Quantifying the dark data in museum fossil collections as palaeontology undergoes a second digital revolution.

Large-scale analysis of the fossil record requires aggregation of palaeontological data from individual fossil localities. Prior to computers, these synoptic datasets were compiled by hand, a laborious undertaking that took years of effort and forced palaeontologists to make difficult choices about what types of data to tabulate. The advent of desktop computers ushered in palaeontology's first digital revolution-online literature-based databases, such as the Paleobiology Database (PBDB). However, the published literature represents only a small proportion of the palaeontological data housed in museum collections. Although this issue has long been appreciated, the magnitude, and thus potential significance, of these so-called 'dark data' has been difficult to determine. Here, in the early phases of a second digital revolution in palaeontology--the digitization of museum collections-we provide an estimate of the magnitude of palaeontology's dark data. Digitization of our nine institutions' holdings of Cenozoic marine invertebrate collections from California, Oregon and Washington in the USA reveals that they represent 23 times the number of unique localities than are currently available in the PBDB. These data, and the vast quantity of similarly untapped dark data in other museum collections, will, when digitally mobilized, enhance palaeontologists' ability to make inferences about the patterns and processes of past evolutionary and ecological changes.

Angioedema in chronic spontaneous urticaria is underdiagnosed and has a substantial impact: Analyses from ASSURE-CSU.

BACKGROUND: ASSURE-CSU revealed differences in physician and patient reporting of angioedema. This post hoc analysis was conducted to evaluate the actual rate of angioedema in the study population and explore differences between patients with and without angioedema. METHODS: This international observational study assessed 673 patients with inadequately controlled chronic spontaneous urticaria (CSU). Physicians abstracted angioedema data from medical records, which were compared with patient-reported data. Patients in the Yes-angioedema category had angioedema reported in the medical record and a patient-reported source. For those in the No-angioedema category, angioedema was reported in neither the medical record nor a patient-reported source. Those in the Misaligned category had angioedema reported in only one source. Statistical comparisons between Yes-angioedema and No-angioedema categories were conducted for measures of CSU activity, health-related quality of life (HRQoL), productivity and healthcare resource utilization (HCRU). Regression analyses explored the relationship between Dermatology Life Quality Index (DLQI) score and angioedema, adjusting for important covariates. RESULTS: Among evaluable patients, 259 (40.3%), 173 (26.9%) and 211 (32.8%) were in the Yes-angioedema, No-angioedema and Misaligned category, respectively. CSU activity and impact on HRQoL, productivity, and HCRU was greater for Yes-angioedema patients than No-angioedema patients. After covariate adjustment, mean DLQI score was significantly higher (indicating worse HRQoL) for patients with angioedema versus no angioedema (9.88 vs 7.27, P < .001). The Misaligned category had similar results with Yes-angioedema on all outcomes. CONCLUSIONS: Angioedema in CSU seems to be under-reported but has significant negative impacts on HRQoL, daily activities, HCRU and work compared with no angioedema.

Transcriptome analysis of ankylosing spondylitis patients before and after TNF-α inhibitor therapy reveals the pathways affected.

Tumor necrosis factor-α (TNF-α) inhibitors are highly effective in suppressing inflammation in ankylosing spondylitis (AS) patients, and operate by suppression of TFN-α and downstream immunological pathways. To determine the mechanisms of action of TNF-α inhibitors in AS patients, we used transcriptomic and bioinformatic approaches on peripheral blood mononuclear cells from AS patients pre and post treatment. We found 656 differentially expressed genes, including the genome-wide significant AS-associated genes, IL6R, NOTCH1, IL10, CXCR2 and TNFRSF1A. A distinctive gene expression profile was found between male and female patients, mainly because of sex chromosome-linked genes and interleukin 17 receptor C, potentially accounting for the differences in clinical manifestation and treatment response between the genders. In addition to immune and inflammation regulatory pathways, like intestinal immune network for IgA production, cytokine-cytokine receptor interaction, Ras signaling pathway, allograft rejection and hematopoietic cell lineage, KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analyses revealed that infection-associated pathways (influenza A and toxoplasmosis) and metabolism-associated pathways were involved in response to TNF-α inhibitor treatment, providing insight into the mechanism of TNF-α inhibitors.

The burden of chronic spontaneous urticaria is substantial: Real-world evidence from ASSURE-CSU.

BACKGROUND: Chronic spontaneous urticaria (CSU) can be debilitating, difficult to treat, and frustrating for patients and physicians. Real-world evidence for the burden of CSU is limited. The objective of this study was to document disease duration, treatment history, and disease activity, as well as impact on health-related quality of life (HRQoL) and work among patients with inadequately controlled CSU, and to describe its humanistic, societal, and economic burden. METHODS: This international observational study assessed a cohort of 673 adult patients with CSU whose symptoms persisted for ≥12 months despite treatment. Demographics, disease characteristics, and healthcare resource use in the previous 12 months were collected from medical records. Patient-reported data on urticaria and angioedema symptoms, HRQoL, and work productivity and activity impairment were collected from a survey and a diary. RESULTS: Almost 50% of patients had moderate-to-severe disease activity as reported by Urticaria Activity Score. Mean (SD) Dermatology Life Quality Index and Chronic Urticaria Quality of Life Questionnaire scores were 9.1 (6.62) and 33.6 (20.99), respectively. Chronic spontaneous urticaria markedly interfered with sleep and daily activities. Angioedema in the previous 12 months was reported by 66% of enrolled patients and significantly affected HRQoL. More than 20% of patients reported ≥1 hour per week of missed work; productivity impairment was 27%. These effects increased with increasing disease activity. Significant healthcare resources and costs were incurred to treat CSU. CONCLUSIONS: Chronic spontaneous urticaria has considerable humanistic and economic impacts. Patients with greater disease activity and with angioedema experience greater HRQoL impairments.

Gastrointestinal side effects in chronic opioid users: results from a population-based survey.

BACKGROUND: Gastrointestinal side effects are commonly associated with opioid treatment for pain. AIM: To understand gastrointestinal side effects associated with opioid treatment. METHODS: This study was a population-based survey of adults in the US who use opioids to manage pain unrelated to cancer. Participants were recruited from an existing Web-enabled panel and a supplemental panel of individuals who previously indicated an interest in participating in Web-based surveys. RESULTS: Overall, 2055 individuals participated in the main phase of the survey. Fifty-seven per cent of participants reported having had constipation that they associated with opioid treatment, and 49% reported constipation in the previous 4 weeks. Thirty-six per cent of participants reported new or worsening constipation in the previous 4 weeks. Thirty-three per cent of participants reported constipation as their most bothersome symptom associated with opioid treatment, 13% reported nausea, 11% abdominal pain and 10% gas. Seventy-three per cent of the participants who reported any GI symptoms did not change the dosage level or frequency of use of opioids because of adverse events, which may be explained by the fact that 72% of participants used over-the-counter laxatives and 12% a prescription laxative. CONCLUSION: Constipation is a frequent and significant event occurring with opioid use.

The relationship between dosing of alosetron and discontinuation patterns reported by patients participating in a follow-up programme.

BACKGROUND: Alosetron was reintroduced for treatment of irritable bowel syndrome with a risk management programme in November 2002. Recommended starting dosage was 1 mg/day for 4 weeks. If symptoms remained uncontrolled, dosage could be changed to 2 mg/day. AIM: To describe alosetron dosages and associated patient characteristics from the Lotronex follow-up survey programme. METHODS: Patients reported dosages of alosetron at start and regular follow-up intervals. Analyses were limited to patients with the potential to have at least 1 year of follow-up (enrolled between 9 December 2002 and 31 December 2003). RESULTS: At baseline, 75% of 2817 respondents reported starting on 1 mg/day, 17% on 2 mg/day and 8% on other doses. Adherence to recommended starting dosage did not vary by status at end of follow-up, previous alosetron experience or age. At last reported dose, 50% of respondents were using 1 mg/day; 29% were using 2 mg/day. Discontinuation was not related to baseline doses. Longer times to discontinuation were associated with previous use, symptoms for more than 6 months and dose change throughout follow-up. CONCLUSIONS: High adherence to recommended dosing at baseline and follow-up suggests that the risk management programme is encouraging safe use of alosetron, including adherence to dosing recommendations.

A patient follow-up survey programme for alosetron: assessing compliance to and effectiveness of the risk management programme.

BACKGROUND: In November 2002, alosetron HCl (Lotronex, GlaxoSmithKline Research Triangle Park, NC, USA) was re-introduced to the US marketplace for women with severe diarrhoea-predominant irritable bowel syndrome. In support of the re-introduction, a risk management programme was implemented, which included a patient follow-up study in which all users of alosetron could participate. AIM: We report on the methods used and the effectiveness of key elements of the risk management programme. METHODS: Patients voluntarily enroled in the study and completed questionnaires at baseline, after 5 and 10 weeks, and quarterly thereafter. Questions focussed on patient eligibility, knowledge of risks and benefits, and adherence to the recommended programme elements for education, prescribing and dispensing. RESULTS: Between December 2002 and 2004, 4,803 patients enrolled in the study, and <3% were lost to follow-up. The average follow-up time was approximately 6 months, and the response rate for each assessment was >95%. A total of 90% of patients at baseline met the full clinical criteria recommended for the treatment. Patient adherence to the risk management programme was >87%. CONCLUSIONS: Using the Lotronex risk management programme, patients met clinical criteria, were knowledgeable about treatment risks and benefits, and were adherent to the process elements of the programme. These patients seemed to engage in active dialogue with their physicians about symptoms and use of alosetron.

Prevalence and demographics of irritable bowel syndrome: results from a large web-based survey.

BACKGROUND: Irritable bowel syndrome is a common gastrointestinal disorder, and its prevalence and demographics have been evaluated by different methodologies with varying results. AIM: To evaluate irritable bowel syndrome demographic and prevalence characteristics utilizing a web-enabled panel. METHODS: From an existing 150 000-member panel, 31 829 individuals were randomly selected and sent screening questionnaires to evaluate irritable bowel syndrome symptoms. Individuals who agreed to participate and completed the screening questionnaire received a second questionnaire related to a diagnosis of irritable bowel syndrome, a more detailed symptom description, and additional burden of illness data. RESULTS: Irritable bowel syndrome prevalence was 7%. Prevalence was higher in women vs. men, unmarried individuals vs. married individuals and unemployed individuals vs. employed individuals. Of those completing the second questionnaire, 51% had seen their physicians for irritable bowel syndrome symptoms in the past year and most had an episode within the past 3 months. During the past year, approximately half of the participants had used a prescription medication, and over 90% had used an over-the-counter medication for irritable bowel syndrome. Participants with irritable bowel syndrome demonstrated quality-of-life reductions relative to norms of the United States population. CONCLUSIONS: Web-enabled data collection represents a novel tool for rapidly surveying a large population of individuals with irritable bowel syndrome symptoms.

Nucleotide excision repair endonuclease genes in Drosophila melanogaster.

Nucleotide excision repair (NER) is the primary pathway for the removal of ultraviolet light-induced damage and bulky adducts from DNA in eukaryotes. During NER, the helix is unwound around the damaged site, and incisions are made on the 5' and 3' sides, to release an oligonucleotide carrying the lesion. Repair synthesis can then proceed, using the intact strand as a template. The incisions flanking the lesion are catalyzed by different structure-specific endonucleases. The 5' incision is made by a heterodimer of XPF and ERCC1 (Rad1p-Rad10p in Saccharomyces cerevisiae), and the 3' incision is made by XPG (Rad2p in S. cerevisiae). We previously showed that the Drosophila XPF homologue is encoded by the meiotic recombination gene mei-9. We report here the identification of the genes encoding the XPG and ERCC1 homologues (XPG(Dm) and ERCC1(Dm)). XPG(Dm) is encoded by the mus201 gene; we found frameshift mutations predicted to produce truncated XPG(Dm) proteins in each of two mus201 alleles. These mutations cause defects in nucleotide excision repair and hypersensitivity to alkylating agents and ultraviolet light, but do not cause hypersensitivity to ionizing radiation and do not impair viability or fertility. ERCC1(Dm) interacts strongly in a yeast two-hybrid assay with MEI-9, indicative of the presumed requirement for these polypeptides to dimerize to form the functional endonuclease. The Drosophila Ercc1 gene maps to polytene region 51D1-2. The nucleotide excision repair gene mus210 maps nearby (51E-F) but is distinct from Ercc1.

High prevalence of antibodies to Neospora caninum in white-tailed deer (Odocoileus virginianus).

Serum samples of 400 white-tailed deer (Odocoileus virginianus) from 16 preserves in northeastern Illinois were tested for Neospora caninum antibodies in the N. caninum agglutination test using mouse-derived N. caninum tachyzoites and mercaptoethanol. Antibodies were found in 162 deer with titres of 1:40 (47 deer), 1:80 (32 deer), 1:160 (17 deer), 1:200 (eight deer), 1:400 (19 deer), 1:800 (17 deer) and > or = 1:1600 (22 deer). There were no significant differences in prevalence between age or sex of the deer. The high prevalence of N. caninum infection in deer is consistent with a sylvatic cycle of N. caninum.

A charged-particle microbeam: II. A single-particle micro-collimation and detection system.

The use of a charged-particle microbeam provides a unique opportunity to control precisely, the number of particles traversing individual cells and the localization of dose within the cell. The accuracy of 'aiming' and of delivering a precise number of particles crucially depends on the design and implementation of the collimation and detection system. This report describes the methods available for collimating and detecting energetic particles in the context of a radiobiological microbeam. The arrangement developed at the Gray Laboratory uses either a 'V'-groove or a thick-walled glass capillary to achieve 2-5 microns spatial resolution. The particle detection system uses an 18 microns thick transmission scintillator and photomultiplier tube to detect particles with > 99% efficiency.

Contemporary research on Pavlovian conditioning. A "new" functional analysis.

Recently, the study of biological function has been reaccepted as a legitimate focus of research in the field of animal learning. This "new" functionalism suffuses 2 distinct perspectives with which researchers approach the study of Pavlovian conditioning. Those who adopt the ecological perspective explore the role of conditioning within functional, naturally occurring categories of behavior, for example, intraspecific defense, reproduction, or food recognition. From this perspective, the central question is, In what ways does conditioning contribute to animals' ability to survive and reproduce? For those researchers who explore the cause rather than the function of conditioning, the central question is, How, and under what circumstances, does conditioning occur? Although, historically, those who studied causal mechanisms eschewed functional considerations, close examination of the new cognitive perspective reveals decidedly functional themes. A brief review of research originating in each of these 2 perspectives demonstrates the ways in which they increasingly are finding common ground in a "new" study of function.

Stimulus representation: a subprocess of imprinting and conditioning.

We suggest a way to reconcile imprinting and associative learning that respects the real differences between the two phenomena but helps to recognize underlying commonalities. Rather than treating each type of learning as the manifestation of a unitary mechanism, we approach learning as a combination of separate subprocesses. Exploration of the literature regarding one of these subprocesses, namely, that governing the representation of stimuli, revealed striking similarities between imprinting and conditioning. These similarities suggest predictions for fresh experimental work that will help to uncover the general rules by which combinations of stimulus features are represented in memory.

The biological function of Pavlovian conditioning: the best defense is a good offense.

Signaled presentations of a rival male produce an aggressive conditional response in several species of fish. Although conditioning of such species-specific display behavior has been described previously, the biological function of this learning phenomenon has remained unknown. I present experimental evidence that signaled territorial intrusion enables a male blue gourami to defend his territory more aggressively than when the intruder is unsignaled. In Experiment 1, pairs of territorial males, with different conditioning histories, confronted one another for the first time. One member of the pair previously had received Pavlovian conditioning, whereas the other pair member had received explicitly unpaired presentations of the same signal--conditional stimulus (CS)--and rival male--unconditional stimulus (US). In the subsequent encounter, which was signaled by CS presentation, Pavlovian males delivered significantly more bites and tailbeatings than did their control group opponents. Experiment 2 relied upon a different control procedure, a US-only condition, but, again, Pavlovian males enjoyed a significant aggressive advantage. These results suggest an important ecological role for Pavlovian conditioning.

Effect of telencephalon ablation on the reinforcing and eliciting properties of species-specific events in Betta splendens.

In male Betta splendens, aggressive behavior is drastically attenuated following telencephalon ablation. Because instrumental training and Pavlovian conditioning experiments with intact fish have suggested that associative factors may play an important role in the performance of agonistic behaviors, the effect of ablation on instrumental learning and Pavlovian conditioning was studied. In Experiment 1, ablation had no effect on the learning of the instrumental tunnel-swimming response reinforced by mirror presentation (i.e., viewing a conspecific), although the mirror presentations in yoked-control groups elicited fewer responses in ablates than in normal and sham-operated control fish. Yoked controls further established that instrumental responding was maintained by the reinforcement contingency and was not merely the result of increased motor activity. Experiment 2 studied Pavlovian conditioning of the components of the agonistic display. Unconditioned fin erection, gill erection, and tail beating (i.e., unconditioned responses, URs) to the mirror US all were less frequent in ablates than in normals or shams. Of these, only gill cover erection showed evidence of true conditioning (i.e., conditioned responses; CRs) in which responses to the conditioned stimulus (CS) are due to the pairings of CS and US (unconditioned stimulus). However, ablates suffered no impairment of conditioned gill erections. Ablates performed fewer fin erections to the CS; however, fin erection responses were not due to CS-US pairings but were attributable to pseudoconditioning. These results are related to hypotheses postulating the involvement of learning mechanisms in ablation-produced deficits and normal aggressive behavior.