and abolition of triggering.
The effects of ethmozin were studied on automatic and triggered impulse initiation in isolated canine cardiac Purkinje fibers using standard microelectrode technique. In driven Purkinje fibers with normal (greater than or equal to -80 mV) maximum diastolic potentials, ethmozin (2-4 mg/l or 4.3-8.6 muM) slightly increased the slope of phase 4 depolarization. However, the rate of normal automatic firing in such fibers was decreased by ethmozin and the threshold (take-off) potential of the pacemaker cells was shifted in the depolarizing direction (toward zero potential). In fibers treated with barium chloride (0.10-0.50 mM), "abnormal automaticity" occurred from maximum diastolic potentials of -38 to -68 MV. Ethmozin (2-4 mg/l) consistently slowed and abolished this abnormal automaticity. This appeared to be associated with a decrease in the rate of diastolic depolarization. When lidocaine, 4 or 10 mg/l (17 or 42 muM), was tested on abnormal automaticity induced by barium, it too was found to decrease the rate of diastolic depolarization and decrease the automatic rate. However, lidocaine never terminated barium-induced abnormal automaticity. Ethmozin also consistently abolished abnormal automaticity in Purkinje fibers taken from the endocardial surface of 24- or 48-h infarct zones. Finally, ethmozin (1-4 mg/l or 2.2-8.6 muM) depressed the amplitude of delayed after depolarizations and terminated triggered activity in Purkinje fibers taken from 24-hr infarct zones. Each of these actions could contribute to the antiarrhythmic effects of ethmozin.


Clinical Outcomes in 3343 Children and Adults With Rheumatic Heart Disease From 14 Low- and Middle-Income Countries: Two-Year Follow-Up of the Global Rheumatic Heart Disease Registry (the REMEDY Study).
There are few contemporary data on the mortality and morbidity associated with rheumatic heart disease or information on their predictors. We report the 2-year follow-up of individuals with rheumatic heart disease from 14 low- and middle-income countries in Africa and Asia. Between January 2010 and November 2012, we enrolled 3343 patients from 25 centers in 14 countries and followed them for 2 years to assess mortality, congestive heart failure, stroke or transient ischemic attack, recurrent acute rheumatic fever, and infective endocarditis. Vital status at 24 months was known for 2960 (88.5%) patients. Two-thirds were female. Although patients were young (median age, 28 years; interquartile range, 18-40), the 2-year case fatality rate was high (500 deaths, 16.9%). Mortality rate was 116.3/1000 patient-years in the first year and 65.4/1000 patient-years in the second year. Median age at death was 28.7 years. Independent predictors of death were severe valve disease (hazard ratio [HR], 2.36; 95% confidence interval [CI], 1.80-3.11), congestive heart failure (HR, 2.16; 95% CI, 1.70-2.72), New York Heart Association functional class III/IV (HR, 1.67; 95% CI, 1.32-2.10), atrial fibrillation (HR, 1.40; 95% CI, 1.10-1.78), and older age (HR, 1.02; 95% CI, 1.01-1.02 per year increase) at enrollment. Postprimary education (HR, 0.67; 95% CI, 0.54-0.85) and female sex (HR, 0.65; 95% CI, 0.52-0.80) were associated with lower risk of death. Two hundred and four (6.9%) patients had new congestive heart failure (incidence, 38.42/1000 patient-years), 46 (1.6%) had a stroke or transient ischemic attack (8.45/1000 patient-years), 19 (0.6%) had recurrent acute rheumatic fever (3.49/1000 patient-years), and 20 (0.7%) had infective endocarditis (3.65/1000 patient-years). Previous stroke and older age were independent predictors of stroke/transient ischemic attack or systemic embolism. Patients from low- and lower-middle-income countries had significantly higher age- and sex-adjusted mortality than patients from upper-middle-income countries. Valve surgery was significantly more common in upper-middle-income than in lower-middle- or low-income countries. Patients with clinical rheumatic heart disease have high mortality and morbidity despite being young; those from low- and lower-middle-income countries had a poorer prognosis associated with advanced disease and low education. Programs focused on early detection and the treatment of clinical rheumatic heart disease are required to improve outcomes.


Cancer Patient Experience of Uncertainty While Waiting for Genome Sequencing Results.
There is limited knowledge about cancer patients' experiences of uncertainty while waiting for genome sequencing results, and whether prolonged uncertainty contributes to psychological factors in this context. To investigate uncertainty in patients with a cancer of likely hereditary origin while waiting for genome sequencing results, we collected questionnaire and interview data at baseline, and at three and 12 months follow up (prior to receiving results). Participants (N = 353) had negative attitudes towards uncertainty (M = 4.03, SD 0.68) at baseline, and low levels of uncertainty at three (M = 8.23, SD 7.37) and 12 months (M = 7.95, SD 7.64). Uncertainty about genome sequencing did not change significantly over time [t(210) = 0.660, p = 0.510]. Greater perceived susceptibility for cancer [r(348) = 0.14, p < 0.01], fear of cancer recurrence [r(348) = 0.19, p < 0.01], perceived importance of genome sequencing [r(350) = 0.24, p < 0.01], intention to change behavior if a gene variant indicating risk is found [r(349) = 0.29, p < 0.01], perceived ability to cope with results [r(349) = 0.36, p < 0.01], and satisfaction with decision to have genome sequencing [r(350) = 0.52, p < 0.01] were significantly correlated with negative attitudes towards uncertainty at baseline. Multiple primary cancer diagnoses [B = -2.364 [-4.238, -0.491], p = 0.014], lower perceived ability to cope with results [B = -0.1.881 [-3.403, -0.359], p = 0.016] at baseline, greater anxiety about genome sequencing (avoidance) [B = 0.347 [0.148, 0.546], p = 0.0012] at 3 months, and greater perceived uncertainty about genome sequencing [B = 0.494 [0.267, 0.721] p = 0.000] at 3 months significantly predicted greater perceived uncertainty about genome sequencing at 12 months. Greater perceived uncertainty about genome sequencing at 3 months significantly predicted greater anxiety (avoidance) about genome sequencing at 12 months [B = 0.291 [0.072, 0.509], p = 0.009]. Semi-structured interviews revealed that while participants were motivated to pursue genome sequencing as a strategy to reduce their illness and risk uncertainty, genome sequencing generated additional practical, scientific and personal uncertainties. Some uncertainties were consistently discussed over the 12 months, while others emerged over time. Similarly, some uncertainty coping strategies were consistent over time, while others emerged while patients waited for their genome sequencing results. This study demonstrates the complexity of uncertainty generated by genome sequencing for cancer patients and provides further support for the inter-relationship between uncertainty and anxiety. Helping patients manage their uncertainty may ameliorate psychological morbidity.


A critical analysis of 57 cases of Hughes-Stovin syndrome (HSS). A report by the HSS International Study Group (HSSISG).
Hughes-Stovin syndrome (HSS) is a systemic disease characterized by widespread vascular thrombosis and pulmonary vasculitis with serious morbidity and mortality. The HSS International Study Group is a multidisciplinary taskforce aiming to study HSS, in order to generate consensus recommendations regarding diagnosis and treatment. We included 57 published cases of HSS (43 males) and collected data regarding: clinical presentation, associated complications, hemoptysis severity, laboratory and computed tomography pulmonary angiography (CTPA) findings, treatment modalities and cause of death. At initial presentation, DVT was observed in 29(33.3 %), thrombophlebitis in 3(5.3%), hemoptysis in 24(42.1%), and diplopia and seizures in 1 patient each. During the course of disease, DVT occurred in 48(84.2%) patients, and superficial thrombophlebitis was observed in 29(50.9%). Hemoptysis occurred in 53(93.0%) patients and was fatal in 12(21.1%). Pulmonary artery (PA) aneurysms (PAAs) were bilateral in 53(93%) patients. PAA were located within the main PA in 11(19.3%), lobar in 50(87.7%), interlobar in 13(22.8%) and segmental in 42(73.7%). Fatal outcomes were more common in patients with inferior vena cava thrombosis (p = 0.039) and ruptured PAAs (p < 0.001). Death was less common in patients treated with corticosteroids (p < 0.001), cyclophosphamide (p < 0.008), azathioprine (p < 0.008), combined immune modulators (p < 0.001). No patients had uveitis; 6(10.5%) had genital ulcers and 11(19.3%) had oral ulcers. HSS may lead to serious morbidity and mortality if left untreated. PAAs, adherent in-situ thrombosis and aneurysmal wall enhancement are characteristic CTPA signs of HSS pulmonary vasculitis. Combined immune modulators contribute to favorable outcomes.


Self-doped colloidal semiconductor nanocrystals with intraband transitions in steady state.
The tunable bandgap energy has been recognized as a prominent feature of the colloidal semiconductor nanocrystal, also called the colloidal quantum dot (CQD). Due to the broken degeneracy caused by the quantum confinement effect, the electronic states of the conduction band (CB) are separated by a few hundred meV. The electronic transition occurring in the conduction band is called the intraband transition and has been regarded as a fast electron relaxation process that cannot be readily observed under steady state. However, recent progress in the studies of intraband transitions allowed the observation of the mid-IR intraband transition in steady state and ambient condition, providing a pathway to exploit the mid-IR electronic transition for various optoelectronic applications. The observation of the steady state intraband transitions has been possible due to the electron filling of the lowest electronic state (1Se) of the conduction band in the semiconductor nanocrystal. Specifically, the nanocrystals are "self-doped" with electrons through chemical synthesis - that is, without the need of adding heterogeneous impurity or applying an electrical potential. In this feature article, we summarize the recent advances in the study on intraband electronic transitions along with the interesting findings on the magnetic and electronic properties of the self-doped colloidal metal chalcogenide semiconductor nanocrystals. The mid-IR intraband transitions of non-toxic nanocrystals, which exclude the toxic mercury and cadmium constituents, are also highlighted, which hold promise for safer applications utilizing the higher quantum states of nanocrystals.


Posterior lumbar interbody fusion for revision disc surgery: review of 50 cases in which carbon fiber cages were implanted.
The authors undertook a study to assess the value of posterior lumbar interbody fusion (PLIF) in which carbon fiber cages (CFCs) were placed in patients undergoing revision disc surgery for symptoms suggesting neural compression with low-back pain. The authors followed their first 50 patients for a maximum of 5 years and a minimum of 6 months after implantation of the CFCs. Patients in whom magnetic resonance (MR) imaging demonstrated "simple" recurrent herniation did not undergo PLIF. Surgery was performed in patients with symptoms of neural root compression, tension signs, and back pain with focal disc degeneration and nerve root distortion depicted on MR imaging compatible with clinical signs and symptoms. In 40 patients (80%) pedicle screws were not used. Clinical outcome was assessed using the Prolo Functional Economic Outcome Rating scale. Fusion outcome was assessed using an established classification. Symptoms in 46 patients (92%) improved after surgery, and given their outcomes, 45 (90%) would have undergone the same surgery again. Two thirds of patients experienced good or excellent outcomes (Prolo score > or = 8) at early and late follow up. There was no difference in clinical outcome between those in whom pedicle screws were and were not implanted (p = 0.83, Mann-Whitney U-test). The fusion rate at 2 years postsurgery was 95%. There were minimal complications, and no patients fared worse after surgery. No patient has undergone additional surgical treratment of the fused intervertebral space. In this difficult group of patients the aim remains to improve symptoms but not cure the disease. A high fusion rate is possible when using the CFCs. Clinical success depends on selecting patients in whom radiological and clinical criteria accord. Pedicle screws are not necessary if facet joints are preserved, and high fusion rates and clinical success are possible without them.


Loss of heterozygosity at 11q22 correlates with low progesterone receptor content in epithelial ovarian cancer.
Forty-seven epithelial ovarian cancers were analyzed for loss of heterozygosity (LOH) at D11S35 (11q22), close to the progesterone receptor (PR) gene, and for tumoral estrogen receptor (ER) and PR content. Thirty-eight of 47 tumors were informative, and, of these, 14 exhibited LOH. There was a significant association (P = 0.014) between D11S35 LOH and low tumoral PR content. For all informative tumors, there was no correlation between ER and PR; however, exclusion of tumors with LOH from the informative series revealed a linear correlation between tumoral ER and PR (P = 0.013), and established ER (P = 0.025) and PR (P = 0.05) content as significant factors in relation to patient survival. Patients with ER-rich tumors with D11S35 LOH had particularly poor survival compared with ER-rich, D11S35 heterozygous, no loss patients (P = 0.014). Analysis of the same tumors using two other microsatellites, D11S935 (11p13) and NM23 (17q22), showed no statistically significant relationships, although there were nonsignificant trends for the correlation of ER and PR expression in informative tumors without allele loss at these loci. We propose that genomic structural alteration at or close to the PR gene locus has biological and clinical sequelae in ovarian cancer.


Does Islet Size Really Influence Graft Function After Clinical Islet Transplantation?
It has been proposed that islet transplants comprised primarily of small rather than large islets may provide better graft function, due to their lower susceptibility to hypoxic damage. Our aim was to determine whether islet size correlated with in vivo graft function in islet transplant recipients with C peptide-negative type 1 diabetes when islets have undergone pretransplant islet culture. Human pancreatic islets were isolated, cultured for 24 hours and infused by standardized protocols. Ninety-minute stimulated C-peptide concentrations were determined during a standard meal tolerance test 3 months posttransplant. The islet isolation index (IEq/islet number) was determined immediately after isolation and again before transplantation (after tissue culture). This was correlated with patient insulin requirement or stimulated C-peptide. Changes in insulin requirement did not significantly correlate with islet isolation index. Stimulated C-peptide correlated weakly with IEq at isolation (P = 0.40) and significantly with IEq at transplantation (P = 0.018). Stimulated C-peptide correlated with islet number at isolation (P = 0.013) and more strongly with the islet number at transplantation (P = 0.001). In contrast, the correlation of stimulated C-peptide and islet isolation index was weaker (P = 0.018), and this was poorer at transplantation (P = 0.034). Using linear regression, the strongest association with graft function was islet number (r = 0.722, P = 0.001). Islet size was not related to graft function after adjusting for islet volume or number. These data show no clear correlation between islet isolation index and graft function; both small and large islets are suitable for transplantation, provided the islets have survived a short culture period postisolation.


Treatment agreement, adherence, and outcome in cognitive behavioral treatments for insomnia.
Patient adherence has been identified as an important barrier to the implementation of evidence-based psychological treatments. In cognitive behavioral treatments (CBT) for insomnia, the current study examined (a) the validity of therapist ratings of patient agreement and adherence against an established behavioral measure of adherence, and (b) the relationship between treatment agreement, adherence, and outcome. Participants were 188 adults meeting DSM-IV-TR criteria for chronic insomnia who were randomized to receive behavior therapy, cognitive therapy, or CBT for insomnia. Treatment agreement/adherence was measured by (a) weekly therapist ratings of patient agreement and homework completion, and (b) adherence to behavioral strategies (ABS) derived from patient-reported sleep diary. Outcome measures were Insomnia Severity Index and insomnia remission (Insomnia Severity Index <8). Therapist ratings of patient agreement as well as homework completion were significantly associated with sleep diary-derived global ABS. Therapist-rated patient agreement and homework completion as well as global ABS predicted greater insomnia symptoms reduction from pretreatment to posttreatment. Patient agreement also predicted insomnia symptoms reduction from pretreatment to 6-month follow-up. Patient agreement, adherence, and ABS measures during treatment significantly predicted insomnia remission at posttreatment, and all but therapist rating of homework completion predicted remission at 6-month follow-up. Greater patient agreement and adherence (therapist ratings and ABS) during treatment predicted better treatment outcome. Therapist-rated treatment agreement and adherence correspond well with patient-reported sleep diary-derived adherence measure. These simple, deployable therapist-rated patient agreement and adherence can potentially be useful for treatments for other disorders. (PsycINFO Database Record


The role of understaffing in central venous catheter-associated bloodstream infections.
To determine risk factors for central venous catheter-associated bloodstream infections (CVC-BSI) during a protracted outbreak. Case-control and cohort studies of surgical intensive care unit (SICU) patients. A university-affiliated Veterans Affairs medical center. Case-control study: all patients who developed a CVC-BSI during the outbreak period (January 1992 through September 1993) and randomly selected controls. Cohort study: all SICU patients during the study period (January 1991 through September 1993). CVC-BSI or site infection rates, SICU patient clinical data, and average monthly SICU patient-to-nurse ratio. When analyzed by hospital location and site, only CVC-BSI in the SICU had increased significantly in the outbreak period compared to the previous year (January 1991 through December 1991: pre-outbreak period). In SICU patients, CVC-BSI were associated with receipt of total parenteral nutrition [TPN]; odds ratio, 16; 95% confidence interval, 4 to 73). When we controlled for TPN use, CVC-BSI were associated with increasing severity of illness and days on assisted ventilation. SICU patients in the outbreak period had shorter SICU and hospital stays, were younger, and had similar mortality rates, but received more TPN compared with patients in the pre-outbreak period. Furthermore, the patient-to-nurse ratio significantly increased in the outbreak compared with the pre-outbreak period. When we controlled for TPN use, assisted ventilation, and the period of hospitalization, the patient-to-nurse ratio was an independent risk factor for CVC-BSI in SICU patients. Nursing staff reductions below a critical level, during a period of increased TPN use, may have contributed to the increase in CVC-BSI in the SICU by making adequate catheter care difficult. During healthcare reforms and hospital downsizing, the effect of staffing reductions on patient outcome (i.e., nosocomial infection) needs to be critically assessed.


A Score Based on NfL and Glial Markers May Differentiate Between Relapsing-Remitting and Progressive MS Course.
Background: The diagnostic use of biomarkers in body fluids of multiple sclerosis (MS) patients allows the monitoring of different pathophysiological aspects of the disease. We previously reported elevated cerebrospinal fluid (CSF) and serum levels of glial fibrillary acidic protein (GFAP) but not neurofilament light chain (NfL) in progressive (PMS) compared to relapsing-remitting MS (RRMS) patients. Objectives: We analyzed the glial marker chitinase-3-like protein 1 (CHI3L1) in the CSF and serum of PMS and RRMS patients. To capture the extent of glial processes in relation to axonal damage in each individual patient, we established a score based on CHI3L1, GFAP, and NfL and compared this score between RRMS and PMS patients and its association with the extended disability status scale (EDSS). Methods: For this retrospective study, we included 86 MS patients (47 RRMS and 39 PMS) and 20 patients with other non-inflammatory neurological diseases (OND) as controls. NfL and GFAP levels were determined by the single-molecule array (Simoa). CHI3L1 levels were measured with classical enzyme-linked immunosorbent assay. A score was calculated based on glial to axonal markers (CHI3L1*GFAP/NfL, referred to as "Glia score"). Results: CHI3L1 showed higher CSF levels in PMS vs. RRMS and controls (p < 0.001 and p < 0.0001, respectively), RMS vs. controls (p < 0.01), and higher serum levels for PMS vs. RRMS (p < 0.05). The Glia score was higher in the CSF of PMS compared to RRMS patients (p < 0.0001) and in the serum of PMS patients compared to RRMS (p < 0.01). Furthermore, the Glia score and CHI3L1 in serum but not in CSF correlated with the disability as determined by EDSS in the PMS group but not in the RRMS group (Spearman ρ = 0.46 and 0.45, p = 0.003 and 0.004, respectively). Discussion: Our data indicate the involvement of glial mechanisms during the pathogenesis of PMS. Moreover, a calculated score may help to differentiate between PMS and RMS in the CSF and monitor disease progression in the serum of PMS patients.


Efficacy and tolerability of a combined moxifloxacin/dexamethasone formulation for topical prophylaxis in phacoemulsification: an open-label single-arm clinical trial.
Background. The use of a fixed-combination antibiotic corticosteroid for infection prophylaxis in Asian patients undergoing phacoemulsification has not been reported. Methods. A 15-day, open-label, single-arm trial of 64 patients for phacoemulsification with intraocular lens (IOL) implantation is described. Patients applied moxifloxacin 0.5%/dexamethasone 0.1% (Vigadexa) eye drops four times daily before and until 15 days after surgery. Anterior chamber (AC) reaction, visual acuity, ocular pain and signs, and intraocular pressure (IOP) were assessed at baseline and on postoperative days 1, 3, 8, and 15. Results. At day 15, 55 (91.7%) patients scored 0 (<5 cells) in AC reaction. No surgery-related infection occurred. Mean best-corrected visual acuity improved 0.5 logMAR from baseline to 0.0 logMAR (P < .0001). Mean IOP remained at 12-13 mm Hg over the 15-day treatment. Only 2 patients (3.1%) reported minimum ocular pain. Two (3.1%) patients were shifted to prednisolone acetate for severe inflammation. At the end of the study period, 8.3% were given fluorometholone for 1 week for AC reaction grade >0. No drug-related adverse event was reported. Conclusion. Following phacoemulsification and IOL implantation, the topical combination moxifloxacin 0.5%/dexamethasone 0.1% was effective in preventing infection and controlling inflammation and was well tolerated.


TYK2-STAT1-BCL2 pathway dependence in T-cell acute lymphoblastic leukemia.
Targeted molecular therapy has yielded remarkable outcomes in certain cancers, but specific therapeutic targets remain elusive for many others. As a result of two independent RNA interference (RNAi) screens, we identified pathway dependence on a member of the Janus-activated kinase (JAK) tyrosine kinase family, TYK2, and its downstream effector STAT1, in T-cell acute lymphoblastic leukemia (T-ALL). Gene knockdown experiments consistently showed TYK2 dependence in both T-ALL primary specimens and cell lines, and a small-molecule inhibitor of JAK activity induced T-ALL cell death. Activation of this TYK2-STAT1 pathway in T-ALL cell lines occurs by gain-of-function TYK2 mutations or activation of interleukin (IL)-10 receptor signaling, and this pathway mediates T-ALL cell survival through upregulation of the antiapoptotic protein BCL2. These findings indicate that in many T-ALL cases, the leukemic cells are dependent upon the TYK2-STAT1-BCL2 pathway for continued survival, supporting the development of molecular therapies targeting TYK2 and other components of this pathway. In recent years, "pathway dependence" has been revealed in specific types of human cancer, which can be important because they pinpoint proteins that are particularly vulnerable to antitumor-targeted inhibition (so-called Achilles' heel proteins). Here, we use RNAi technology to identify a novel oncogenic pathway that involves aberrant activation of the TYK2 tyrosine kinase and its downstream substrate, STAT1, which ultimately promotes T-ALL cell survival through the upregulation of BCL2 expression


The partial purification and characterization of GnRH-like activity from prostatic biopsy specimens and prostatic cancer cell lines.
We have investigated the possibility of the secretion of gonadotrophin-releasing-hormone (GnRH)-like peptides by prostatic cancer cells in culture and their presence in cytosolic preparations from human prostatic biopsy specimens. A GnRH-specific radioimmunoassay showed GnRH-like activity in concentrated cytosolic preparations and conditioned media from DU 145, an androgen-insensitive human prostatic cell line and from LNCaP, an androgen-responsive prostatic cancer cell line. GnRH immunoreactivity in culture media correlated directly with cell numbers. HPLC demonstrated that this GnRH-like material co-migrated with synthetic GnRH. This homology between synthetic GnRH and partially purified prostatic GnRH was confirmed following V8 protease and trypsin digestion which resulted in similar alterations in HPLC characteristics. The mean content of GnRH-like activity/g specimen tissue was significantly more in malignant tissue (88.5 +/- 80.5 fmol) than in benign (29.6 +/- 22 fmol), though more specimens of benign tissue were positive (37/54) than malignant tissue (6/22). This observation, taken with an earlier finding of GnRH-specific receptors in a hormone-sensitive cell line and human cancer specimens provides supportive evidence for the autocrine hypothesis of cell regulation.


Development of Titania Nanotube-based Electrochemical Immunosensor and Determination of Prostate Specific Antigen.
Early diagnosis of cancer is the most important factor that increases the success of treatment. Therefore, the development of new diagnostic tools is a necessity. In this study, a new electrode surface was developed via modification of a disposable titanium electrode with anodic oxidation and coating of gold nanoparticle and chitosan. Titanium electrodes were anodized by several anodization parameters to obtain a nanoporous surface and characterized by scanning electron microscopy. Electrodes anodized in optimum conditions were modified with gold nanoparticles and chitosan for enhancing conductivity and functionalizing the surface of electrode, respectively. To detect prostate specific antigen (PSA), anti-PSA was bound onto the functional electrode surface. Modified electrodes were characterized with scanning electron microscopy and cyclic voltammetry and used for chronoamperometric detection of PSA. Limit of detection (LOD) of the designed electrode was found to be 7.8 ng mL-1 for PSA in a linear range of 0 - 100 ng mL-1.


Modeling of loops in protein structures.
Comparative protein structure prediction is limited mostly by the errors in alignment and loop modeling. We describe here a new automated modeling technique that significantly improves the accuracy of loop predictions in protein structures. The positions of all nonhydrogen atoms of the loop are optimized in a fixed environment with respect to a pseudo energy function. The energy is a sum of many spatial restraints that include the bond length, bond angle, and improper dihedral angle terms from the CHARMM-22 force field, statistical preferences for the main-chain and side-chain dihedral angles, and statistical preferences for nonbonded atomic contacts that depend on the two atom types, their distance through space, and separation in sequence. The energy function is optimized with the method of conjugate gradients combined with molecular dynamics and simulated annealing. Typically, the predicted loop conformation corresponds to the lowest energy conformation among 500 independent optimizations. Predictions were made for 40 loops of known structure at each length from 1 to 14 residues. The accuracy of loop predictions is evaluated as a function of thoroughness of conformational sampling, loop length, and structural properties of native loops. When accuracy is measured by local superposition of the model on the native loop, 100, 90, and 30% of 4-, 8-, and 12-residue loop predictions, respectively, had <2 A RMSD error for the mainchain N, C(alpha), C, and O atoms; the average accuracies were 0.59 +/- 0.05, 1.16 +/- 0.10, and 2.61 +/- 0.16 A, respectively. To simulate real comparative modeling problems, the method was also evaluated by predicting loops of known structure in only approximately correct environments with errors typical of comparative modeling without misalignment. When the RMSD distortion of the main-chain stem atoms is 2.5 A, the average loop prediction error increased by 180, 25, and 3% for 4-, 8-, and 12-residue loops, respectively. The accuracy of the lowest energy prediction for a given loop can be estimated from the structural variability among a number of low energy predictions. The relative value of the present method is gauged by (1) comparing it with one of the most successful previously described methods, and (2) describing its accuracy in recent blind predictions of protein structure. Finally, it is shown that the average accuracy of prediction is limited primarily by the accuracy of the energy function rather than by the extent of conformational sampling.


Reproducibility of near-infrared spectroscopy parameters measured during brachial artery occlusion and reactive hyperemia in healthy men.
Near-infrared spectroscopy (NIRS) is a noninvasive technique evaluating microvascular function. The aim of this study was to assess the reproducibility of NIRS parameters during reactive hyperemia induced by a 5 min brachial artery occlusion. Twenty-four healthy young males (mean 34 ± 8 years old) had two microvascular function evaluations by NIRS over a 7 to 30-day period (mean 16 ± 10 days). Intra-subject and inter-observer reproducibility were evaluated with intraclass correlation coefficient (ICC), coefficient of variation (CV), and standard error of measurement (SEM%) for every parameter. Mean NIRS parameters did not differ between both evaluations. Reproducibility was greatest for muscle oxygen consumption (ICC: 0.84; CV: 6.51%; SEM: 7.11%), time to basal O(2)Hb (ICC: 0.63, CV: 20.04%, SEM 27.22%), time to maximal O(2)Hb (ICC: 0.71; CV: 15.61%; SEM: 19.27%), peak of O(2)Hb (ICC: 0.63, CV: 6.68%, SEM 8.53%), time to maximal tHb (ICC: 0.73, CV: 19,61%, SEM 24.56%) and area under the O(2)Hb and tHb curves (ICC: 0.68, CV: 16.15%, SEM 22.93% and ICC: 0.62, CV: 18.59%, SEM 26.64%, respectively). Moreover, inter-observer reproducibility ranged from excellent to perfect (ICC from 0.85 to 1.00) for every parameter. NIRS parameters during reactive hyperemia are highly reproducible which enables their repeated measurement to study microvascular function in healthy subjects.


Sensor positioning for activity recognition using wearable accelerometers.
Activities of daily living are important for assessing changes in physical and behavioral profiles of the general population over time, particularly for the elderly and patients with chronic diseases. Although accelerometers have been used widely in wearable devices for activity classification, the positioning of the sensors and the selection of relevant features for different activity groups still pose significant research challenges. This paper investigates wearable sensor placement at different body positions and aims to provide a systematic framework that can answer the following questions: 1) What is the ideal sensor location for a given group of activities? and 2) Of the different time-frequency features that can be extracted from wearable accelerometers, which ones are the most relevant for discriminating different activity types?


Single-Vesicle Infrared Nanoscopy for Noninvasive Tumor Malignancy Diagnosis.
Protein heterogeneity in molecular expression and structures determines tumorigenesis and is the diagnostic and therapeutic cancer biomarker. Small extracellular vesicles (sEVs) are cell-released nanoscaled membrane-bound vesicles transferring bioactive molecules for intercellular communication and playing essential roles in tumor progression and metastasis. Therefore, protein heterogeneity in tumor-derived sEVs indicates the degree of malignant transformation, providing a noninvasive biomarker for cancer diagnosis and malignancy evaluation. We employ near-field infrared (nano-FTIR) spectroscopy to investigate malignancy-related protein heterogeneity in a single sEV and demonstrate the discriminability of sEV protein heterogeneity to evaluate tumor malignancy and metastasis. We found that the amide I/II adsorption ratio of the sEVs increases with tumor malignancy, the proportion of α-helix + random coil (α-helix and random coil) in sEV proteins decreases with tumor malignancy, and the proportion of β-sheet + β-turn (β-sheet and β-turn) increases with tumor malignancy. These nano-FTIR spectral signatures of the sEVs from the primary tumor tissue of breast cancer patients show high sensitivity and specificity in evaluating tumor metastasis. This study shows the advantages of nano-FTIR in single sEV characterization and demonstrates the significance of sEV protein heterogeneity in cancer diagnosis. It provides a noninvasive solution to elucidate cancer development and facilitates the exploitation of potential cancer biomarkers.


HLA polymorphism and evaluation of European, African, and Amerindian contribution to the white and mulatto populations from Paraná, Brazil.
Polymorphism of classical HLA-A, HLA-B, HLA-C, HLA-DR, and HLA-DQ genes differs greatly among populations, both in frequencies and in the presence of alleles and haplotypes particular to population groups, making these genes powerful tools for the study of origins of populations and their degree of admixture. Antigen, allele, and haplotype frequencies, together with linkage disequilibrium patterns, are reported for 2 populations in the southern Brazilian state of Paraná, one of predominantly European ancestry (white), the other of predominantly African and European ancestry (mulatto). Genetic distance estimates between the 2 groups and other populations studied previously, and of degree of admixture, were performed. In accordance with phenotypic classification, the white population is of predominantly European origin (80.6%), with a smaller contribution of African (12.5%) and Amerindian (7.0%) genes. The mulatto population consists of African (49.5%) and European (41.8%) ancestry, with a smaller but significant contribution of Amerindian (8.7%) ancestry. On the basis of history and population genetics, there is controversy regarding the Amerindian contribution to Paraná's gene pool. These results provide a better picture of Paraná's ethnic constitution and on the Amerindian contribution to the white and mulatto populations.


Self-Organized Attractor Dynamics in the Developing Head Direction Circuit.
Head direction (HD) cells are neurons found in an extended cortical and subcortical network that signal the orientation of an animal's head relative to its environment [1-3]. They are a fundamental component of the wider circuit of spatially responsive hippocampal formation neurons that make up the neural cognitive map of space [4]. During post-natal development, HD cells are the first among spatially modulated neurons in the hippocampal circuit to exhibit mature firing properties [5, 6], but before eye opening, HD cell responses in rat pups have low directional information and are directionally unstable [7, 8]. Using Bayesian decoding of HD cell ensemble activity recorded in the anterodorsal thalamic nucleus (ADN), we characterize this instability and identify its source: under-signaling of angular head velocity, which incompletely shifts the directional signal in proportion to head turns. We find evidence that geometric cues (the corners of a square environment) can be used to mitigate this under-signaling and, thereby, stabilize the directional signal even before eye opening. Crucially, even when directional firing cannot be stabilized, ensembles of unstable HD cells show short-timescale (1-10 s) temporal and spatial couplings consistent with an adult-like HD network. The HD network is widely modeled as a continuous attractor whose output is one coherent activity peak, updated during movement by angular head velocity signals and anchored by landmark cues [9-11]. Our findings present strong evidence for this model, and they demonstrate that the required network circuitry is in place and functional early during development, independent of reference to landmark information.


ERP correlates of feedback and reward processing in the presence and absence of response choice.
The feedback negativity is a component of the event-related brain potential that is elicited by feedback stimuli associated with unfavorable outcomes. The present research investigated whether this component reflects an evaluation of the valence of experienced outcomes or a process of learning about actions that led to those outcomes. The latter hypothesis predicts that the feedback negativity should be observed only when negative outcomes are experienced in relation to executed actions. Contrary to this prediction, feedback negativities were observed in simple monetary gambling tasks in which participants made no active choices (experiment 1) and no overt actions (experiment 2). However, the amplitude of the component was reduced in these tasks relative to a gambling task in which the outcomes appeared to be contingent upon participants' response choices. This reduction was correlated with changes in participants' subjective ratings of involvement in the tasks, suggesting that the evaluative process indexed by the feedback negativity is sensitive to the motivational significance of ongoing events.


[Electromagnetic poles and reproduction].
The authors review epidemiological data concerning the relationship between reproduction disorders and the exposure to electromagnetic fields (EMF) emitted by power lines, industrial power-charged devices, diagnostic and therapeutical appliances, video display terminals (VDTs) and electric household devices. The studies involved the analysis of the EMF effect on female and male reproduction, including the risk of spontaneous abortion, still birth and premature birth, low birth weight and congenital malformations as well as on the progeny gender proportion, among persons employed under the condition of EMF exposure. It was observed that the findings were frequently inconsistent, i.e. under the same conditions of EMF exposure some date indicated its negative effect on the reproduction process and some did not. No data confirming an acute effect of occupational exposure to EMF on the risk of spontaneous abortion, low birth weight, congenital malformations or other reproduction disorders were obtained, however, the negative effect of EMF cannot be explicitly excluded.


Early Help in Early Years: Developing a Universal Assessment Tool.
Effective assessment tools are an essential element of early identification of problems, enabling early intervention in the first two or so years of life. This article reports on the development and evaluation of a Universal Assessment Tool for Early Help in Early Years. The project aim was to develop, pilot and evaluate a new universal assessment tool named "My Family Profile" for use within Northamptonshire, United Kingdom, from pregnancy until a child reaches 2/2.5 years of age. A flowchart demonstrates the stages of the process including how each step contributed toward the tool and end report (Neill et al., 2015). The project used an intervention design enabling collaborative inter-agency working and ensured parents were engaged throughout the process. The methods used in developing the tool incorporated collaborative working, content analysis, format requirements, questioning styles and information sharing. The tool was evaluated using focus groups and individual interviews with parents, an online evaluation questionnaire and audit of completed assessment forms with practitioners. The resulting report (Neill et al., 2015) contained "My Family Profile" highlighted five key recommendations: (1) It is developed in a digital format with secure "cloud" storage, accessible from all IT platforms in use by child health/care professionals; (2) it is implemented with a comprehensive training program for professionals; (3) it is formally evaluated following implementation; (4) it is extended up to school entry and through school years; and (5) it is developed for use within other locations in the United Kingdom.


Prospective strategies underlie the control of interceptive actions.
The purpose of this study was to test whether a constant bearing angle strategy could account for the displacement regulations produced by a moving observer when attempting to intercept a ball following a curvilinear path. The participants were asked to walk through a virtual environment and to change, if (deemed) necessary, their walking speed so as to intercept a moving ball that followed either a rectilinear or a curvilinear path. The results showed that ball path curvature did indeed influence the participants' displacement kinematics in a way that was predicted by adherence to a constant bearing angle strategy mode of control. Velocity modifications were found to be proportional to the magnitude of target curvature with opposing curvatures giving rise to mirror displacement velocity changes. The role of prospective strategies in the control of interceptive action is discussed.


Foraging rates of larval dragonfly colonists are positively related to habitat isolation: results from a landscape-level experiment.
There is increasing evidence of intraspecific variation in dispersal behavior. Individual differences in dispersal behavior may be correlated with other traits that determine the impact individuals have on patches they colonize. We established habitat patches-artificial pools-across a landscape, and these pools were naturally colonized by dragonfly larvae. Larvae were collected from pools at different levels of isolation and held under common lab conditions for 5 months. We then compared larval foraging rates. Foraging rate was positively related to habitat isolation, and colonists from the most isolated artificial pools had significantly higher foraging rates than individuals from the least isolated pools. Our results indicate that spatial patterns in colonist behavior can develop across a landscape independent of species-level dispersal limitation. This finding suggests that studies of community structure across space should include an assessment of the distribution of phenotypes as well as species-level dispersal limitation patterns.


Quantitative Profiling of the Lymph Node Clearance Capacity.
Transport of tissue-derived lymphatic fluid and clearance by draining lymph nodes are pivotal for maintenance of fluid homeostasis in the body and for immune-surveillance of the self- and non-self-proteomes. Yet a quantitative analysis of nodal filtration of the tissue-derived proteome present in lymphatic fluid has not been reported. Here we quantified the efficiency of nodal clearance of the composite proteomic load using label-free and isotope-labeling proteomic analysis of pre-nodal and post-nodal samples collected by direct cannulation. These results were extended by quantitation of the filtration efficiency of fluorophore-labeled proteins, bacteria, and beads infused at physiological flow rates into pre-nodal lymphatic collectors and collected by post-nodal cannulation. We developed a linear model of nodal filtration efficiency dependent on pre-nodal protein concentrations and molecular weight, and uncovered criteria for disposing the proteome incoming from defined anatomical districts under physiological conditions. These findings are pivotal to understanding the maximal antigenic load sustainable by a draining node, and promote understanding of pathogen spreading and nodal filtration of tumor metastasis, potentially helping to improve design of vaccination protocols, immunization strategies and drug delivery.


Landscape genetics informs mesohabitat preference and conservation priorities for a surrogate indicator species in a highly fragmented river system.
Poor dispersal species represent conservative benchmarks for biodiversity management because they provide insights into ecological processes influenced by habitat fragmentation that are less evident in more dispersive organisms. Here we used the poorly dispersive and threatened river blackfish (Gadopsis marmoratus) as a surrogate indicator system for assessing the effects of fragmentation in highly modified river basins and for prioritizing basin-wide management strategies. We combined individual, population and landscape-based approaches to analyze genetic variation in samples spanning the distribution of the species in Australia's Murray-Darling Basin, one of the world's most degraded freshwater systems. Our results indicate that G. marmoratus displays the hallmark of severe habitat fragmentation with notably scattered, small and demographically isolated populations with very low genetic diversity-a pattern found not only between regions and catchments but also between streams within catchments. By using hierarchically nested population sampling and assessing relationships between genetic uniqueness and genetic diversity across populations, we developed a spatial management framework that includes the selection of populations in need of genetic rescue. Landscape genetics provided an environmental criterion to identify associations between landscape features and ecological processes. Our results further our understanding of the impact that habitat quality and quantity has on habitat specialists with similarly low dispersal. They should also have practical applications for prioritizing both large- and small-scale conservation management actions for organisms inhabiting highly fragmented ecosystems.


Direct muscle delivery of GDNF with human mesenchymal stem cells improves motor neuron survival and function in a rat model of familial ALS.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease in which there is a progressive loss of motor neurons and their connections to muscle, leading to paralysis. In order to maintain muscle connections in a rat model of familial ALS (FALS), we performed intramuscular transplantation with human mesenchymal stem cells (hMSCs) used as "Trojan horses" to deliver growth factors to the terminals of motor neurons and to the skeletal muscles. hMSCs engineered to secrete glial cell line-derived neurotrophic factor (hMSC-GDNF) were transplanted bilaterally into three muscle groups. The cells survived within the muscle, released GDNF, and significantly increased the number of neuromuscular connections and motor neuron cell bodies in the spinal cord at mid-stages of the disease. Further, intramuscular transplantation with hMSC-GDNF was found to ameliorate motor neuron loss within the spinal cord where it connects with the limb muscles receiving transplants. While disease onset was similar in all the animals, hMSC-GDNF significantly delayed disease progression, increasing overall lifespan by up to 28 days, which is one of the largest effects on survival noted for this rat model of FALS. This preclinical data provides a novel and practical approach toward ex vivo gene therapy for ALS.